Immune Dysregulation Leading to Chronic Autoimmunity

Chapter 23

Immune Dysregulation Leading to Chronic Autoimmunity James W. Verbsky1 and Talal A. Chatila2 1

Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA, 2Division of Immunology, The Boston

Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA

Chapter Outline Autoimmune Polyendocrinopathy
Candidiasis
Ectodermal Dystrophy Definition Genetics Pathogenesis Clinical Presentation Diagnostics Management Prognosis IPEX Definition and Genetics Clinical Manifestations Pathogenesis Diagnostics Management Prognosis CD25 Deficiency Definition Genetics Clinical Presentation Pathogenesis Diagnostics Management

497 497 498 498 499 499 500 500 501 501 501 502 504 504 505 505 505 505 505 506 507 507

AUTOIMMUNE POLYENDOCRINOPATHY
CANDIDIASIS
ECTODERMAL DYSTROPHY (OMIM #204300) Definition Autoimmune polyendocrinopathy
candidiasis
ectodermal dystrophy (APECED) syndrome was initially proposed by Neufeld and colleagues to describe the association of

Prognosis STAT5b Deficiency Definition Genetics Clinical Presentation Pathogenesis Diagnostics Management IPEX-Like Disease Due to STAT1 Mutations Definition and Genetics Pathogenesis Clinical Presentation Diagnostics Management and Prognosis ITCH Definition and Genetics Pathogenesis Clinical Presentation Diagnostics Management Prognosis References

507 507 507 507 507 508 509 509 509 509 509 510 510 510 510 510 510 510 511 511 511 511

autoimmune adrenal disease (i.e., Addison disease) with other autoimmune endocrinopathies.1 Later, four patterns of involvement were defined and labeled autoimmune polyglandular syndrome types 1
4 (APS-1, APS-2, APS-3, and APS-4). All disorders had autoimmune disease of multiple endocrine glands, but the age of onset, mode of inheritance, pattern of endocrinopathies, and sex predilection were distinct (Table 23.1). APS-1 is strongly associated with Addison disease, hypoparathyroidism, and mucocutaneous candidiasis. APS-2 presents with

K.E. Sullivan and E.R. Stiehm (Eds): Stiehm’s Immune Deficiencies. DOI: http://dx.doi.org/10.1016/B978-0-12-405546-9.00023-6 © 2014 Elsevier Inc. All rights reserved.

497

498

PART | 2

Primary Immune Deficiencies

TABLE 23.1 Classification of Autoimmune Polyglandular Syndromes (after Neufeld et al., 19811) Clinical Findings

Genetic Association

APS-1

Chronic candidiasis, chronic hypoparathyroidism, Addison disease (at least two present)

AIRE

APS-2

Addison disease (always present) 1 autoimmune thyroid diseases and/or type 1 diabetes mellitus

DR3/DR4

APS-3

Autoimmune thyroid diseases associated with other autoimmune diseases (excluding Addison disease and/or hypoparathyroidism)

Unknown

APS-4

Combinations not included in the previous groups

Unknown

autoimmune thyroiditis, type 1 diabetes mellitus, and Addison disease, is more common in women, and is associated with the HLA alleles DR3 and DR4. APS-3 indicates the presence of autoimmune thyroid disease with other endocrinopathies, excluding Addison disease. APS4 includes a combination of endocrinopathies not included in the other three subgroups.

Genetics APS-1, or APECED, is caused by loss of function mutations in the autoimmune regulator gene (AIRE).2,3 AIRE is a 545 amino-acid long nuclear protein that has several structural domains common to other transcription factors, consistent with its functioning as a transcriptional regulator.4,5 An N-terminal caspase recruitment domain (CARD) may participate in homodimerization or heterodimerization with other transcription factors, and is the site of many APECED-causing mutations.6 It is followed by a SAND domain, common to many transcriptional regulators from plants to mammals, that may mediate nonspecific binding of AIRE to DNA.4,7 Two plant homeodomain (PHD) fingers are found towards the C-terminal of the protein, bisected by a proline-rich region. AIRE’s PHD1 finger recruits AIRE to regions of relative chromatin inactivity by binding histone-3 proteins with an unmethylated lysine at position 4 (H3K4), a mark for transcriptionally repressed loci.8,9 The PHD2 finger aids in this process by binding to protein partners involved in chromatin structure/binding or transcription.10 Once bound to inactive chromatin, AIRE helps initiate the transcription of silenced genes found therein, by several mechanisms. These include promoting the formation of transcription initiation complexes, and rescuing sterile initiation complexes that are unable to proceed due to a paused RNA polymerase-II by recruiting the positive tissue elongation factor (P-TEFb). AIRE also interacts with splicing complexes, thus favoring the maturation and export of nascent transcripts.4,11 APECED is a relatively rare disease inherited in an autosomal recessive manner, and prevalence varies by region and ethnic group. More than 60 APECED-causing

AIRE mutations have been described to date, including nonsense and missense mutations, deletions, and small insertions. While AIRE mutations tend to cluster in the CARD domain, the SAND and PHD domains are also involved. Two disease-causing mutations seem to account for the majority of patients.2,3 The first, R257X, accounts for more than 80% of the AIRE mutations in the Finnish population, and is common in patients of European descent.12,13 The second, a 13-bp deletion (1094
1106del) in exon 8 of AIRE is common in Britons, Norwegians, Northern Italians, and North Americans.13,14 One mutation in the SAND domain, G228W, has been reported to transmit in an autosomal dominant fashion in an Italian kindred.15,16 Patients with the G228W mutation present with APECED with autoimmune thyroiditis. The G228W substitution acts as a dominant negative mutation that inhibits the function of wild-type AIRE protein.

Pathogenesis The autoimmunity in APECED reflects the failure to delete autoreactive T cells as they develop in the thymus, a process referred to as central tolerance. This is in contrast to IPEX and IPEX-like diseases, discussed later in the chapter, which reflect failure of tolerance imposition in peripheral lymphoid tissues
a process referred to as peripheral tolerance. AIRE is a key regulator of clonal deletion in the thymus, and its deficiency leads to the emergence of mature autoreactive T cells that unleash the autoimmune manifestations of APECED. Central tolerance is enabled by the capacity of stromal medullary epithelial cells (MECs) to transcribe thousands of genes whose expression is normally restricted to parenchymal organs.17 Peptides derived from proteins encoded by these genes are presented as self-antigens to developing thymocytes by major histocompatibility complex proteins, thus recapitulating the encounter of mature T cells with those same antigens in peripheral tissues. Key to the pathogenesis of the disease is that the expression of many of these ectopic transcripts is regulated by the AIRE protein.18 As a result of AIRE deficiency, developing T cells are exposed to only a subset of the repertoire of peripheral

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

antigens normally expressed in the thymus, leading to ineffective negative selection of autoreactive thymocytes and their escape to the periphery.4 AIRE deficiency has been associated with defects in the regulatory T (Treg) cell population, even while it does not seem to result in compromise of the Treg cell compartment at a global level.4,19
21 It remains possible that AIRE deficiency may influence the TCR repertoire of Treg cells, given that the latter are frequently selected at a higher TCR/ MHC-peptide antigen avidity window that would normally be associated with clonal deletion of developing thymocytes. Recent studies have linked the mucocutaneous candidiasis of APECED with autoimmune neutralizing antibodies to IL-17 and IL-22, T helper cell type 17 (Th17) cytokines critical to immunity against Candida.22,23 These autoantibodies are highly specific and prevalent, and develop very early in the disease course.24 Autoantibodies to type I interferons, in particular interferon-ω, are detected in APECED and appear to occur in nearly all patients.25
27 Thus, all the key clinical phenotypes of APECED, including mucocutaneous candidiasis, are united by an underlying predilection to autoimmunity.

Clinical Presentation Several series have defined clinical characteristics of APECED.1,28
33 The triad of Addison disease, hypoparathyroidism, and candidiasis was the most common manifestation (Box 23.1). Candidiasis occurs in 75
100% of affected individuals in these series, with the exception of a series of Jewish patients from Iran where only 18% developed this complication.28 Candidiasis is one of the earliest manifestations, with the mean age of presentation under 5 years. Oral candidiasis occurs in most affected individuals, ungual involvement is observed in up to 71% of affected individuals, while dermal and esophageal candidiasis occur less frequently. Hypoparathyroidism was the most

Box 23.1 Clinical Manifestations of APECED G G G G G G G G G G G G G

Candidiasis Hypoparathyroidism Addison disease Ectodermal dystrophy Alopecia Gonadal failure Autoimmune hepatitis Vitiligo Malabsorption Pernicious anemia Thyroiditis Type 1 diabetes mellitus Hypophysitis

499

common endocrinopathy, occurring in 75
100% of affected individuals with a mean age of presentation around 10 years. Adrenal failure (Addison disease) occurred in 72
100% of affected subjects in most series, except in the Iranian Jewish cohort (22%). Addison disease presented between 6 months and 40 years of age, with a mean presentation of approximately 15 years of age. Other manifestations and their prevalence in these series includes alopecia (13
72%), gonadal failure (17
40%, affecting 60% of women and 14% of men), keratitis (0
35%), autoimmune hepatitis (5
31%), vitiligo (0
25%), malabsorption (6
22%), pernicious anemia (0
15%), thyroiditis (4
36%), type 1 diabetes mellitus (0
12%), and, rarely, hypophysitis. Ectodermal dystrophy with enamel hypoplasia and nail pitting or nail dystrophy occurred in 10
52% of affected individuals, and even in the absence of candidal infections. The number of manifestations of APECED present in patients varied from one to eight, with four being the most common.29 The classic triad of candidiasis, hypoparathyroidism, and adrenal failure occurred in 51% of individuals.29,34

Diagnostics The diagnosis of APECED should be considered in any patient with chronic candidiasis who develops endocrinopathies. Although chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency are the main characteristics of this disease, only two of these manifestations are required for diagnosis (Table 23.1). In the absence of candidiasis, the development of multiple endocrinopathies raises the possibility of other autoimmune polyglandular syndromes, as well as IPEX (see below). Numerous autoantibodies are present in APECED, and the type of autoantibody correlates with disease manifestation (Table 23.2).34 Although evaluation for autoantibodies is not diagnostic of APECED, they do aid in the diagnosis of autoimmune endocrine diseases. Particularly useful is the virtually universal association of autoantibodies to interferons, in particular interferon-ω, with APECED.25
27 Anti-interferon-ω antibodies provide .98% sensitivity and specificity for APECED, and occur in very few other conditions, such as thymoma and myasthenia gravis. As such, screening for anti-interferon-ω antibodies is particularly useful in the absence of mutational analysis, and in the context of ambiguous results or unusual clinical manifestations, since the failure to detect these autoantibodies essentially rules out the diagnosis. Finally, although the diagnosis of APECED is generally made based on clinical symptoms, genetic sequencing of AIRE should confirm the diagnosis. Clinical symptoms should guide work-up of any suspected endocrine disorder. Muscular tetany, seizures, paresthesias, bone and abdominal pain, and enamel nail

500

PART | 2

TABLE 23.2 Autoantibodies and Associated Disease Manifestations in APECED Autoantibody

Disease Manifestation

21-Hydrolase

Addison

Side chain cleavage enzyme

Addison, hypogonadism

Aromatic-l-amino acid decarboxylase

Autoimmune hepatitis, vitiligo

Tryptophan hydroxylase

Autoimmune hepatitis, intestinal dysfunction

17α-Hydrolase

Addison

Glutamic acid decarboxylase 65

Vitiligo, intestinal dysfunction

Cytochrome P450 1A2

Autoimmune hepatitis

Protein IA-2

Diabetes mellitus

dystrophy are indicative of hypocalcemia due to hypoparathyroidism. Laboratory studies demonstrate hypocalcemia, hyperphosphatemia, hypocalciuria, hyperphosphaturia, and low serum parathyroid hormone levels. Although autoantibodies to the calcium sensing receptor and NALP5 have been reported in idiopathic hypoparathyroidism and in APECED, their role in the diagnosis of hypoparathyroidism in this disorder is not well established.35
37 Addison disease presents with weakness, fatigue, malaise, musculoskeletal pains, abdominal pain, nausea, vomiting, and disturbances of mood and cognition. Orthostatic hypotension and hyperpigmentation due to elevated ACTH levels can occur. Hypercalcemia, hypoglycemia, hyponatremia, hyperkalemia, eosinophilia, and lymphocytosis are common laboratory features. A low morning cortisol and elevated ACTH are suggestive of Addison disease, which can be confirmed by an ACTH stimulation test. Autoantibodies to 21-hydroxylase, 17-hydroxylase, and side chain cleavage enzymes may be present (Table 23.2). Other autoimmune manifestations should be considered when considering the diagnosis of APECED (Table 23.2). Physical examination of the teeth, nails, and skin should evaluate for ectodermal dystrophy, dysplasia of enamel, vitiligo, and alopecia. Evaluation of atrophic gastritis and pernicious anemia is necessary, including evaluation of complete blood counts to detect megaloblastic anemia, serum vitamin B12 levels, and anti-parietal cell antibodies. Liver enzymes should be evaluated for signs of autoimmune hepatitis, and autoantibodies to tryptophan hydroxylase and cytochrome P450 1A2 may be helpful if available. Signs of intestinal malabsorption

Primary Immune Deficiencies

require endoscopic analysis of the stomach and intestines, since autoimmune enteropathy can occur in this disorder. Thyroid studies (i.e., T4, TSH) should be evaluated for signs of hypothyroidism. Infertility or lack of secondary sex characteristics could signal autoimmune hypogonadism. Evaluation of LH, FSH, and testosterone or estradiol levels will help to diagnose hypergonadotrophic hypogonadism. Autoantibodies to side chain cleavage enzyme can be helpful.

Management There is no curative therapy for APECED. Since the major defect is in the thymic epithelium, bone marrow transplantation or other immune therapies will not cure this disease. Management of APECED involves hormone replacement of endocrinopathies, and antifungal therapies. Oral fluconazole and ketoconazole are used to treat mucocutaneous candidiasis. Fluconazole is preferable since ketoconazole absorption can be affected by atrophic gastritis, and can also affect steroid synthesis and worsen adrenocortical insufficiency. Fluconazole resistance has been reported due to long-term azole use.38 In these cases, topical amphotericin-B, posaconazole, voriconazole, and echinocandins should be used.39 Hypoparathyroidism is treated with oral calcium and vitamin D supplementation. High doses of vitamin D may be necessary, and calcitriol is preferred. In acute cases of hypocalcemia with tetany or seizure, intravenous calcium gluconate and magnesium may be required. Adrenal insufficiency is treated with oral corticosteroids and mineralocorticoids, and blood pressure and serum electrolytes should be monitored for an adequate response. During illness, trauma, or other physical stressors, adrenal crisis can occur, with worsening of these symptoms and, potentially, death. In the setting of an adrenal crisis, intravenous fluids and mineralocorticoids are recommended.

Prognosis Before 1970 the prognosis of patients with APECED was poor, with 16 of 30 (53%) affected individuals expiring before the age of 30 years.40 With the use of appropriate hormone replacement therapies, the prognosis of APECED has improved considerably. In a series of Finnish patients with APECED, 9 of 68 (13%), and in a second recent series 4 of 41 (10%), of affected individuals had died.29,41 Fulminant hepatic failure, adrenal crisis, diabetic ketoacidosis, hypoparathyroidism, and squamous cell carcinoma of the oral mucosa were causes of death likely related to APECED. This highlights the importance of proper hormone replacement therapy, in particular for Addison disease. The association of squamous cell carcinoma with APECED may reflect the carcinogenic effects

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

of long-term Candida exposure. Aggressive treatment of candidiasis and monitoring for malignancy are recommended. It is important to follow these patients closely, not only to ensure adequate compliance with hormone replacement but also to watch for the development of additional autoimmune diseases. Additional autoimmune endocrinopathies and other manifestations can occur decades after the initial diagnosis of APECED.29,41

autoimmune hemolytic anemia, and autoimmune enteropathy. Another prominent feature of IPEX is severe allergic inflammation with eczema and food allergy. In both mice and humans, female carriers are asymptomatic, consistent with X-linked recessive inheritance.

Clinical Manifestations In most patients, IPEX presents early in life with a triad of enteropathy, endocrinopathy, and dermatitis42
46 (Figure 23.1). Other autoimmune phenomena include autoimmune cytopenias, liver, and kidney disease (Box 23.2). Allergic dysregulation with eczema and food allergy is common, with extremely elevated IgE levels accompanied by intense peripheral eosinophilia and evidence of overt Th2 skewing.42,48 The enteropathy in IPEX is one of the earliest and most consistent presentations of the disease, manifesting early in life as watery diarrhea that may also be mucoid and/or bloody. Histopathologically, the normal architecture

IPEX (OMIM #304790) Definition and Genetics Immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) (also known as X-linked autoimmunityallergic dysregulation syndrome or XLAAD) is a heritable autoimmune lymphoproliferative disease caused by loss-of-function mutation in FOXP342
44 (reviewed in Wildin et al.,45 Torgerson & Ochs,46 Barzaghi et al.47). Males with this syndrome present with a variety of autoimmune manifestations, including endocrinopathies,

FOXP3

(D) (A)

Zinc finger

Proline-rich

1

2

3

4

ATG (B) Immunosuppression

IgE (IU/ml)

30,000

501

5

Forkhead

Zip

6

7

8

9

10

11

TGA

R347H ΔK250 ΔE251 +4 A→G

227 deIT

A→G

F371C

20,000 10,000

1318–1319 DEL

A384T

0 0

30 10 20 Age (months)

Poly-A

1290–1309 del/ins TGG R397W

40

(C) (E) Proline-rich

Transcriptional regulation

Zn

Protein/DNA

Zip

Dimerization

FKH

DNA binding

FIGURE 23.1 Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). (A) Severe, early onset eczema in a boy affected with IPEX. (B) Hyper-immunogloblulinemia E in IPEX, and response to immunosuppressive treatment. (C) Small-intestine biopsy in IPEX demonstrating lymphocytic infiltrates. (D) Examples of disease causing mutations in IPEX. (E) Schematic of functional domains of FOXP3. Zn, zinc finger; Zip, leucine zipper domain; FKH, forkhead domain

502

PART | 2

Box 23.2 Clinical Manifestations of IPEX G G G G G G G G G G G

Autoimmune enteropathy Eczema Type 1 diabetes mellitus Allergic disease Autoimmune thyroiditis Autoimmune cytopenias Autoimmune hepatitis Autoimmune renal disease Interstitial lung disease Hypopituitarism Autoimmune adrenal failure

may be altered, with ulcerations and hyperemic mucosa. The small bowel is typically most significantly involved, although the colon may also be affected. Biopsy findings in IPEX include villous atrophy, crypt hyperplasia or abscesses, and an extensive mixed cellular infiltrate, mainly lymphocytic, of the bowel mucosa. These lesions are not specific for IPEX and resemble those in other immune-mediated enteropathies, such as graft-versus-host, celiac disease, and other autoimmune enteropathies.49 The enteropathy is frequently complicated by severe food allergies, which are very common in IPEX.42,50 Adverse reactions to foods in IPEX are typically associated with food allergen-specific IgE responses. IPEX patients may develop increased diarrhea and/or dermatitis, as well as other manifestations of disease, following ingestion of dietary allergens. Typical manifestations of IgE-mediated food allergy, such as acute urticaria, vomiting, or anaphylaxis, may also occur in IPEX. Early-onset autoimmune endocrinopathies, typically diabetes and/or thyroiditis, are hallmark features of IPEX, and may present sequentially. Onset of type 1 diabetes mellitus is generally during the first year of life, and can present in the immediate neonatal period with hyperglycemia at birth. Disease progression results in the complete immune-mediated destruction of islet cells with or without detectable anti-islet cell antibodies in addition to lymphocytic infiltration of the pancreas.45,51,52 Thyroiditis may result in either hypo- or hyperthyroidism, although hypothyroidism with elevated anti-thyroid antibodies is most common.45,46 Other immune endocrinopathies are uncommon; however, atypical findings of growth hormone deficiency and hypoadrenalism have been described.53 The third component of the IPEX triad is dermatitis, which consists of an eczematous rash that ranges from mild to severe.48,54 The presence of atopic dermatitis correlates with elevated titers of serum IgE and peripheral blood eosinophilia.54 The rash typically appears in early infancy,

Primary Immune Deficiencies

and its appearance may be concurrent with the onset of clinical manifestations of enteropathy and endocrinopathy. Other skin findings may include diffuse erythema, alopecia universalis, psoriasiform rashes, painful fissurary cheilitis, and pemphigoid nodularis; most are characterized by lymphocytic infiltrates that may respond to treatment with topical steroids or other immunomodulators.46,48,54,55 Immune-mediated cytopenias affect about half of the patients, who frequently have associated autoantibodies. Coombs-positive hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neutropenia are most common.46 Autoimmunity in IPEX may involve several organ systems. Autoimmune hepatitis is frequently seen in conjunction with autoimmune enteropathy. Renal disease is reported in up to one-third of patients.46 Interstitial nephritis is the most frequent disorder, and other findings range from mild hematuria and proteinuria to rapidly progressive glomerulonephritis.56
58 Renal disease may also be worsened and/or induced by treatment with calcineurin inhibitors. Infection-related pulmonary disease is well described in IPEX patients. Primary lung disease is a feature of the murine model, and is characterized by both perivascular and interstitial lymphocytic and mixed inflammatory cell infiltrates.59,60 Although an increased susceptibility to infections is reported in this syndrome, it is difficult to determine if this is due to a defect in controlling infections, or secondary causes due to the overall ill health of these infants, or to the immunosuppressive medications that must be used to treat these infants.

Pathogenesis IPEX was the first example of an immunological disorder resulting from defective function of regulatory T (Treg) cells. The discovery of FOXP3 as the gene targeted by mutations in IPEX ushered in a dramatic expansion in our understanding of mechanisms of peripheral tolerance and the role of Treg cells in this process. The maintenance of peripheral tolerance is critically dependent on CD41CD251 T regulatory cells, which act to suppress self-reactivity and to prevent autoimmunity.61,62 The majority of Treg cells are generated in the thymus as a committed regulatory cell population that expresses the lineage-specific transcription factor Foxp3, and are specific for self-antigens. These cells, also referred to as natural Treg (nTreg) cells, first develop from CD41C251Foxp32 single positive (SP) thymocytes, whose development is dependent on high-affinity TCR interactions.63 Subsequent exposure to IL-2 and, to a lesser extent IL-15, results in the upregulation of Foxp3 expression. A series of studies have shown that the TCR repertoires of nTreg and conventional CD4 1 T cells are different, with the former possessing TCRs with higher

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

affinity for self-peptide/MHC ligands than conventional CD41 T cells.64,65 While the majority of peripheral Foxp31 Treg cells are thymus-derived nTreg cells, some Foxp31 Treg cells can be also be induced de novo in vivo from peripheral Foxp32CD41 cells, resulting in a population of cells that have regulatory properties but with a distinct TCR repertoire (iTreg cells).66,67This process can also be recapitulated in vitro by TCR activation of naı¨ve CD4 1 T cells in the presence of TGF-β and IL-2. iTreg cells are particularly enriched at the mucosal surfaces, especially in the gastrointestinal tract, where they are endowed with a TCR repertoire specific for bacterial antigens.68,69 nTreg and iTreg cells act in synergy to induce peripheral tolerance.66 While nTreg cells are phenotypically stable, some iTreg cell populations can lose expression of Foxp3 and become effector cells, including Th1 and Th17 cells.70 Several suppressive mechanisms for Treg cells have been demonstrated, such as CTLA-4 engagement of B7 molecules on target cells,71,72 expression of immunosuppressive cytokines such as IL-10 and TGF-β,73
75 cytotoxicity of target cells through the perforin/granzyme pathway,76 induction of indoleamine 2,3-dioxygenase (IDO) and the catabolism of tryptophan in target cells, as well as consumption of adenosine by expression of CD73, and competition with effector T cells for IL-2 since Treg cells constitutively express CD25.77
80 Several of these pathways are targeted by mutations in human subjects, including the IL-2 receptor alpha chain (CD25; discussed later in this chapter), IL-10/IL-10 receptor, and the perforin/granzyme pathway.81
83 Abnormal Treg cell function is a key feature of these diseases.84 Foxp3 is a member of the Forkhead family of transcription factors, defined by the presence of a winged helix (forkhead) DNA binding domain (Figure 23.1). In addition to the C-terminally-located forkhead homology domain, Foxp3 also contains a proline-rich N-terminal domain, and a C2H2 zinc finger motif and a leucine zipper domain, both located midway through the protein. The leucine zipper domain has been implicated in studies on other Foxp subfamily members (Foxp1, 2, and 4) in the formation of Foxp homo- and heterodimers and higher-order assembly of Foxp3 complexes.42,85 The results of many studies have outlined an array of molecular interactions mediated by different FOXP3 domains and by submodules within individual domains. A number of transcriptional factors and regulators interact with Foxp3 at its N-terminus, including the transcription factors Hif1a, IRF4, and Eos, the histone acetyltransferases Tip60 and p300, and the histone deacetylase HDAC7, which help regulate the levels of Foxp3 protein.85,86 A linker region between the leucine zipper and C-terminal forkhead domain interacts with the transcription factor AML1/RUNX1, which cooperates with Foxp3 in the

503

suppression of IL-2 expression.87 The Forkhead domain itself interacts with the transcription factor NFAT, relevant to the expression in components of the Treg cell transcriptome, including IL-2 receptor alpha chain (CD25), GITR, and CTLA-4.88 FOXP3 may act to induce (e.g., CD25) or suppress (e.g., IL-2) gene expression depending on the nature of the interactions with different transcriptional partners at the respective promoter region.61 The modular nature of FOXP3 domains and their specific interactions with partner transcription factors suggest that the clinical phenotypes of mutations targeting the respective domain may be distinct. While detailed genotype/phenotype analyses of Foxp3 mutations in IPEX have not yet been undertaken, some conclusions can be drawn from the clinical phenotypes reported for different human FOXP3 mutations and from studies on Foxp3 molecular structure and interactions.47,89 Missense mutations or small in-frame deletions that do not destroy functional domains of Foxp3 can be associated with nearnormal expression of Foxp3 protein and Treg cell numbers but with compromised regulatory function. Discrete deletions and mutations in the promoter and 50 untranslated regions of Foxp3 may be associated with a milder phenotype. Fox example, a 1388-bp deletion (g.del 2 6247
4859) affecting the first untranslated exon and the adjacent intron of FOXP3, a region relevant to the formation of induced Treg cells, gave rise to enteropathy, eczema and food allergies, and elevated IgE, but no endocrinopathy or cytopenias.50 Similarly, some N-terminal Foxp3 mutations (e.g., Q70H and T108M) gave rise to a milder phenotype without endocrinopathy.90,91 Leucine zipper domain and forkhead domain mutations are usually associated with more severe phenotypes.47,89 It is also likely that the genetic background may affect organ involvement. In Foxp3-deficient mice, the spectrum of organ involvement and disease manifestations vary depending on the strain background.60 The immunopathology of Foxp3 deficiency results from unchecked T cell activation secondary to loss of Treg cells that act in a dominant manner to suppress T cell activation.92,93 This is evidenced by the capacity of perinatal adoptive transfer of CD41CD251 Treg cells to cure Foxp3-deficient mice from disease.66 Affected mice, both the original scurfy mice and the more recently derived strains with targeted loss of function FOXP3 mutations/deletions, are phenotypically indistinguishable from their healthy littermate controls during the first week to 10 days of life; thereafter the disease evolves aggressively and death can ensue within a few days to weeks.59,94
96 Disease progression is associated with lymphoid and myeloid hyperplasia and concomitant intense mixed inflammatory infiltrates involving several organs, including the liver, lung, pancreas, stomach, skin,

504

PART | 2

and gut.59,94
96 The overwhelming majority of CD4 1 and CD8 1 T cells are activated, and Th1, Th2, and Th17 cytokines are abundantly expressed. The aforementioned cytokines are also found at high levels in the circulation.60 Inflammation at the mucosal surfaces, including the gut, skin, and lungs, may be driven by unrestrained T cell reactivity to antigens of the commensal flora.97,98 It is attenuated in germ-free Foxp3-deficient mice and by deficiency of the Toll-like receptor adaptor MyD88.98 In contrast, the systemic autoimmunity of Foxp3 deficiency is unaffected by these interventions.

Diagnostics Any male infant with enteropathy, eczema, and endocrinopathies should be evaluated for IPEX (Table 23.3). Laboratory testing is guided by the suspected autoimmune manifestations. Autoimmune enteropathy is nearly universal in this disorder, and this is typically one of the earliest manifestations. One series of early-onset autoimmune enteropathy detected Foxp3 mutations in 60% of patients.99 Endoscopy to evaluate for autoimmune enteritis should be undertaken in children with diarrhea or other signs of malabsorption. Autoimmune endocrinopathies should be evaluated by serum glucose and T4/TSH determinations. Allergic disease should be evaluated for specific allergens (RAST or skin testing), since elimination of suspected triggers may improve the eczematous lesions as well as gastrointestinal complaints. Anemia and thrombocytopenia should be evaluated for autoimmune etiologies. Immunologic laboratory testing in IPEX is non-specific, and typically reflects widespread immune activation. Immunoglobulin levels, in particular of IgE, are typically elevated. Immune profiling demonstrates widespread T cell activation with a paucity of CD45RA1 naı¨ve T cells. Foxp3 can be assayed by flow cytometry, and in cases

Primary Immune Deficiencies

where the mutations result in decreased protein stability this is a rapid means to diagnosis IPEX. However, normal expression does not rule out IPEX, as it may be normal in the case of missense mutations. Sequence analysis is recommended for formal diagnosis of this disease.

Management Patients with IPEX and “IPEX-like” syndromes typically require intensive immunosuppression to control autoimmunity and lymphoproliferation. They also require dietary modifications to avoid food allergens and optimize nutrition. Immunosuppression can be effective in ameliorating autoimmune and allergic disease; however, it is not curative and neither is it sufficient in many cases to prevent the development of an autoimmune “march”
i.e., the development of sequential autoimmune phenomena. Immunosuppression is also associated with significant adverse side effects, and growth is often compromised.45,46,100 Glucocorticoids are typically used for induction therapy at the time of presentation, and for chronic management of disease and disease flare-ups. A steroid-sparing agent, such as the calcineurin inhibitors, rapamycin, and/ or azathioprine, should be used in conjunction with glucocorticoid therapy. Rapamycin has the theoretical advantages of preferential induction of Foxp3 1 Treg cells by virtue of its inhibition of the mTOR pathway, itself an inhibitory pathway in Treg cells.101,102 Its use has been associated with significant benefit in a small number of IPEX patients, especially those with milder mutations, although rare serious adverse effects have also been reported.90 Once disease control is obtained, a slow glucocorticoid wean should be attempted, and the steroidsparing agent should be continued as maintenance therapy. Multiple immunosuppressive agents are typically

TABLE 23.3 Diagnostic Findings in IPEX, CD25 Deficiency, STAT5b Deficiency, and Gain-of-Function STAT1 Mutations IPEX

CD25 Deficiency

Stat5b Deficiency

STAT-1

T cell mitogens

Normal

Low, reversed by High-dose IL-2

Low

Normal or low

Serum immunoglobulins

Elevated

Elevated or normal

Elevated or normal

Low, normal, or high

Serum IgE

Elevated

Normal or elevated

Normal or elevated

Normal or mildly elevated

CD25 expression

Normal

Absent

Normal or low

Normal

CD41/CD45RO1

Elevated

Elevated

Elevated

Normal or high

Foxp3 expression

Absent or normal

Normal or low

Normal or low

Normal

IGF-1, IGFBP-3

Normal

Normal

Elevated

Normal

Prolactin

Normal

Normal

Elevated

Normal

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

required to obtain disease control, and it may not be possible to wean most patients entirely from glucocorticoid therapies. In the overwhelming majority of patients, IPEX is ultimately lethal unless rescued by hematopoietic stem cell transplantation (HSCT), which has been a curative therapy in a number of IPEX patients.45,103
111 Many of the features of IPEX remit after successful transplantation, although endocrinopathies such as type 1 diabetes mellitus frequently persist due to permanent end-organ damage. Potential complications of HSCT in IPEX patients include macrophage activation syndrome, infection, graft-versus-host disease, and growth failure. Reduced intensity conditioning regimens have been increasingly used, which offer the potential benefit of decreased myeloablation and less risk of mortality and morbidity.104,106
110 Selective engraftment of donor CD41 CD25highFoxp31 cells with resultant normal levels of FOXP3 expression following non-myeloablative conditioning has proven sufficient to prevent manifestations of autoimmunity.107
110 Sources of stem cells have included cord blood, peripheral blood, and bone marrow from matched related and unrelated donors. Early HSCT offers the greatest potential to correct the underlying disease process and thereby minimize endorgan damage. As with SCID, patients may be more likely to survive the transplant period if they are less compromised at the time of conditioning. Therefore, extensive evaluations are required to determine the availability of appropriate donors, and the optimal timing of the procedure for each individual

Prognosis In the majority of patients, and despite aggressive immunosuppressive therapy, the disease is ultimately fatal unless rescued by HSCT.

CD25 DEFICIENCY (OMIM #606367) Definition Interleukin 2 is the prototypical T cell growth factor. First described in the 1980s as T cell growth factor based on its ability to promote the growth of lymphocytes in vitro, IL-2 is produced predominantly by activated T lymphocytes.112,113 The receptor for IL-2 is composed of three subunits; the IL-2 receptor alpha (CD25), beta (CD122), and gamma chains (CD132).114
120 The IL-2 receptor gamma and beta chains form an intermediateaffinity (Kd B1029 M) receptor that is the signal transducing subunit of the receptor. CD25 is a low-affinity receptor by itself (KdB1028 M), but in combination with the beta and gamma chain it forms the high-affinity

505

IL-2 receptor (Kd B10211 M). Similarly, the IL-15 receptor is made up of the IL-2 receptor beta and gamma chains, but has a unique IL-15-specific binding subunit.121 CD25 is strongly induced in T cells with T cell receptor activation and by IL-2.122,123 The crystal structure of the IL-2 complexed to its receptor demonstrates that CD25 acts to shuttle IL-2 to the signaling subunits IL-2 receptor β and IL-2 receptor γc chains.124,125 Given the importance of IL-2 as a T cell growth factor, it was surprising that mouse models deficient in CD25 were found to exhibit autoimmunity and inflammatory bowel disease.126 Several cases of CD25 deficiency have been described in humans with similarities to the defect in CD25-deficient mice.

Genetics CD25 is located at chromosome 10p15, and deficiency in CD25 is inherited in an autosomal recessive manner. Consanguinity was reported in two of the reported cases, but compound heterozygous mutations have also been reported.

Clinical Presentation Although no humans have been described with deficiency of IL-2, deficiency of CD25 has been detected in several individuals. The first description was of a male subject of consanguineous parents who presented with CMV pneumonitis, oral and esophageal candidiasis, adenoviral gastroenteritis, diarrhea, and failure to thrive.127,128 He eventually developed gingivitis and hepatosplenomegaly, and was found to have CMV enteritis and Torovirus. Histological analysis demonstrated widespread lymphocytic infiltrates in his lungs, liver, duodenum, and stomach without evidence of an infectious etiology. Further studies on this patient demonstrated primary biliary cirrhosis.129 Laboratory evaluation demonstrated elevated IgG levels, and moderately low T cells (933 cells/μl) with a reduced CD4 to CD8 ratio, non-hemolytic anemia, and low mitogenic responses not corrected with exogenous IL-2(500 U/ml). Serum IgG levels were elevated, IgM levels were normal, and IgA levels were low. CD25 was not detectable on the surface of EBV-transformed B cells, and a 4-bp deletion (nucleotides 60
64) resulted in a frameshift and a stop codon at amino acid 45. The second case of CD25 deficiency was described in a boy born to unrelated parents who developed severe diarrhea, insulin-dependent diabetes mellitus, and eventual respiratory failure within the first months of life.83 Urine and blood cultures were positive for CMV, and lung biopsy showed dense mononuclear infiltrates containing plasma cells and evidence of CMV. Intestinal biopsies demonstrated chronic inflammation and villous

506

atrophy consistent with autoimmune enteropathy complicated by CMV inclusion bodies. He later developed diffuse eczema, gingivitis, asthma, recurrent sinopulmonary infections, systemic lymphadenopathy (EBV positive), hepatosplenomegaly, autoimmune thyroiditis, autoimmune hemolytic anemia, and autoimmune neutropenia. Laboratory studies demonstrated mildly elevated IgG but normal IgM, IgA, and IgE levels. T cell counts were within the normal range but with a reduced CD4:CD8 ratio, and a profound skewing of CD4 cells toward a memory phenotype (CD45RO1 ) was detected.83 Further studies demonstrated defective mitogenic responses that were not corrected by low-dose IL-2 (10 U/ml), but proliferative responses were rescued with high-dose IL-2 (1000 U/ml) or IL-15 (10 U/ml). CD25 was not detected on activated T cells, while CD69 expression was normal, indicating appropriate T cell activation. Interestingly, a normal percentage of CD4 1 Foxp3 1 T cells was detected in peripheral blood. Sequence analysis demonstrated compound heterozygous mutations in CD25, including a missense mutation and a frameshift mutation.83 A third case of CD25 deficiency was described in a female child of consanguineous parents.130 Eczema and severe diarrhea developed in the first months of life, and autoimmune enteropathy, which was complicated by CMV, was diagnosed. Further autoimmune complications developed, including bullous pemphigoid, autoimmune thyroiditis, and alopecia universalis. Her eczema progressed to erythroderma with severe lymphadenopathy, and skin superinfections with Staphylococcus and Pseudomonas. Laboratory studies demonstrated normal CD4 counts, elevated CD8 counts resulting in an inverted CD4:CD8 ratio, and normal IgG and IgM levels but elevated IgA and greatly elevated IgE. Protective titers to tetanus, CMV, and hepatitis B were detected. A normal percentage of Foxp3 expressing CD4 was found, but there was evidence of immune dysregulation with severe memory skewing of CD4 and CD8 cells. Mitogenic responses were low and partially restored with exogenous IL-2. A summary of the clinical findings in CD25 deficiency is provided in Box 23.3.

Pathogenesis The presentation of CD25 deficiency has many features of IPEX, but exhibits unique features not seen in the disease
namely, chronic viral, fungal, and bacterial infections83,127,130 (Box 23.3). The autoimmune findings can be expected since one of the defining characteristics of Treg cells is the constitutive expression of CD25, and this marker was the first to define the Foxp31 Treg cell population.131,132 IL-2 appears critical for the growth of Treg cells, and it has been proposed that one of the key

PART | 2

Primary Immune Deficiencies

Box 23.3 Clinical Findings in CD25 Deficiency G

G

Autoimmune complications of CD25 deficiency G Eczema G Inflammatory bowel disease (autoimmune enteropathy, colitis) G Gingivitis G Type 1 diabetes mellitus G Hypothyroidism G Autoimmune thrombocytopenia G Autoimmune neutropenia G Bullous pemphigoid G Alopecia universalis G Hepatosplenomegaly Infectious complications G CMV pneumonitis, enteritis G EBV lymphoproliferative disease G Recurrent sinopulmonary infections G Cellulitis

features of IL-2 is to expand Treg cells.133,134 However, two of the reported patients with CD25 deficiency were found to have relatively normal percentages of Foxp3 1 cells in the peripheral blood, suggesting that CD25 signaling is not required for the development of Treg cells, which is supported in mouse models.134 Although CD25 is dispensable for the generation of Treg cells, deficiency of CD25 leads to widespread immune dysregulation, arguing that functional responses of Treg cells critically depend on IL-2. In support of this, in vivo and in vitro treatment of T regulatory cells with IL-2 appears to enhance their suppressive abilities.134
136 In addition, the constitutive expression of CD25 on Treg cells allows them to effectively compete for IL-2 and act as a cytokine sink that promotes apoptosis in a Bim-dependent manner in effector cells.137,138 Finally, IL-2 is essential to the generation of induced Treg cell populations.139,140 In one case of CD25 deficiency thymic Bcl-2 expression was elevated, and the inability to downregulate Bcl-2 may play a role in the failure to delete T cells in the thymus.127 The infection complications in CD25 deficiency also confirm a role for IL-2 in generating effective immunity of T cells (reviewed in Liao et al.141). IL-2 promotes the proliferation and development of Th1 cells through the STAT5-dependent induction of IL-12 receptor subunits increasing the sensitivity of these cells to IL-12.142
144 IL-2 signaling also promotes Th2 cell development by inducing IL-4 and IL-4 receptor expression.145 In contrast, IL-2 appears to inhibit Th17 development, but, once generated, Th17 cells may utilize IL-2 to expand.146,147 IL-2 also inhibits T follicular helper T cells by inducing the transcription factor BLIMP, which suppresses Bcl-6, a transcription factor critical to T follicular helper cell

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

507

(Tfh) development.148,149 IL-2 is important in generating cytotoxic CD8 effector cells as well as memory CD8 cells through the induction of IFN-γ, perforin, and granzyme expression.150 Interestingly, CD25 has been shown to be dispensable for primary CD8 T cell responses but critical for the generation of memory CD8 cells.151 IL-2 can activate NK cells to become lymphokine-activated killer cells, and IL-2 has been reported to promote B cell response.152,153 The pleiotropic effects of IL-2 on the effector function of the adaptive immune response help to explain why individuals lacking CD25 exhibit increased susceptibility to infections, including fungal, bacterial, and viral.

CD25 deficiency presents with aggressive autoimmunity and inflammation. It is important that treatment is appropriate and aggressive to control the disease manifestations. Ultimately, bone marrow transplantation has been curative in this disorder.127

Diagnostics

STAT5b DEFICIENCY (OMIM #245590)

In patients with the correct clinical symptoms, the diagnosis of CD25 deficiency is made through several laboratory findings. Hypergammaglobulinemia may occur, and IgE levels can be normal or elevated. In all three cases of CD25 deficiency described here, inverted CD4 to CD8 ratios were detected, and an increased percentage of CD45RO memory CD4 and CD8 cells was present in two of the cases. Since IL-2 is required for growth of T cells in vitro, T cell mitogenic assays are abnormal, and these assays are readily available. A normal mitogenic response rules outs functional CD25 deficiency. High doses of IL2 or IL-15 can be used to overcome a defect in CD25 deficiency.83,130 Flow cytometry can be used to detect expression of CD25. Unstimulated PBMCs will express CD25 mainly in T regulatory cells, since these cells constitutively express CD25. This is a rare population, but upon mitogenic stimulation all T cells strongly express CD25. Thus, to increase the sensitivity of detection, activated PBMCs can be analyzed for CD25 expression several days after activation and these cells should be highly positive for CD25. Flow cytometry, however, only detects presence of the protein and not function. Although never described, point mutations affecting CD25 function but not protein stability could be missed in CD25 deficiency. Genetic testing can confirm flow cytometric and functional studies that are consistent with CD25 deficiency. A summary of comparative diagnostic tests in IPEX and IPEX-like syndromes, including CD25 deficiency, is presented in Table 23.3.

Definition

Management Due to the rarity of this disorder, no published series have addressed its optimal treatment. Of the reports above, many treatments have been tried empirically including corticosteroids, antimetabolites (i.e., methotrexate, mycophenolate, azathoprine), cyclophilin inhibitors (i.e., cyclosporin and FK506), and the mTor inhibitor rapamycin.

Prognosis The natural history of CD25 deficiency is of aggressive autoimmune and chronic infectious complications that can be life-threatening. In addition, although HSCT can be curative, the acquisition of chronic viral infections that complicate HSCT can be problematic in CD25 deficiency.

STAT5b is one of two STAT5 proteins that are involved in signal transduction of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. However, STAT5 is involved in the signaling for growth hormone and other hematopoietic factors. Since CD25 deficiency results in a severe immune dysregulation syndrome, deficiency in STAT5b also results in varying degrees of immune dysregulation with features of growth hormone deficiency.

Genetics STAT5 consists of two closely related proteins, STAT5a and STAT5b, which are 90% homologous.154,155 Complete deficiency in STAT5 proteins in mice results in perinatal lethality since these proteins are involved in the signal transduction of a variety of growth factors, including growth hormone, prolactin, erythropoietin, IL-3, IL-5, and GM-CSF.156,157 Perinatal examination of these mice demonstrated a severe combined immunodeficiency phenotype.158 Defects in Stat5a have not been described in humans. Defects in Stat5b have been described, and are inherited in an autosomal recessive manner. Defects in Stat5b may exhibit reduced penetrance, possibly due to the presence of Stat5a.

Clinical Presentation The clinical manifestations of STAT5b deficiency are summarized in Box 23.4. The original description of STAT5b deficiency was of an Argentinian girl with growth failure, delayed puberty, prominent forehead, saddle nose, and high-pitched voice
all features of growth hormone deficiency.159 At the age of 7 years, lymphoid interstitial pneumonia and bronchial obstruction was diagnosed. Work-up at the time was negative for viruses, including HIV, EBV, and CMV. Severe hemorrhagic

508

PART | 2

Box 23.4 Clinical Findings in STAT5b Deficiency G

G

Autoimmune complications of STAT5b deficiency G Interstitial pneumonitis, bronchiectasis G Eczema G Diarrhea G Type 1 diabetes mellitus G Hypothyroidism G Autoimmune thrombocytopenia G Autoimmune neutropenia G Bullous pemphigoid G Alopecia universalis G Hepatosplenomegaly Infectious complications G Varicella, herpes zoster G Herpes keratitis G Recurrent sinopulmonary pulmonary infections G Cellulitis

varicella developed, then recurrent bouts of herpes zoster. Her pulmonary status worsened, and work-up detected Pneumocystis. Laboratory evaluation demonstrated normal GH expression in response to insulin, and normal serum GH binding protein. There was markedly low IGF-1 and IGFBP-3 expression, and supplementation with GH was ineffective. Expression of STAT5 proteins demonstrated normal Stat5a protein, but no STAT5b. Sequence analysis demonstrated an alanine to proline substitution at A630P. Parents were heterozygous for the mutation. The mutant STAT5b protein could be detected when over-expressed in cell lines, although at lower levels than wild-type STAT5b, and no phosphor-STAT5b was detected in response to GH. A second case involved a Turkish girl, born to consanguineous parents, with growth delay, eczema skin lesions, recurrent pulmonary infections, and lung CT findings of ground-glass opacities with micronodular infiltrates.160 GH levels were normal, but serum IGF-1, IGFBP-3, and acid-labile substance were low. Further laboratory studies demonstrated hypergammaglobulinemia, but normal T, B, and NK cell numbers, and normal mitogenic responses. Sequence analysis demonstrated a G insertion at 1191. Two reports described a patient with congenital ichthyosis, growth failure, and delayed puberty.161,162 Hemorrhagic varicella occurred, but there were few other infection complications. Unlike previous reported cases, there was no reported pulmonary disease. Laboratory analysis demonstrated decreased proliferation to IL-2, IL-15 or CD3/28 in T cell blasts that could be rescued with CD3/281IL-2. Further analysis of this patient demonstrated low normal CD4, CD8, NK, and B cells. A child was reported with growth failure, eczema, recurrent severe infections of the skin and respiratory tract, and chronic diarrhea early in life.163 Prolonged

Primary Immune Deficiencies

varicella and herpes keratitis developed. Physical features were consistent with growth hormone deficiency, including a prominent forehead, saddle nose, high-pitched voice, and delayed puberty/bone age. Chronic pulmonary disease with clubbing developed, and imaging detected ground-glass opacities and bronchiectasis. Pulmonary function tests exhibited a mixed restrictive/obstructive pattern that was unresponsive to antibiotics but may have improved with corticosteroids. Laboratory studies demonstrated mild T lymphopenia with normal CD4 counts, low CD8 counts, and very low γδ T cell counts. Generalized immune activation included a greatly increased percentage of HLA-DR-positive lymphocytes and significant memory skewing based on CD45RO expression. Serum IgG, IgM, and IgE were elevated, and protective titers to tetanus and Streptococcus were detected. Mitogenic responses to PHA, SEB, and CD3 were low and not corrected with IL2. Antigen-specific mitogenic responses to Candida, tetanus, and PPD were very low. A homozygous R152X was detected. Two siblings from Kuwait with growth failure and features of growth hormone deficiency were also found to have STAT5b deficiency.164 One exhibited juvenile idiopathic arthritis, and the other bronchiectasis and interstitial pneumonitis. IGF-1, IGFBP3, and acid labile substance were all low. A splice site mutation was detected. Pugliese-Pires et al. described two Brazilian brothers with short stature, delayed bone age, eczema, and interstitial lung disease.165 One brother developed thrombotic thrombocytopenia purpura and pulmonary disease requiring steroids and hydroxychloroquine. Laboratory studies demonstrated low IGF-1, low IGFBP-3, and high prolactin. There was mild to moderate lymphopenia. One brother was found to have elevated serum IgG, while the other was normal. A 4nt deletion in stat5b was detected (L142fsX161). Finally, Scaglia et al. described a patient with infections from infancy, and growth failure.166 Seborrheic dermatitis developed at 1 year of age, followed by autoimmune thyroiditis, severe varicella, and Streptococcus pyogenes sepsis. Laboratory evaluation demonstrated low IGF-1 and IGFBP-3, and high prolactin. Serum immunoglobulins demonstrated elevated IgA and IgG, but normal IgE levels. CD4, CD8, and NK cell counts were low, while B cell counts were normal. There was severe memory skewing of T cells, and a mildly decreased percentage of Foxp31 cells. T cell mitogenic responses were low, but were restored with exogenous IL-2. A F646S transition was detected in the Stat5 gene.

Pathogenesis Deficiency in STAT5b, one of two STAT5 proteins, leads to a syndrome of immune deficiency with autoimmunity

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

since signaling through the IL-2 receptor requires the signal transducer and activator of transcription protein 5 (STAT5). Many of the features of STAT5b deficiency are similar to findings in CD25 deficiency, including eczema, chronic diarrhea, and increased susceptibility to infections, although the severity of involvement varies considerably. Pulmonary disease appears more prominent in STAT5b deficiency, although it is unclear whether this is driven by infectious processes or is the result of defective immune regulation. In CD25 deficiency, pulmonary disease is typically associated with CMV infection. STAT5b deficiency also exhibits varying degrees of autoimmunity, such as thyroiditis. Similarly to CD25 deficiency, signs of immune activation may be apparent, including hypergammaglobulinemia and increased percentages of CD45ROpositive T cells. The severity of disease in STAT5b deficiency appears more variable and less severe compared to CD25 deficiency, likely due to the fact that STAT5a may substitute for some of the functions of STAT5b deficiency. The increased susceptibility to infections and autoimmune manifestations of STAT5b deficiency are likely due to defects in responsiveness to IL-2, as outlined in CD25 deficiency above.

Diagnostics The key clinical findings of pulmonary disease with or without detectable infections, growth failure, eczema, and recurrent viral and bacterial infections should instigate an evaluation of STAT5b deficiency. Signs of growth hormone deficiency should be evaluated by examining growth hormone, IGF-1 and IGFBP-3, and prolactin levels. A pattern of normal growth hormone but low IGF1 and IGFBP-3, and elevated prolactin levels, would be consistent with STAT5b deficiency. Immune abnormalities are more variable in this disorder (Box 23.4). T, B, and NK cell numbers can be low or normal. One report described very low γδ T cell numbers, although it is unclear if this is a universal finding. Serum IgG and IgE levels can be normal or elevated. T cell mitogenic responses can be normal or low, and may or may not be reversed by exogenous IL-2. Increases in CD45RO memory T cells may be present. CD25 expression may be low, normal, or elevated, and Foxp3-positive cells may be low (Box 23.3).

Management Due to the rarity of this disorder, no published series have addressed its optimal treatment. Corticosteroids and hydroxychloroquine have been used to treat pulmonary disease, with questionable improvement. If the autoimmune complications are severe enough, empiric therapy with antimetabolites, cyclophilin inhibitors, and

509

rapamycin may be tried, since these are used in IPEX and CD25 deficiency. However, they should be used with caution, as these agents could worsen the infection complications
in particular with varicella and other herpetic infections. Lung transplantation has been used to treat the pulmonary disease, but this is unlikely to halt the autoimmune manifestations unless given in combination with immune suppression.

IPEX-LIKE DISEASE DUE TO STAT1 MUTATIONS (OMIM #600555) Definition and Genetics Autosomal dominant heterozygous gain-of-function mutations in Stat1 have been found in subjects with mucocutaneous candidiasis. Some of the affected subjects suffered from autoimmunity, mainly autoimmune thyroiditis, but otherwise lacked further characteristics of the AEPECD phenotype, including characteristic end-organ targets of autoimmunity and ectodermal dysplasia.167
169 The mutations resulted in increased STAT1 phosphorylation on the regulatory tyrosine 701 residue, which is essential for STAT1 activation, and in STAT1 binding to its DNA response elements. Three-dimensional modeling of phosphorylated STAT1 molecules revealed that the mutations affected a cluster of residues located in a specific pocket of the coiled-coil domain, near residues essential for STAT1 dephosphorylation.167 By screening 78 patients from three separate cohorts with IPEX-like phenotype with or without mucocutaneous candidiasis, Uzel et al. identified five patients with heterozygous gain-of-function STAT1 mutations.170 The mutations involved the coiled-coil (R210I, V266I) and DNA binding domains (L358W, T385M (two patients) of STAT1. These mutations resulted in increased STAT1 phosphorylation at the regulatory tyrosine 701, consistent with the gain-of-function phenotype of the mutations.

Pathogenesis Gain-of-function Stat1 mutations inhibit Th17 cell differentiation, a phenotype associated with heightened susceptibility to mucocutaneous candidiasis. However, the mechanisms of IPEX-like disease in some of the patients remains unclear. The number of Treg cells and their in vitro suppressor function appeared normal.170 It is possible that the gain-of-function STAT1 mutant destabilizes the Treg cells by reprogramming them into Th1-like cells, but this remains to be determined. IL-10 production by peripheral blood lymphocytes was profoundly decreased, suggesting a role for functional IL-10 deficiency in certain aspects of disease manifestation (such as enteritis).

510

Clinical Presentation All five patients with IPEX-like phenotype presented with eczema and enteropathy.170 Three of the patients also developed type 1 diabetes, three developed hypothyroidism and/or thyroid autoantibodies, and one developed growth hormone insufficiency. All five patients suffered recurrent infections, with various combinations of sinopulmonary infections and pneumonias (with or without bronchiectasis), herpes virus infections, and blood-borne infections. The patients also suffered from a variety of cardiovascular problems, including hypertension, vascular aneurysms, and calcifications. Four of the five patients exhibited mucocutaneous candidiasis, suggesting that the disease may occasionally present in the absence (or cryptic presence) of candidiasis.170 Disseminated aspergillosis and candidemia have been noted in two patients, under conditions of immunosuppression and catheter-related, respectively.

Diagnostics IPEX-like subjects with normal Foxp3 sequencing should be screened for Stat1 mutations, especially in the context of co-existing mucocutaneous candidiasis and ancillary findings associated with autosomal dominant gain-offunction Stat1 mutations. Treg cell numbers and Foxp3 expression were within the normal range.170 Serum IgE antibody concentrations were normal in four of five patients and modestly elevated in the fifth, unlike the situation in the majority of IPEX patients, who have high IgE levels (Table 23.3).

Management and Prognosis Patients with IPEX-like disease due to gain-of-function Stat1 mutations would be managed for their autoimmunity in the same manner as IPEX patients. Because of their heightened susceptibility to infections, appropriate prophylaxis with antibacterial, -viral and -fungal agents should be considered. Bone marrow transplantation may be considered in severe cases.

ITCH (OMIM #613385) Definition and Genetics Using genetic mapping of a an extended Amish family with findings of multisystem autoimmunity, dysmorphic features, and developmental abnormalities, Lohr et al. mapped the genetic defect to chromosome 20q11. Using a candidate gene approach, a single adenine nucleotide insertion in codon 132 was detected in the ITCH gene, resulting in a frameshift and premature stop.171 Ten affected individuals were found to carry this mutation.

PART | 2

Primary Immune Deficiencies

Autosomal recessive inheritance was apparent in this extended family, and prominent consanguinity was noted.

Pathogenesis A naturally occurring mutation in Itch, the mouse homolog of human ITCH, recapitulates many features of the human disease, including a severe autoimmune disorder characterized by dermatitis, chronic pulmonary inflammation, alveolar proteinosis, and lymphoid hyperplasia.172 Studies with Itch-deficient mice have elucidated some of the potential mechanisms of immune dysregulation in these mice. ITCH is a ubiquitin ligase with diverse function in T cells.172 T cells from Itch 2/2 mice show an activated phenotype with enhanced proliferation and expression of the Th2 cell cytokines IL-4 and IL-5.173 IgG1 and IgE levels were elevated, consistent with a prominent Th2 response in these mice. These studies identified JunB, a transcription factor that is involved in Th2 differentiation, as a target of ITCH.174,175 Other studies have shown that ITCH is upregulated in anergic T cells, and ITCH associates with PLC-γ1 and PKC-θ, two key signaling molecules induced by Ca21/calcineurin signaling.176 Following ITCH-mediated ubiquitination, PLC-γ1 and PKC-θ are targeted to the lysosome for degradation, leading to reduced levels of PLC-γ1 and PKC-θ, and defective T cell activation. ITCH has also been implicated in Treg cell function and generation, mainly through its effects on TGF-β signaling and Foxp3 expression in CD4 T cells.177 The loss of ITCH compromises TGF-β-induced Foxp3 expression and TGFβ-mediated inhibition of T cell proliferation through ubiquitination of the transcription factor TIEG1. Upon ubiquitination by ITCH, TIEG1 translocates to the nucleus, and binds GC-rich sequences in the Foxp3 promoter.177

Clinical Presentation All affected individuals displayed failure to thrive, developmental delay, and dysmorphic features. Growth was stunted, and weight and height below the third percentile for age was apparent with relative macrocephaly ( . 90 %). Craniofacial features included frontal bossing, dolichocephaly, orbital proptosis, flattened midface with prominent occiput, small chin, and low posteriorly rotated ears. Other features include decreased tone, delayed motor skills, cognitive delay, and campto- or clinodactyly. Hepatosplenomegaly and chronic lung disease resembling interstitial pneumonitis was apparent in nine of ten individuals, with three individuals on chronic oxygen therapy and one child on ventilator support. Four individuals exhibited hypothyroidism with anti-thyroid peroxidase or anti-thyroglobulin autoantibodies. Three children had autoimmune hepatitis with anti-liver kidney

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

microsomal, anti-nuclear, or anti-neutrophil cytoplasmic antibodies. Biopsies showed a dense periportal mixed inflammatory infiltrate. Autoimmune enteropathy was diagnosed in two individuals with anti-enterocyte antibodies. One child developed diabetes mellitus.171

Diagnostics The diagnosis of ITCH deficiency should be considered in any subject presenting with failure to thrive, developmental delay, characteristic facial features, and autoimmunity
in particular, chronic lung disease.171 In suspected cases, evaluation for lung disease, autoimmune enteropathy, autoimmune hepatitis, and autoimmune endocrinopathies is necessary. No consistent laboratory test has been reported to aid in diagnosis, and sequence analysis of the ITCH gene is required for diagnosis.

Management Autoimmune endocrinopathies are treated with hormone replacement. Lung disease, autoimmune hepatitis, and autoimmune enteropathy have been treated with a variety of immunosuppressants, including steroids, rapamycin, azathioprine, and tacrolimus. Details on responses were not reported, although steroids did improve hepatitis and lung diseases in selected patients.171

Prognosis Three of the 10 children died at a young age (6 months and 3 years) due to respiratory failure secondary to lung disease. The remaining cases reported vary between 2 and 23 years of age.

REFERENCES 1. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981;60(5):355
62. 2. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet 1997;17(4):393
8. 3. Finnish-German AC. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 1997;17(4):399
403. 4. Mathis D, Benoist C. Aire. Annu Rev Immunol 2009;27:287
312. 5. Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol 2008;8(12):948
57. 6. Ferguson BJ, Alexander C, Rossi SW, Liiv I, Rebane A, Worth CL, et al. AIRE’s CARD revealed, a new structure for central tolerance provokes transcriptional plasticity. J Biol Chem 2008;283(3):1723
31. 7. Gibson TJ, Ramu C, Gemund C, Aasland R. The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor. Trends Biochem Sci 1998;23(7):242
4.

511

8. Koh AS, Kuo AJ, Park SY, Cheung P, Abramson J, Bua D, et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organspecific autoimmunity. Proc Natl Acad Sci USA 2008; 105(41):15878
83. 9. Org T, Chignola F, Hetenyi C, Gaetani M, Rebane A, Liiv I, et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep 2008;9 (4):370
6. 10. Yang S, Bansal K, Lopes J, Benoist C, Mathis D. Aire’s plant homeodomain (PHD)-2 is critical for induction of immunological tolerance. Proc Natl Acad Sci USA 2013;110(5):1833
8. 11. Abramson J, Giraud M, Benoist C, Mathis D. Aire’s partners in the molecular control of immunological tolerance. Cell 2010;140 (1):123
35. 12. Bjorses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, et al. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy
candidiasis
ectodermal dystrophy protein. Am J Hum Genet 2000;66(2):378
92. 13. Heino M, Scott HS, Chen Q, Peterson P, Maebpaa U, Papasavvas MP, et al. Mutation analyses of North American APS-1 patients. Hum Mutat 1999;13(1):69
74. 14. Wolff AS, Erichsen MM, Meager A, Magitta NF, Myhre AG, Bollerslev J, et al. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab 2007;92(2):595
603. 15. Cetani F, Barbesino G, Borsari S, Pardi E, Cianferotti L, Pinchera A, et al. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy
candidiasis
ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab 2001;86(10):4747
52. 16. Su MA, Giang K, Zumer K, Jiang H, Oven I, Rinn JL, et al. Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire. J Clin Invest 2008;118(5): 1712
26. 17. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol 2006;24:571
606. 18. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002;298(5597):1395
401. 19. Kekalainen E, Tuovinen H, Joensuu J, Gylling M, Franssila R, Pontynen N, et al. A defect of regulatory T cells in patients with autoimmune polyendocrinopathy
candidiasis
ectodermal dystrophy. J Immunol 2007;178(2):1208
15. 20. Laakso SM, Laurinolli TT, Rossi LH, Lehtoviita A, Sairanen H, Perheentupa J, et al. Regulatory T cell defect in APECED patients is associated with loss of naı¨ve FOXP3(1) precursors and impaired activated population. J Autoimmun 2010;35(4):351
7. 21. Ryan KR, Lawson CA, Lorenzi AR, Arkwright PD, Isaacs JD, Lilic D. CD41CD251 T-regulatory cells are decreased in patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Allergy Clin Immunol 2005;116(5):1158
9. 22. Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 2010;207(2):291
7.

512

23. Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med 2010;207(2):299
308. 24. Kisand K, Peterson P. Autoimmune polyendocrinopathy
candidiasis
ectodermal dystrophy: known and novel aspects of the syndrome. Ann N Y Acad Sci 2011;1246:77
91. 25. Kisand K, Link M, Wolff AS, Meager A, Tserel L, Org T, et al. Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes. Blood 2008;112 (7):2657
66. 26. Meager A, Visvalingam K, Peterson P, Moll K, Murumagi A, Krohn K, et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med 2006;3(7):e289. 27. Meloni A, Furcas M, Cetani F, Marcocci C, Falorni A, Perniola R, et al. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2008;93(11):4389
97. 28. Zlotogora J, Shapiro MS. Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet 1992;29(11):824
6. 29. Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy
candidiasis
ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322(26):1829
36. 30. Myhre AG, Halonen M, Eskelin P, Ekwall O, Hedstrand H, Rorsman F, et al. Autoimmune polyendocrine syndrome type 1 (APS I) in Norway. Clin Endocrinol (Oxf) 2001;54(2):211
17. 31. Perniola R, Falorni A, Clemente MG, Forini F, Accogli E, Lobreglio G. Organ-specific and non-organ-specific autoantibodies in children and young adults with autoimmune polyendocrinopathy
candidiasis
ectodermal dystrophy (APECED). Eur J Endocrinol 2000;143(4):497
503. 32. Betterle C, Dal PC, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002;23(3):327
64. 33. Wang CY, Davoodi-Semiromi A, Huang W, Connor E, Shi JD, She JX. Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1). Hum Genet 1998;103 (6):681
5. 34. Soderbergh A, Myhre AG, Ekwall O, Gebre-Medhin G, Hedstrand H, Landgren E, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2004;89(2):557
62. 35. Gavalas NG, Kemp EH, Krohn KJ, Brown EM, Watson PF, Weetman AP. The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2007;92(6):2107
14. 36. Kemp EH, Gavalas NG, Krohn KJ, Brown EM, Watson PF, Weetman AP. Activating autoantibodies against the calcium-sensing receptor detected in two patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2009;94(12):4749
56. 37. Li Y, Song YH, Rais N, Connor E, Schatz D, Muir A, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996;97(4):910
14. 38. Rautemaa R, Richardson M, Pfaller M, Perheentupa J, Saxen H. Reduction of fluconazole susceptibility of Candida albicans in

PART | 2

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

Primary Immune Deficiencies

APECED patients due to long-term use of ketoconazole and miconazole. Scand J Infect Dis 2008;40(11
12):904
7. Rautemaa R, Richardson M, Pfaller MA, Perheentupa J, Saxen H. Activity of amphotericin B, anidulafungin, caspofungin, micafungin, posaconazole, and voriconazole against Candida albicans with decreased susceptibility to fluconazole from APECED patients on long-term azole treatment of chronic mucocutaneous candidiasis. Diagn Microbiol Infect Dis 2008;62(2):182
5. Gass JD. The syndrome of keratoconjunctivitis, superficial moniliasis, idiopathic hypoparathyroidism and Addison’s disease. Am J Ophthalmol 1962;54:660
74. Betterle C, Greggio NA, Volpato M. Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab 1998;83(4):1049
55. Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic dysregulation syndrome. J Clin Invest 2000;106(12):R75
81. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001;27(1):18
20. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27(1):20
1. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Med Genet 2002;39 (8):537
45. Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol 2007;120 (4):744
50, quiz 51
2. Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol 2012;3:211. Nieves DS, Phipps RP, Pollock SJ, Ochs HD, Zhu Q, Scott GA, et al. Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol 2004;140(4):466
72. Patey-Mariaud de Serre N, Canioni D, Ganousse S, Rieux-Laucat F, Goulet O, Ruemmele F, et al. Digestive histopathological presentation of IPEX syndrome. Mod Pathol 2009;22(1): 95
102. Torgerson TR, Linane A, Moes N, Anover S, Mateo V, RieuxLaucat F, et al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology 2007;132(5):1705
17. Levy-Lahad E, Wildin RS. Neonatal diabetes mellitus, enteropathy, thrombocytopenia, and endocrinopathy: further evidence for an X-linked lethal syndrome. J Pediatr 2001;138(4): 577
80. Scaillon M, Van Biervliet S, Bontems P, Dorchy H, Hanssens L, Ferster A, et al. Severe gastritis in an insulin-dependent child with an IPEX syndrome. J Pediatr Gastroenterol Nutr 2009;49 (3):368
70.

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

53. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med 2004;350(20):2068
79. 54. Halabi-Tawil M, Ruemmele FM, Fraitag S, Rieux-Laucat F, Neven B, Brousse N, et al. Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br Dermatol 2009;160(3):645
51. 55. McGinness JL, Bivens MM, Greer KE, Patterson JW, Saulsbury FT. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) associated with pemphigoid nodularis: a case report and review of the literature. J Am Acad Dermatol 2006;55(1):143
8. 56. Kobayashi I, Imamura K, Yamada M, Okano M, Yara A, Ikema S, et al. A 75-kD autoantigen recognized by sera from patients with X-linked autoimmune enteropathy associated with nephropathy. Clin Exp Immunol 1998;111(3):527
31. 57. Moudgil A, Perriello P, Loechelt B, Przygodzki R, Fitzerald W, Immunodysregulation Kamani N. polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: an unusual cause of proteinuria in infancy. Pediatr Nephrol 2007;22(10):1799
802. 58. Hashimura Y, Nozu K, Kanegane H, Miyawaki T, Hayakawa A, Yoshikawa N, et al. Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr Nephrol 2009;24(6):1181
6. 59. Godfrey VL, Wilkinson JE, Russell LB. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am J Pathol 1991;138 (6):1379
87. 60. Lin W, Truong N, Grossman WJ, Haribhai D, Williams CB, Wang J, et al. Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 2005;116(5):1106
15. 61. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012;30:531
64. 62. Benoist C, Mathis D. Treg cells, life history, and diversity. Cold Spring Harbor Perspect Biol 2012;4(9):a007021. 63. Lio CW, Hsieh CS. Becoming self-aware: the thymic education of regulatory T cells. Curr Opin Immunol 2011;23(2):213
19. 64. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD251 CD41 T cell receptors. Immunity 2004;21(2):267
77. 65. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006;7(4):401
10. 66. Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 2011;35(1):109
22. 67. Bilate AM, Lafaille JJ. Induced CD41 Foxp31 regulatory T cells in immune tolerance. Annu Rev Immunol 2012;30:733
58. 68. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011;331(6015):337
41. 69. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011;478(7368):250
4. 70. Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, MartinezLlordella M, Ashby M, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009;10(9):1000
7.

513

71. Paust S, Lu L, McCarty N, Cantor H. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA 2004;101(28):10398
403. 72. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyteassociated antigen 4 plays an essential role in the function of CD25 (1)CD4(1) regulatory cells that control intestinal inflammation. J Exp Med 2000;192(2):295
302. 73. Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999;190 (7):995
1004. 74. Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(1)CD25(1) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001;194(5):629
44. 75. Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA. CD4 1 CD25 1 T regulatory cells control anti-islet CD8 1 T cells through TGF-beta
TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci USA 2003;100(19):10878
83. 76. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004;21 (4):589
601. 77. Shevach EM. Mechanisms of foxp31 T regulatory cell-mediated suppression. Immunity 2009;30(5):636
45. 78. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008;8(7):523
32. 79. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204(6):1257
65. 80. Mellor AL, Chandler P, Baban B, Hansen AM, Marshall B, Pihkala J, et al. Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int Immunol 2004;16 (10):1391
401. 81. Glocker EO, Kotlarz D, Klein C, Shah N, Grimbacher B. IL-10 and IL-10 receptor defects in humans. Ann N Y Acad Sci 2011;1246:102
7. 82. Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives. Ann Med 2006;38(1):20
31. 83. Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol 2007;119(2):482
7. 84. Verbsky JW, Chatila TA. T-regulatory cells in primary immune deficiencies. Curr Opin Allergy Clin Immunol 2011;11(6):539
44. 85. Li B, Samanta A, Song X, Iacono KT, Brennan P, Chatila TA, et al. FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease. Int Immunol 2007;19(7):825
35. 86. Chatila TA, Williams CB. Foxp3: shades of tolerance. Immunity 2012;36(5):693
4. 87. Ono M, Yaguchi H, Ohkura N, Kitabayashi I, Nagamura Y, Nomura T, et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007;446(7136):685
9.

514

88. Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006;126(2):375
87. 89. d’Hennezel E, Bin Dhuban K, Torgerson T, Piccirillo CA. The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2012;49 (5):291
302. 90. Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol 2008;28(5):581
7. 91. De Benedetti F, Insalaco A, Diamanti A, Cortis E, Muratori F, Lamioni A, et al. Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Clin Gastroenterol Hepatol 2006;4(5):653
9. 92. Clark LB, Appleby MW, Brunkow ME, Wilkinson JE, Ziegler SF, Ramsdell F. Cellular and molecular characterization of the scurfy mouse mutant. J Immunol 1999;162(5):2546
54. 93. Blair PJ, Bultman SJ, Haas JC, Rouse BT, Wilkinson JE, Godfrey VL. CD41CD82 T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J Immunol 1994;153 (8):3764
74. 94. Lyon MF, Peters J, Glenister PH, Ball S, Wright E. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome. Proc Natl Acad Sci USA 1990;87(7):2433
7. 95. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD41CD251 regulatory T cells. Nat Immunol 2003;4(4):330
6. 96. Lin W, Truong N, Grossman WJ, Haribhai D, Williams CB, Wang J, et al. Allergic dysregulation and hyper immunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 2005;116(5):1106
15. 97. Chinen T, Volchkov PY, Chervonsky AV, Rudensky AY. A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota. J Exp Med 2010;207 (11):2323
30. 98. Rivas MN, Koh YT, Chen A, Nguyen A, Lee YH, Lawson G, et al. MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice. J Clin Invest 2012;122(5):1933
47. 99. Moes N, Rieux-Laucat F, Begue B, Verdier J, Neven B, Patey N, et al. Reduced expression of FOXP3 and regulatory T-cell function in severe forms of early-onset autoimmune enteropathy. Gastroenterology 2010;139(3):770
8. 100. Kobayashi I, Nakanishi M, Okano M, Sakiyama Y, Matsumoto S. Combination therapy with tacrolimus and betamethasone for a patient with X-linked auto-immune enteropathy. Eur J Pediatr 1995;154(7):594
5. 101. Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD41Foxp31 cells. J Exp Med 2008;205(3):565
74. 102. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 2008;105(22):7797
802. 103. Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol 2008;122(6):1105
12.e1.

PART | 2

Primary Immune Deficiencies

104. Lucas KG, Ungar D, Comito M, Bayerl M, Groh B. Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX syndrome. Bone Marrow Transplant 2007;39(1):55
6. 105. Baud O, Goulet O, Canioni D, Le Deist F, Radford I, Rieu D, et al. Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. N Engl J Med 2001;344(23):1758
62. 106. Rao A, Kamani N, Filipovich A, Lee SM, Davies SM, Dalal J, et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood 2007;109(1):383
5. 107. Seidel MG, Fritsch G, Lion T, Jurgens B, Heitger A, Bacchetta R, et al. Selective engraftment of donor CD41 25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Blood 2009;113(22):5689
91. 108. Dorsey MJ, Petrovic A, Morrow MR, Dishaw LJ, Sleasman JW. FOXP3 expression following bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Immunol Res 2009;44(1
3):179
84. 109. Burroughs LM, Torgerson TR, Storb R, Carpenter PA, Rawlings DJ, Sanders J, et al. Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol 2010;126(5):1000
5. 110. Kasow KA, Morales-Tirado VM, Wichlan D, Shurtleff SA, Abraham A, Persons DA, et al. Therapeutic in vivo selection of thymic-derived natural T regulatory cells following nonmyeloablative hematopoietic stem cell transplant for IPEX. Clin Immunol 2011;141(2):169
76. 111. Mazzolari E, Forino C, Fontana M, D’Ippolito C, Lanfranchi A, Gambineri E, et al. A new case of IPEX receiving bone marrow transplantation. Bone Marrow Transplant 2005;35(10):1033
4. 112. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 1976;193(4257):1007
8. 113. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature 1983;302(5906):305
10. 114. Leonard WJ, Depper JM, Crabtree GR, Rudikoff S, Pumphrey J, Robb RJ, et al. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature 1984;311(5987):626
31. 115. Nikaido T, Shimizu A, Ishida N, Sabe H, Teshigawara K, Maeda M, et al. Molecular cloning of cDNA encoding human interleukin-2 receptor. Nature 1984;311(5987):631
5. 116. Leonard WJ, Depper JM, Uchiyama T, Smith KA, Waldmann TA, Greene WC. A monoclonal antibody that appears to recognize the receptor for human T-cell growth factor; partial characterization of the receptor. Nature 1982;300(5889):267
9. 117. Sharon M, Klausner RD, Cullen BR, Chizzonite R, Leonard WJ. Novel interleukin-2 receptor subunit detected by cross-linking under high-affinity conditions. Science 1986;234(4778):859
63. 118. Teshigawara K, Wang HM, Kato K, Smith KA. Interleukin 2 high-affinity receptor expression requires two distinct binding proteins. J Exp Med 1987;165(1):223
38. 119. Tsudo M, Kozak RW, Goldman CK, Waldmann TA. Demonstration of a non-Tac peptide that binds interleukin 2: a potential participant in a multichain interleukin 2 receptor complex. Proc Natl Acad Sci USA 1986;83(24):9694
8.

Chapter | 23

Immune Dysregulation Leading to Chronic Autoimmunity

120. Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S, Tanaka N, et al. Cloning of the gamma chain of the human IL-2 receptor. Science 1992;257(5068):379
82. 121. Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, et al. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J 1994;13 (12):2822
30. 122. Depper JM, Leonard WJ, Kronke M, Noguchi PD, Cunningham RE, Waldmann TA, et al. Regulation of interleukin 2 receptor expression: effects of phorbol diester, phospholipase C, and reexposure to lectin or antigen. J Immunol 1984;133(6):3054
61. 123. Depper JM, Leonard WJ, Robb RJ, Waldmann TA, Greene WC. Blockade of the interleukin-2 receptor by anti-Tac antibody: inhibition of human lymphocyte activation. J Immunol 1983;131(2):690
6. 124. Rickert M, Wang X, Boulanger MJ, Goriatcheva N, Garcia KC. The structure of interleukin-2 complexed with its alpha receptor. Science 2005;308(5727):1477
80. 125. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci USA 2006;103(8):2788
93. 126. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995;3 (4):521
30. 127. Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci USA 1997;94(7):3168
71. 128. Roifman CM. Human IL-2 receptor alpha chain deficiency. Pediatr Res 2000;48(1):6
11. 129. Aoki CA, Roifman CM, Lian ZX, Bowlus CL, Norman GL, Shoenfeld Y, et al. IL-2 receptor alpha deficiency and features of primary biliary cirrhosis. J Autoimmun 2006;27(1):50
3. 130. Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini MS, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol 2013;146(3):248
61. 131. Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996;184(2):387
96. 132. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155(3):1151
64. 133. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(1) CD25(1) CD4(1) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005;201(5):723
35. 134. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005;6(11):1142
51. 135. de la Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin-2 is essential for CD41CD251 regulatory T cell function. Eur J Immunol 2004;34(9):2480
8. 136. Furtado GC. Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(1) regulatory T cell function. J Exp Med 2002;196(6):851
7.

515

137. Barron L, Dooms H, Hoyer KK, Kuswanto W, Hofmann J, O’Gorman WE, et al. Cutting edge: mechanisms of IL-2dependent maintenance of functional regulatory T cells. J Immunol 2010;185(11):6426
30. 138. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD41CD251Foxp31 regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4 1 T cells. Nat Immunol 2007;8(12):1353
62. 139. Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp31 T regulatory cells. J Immunol 2007;178(7):4022
6. 140. Zheng SG, Wang J, Horwitz DA. Cutting edge: Foxp31CD41CD251 regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol 2008;180(11):7112
16. 141. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 2013;38(1):13
25. 142. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282(5396):2085
8. 143. Liao W, Lin JX. Wang L, Li P, Leonard WJ. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol 2011;12(6):551
9. 144. Shi M, Lin TH, Appell KC, Berg LJ. Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. Immunity 2008;28(6):763
73. 145. Liao W, Schones DE, Oh J, Cui Y, Cui K, Roh TY, et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat Immunol 2008;9(11):1288
96. 146. Laurence A, O’Shea JJ. T(H)-17 differentiation: of mice and men. Nat Immunol 2007;8(9):903
5. 147. Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 2007;13(6):711
18. 148. Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, Lund FE, et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 2012;36(5):847
56. 149. Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med 2012;209(2):243
50. 150. Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ, Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 2010;32(1):79
90. 151. Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD81 memory T cells. Nature 2006;441(7095):890
3. 152. Siegel JP, Sharon M, Smith PL, Leonard WJ. The IL-2 receptor beta chain (p70): role in mediating signals for LAK, NK, and proliferative activities. Science 1987;238(4823):75
8. 153. Mingari MC, Gerosa F, Carra G, Accolla RS, Moretta A, Zubler RH, et al. Human interleukin-2 promotes proliferation of activated B cells via surface receptors similar to those of activated T cells. Nature 1984;312(5995):641
3.

516

154. Leonard WJ, O’ Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 1998;16:293
322. 155. Ihle JN. The Stat family in cytokine signaling. Curr Opin Cell Biol 2001;13(2):211
17. 156. Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF. Fetal anemia and apoptosis of red cell progenitors in Stat5a2/25b2/2 mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 1999;98(2):181
91. 157. Cui Y, Riedlinger G, Miyoshi K, Tang W, Li C, Deng CX, et al. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol 2004;24(18):8037
47. 158. Yao Z, Cui Y, Watford WT, Bream JH, Yamaoka K, Hissong BD, et al. Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci USA 2006;103(4):1000
5. 159. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003;349(12):1139
47. 160. Hwa V, Little B, Adiyaman P, Kofoed EM, Pratt KL, Ocal G, et al. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b. J Clin Endocrinol Metab 2005;90(7):4260
6. 161. Vidarsdottir S, Walenkamp MJ, Pereira AM, Karperien M, van DJ, van Duyvenvoorde HA, et al. Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J Clin Endocrinol Metab 2006;91(9):3482
5. 162. Walenkamp MJ, Vidarsdottir S, Pereira AM, Karperien M, van DJ, van Duyvenvoorde HA, et al. Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation. Eur J Endocrinol 2007;156(2):155
65. 163. Bernasconi A, Marino R, Ribas A, Rossi J, Ciaccio M, Oleastro M, et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 2006;118(5):e1584
92. 164. Hwa V, Camacho-Hubner C, Little BM, David A, Metherell LA, El-Khatib N, et al. Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. Horm Res 2007;68(5):218
24. 165. Pugliese-Pires PN, Tonelli CA, Dora JM, Silva PC, Czepielewski M, Simoni G, et al. A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings. Eur J Endocrinol 2010;163(2):349
55. 166. Scaglia PA, Martinez AS, Feigerlova E, Bezrodnik L, Gaillard MI, Di GD, et al. A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack

PART | 2

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

Primary Immune Deficiencies

of pulmonary disease. J Clin Endocrinol Metab 2012;97(5): E830
9. Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011;208(8):1635
48. van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 2011;365(1):54
61. Boisson-Dupuis S, Kong XF, Okada S, Cypowyj S, Puel A, Abel L, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol 2012;24(4):364
78. Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation polyendocrinopathy enteropathy X-linked-like syndrome. J Allergy Clin Immunol 2013;131(6):1611
23.e3. Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, et al. Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet 2010;86(3):447
53. Perry WL, Hustad CM, Swing DA, O’Sullivan TN, Jenkins NA, Copeland NG. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat Genet 1998;18 (2):143
6. Fang D, Elly C, Gao B, Fang N, Altman Y, Joazeiro C, et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol 2002;3(3):281
7. Gao M, Labuda T, Xia Y, Gallagher E, Fang D, Liu YC, et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 2004;306(5694):271
5. Fang D, Kerppola TK. Ubiquitin-mediated fluorescence complementation reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes. Proc Natl Acad Sci USA 2004;101 (41):14782
7. Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 2004; 5(3):255
65. Venuprasad K, Huang H, Harada Y, Elly C, Subramaniam M, Spelsberg T, et al. The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol 2008;9(3):245
53.