12. Primary immunodeficiency diseases

Immunologic disorders 12. Primary immunodeficiency diseases Francisco A. Bonilla, MD, PhD, and Raif S. Geha, MD Boston, Mass Although primary immunodeficiency disorders are relatively rare, intensive investigation of these disorders has yielded a great wealth of understanding of basic immunologic mechanisms in host defense, inflammation, and autoimmunity. These advances have led to important developments for the treatment not only of the primary immunodeficiencies but also for patients with secondary immunocompromised states, autoimmune disorders, hypersensitivity, graft rejection, and graft versus host disease. Correction of a form of severe combined immunodeficiency represents the first true success of human gene therapy. This review introduces the major clinical manifestations of primary immunodeficiency disorders, along with descriptions of essential elements of the pathophysiology of those disorders that have been defined at the molecular level. Key concepts in treatment are also presented. It is critical for the practicing primary care provider and allergist to maintain an index of suspicion for immunodeficiency. Early diagnosis offers the best opportunity for reduced morbidity and survival and is critical for accurate genetic counseling. (J Allergy Clin Immunol 2003;111:S571-81.) Key words: Genetic diseases, human immunodeficiency, immunology, infection

Primary immunodeficiency diseases are heritable disorders of immune system function. Many are associated with single gene defects, whereas others may be polygenic or may represent interactions of genetically determined characteristics with environmental or infectious stresses. These diseases are estimated to occur in from 1 in 10,000 to 1 in 2000 live births1,2 and are classified according to the types of immunologic mechanisms that are disrupted by the particular gene defect. Diseases in which lymphocyte function is principally affected are commonly divided into three main groups. In the antibody deficiencies, also referred to as B-cell or humoral immunodeficiencies, the genetic lesion selectively affects antibody production, whereas cell-mediated immunity is intact. In the cellular deficiencies, the opposite is true; antibody production is largely normal, whereas cellular effector mechanisms are compromised. In the combined immunodeficiencies, both effector arms of specific immunity are impaired. This category con-

From the Division of Immunology, Children’s Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass. Reprint requests: Francisco A. Bonilla, MD, PhD, Children’s Hospital, Immunology, Enders 809, 300 Longwood Ave, Boston, MA 02115. © 2003 by Mosby, Inc. All rights reserved. 0091-6749/2003 $30.00 + 0 doi:10.1067/mai.2003.86

Abbreviations used ADAD: Adenosine deaminase deficiency AICDA: Activation-induced cytidine deaminase AIRE: Autoimmune regulator APECED: Autoimmune polyendocrinopathy-candidiasisectodermal dystrophy APS-1: Autoimmune polyglandular syndrome type 1 A-T: Ataxia-telangiectasia ATM: Ataxia-telangiectasia mutated BCR: B-cell receptor BLNK: B-cell linker protein BTK: Bruton tyrosine kinase CGD: Chronic granulomatous disease CVID: Common variable immunodeficiency G-CSF: Granulocyte–colony stimulating factor G-CSFR: Granulocyte–colony stimulating factor receptor GM-CSF: Granulocyte-macrophage–colony stimulating factor HIGM: Hyper IgM syndrome IFNGR: Interferon-γ receptor Ig: Immunoglobulin IGAD: IgA deficiency IGGSD: IgG subclass deficiency IκB: Inhibitor of nuclear factor-κB IKK: Inhibitor of nuclear factor-κB kinase IL: Interleukin IVIG: Intravenous immunoglobulin LAD: Leukocyte adhesion deficiency LFA-1: Leukocyte function associated molecule 1 MBL: Mannose binding lectin NBS: Nijmegen breakage syndrome NEMO: NF-κB essential modifier NF-κB: Nuclear factor κB PNPD: Purine nucleoside phosphorylase deficiency RAG: Recombinase activating gene SADNI: Specific antibody deficiency with normal immunoglobulins SCID: Severe combined immunodeficiency TAP: Transporter of antigenic peptides TCR: T-cell receptor TNFSF: Tumor necrosis factor superfamily TNFRSF: Tumor necrosis factor receptor superfamily THI: Transient hypogammaglobulinemia of infancy WAS: Wiskott-Aldrich syndrome WASP: Wiskott-Aldrich syndrome protein WHN: Winged-helix nude XLA: X-linked agammaglobulinemia XLP: X-linked lymphoproliferative disorder

tains the subgroup of severe combined immunodeficiency (SCID), in which lymphocyte-dependent specific immunity is completely absent. There are two remaining major classes of primary immunodeficiency: defects in phagocyte function and complement deficiencies. S571

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TABLE I. Infectious organisms associated with major categories of immune deficiency Organism

Antibody deficiency

Cellular deficiency

Viruses Bacteria

Enteroviruses S pneumoniae, H influen- S typhi zae, S aureus, P aeruginosa, C fetus, N meninigitidis, M hominis, U ureolyticum Mycobacteria No Nontuberculous, including BCG Fungi No C albicans, H capsulatum, A fumigatus, C immitis Protozoa G lamblia

Each of these principal forms of immunodeficiency is characterized by some degree of increased susceptibility to infection. The diagnosis will most often be considered when infections are considered to be more frequent or severe, unusually resistant to standard therapies, or caused by unusual (opportunistic) organisms. Each class of immunodeficiency has a characteristic set of infectious predispositions that often guide initial diagnostic studies. Of course, there is considerable overlap in the types of organisms that may cause infection in patients with antibody or cellular immunodeficiency, complement deficiency, and so forth. As a result, several “arms” of the immune system may require scrutiny to arrive at a definitive diagnosis. Also, many syndromes of immunodeficiency will have characteristic associated clinical features that may also guide early diagnostic evaluation. Table I contains a listing of the most common infectious organisms associated with each category of immunodeficiency described in the following sections.

ANTIBODY DEFICIENCIES The human fetus acquires adult levels of immunoglobulin (Ig)G during late gestation. This IgG gradually wanes during the first 6 to 12 months of life, as endogenous IgG production begins. As a result, the infectious complications of antibody deficiencies may be delayed until 6 to 12 months of age or even later.3 These disorders are characteristic in early childhood with bacterial infections of the upper and lower respiratory tract. Bacterial infections of other organ systems and sepsis also occur, as well as infections with enteroviruses. The antibody deficiencies include the X-linked and autosomal recessive agammaglobulinemias, as well as common variable immunodeficiency, IgA deficiency, IgG subclass deficiency, transient hypogammaglobulinemia of infancy, and specific antibody deficiency. The types of infectious complications characteristic of antibody deficiency are also notable in combined immunodeficiencies such as Wiskott-Aldrich syndrome, ataxia-telangiectasia, and hyper-IgM syndrome.

Combined deficiency

Phagocyte defect

Complement deficiency

All No No As for antibody defi- S aureus, enteric flora, As for antibody deficiency, also: L mono- P aeruginosa, S typhi, ciency, esp N menincytogenes, S typhi, N asteroides gitidis enteric flora Nontuberculous, including BCG As for cellular deficiency

Nontuberculous, including BCG A fumigatus, C albicans

No

P carinii, T gondii

P carinii

No

No

Five genetic lesions have been identified in patients lacking B cells and serum immunoglobulin (Table II).4 The most common disorder is X-linked agammaglobulinemia (XLA, defect in Bruton tyrosine kinase or BTK), which accounts for between 80% and 90% of all cases. Additional forms are mutations of the IgM heavy chain gene (about a dozen patients found to date) and mutations of genes encoding components of the surrogate light chain (λ5 or 14.1, also called CD179b), the Ig-α component of the B-cell receptor (CD79a), and the signal transducing scaffold protein B-cell linker protein, or BLNK. Only one case each of these three defects has been described. Interestingly, all of these defects block B-cell development in the bone marrow at the pre–B-cell stage. Transition through this stage depends on signaling through the pre–B-cell receptor (pre-BCR), a complex of IgM heavy chain, surrogate light chain (λ5/VpreB heterodimer), and the Ig-α/β signal transducing heterodimer. Defects in the IgM heavy chain, λ5 and Ig-α, prevent cell surface expression of the pre-BCR. Defects in BTK and BLNK prevent signal transduction by the pre-BCR, such that critical activating intracellular pathways remain dormant. One form of severe hypogammaglobulinemia within a group of disorders known as hyper-IgM syndrome (low IgG and IgA with normal or elevated IgM) results from a defect in the RNA editing enzyme, activation-induced cytidine deaminase (AICDA).5 This enzyme is expressed only in B cells and is required for the processes of classswitching and somatic hypermutation of immunoglobulin genes. During a primary antibody response, B cells initially produce IgM and IgD. As the response progresses, through a process of DNA rearrangement, B cells switch to the production of IgG, IgA, and IgE (class switching). This process depends on transcription of these heavy chain genes before DNA rearrangement. Somatic hypermutation is associated with class switching and is the sequential accumulation of point mutations in immunoglobulin-variable region genes leading to increased antibody affinity for antigen (affinity matura-

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TABLE II. Immunodeficiencies associated with known genetic lesions Disorders

Antibody deficiencies The agammaglobulinemias Hyper-IgM syndrome, autosomal recessive Cellular deficiencies Interferon-γ–interleukin IL-12 axis Autoimmune polyglandular syndrome type 1 Defective NK function (CD16 deficiency) Combined deficiencies Severe (SCID) Defective cytokine signaling Defective T-cell receptor signaling Defective receptor gene recombination Defective nucleotide salvage pathway Defective MHC class I expression Defective MHC class II transcription Other Wiskott-Aldrich syndrome Ataxia-telangiectasia group DiGeorge syndrome Hyper-IgM syndrome X-linked lymphoproliferative syndrome Phagocyte defects Chronic granulomatous disease Chronic granulomatous disease variant Chediak-Higashi syndrome Leukocyte adhesion deficiency Neutrophil specific granule deficiency Cyclic neutropenia Congenital agranulocytosis (Kostmann syndrome) Complement defects

tion). Because of disruption of these processes of antigendependent B-cell development within germinal centers, these structures become massively enlarged, leading to the impressive lymphadenopathy and intestinal lymphoid hyperplasia that is characteristic of this disease. The remainder of the disorders classified as humoral immunodeficiencies are clinically defined, and they have not yet been elucidated at the molecular level. Common variable immunodeficiency (CVID) is defined principally as low IgG (often with low IgA) together with a significant impairment of specific antibody production in response to vaccine or natural infectious challenge.6,7 These individuals also may have a variety of autoimmune phenomena (seronegative arthritis, vasculitis, cytopenias) as well as benign lymphoproliferative disease (approximately one third of patients) and lymphoma (the relative risk may be as high as 300-fold). Approximately 10% of patients with CVID have asthma and rhinitis similar to patients with atopy, but no specific IgE is produced (C. Cunningham-Rundles, personal communication). There are genetic links with the MHC locus in many patients,8 but the actual genes involved have not yet been identified. Approximately 1 in 700 whites in the United States have absent serum IgA.9 Most of these are asympto-

Gene(s)

BTK, IGHM, CD79A, CD179B, BLNK AICDA IFNGR1, IFNGR2, IL12B, IL12RB1, STAT1 AIRE FCGR3A

IL2RG, IL2RA, IL7RA, JAK3 PTPRC, CD3G, CD3E, ZAP70 RAG1, RAG2 ADA, NP TAP1, TAP2 MHC2TA, RFXANK, RFX5, RFXAP DCCRE1C, WHN WASP ATM, NBS1, MRE11A del22q11 TNFSF5, TNFRSF5, IKBKG SH2D1A CYBA, CYBB, NCF1, NCF2 RAC2 LYST ITGB2, FLJ11320 CEBPE ELA2 CSF3R All soluble complement components except factor B

matic, but long-term (20-year) prospective follow-up of a large cohort of these patients has revealed an increased rate of respiratory tract infections such as sinusitis and bronchopneumonia.10 In healthy blood donors, IgG2 deficiency (see below) is found in 9% of IgA-deficient individuals; the proportion rises to 31% of those with IgA deficiency and recurrent infections.11 Additional clinical manifestations of IgA deficiency (IGAD) may be similar to what is seen in CVID, and similar HLA associations have been described. Specific antibody production is intact in IGAD, and atopic manifestations are generally associated with positive IgE responses. There are four subclasses of human IgG, designated IgG1, IgG2, IgG3, and IgG4. They are numbered consecutively with respect to their relative prevalence in serum, with IgG1 being the most abundant and IgG4 the least. As is the case with IGAD, most individuals with selective low levels of one or more IgG subclasses are asymptomatic. However, bacterial infections of the upper and lower respiratory tract, as well as viral infections, do occur with greater frequency in this population.12,13 Specific antibody production may be impaired in some patients with IgG subclass deficiency (IGGSD); this may be more pronounced with respect to polysaccharide anti-

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TABLE III. Lymphocyte phenotypes characteristically associated with particular forms of SCID T cells Form of SCID

CD3 CD4

CD8 B cells

X-linked, Jak3, IL-2R, IL-7R RAG1/2 ADA MHC II ZAP-70, MHC I

↓ ↓ ↓ NL NL

↓ ↓ ↓ NL ↓

↓ ↓ ↓ ↓ NL

NL ↓ ↓ NL NL

NK cells

↓ NL ↓ NL NL

gens (eg, those of the pneumococcal capsule) and may occur more frequently in those with selective deficiency of IgG2. Molecular lesions in specific IgG subclass genes have been described in only a few rare individuals.14 The molecular basis in the majority has not been described. Transient hypogammaglobulinemia of infancy (THI) is defined simply as an association of abnormally low IgG with recurrent bacterial and viral illnesses, mainly involving the respiratory tract, which resolves spontaneously by approximately 4 years of age.15 Most (not all) patients have completely normal specific antibody production, and serious infections have only been reported in a few patients. There are an unknown but possibly large number of individuals who have transient low IgG but who completely escape clinical attention as the result of being asymptomatic or of failure to recognize excessive incidence of infections in early childhood. Some patients with recurrent respiratory tract bacterial infections have impaired specific antibody production (particularly against polysaccharide antigens) in the context of completely normal levels of IgG, IgA, and IgM and IgG subclasses. This has been called specific antibody deficiency with normal immunoglobulins (SADNI).16 The relative proportions of patients with CVID, IGAD, IGGSD, THI, and SADNI are not entirely clear. In one retrospective survey at a tertiary care center, SADNI was the most frequent diagnosis, accounting for 23% of immunodeficiency diagnoses.17

CELLULAR DEFICIENCIES There are several genetic lesions that selectively impede cellular effector mechanisms involving T and NK cells and mononuclear cells while leaving antibody production intact (Table II). Five of the described genetic lesions all affect the same cytokine pathway: the interferon (IFN)-γ–IL-12 axis.18 IL-12 is the major stimulus for production of IFN-γ by TH1-type T cells and natural killer cells. IFN-γ is a critical stimulus activating cytotoxic mechanisms of mononuclear cells. If this cytokine axis is impaired, the host becomes highly susceptible to infection with organisms that replicate intracellularly, especially the nontuberculous mycobacteria, and salmonella. Mutations have been described in the p40 subunit of the IL-12 heterodimer, the β1 chain of the IL-12

receptor, both α and β chains of the IFN-γ receptor (IFNGR1, 2), and the STAT-1 signal transducing molecule, which is required for signaling through the IFNGR. The autoimmune regulator (AIRE) is a molecule of unknown function that has been shown to be responsible for a subgroup within the disorders known as chronic mucocutaneous candidiasis.19 AIRE mutation is associated with a form in which autoimmune responses to the gamut of endocrine tissues are characteristic. The disease is also called autoimmune polyglandular syndrome type 1 (APS-1), or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). One patient has been reported to have recurrent infections with defective natural killer cell function as a result of a mutation in the CD16 (FcγRIIIa) molecule.20

COMBINED DEFICIENCIES The largest group of disorders for which molecular lesions have been defined are the severe combined immunodeficiencies (SCID) (Table II).3,21,22 These are the most profound defects of specific immunity, often with complete absence of normal lymphocyte function. The most common clinical manifestations include chronic diarrhea with failure to thrive, recurrent and chronic respiratory infections, as well as opportunistic and disseminated infections. As is the case with the antibody and cellular deficiencies, some phenotypes arise as a result of mutations in a series of genes with related function. Some patients have absent T cells with normal or elevated numbers of poorly functional B cells. This is called T–B+ SCID (see Table III). Four related mutations have been described in these patients. The most commonly occurring is the basis of X-linked SCID, the IL2RG gene, which encodes a protein now called the cytokine receptor common gamma chain (γc). This molecule is a component of the receptors for 6 different cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21).23 The common γ chain functions as a signal transducer through its interaction with the JAK3 tyrosine kinase. Therefore, mutations of JAK3 are associated with a very similar phenotype.24 A few T–B+ SCID patients have also been found to have mutations in the genes encoding the α chains of the IL225 or IL-726 receptors. Another group of patients with SCID has alymphocytosis, and this is sometimes called T–B– SCID (Table III). About half of these patients have mutations of one of two genes that regulate the somatic recombination of immunoglobulin and T-cell receptor genes during B- and T-cell development. These are the recombinase activating genes 1 and 2 (RAG1/2).27 Without RAG1 and RAG2, mature Ig and T-cell receptor (TCR) genes cannot be assembled, and lymphocyte development is arrested at very early stages. A variant of SCID in which mutations allow partial function of RAG1 or RAG2 is known as Omenn syndrome. The most common form of SCID with autosomal recessive inheritance is adenosine deaminase deficiency (ADAD), accounting for approximately 15% of SCID

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overall.3,21,22 Deficiency of a closely related enzyme, purine nucleoside phosphorylase (PNPD), is more rare (about 35 cases reported).28 Both of these defects affect the salvage pathway of nucleotide biosynthesis. ADAD and PNPD lead to impaired development and reduced lifespan of both B and T cells by mechanisms that are not completely understood. The phenotype of ADAD is generally more severe than PNPD, in which there may be Tand B-cell function early in the course of the disease, which gradually wanes. Another group of mutations primarily affects signaling through the T-cell antigen receptor. These include the protein tyrosine phosphatase CD45,29 the γ and ε chains of the CD3 complex,30,31 and the ZAP70 tyrosine kinase.32 The clinical and laboratory phenotypes associated with these mutations are variable. ZAP70 deficiency is characterized by absence of circulating CD8+ T cells, although the CD4+ T cells that do develop have impaired function. Expression of MHC class I molecules is inhibited if either of the two transporters of antigenic peptides 1 and 2 (TAP1/2) are absent.33 These proteins shuttle cytosolic peptides across the endoplasmic reticulum to be loaded onto MHC class I molecules after synthesis. In the absence of these peptides, MHC class I molecules are unstable and do not reach the cell surface. MHC class I molecules are required for the interaction of CD8+ T cells with antigen presenting cells and target cells. If MHC class I is absent, there is a selective deficiency of CD8+ T cells, along with a somewhat milder SCID phenotype. Deficiency of MHC class II, on the other hand, leads to a severe SCID phenotype, with a poor prognosis.34 Four gene defects have been described in these patients. All of them encode components of a transcription complex that is required for the expression of MHC class II genes. If any component of the complex is absent, it cannot function, and no MHC class II molecules are produced. MHC class II is required for the interaction of CD4+ T cells with antigen presenting cells and B cells. MHC class II deficiency is associated with selective reduction in circulating CD4+ T cells and profound immunodeficiency. A few additional mutations have been described in patients with SCID. One group of patients with SCID with the additional feature of sensitivity to radiation was found to harbor mutations of the gene (provisional designation DCCRE1C) encoding a protein of unknown function called ARTEMIS.35 Recently, a single athymic patient with SCID, alopecia, and nail dystrophy was found to have a mutation in the winged-helix nude transcription factor (WHN), the same gene that is mutated in the spontaneous mutant nude mouse.36 There are several additional gene defects associated with combined immunodeficiency of varying severity. The X-linked Wiskott-Aldrich syndrome (WAS) consists of the classic triad of eczema, thrombocytopenia, and immunodeficiency.37 The mutated protein is called WASP (WAS protein). Interestingly, mutations in this protein are also found in patients with X-linked thrombocytopenia and in

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one patient with X-linked neutropenia. The WASP protein connects T-cell signaling pathways to critical cytoskeletal regulatory mechanisms necessary for T-cell activation. Ataxia-telangiectasia (A-T), as the name implies, consists of a cerebellar ataxia and oculocutaneous telangiectasias along with immunodeficiency.38 This disorder is also associated with sensitivity to ionizing radiation and a high rate of malignancy (mainly lymphoma and leukemia). The gene affected in this disease is called ATM (A-T mutated). ATM has a critical role in detection of double-strand breaks in DNA. In the absence of ATM, the cell cycle bypasses a normal checkpoint that halts cell division if DNA is damaged. This clearly underlies the radiation sensitivity in this disorder and leads to impaired lymphocyte development and function, at least in part by interference with the process of assembly of Ig and TCR genes. Approximately 95% of patients with A-T have elevated serum α-fetoprotein, and this may be a convenient method of establishing the diagnosis. The clinically similar disorder Nijmegen breakage syndrome results from mutations of NBS1, which encodes a substrate of ATM in the DNA-damage sensing pathway.39 The MRE11A molecule is another element of this pathway; mutations affecting this protein lead to another clinically similar disorder.40 The DiGeorge syndrome is associated with deletions in chromosome 22q11.41 Clinical features may include absent or diminished thymus development, cardiac malformations, hypoparathyroidism and hypocalcemia, and facial dysmorphism. There is a wide spectrum of clinical expression of 22q11 deletions. Complete absence of the thymus (hence, no T cells) is a SCID-like phenotype. Partially diminished thymus development occurs more commonly, and the severity of the immune defect depends on the amount of thymus tissue present. Some patients with deletions in this region have normal thymuses and cardiac defects (velocardiofacial syndrome). Hemizygosity of the gene encoding the transcription factor TBS-1 in a murine model has recently been shown to recapitulate the cardiac defects associated with human 22q11 deletion.42 The X-linked hyper-IgM syndrome (XHIGM or HIGM1) results from a mutation in the TNFSF5 (tumor necrosis factor superfamily member 5) gene.5,43 The encoded protein has also been called CD40 ligand, or CD154. This molecule interacts with CD40 on B cells and antigen presenting cells, and this interaction plays a critical role in promoting the accessory cell function of antigen presenting cells as well in the cooperation of T cells and B cells in inducing antibody production. Without this interaction, T cells are not appropriately stimulated after antigen exposure, and B-cell class-switching cannot occur (see Antibody Deficiencies). The clinical phenotype consists of low IgG and IgA with normal or elevated IgM. In addition, opportunistic infections characteristic of T-cell dysfunction (eg, P carinii pneumonia, or PCP) are also seen. PCP is a component of the clinical presentation in 35% to 40% of patients. A variable degree of neutropenia is found in 65%, as well. An identical phenotype with autosomal recessive inheritance has

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FIG 1. The phagocyte NADPH oxidase complex illustrates well how genetic lesions in proteins with related function lead to similar phenotypes. The active oxidase complex is formed by two membrane proteins (p22phox and gp91phox, also called the cytochrome b558 α and β chains, respectively), and three additional polypeptides: p47phox ([neutrophil cytosolic factor 1 (NCF1), p67phox (NCF2), and p40phox]. Assembly and activity of the oxidase complex is regulated by two GTPases, Rac2, and Rap1. Mutations in the genes encoding each of the red components have been identified in patients with CGD. Mutations of CYBB are the most common and underlie the X-linked form of CGD. Mutations of CYBA, NCF1, NCF2, and RAC2 lead to autosomal recessive forms with similar phenotypes, since function of the same multisubunit complex is impaired.

recently been ascribed to mutations in the gene encoding the ligand for TNFSF5, ie, TNFRSF5 (TNF receptor superfamily member 5), also called CD40.44 The transcription factor nuclear factor κB (NF-κB) is critical for regulating expression of a variety of genes important for immunity and inflammation (eg, acute phase response, adhesion molecules IL-1, IL-2, IL-6, IL8, G- and GM-CSF, TNF).45 The activity of NF-κB is controlled by the inhibitor of κB (IκB). When this is phosphorylated by the IκB kinase (IKK), the inhibitor is degraded and NF-κB is active. Mutations allowing partial function of the IKK γ chain (also called NF-κB essential modifier, or NEMO) occur in a group of patients with antibody deficiency combined with exquisite susceptibility to infection with nontuberculous mycobacteria and having ectodermal dysplasia.46 Interestingly, null mutations of this gene on the X chromosome are associated with incontinentia pigmenti in heterozygous females, a mutation that is lethal in males. X-linked lymphoproliferative disorder (XLP) is the name given to a pleomorphic disease arising from mutations in the gene encoding the protein SH2D1A.47 This is a member of a group of signal transducing proteins that

couple a variety of leukocyte surface molecules to intracellular signaling pathways. One of the most common manifestations of this disorder is fatal infectious mononucleosis. Additional features may include aplastic anemia, pulmonary lymphoid granulomatosis with vasculitis, lymphoma, and lymphoproliferation with hemophagocytosis. A few patients with XLP have been misdiagnosed as having CVID.48

PHAGOCYTE DEFECTS The classic form of phagocytic cell dysfunction is chronic granulomatous disease (CGD), which occurs in both X-linked (accounting for 75% of all cases) and autosomal recessive forms.49 All are caused by mutations affecting elements of the phagocyte oxidase complex, which is required for producing microbicidal substances such as hydrogen peroxide and superoxide radicals (Fig 1). The clinical manifestations include extreme susceptibility to infection with S aureus and Aspergillus, along with granulomatous inflammation that may affect any organ system. A variant of CGD results from mutation of the Rac2 GTPase.45

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Chediak-Higashi syndrome is caused by mutations affecting the lysosomal transport protein LYST, also affected in the beige mutant mouse.50 This defect prevents normal formation of phagolysosomes and melanosomes. On peripheral blood smears, neutrophils have characteristic giant lysosomes, and there is an associated partial albinism and variable neurologic defect. The clinical course is characteristically one of recurrent severe infections with S aureus that eventually culminates in the so-called “accelerated phase” of lymphoproliferation with hemophagocytosis that is often fatal. There are two forms of leukocyte adhesion deficiency (LAD1 and 2).51 Type 1 results from mutations in the gene encoding CD18 or β2 integrin. This molecule is a component of three heterodimers: with CD11a (integrin α L) to make leukocyte function associated molecule 1 (LFA-1); with CD11b (integrin α M) to make Mac-1 or complement receptor 3 (CR3); and with CD11c (integrin αX) to make complement receptor 4 (CR4). LFA-1 is the ligand for intercellular adhesion molecule–1 and mediates tight adhesion of leukocytes to endothelial cells before diapedesis. Without LFA-1, leukocytes are trapped in the circulation and cannot reach sites of infection. Skin and other organ abscesses do not suppurate, and leukocyte counts in the blood can reach 100,000 cells/mm3. LAD type 2 results from mutations in a GDP-fucose transporter that takes fucose into the Golgi apparatus for posttranslational fucosylation of newly synthesized proteins. In the absence of this transporter, the molecule sialyl-LewisX is not made. This is the ligand for E-selectin; without it, leukocytes cannot make initial attachment to vascular endothelium. Neutrophil-specific granules contain important microbicidal components such as lysozyme, lactoferrin, and vitamin B12–binding protein, as well as enzymes that degrade extracellular matrix proteins. In the absence of the transcription factor C-EBP-ε, the specific granules do not form, leading to neutrophil-specific granule deficiency, a rare clinical syndrome of pyogenic skin and respiratory tract infections.52 The genetic basis of cyclic neutropenia has recently been described. Deficiency of elastase leads to regularly (approximately every 21 days) fluctuating levels of neutrophils.53 Fever, stomatitis, and periodontitis and skin infections occur during periods when the neutrophil count is low. Congenital agranulocytosis, or Kostmann syndrome, results from mutations in the gene encoding the receptor for granulocyte–colony stimulating factor (G-CSFR).54 Clinical features include pneumonia, otitis media, gingivostomatitis, and perineal abscesses. The GCSFR mutations do not completely abolish protein function, and both of these disorders respond to pharmacotherapy with G-CSF. The genetic defect underlying the hyper-IgE syndrome has not yet been described.55 This disorder is characterized by coarse and asymmetric facial features with a chronic eczematous dermatitis with frequent Staphylococcal superinfection. Lung infections with

Aspergillus with pneumatocele formation are also common. Serum IgE levels are usually measured in the thousands to tens of thousands of nanograms per milliliter, and staph-binding IgE is usually present. However, the latter finding is not pathognomonic because it is also found in some patients with severe atopic dermatitis.

COMPLEMENT DEFICIENCY Deficiencies of all of the soluble complement components have been described, with the exception of factor B.56 Defects of early components of the classical pathway of complement activation (C1q, C1r, C2, and C4) lead to autoimmune inflammatory pathology resembling systemic lupus erythematosus. Deficiencies of the terminal complement components C5 through C8 have been associated with both recurrent infections with N meningitidis as well as rheumatic disease. Some patients with deficiency of C9 are healthy, whereas some have been reported to have recurrent Neisserial infections, as have patients lacking the alternative pathway components factor D and properdin. Absence of the central complement component C3, along with the regulatory proteins factor I and factor H, have been associated with recurrent infectious complications similar to what is seen in the antibody deficiencies. Membranoproliferative glomerulonephritis and vasculitis have also been associated with C3 deficiency. These features reflect impaired clearance of immune complexes, which depends on C3. Factor H deficiency is also associated with familial relapsing hemolytic uremic syndrome.57 There is a third pathway of complement activation, the lectin pathway initiated by mannose binding lectin (MBL).58 In some patients, MBL deficiency appears to be associated with recurrent infections. The determinants of clinically significant MBL deficiency are not entirely clear. Deficiency of the complement regulator C1 esterase inhibitor does not lead to immunodeficiency but to hereditary angioedema.59 This disorder has autosomal dominant inheritance and consists of recurrent attacks of subepithelial swelling involving the genitalia or extremities, the intestinal mucosa, or the larynx, which may be fatal.

CLINICAL APPROACH TO SUSPECTED IMMUNODEFICIENCY History As mentioned above, most patients with primary immunodeficiency come to medical attention because of a history of infections of unusual frequency, chronicity, or severity. Particular attention should be given to the family history of infectious problems or early deaths. The possibility of consanguinity should also be investigated.

Physical examination The physical examination of an immune-deficient patient may lead to important clues for diagnosis. Examples include the absence of tonsils and other lymphoid tissue in X-linked agammaglobulinemia, the partial

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albinism of Chediak-Higashi syndrome, early ocular telangiectasias in A-T, and so forth. Apart from such findings, physical examination most commonly reveals simply the presence or sequelae of infectious processes. These may also tend to guide the clinician to one set of diagnostic possibilities or another (eg, otitis media or pneumonia versus superinfected eczema).

Radiologic evaluation Again, these studies may most commonly be ordered to investigate or document the progress of infectious complications of immunodeficiency. However, there may be specific findings that may aid in early diagnostic considerations. Examples include absence of a thymic shadow on the chest radiograph of a newborn infant with SCID or complete DiGeorge syndrome and characteristic flared anterior ribs and other findings in ADAD, the presence of pneumatoceles in hyper-IgE syndrome, and so forth.

Laboratory evaluation of immunodeficiency The key to the definitive diagnosis of immunodeficiency lies in the clinical immunology laboratory. Although definitive diagnosis is possible in many cases without determining the specific molecular lesion (ie, the nature of the gene alteration in the individual), it should be pursued wherever possible to accumulate additional data regarding genotype/phenotype correlations as well as to better understand, eventually, other features of an individual that may alter the expression of a particular gene defect. Details regarding methods used to evaluate each of these immune mechanisms is found in Chapter 24. The evaluation of antibody deficiency should include both determination of serum Ig classes (IgG, IgA, IgM) and IgG subclasses as well as the levels of specific antibodies to both protein and polysaccharide antigens. This is because these types of antigens are handled somewhat differently by the immune system, and it is possible to have clinical immunodeficiency with a selective defect in the production of polysaccharide antibodies while protein responses remain intact (see SADNI, above). Note that as the result of the conjugation of certain bacterial polysaccharides with protein carriers, measurement of polysaccharide antibodies in some individuals may be indicative of responses to protein antigens. This would be the case for measurement of polyribose phosphate (PRP) antibodies in a recipient of a conjugate H influenzae type B vaccine or serotype-specific capsular polysaccharide antibodies in a recipient of conjugated pneumococcal vaccine. The production of serum isohemagglutinins specific for ABO blood group antigens is generated in response to polysaccharides of gut flora, and these antibodies may serve as indicators of polysaccharide immune responses in unimmunized individuals reliably by about 6 months of age. With respect to protein antigens, antibodies to tetanus and diphtheria toxoids are routinely assayed. Antibody responses against other vaccine organisms such as measles or varicella may also be measured, but serocon-

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version may not be as consistent in the general population. Note that the stimulus for antibody production in an individual may also be via natural infection. Determination of B-cell number may also be important in the diagnosis of antibody deficiency. Near absence of B cells would be indicative of a form of agammaglobulinemia, whereas normal B-cell number with low IgG might be consistent with CVID or XHIGM, for example. If the pattern of infections or other finding (eg, absent thymic shadow) suggest the possibility of cellular or combined immunodeficiency, the evaluation will extend beyond determination of humoral immune status to include determination of T-cell number and function (see Chapter 24). If the clinical characteristics of the patient are consistent with phagocytic cell or complement system disorders, specific evaluation of each of these areas is indicated (also see Chapter 24).

Carrier detection and prenatal diagnosis The great majority of patients with primary immunodeficiency with autosomal recessive inheritance are homozygous or compound heterozygous for the underlying genetic lesion, and parents are heterozygous carriers. On the other hand, about one third to one half of cases of X-linked immunodeficiencies arise as new mutations.60 Thus, carrier detection assumes great importance for appropriate genetic counseling. Analysis of the pattern of X chromosome inactivation (lyonization) may be informative in this regard. For example, in a heterozygous female carrier of X-linked SCID, T cells cannot develop from blood stem cells that have lyonized the X chromosome carrying the functional copy of the IL2RG gene. As a result, all T cells will have the same active X chromosome.61 The same is true of B cells in carriers of XLA62 and all leukocytes in carriers of WAS.63 Phenotypic and functional analyses of lymphocytes may be performed on umbilical cord blood samples during gestation to diagnose immunodeficiencies in pregnancies at risk. If the gene defect or associated chromosomal DNA markers are known, molecular genetic methods may also be applied. If the choice is made to continue the pregnancy, attempts to correct the defect, such as bone marrow or stem cell transplantation, may be applied before birth.64

THERAPY OF IMMUNODEFICIENCY Regular intravenous or subcutaneous infusions of purified human immunoglobulin (IVIG) are the mainstay of therapy for the agammaglobulinemias and common variable immunodeficiency.65,66 IVIG is an important component of therapy for combined immunodeficiencies such as WAS, A-T, and hyper-IgM syndrome as well. IVIG should also be administered to all patients with SCID while they are prepared for definitive therapy. Many patients with antibody or combined immunodeficiency will require periodic antibiotic treatment for acute bacterial infections; sinusitis may be especially problematic. Occasionally, response to IVIG is not com-

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plete, and maintenance antibiotic therapy may also be necessary. IGAD, IGGSD, THI, and SADNI may frequently be managed initially with antibiotic prophylaxis. IVIG may be reserved for the most difficult patients who break through preventive antibiotic treatment. Again, some patients with these disorders may require both IVIG and antibiotics for treatment. There are no “replacement” therapies that are routinely effective for the cellular deficiencies. Treatment focuses principally on aggressive treatment of infectious complications as they occur and preventive treatment when appropriate.49 Some patients with partial deficiency of the interferon-γ receptor, or with defects of IL-12 or IL12R, may benefit from subcutaneous injections of IFN-γ. As mentioned above, IVIG replacement is indicated for treatment of the antibody deficiency component of the combined immunodeficiencies. However, this therapy alone is not sufficient. For decades, bone marrow transplantation has remained the only hope for long-term survival in patients with SCID.22,67 This is still true for the majority of these disorders. Depending on the age at transplantation, the type of SCID, and the type of donor (identical versus haploidentical versus unrelated), success rates vary from approximately 50% to almost 100%. The first true success of human gene therapy was recently reported with the correction of several patients with Xlinked SCID by ex vivo transduction and reinfusion of stem cells with a functional copy of the γc gene.68 Enzyme replacement may be used for some patients with ADAD. Polyethylene glycol–conjugated bovine ADA may be administered by subcutaneous injection. Partial reconstitution of T-cell function may be achieved after a few months of therapy. This form of treatment is less commonly used at present, with the general availability of bone marrow transplantation. In WAS, IVIG therapy is routine, and splenectomy is indicated for problematic thrombocytopenia.37 WAS is also curable by bone marrow transplantation. IVIG replacement and prophylaxis for PCP are indicated for X-linked hyper-IgM syndrome.43 G-CSF may be used to treat the neutropenia, but response is variable. XHIGM is also curable by bone marrow transplantation. In DiGeorge syndrome, since there is no thymus in which transplanted stem calls may develop into T cells, cure is only possible with thymus transplantation or infusion of compatible mature T cells.69 A-T is not amenable to bone marrow transplantation because of toxicity of myeloablation.38 Only supportive treatment is possible. Some patients with CGD have been treated successfully with bone marrow transplantation.49 Others may be treated by careful hygiene, preventive antibiotics, and injections of IFN-γ. Complement deficiencies may be difficult to treat. The autoimmune phenomena that may occur may be resistant to immunosuppressive therapy. Patients should be thoroughly immunized with respect to common pathogens, and febrile illnesses should be investigated and treated aggressively with a high index of suspicion for bacteria.56 If patients have frequent infections, antibiotic prophylaxis may be considered.

CONCLUDING REMARKS Recent decades have witnessed an explosive advance in the molecular understanding of many previously mysterious immunodeficiency disorders. Along the way, we have gained a wealth of knowledge of immune system biology that has paved the way for novel therapies not only for the immunodeficiencies themselves but also for a variety of autoimmune-, inflammatory-, or transplantation-related disorders. The pace of progress is increasing, and the next decade probably will bring deeper understanding of the influence of the environment, as well as a host of immunologically important gene polymorphisms, in the expression of these diseases.

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