Agammaglobulinemia

Chapter 13

Agammaglobulinemia Alessandro Plebani and Vassilios Lougaris Pediatrics Clinic and Institute of Molecular Medicine “A. Nocivelli,” Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy

Chapter Outline X-Linked Agammaglobulinemia BTK Genetics Pathogenesis Clinical Presentation Bacterial Infections Enteroviral Infections Other Infections Arthritis Neutropenia Other Manifestations Laboratory Findings Management Antibiotics Gene Therapy Complications and Prognosis Autosomal Recessive Agammaglobulinemia Mu (μ Heavy Chain) Genetics Pathogenesis Clinical Presentation L5 (λ5/14.1) Genetics Pathogenesis Clinical Presentation

329 329 329 330 330 330 332 333 333 333 334 335 336 336 336 336 337 337 337 337 337 337 337 339 339

X-LINKED AGAMMAGLOBULINEMIA BTK (OMIM #300755) X-linked agammaglobulinemia (XLA) is a rare primary immune deficiency characterized by absence of circulating B cells with severe reduction in all serum immunoglobulin levels due to mutations in the BTK gene. T cell counts and function are in the normal range. Affected patients present an early onset of recurrent bacterial

CD79A (Igα) Genetics Pathogenesis Clinical Presentation CD79B (Igβ) Genetics Pathogenesis Clinical Presentation BLNK Genetics Pathogenesis Clinical Presentation PI3K Genetics Pathogenesis Clinical Presentation LRRC8 Genetics Pathogenesis Clinical Presentation Laboratory Findings Management and Prognosis Acknowledgments References

339 339 339 339 340 340 340 340 340 340 340 340 340 340 341 341 341 341 341 341 341 342 342 342

infections. The incidence of the disease varies from 1:100,000 to 1:200,000 depending on ethnicity.

Genetics XLA represents the prototype for primary immune deficiencies, and was the first immunological disorder for which the genetic cause was discovered. Although the disease was described by Colonel Bruton in 1952,1 the

K.E. Sullivan and E.R. Stiehm (Eds): Stiehm’s Immune Deficiencies. DOI: http://dx.doi.org/10.1016/B978-0-12-405546-9.00013-3 © 2014 Elsevier Inc. All rights reserved.

329

330

PART | 2

Deletions 4.8% Splice site 12.8%

HSC

Primary Immune Deficiencies

Pro-B

Pre-B

Immature B

Healthy control Frameshift 12.8%

Missense 47.2%

Nonsense 17.6%

Mutations in BTK XLA

FIGURE 13.1 Distribution of BTK mutations in 125 patients affected with X-linked agammaglobulinemia. Data from the Italian Network for Primary Immunodeficiencies IPINET (numbers refer to percentages).

underlying genetic defect was only identified in the early 1990s by two different groups.2,3 Bruton’s tyrosine kinase (BTK), a member of the Tec family of kinases that maps to the X chromosome, was found to be mutated in the majority of male patients with agammaglobulinemia. BTK is a kinase that acts downstream of the pre-BCR and the BCR signaling complex, and its activation is essential for B cell activation and maturation.4 6 Mutations causing XLA have been identified in all BTK domains, as well as in the non-coding sequences of the gene.7 9 The majority of the reported mutations are missense, followed by nonsense mutations, while the deletions represent the minority of the disease-causing mutations.7 9 Figure 13.1 represents an example of this trend: it depicts the distribution of BTK mutations in 125 Italian patients (data from the Italian Network for Primary Immunodeficiencies, IPINET) and is in line with already reported data.8,9,10 13 Mutations in BTK can be both familial and de novo ones; in the former case, mothers of affected individuals are healthy carriers. One case of a female patient with agammaglobulinemia due to BTK mutation has been reported so far, due to skewed X-chromosome inactivation.14 Although national and international BTK mutation databases have been established gathering together hundreds of affected patients, it is not clear yet whether a genotype phenotype correlation exists.15 17

Pathogenesis The identification of mutations in BTK in the majority of male patients with agammaglobulinemia led to further studies in order to better understand the role of BTK in B cell development. The animal model deficient for BTK (xid mouse) showed similarities with the human phenotype,18 although the effect was less severe from an immunological point of view. It helped elucidate the pathogenetic mechanism responsible for the B cell defect in XLA.19 B cell development takes place in the bone marrow, and depends on the sequential expression of specific gene products that regulate B cell maturation. B cell maturation follows specific steps starting from pro-B to pre-B to transitional B cells that exit the bone marrow and enter the periphery.20 22 Pre-B cells express the pre-BCR

Bone marrow

FIGURE 13.2 B cell developmental arrest in the bone marrow at the pro-B to pre-B stage in the presence of mutations in BTK.

complex that requires BTK for the initiation of the downstream signaling cascade, necessary for further maturation.23 25 Mutations in BTK result in a block of B cell development in the bone marrow at the pro-B to preB stage (Figure 13.2). Studies performed both on patients and on animal models have underscored the importance of this checkpoint for B cell maturation in the bone marrow.26 28 As a result of this early developmental block, less than 1 2% of lymphocytes are B cells in the periphery of these patients. Immunoglobulin levels are very low for all classes, and there is virtually no humoral response to recall antigens. BTK deficiency specifically affects the B cell lineage, resulting in reduced size of lymph nodes and tonsils tissues normally highly populated by B cells.29 On the other hand, both number and function of T cells are conserved, with the former being slightly increased. BTK is expressed in platelets, where its function is unclear, and in monocytes, where it appears to regulate TLR signaling.

Clinical Presentation The protective role of maternal IgG transferred through the placenta is underscored in XLA. In fact, clinical symptoms in affected patients initiate between the age of 6 and 12 months, when the maternal IgGs are catabolized. Recurrent bacterial respiratory and/or gastrointestinal infections are the hallmark of this disorder.30 However, some patients may remain asymptomatic for the first years of life. Rare cases of young adolescents or even adults affected with XLA but without symptoms until that age have been reported.31 33 The frequency and type of infections is variable based on the different cohorts of patients investigated.10 13,33 36

Bacterial Infections Bacterial infections are the hallmark of XLA, both as presenting symptoms and as complications once IVIG therapy is initiated. Such infections are mainly caused by encapsulated bacteria, namely Streptococcus pneumoniae,

Chapter | 13

Agammaglobulinemia

331

Pathogens involved in chronic sinusitis in XLA

Etiology of pneumonia in XLA 17%

10%

3% 3%

3%

8% 58% 14%

17%

67%

H. influenzae

S. pneumoniae

P. aeruginosa

Staphylococcus

FIGURE 13.3 Encapsulated bacteria represent the most frequent isolates from XLA patients with pneumonia. Data from IPINET on 125 XLA patients (numbers refer to percentages).

Haemophilus influenzae, Staphylococcus aureus, and others. The most frequent type of upper respiratory tract infection in large cohorts of XLA patients is otitis media (70%), followed by sinusitis (almost 60%).10 13,33 36 Recurrent otitis media may be the only infectious manifestation prior to diagnosis in XLA patients, and should therefore always be considered as an alarm sign for immune deficiency during routine clinical practice.37 Pneumonia episodes are frequent features of the clinical history leading to the diagnosis of XLA (almost 60% of affected patients); although identification of the etiologic agent is not always possible, the majority of isolated agents are encapsulated bacteria (Pneumococcus, H. influenzae, etc.).12,13 Figure 13.3 represents an example of the distribution of these pathogens in 125 XLA Italian patients; in this case series, Haemophilus infuenzae appears the most frequent isolated pathogen, followed by Streptococcus pneumoniae and Staphyloc staphylococcus. The different etiologic agents reported in the various series cases may be due to different epidemiological conditions.10 13,33 36 Rare cases of Pneumocystis jirovecii pneumonia in XLA patients have been reported.38 40 Pseudomonas has been reported to be the most frequently isolated pathogen in septicemia, followed by H. influenzae, S. pneumoniae, and S. aureus.12,13 Septic arthritis in these patients is mainly caused by H. influenzae and S. pneumoniae before IVIG therapy, whereas after IVIG therapy a viral cause is mainly responsible. Bacterial meningitis can also complicate the history of these patients, especially before initiation of appropriate treatment, and is caused by the abovementioned pathogens as well.10 13,33 36 Chronic sinusitis is present in almost 60% of patients; Figure 13.4 shows the distribution of infectious agents involved in 125 Italian patents with XLA (data from IPINET). Pathogens are mainly represented by encapsulated bacteria, with Haemophilus influenzae being the most frequently isolated. Recurrent bronchitis and/or pneumonia, and in general infections at the mucosal surfaces, continue to occur even when immunoglobulin

H. influenzae

S. pneumoniae

P. aeruginosa

Staphylococcus

Klebsiella

Moraxella

FIGURE 13.4 Pathogens isolated from XLA patients with chronic sinusitis. Data from IPINET on 125 XLA patients (numbers refer to percentages).

FIGURE 13.5 CT scan showing development of bronchiectasis in a patient with X-linked agammaglobulinemia (XLA).

Box 13.1 XLA patients may develop CLD even when under regular Ig replacement treatment.

replacement therapy is appropriately administered, and are the major causes of bronchiectasis and chronic lung disease (CLD). Figure 13.5 shows the CT scan of an XLA patient who developed bronchiectasis while on regular replacement treatment. In fact, even while on regular replacement treatment, affected patients tend to develop CLD in a manner directly proportional to the years of disease (see Box 13.1 and Figure 13.6).12 This is partially due to the inability of immunoglobulin substitution to reach the mucosal surface, where it is expected to play a crucial protective role. However, it is likely that an early diagnosis and an aggressive and timely control of

332

PART | 2

Primary Immune Deficiencies

Chronic lung disease (CLD) in XLA 1.00

Cumulative risk

0.75

0.50

0.25

0 0

5

10

15

20

25

30

Length of follow-up (years)

FIGURE 13.6 Cumulative risk for the development of chronic lung disease (CLD) in patients affected with X-linked agammaglobulinemia (XLA).

Pathogens involved in gastrointestinal infections in XLA 8%

4%

20%

8%

60% Salmonella

Giardia

Campylobacter

E. coli

Blastocystis

FIGURE 13.7 Pathogens isolated from XLA patients with gastrointestinal infections. Data from IPINET on 125 XLA patients.

Box 13.2 Giardia lamblia in XLA often manifests as falling IgG levels or unexplained weight loss.

FIGURE 13.8 Skin manifestation in an XLA patient with systemic infection caused by Flexispira rappini (Helicobacter-like organism).

manifestations and fever.41,42 Salmonella has also been described as a cause of gastrointestinal infection in XLA patients.10 13,33 36 Helicobacter species have also been reported in XLA patients. Clinical manifestations may vary, including pyoderma gangrenosum-like ulcer (Helicobacter cinaedi),43 45 skin infection (Helicobacter bilis),46,47 refractory chronic pleurisy (Helicobacter equorum-like),48 and systemic infection (Flexispira rappini, a Helicobacter-like organism) (Figure 13.8). Mycoplasma species are also frequently responsible for infections in XLA patients, mainly involving the respiratory and urogenital tract, and in some cases the joints. Since the isolation of these microorganisms is often difficult, requiring PCR detection, diagnosis may be delayed with prolonged course of the infection and increasing severity of symptoms. Frequently, combined infections with Mycoplasma species and other bacteria can increase disease severity.10 13,33 36 Recurrent bacterial conjunctivitis is also rather frequent (5 8%), and the pathogens involved are the ones so far described. Cardiac involvement is infrequent during infectious episodes, although infectious pericarditis (Morganella morganii) has been reported in XLA patients.49

Enteroviral Infections infectious episodes may have a positive effect in reducing the progressive lung damage in XLA. Infections of the gastrointestinal tract are frequent in XLA patients, both at diagnosis and during follow-up. Giardia lamblia (Box 13.2) is frequently isolated from stool samples from these patients12,13 (Figure 13.7), and unfortunately its eradication is frequently unsuccessful, resulting in chronic diarrhea and malabsorption.13 Similar clinical findings are caused by Campylobacter jejuni infections. These can sometimes be accompanied by skin

The intrinsic B cell defect that underlies XLA does not influence host defense against viral infections, with certain exceptions. Affected patients are particularly susceptible to enterovirus, namely poliovirus, echovirus, and coxsackievirus. Vaccine-associated poliomyelitis after live attenuated oral vaccine (Sabin) has been reported, and is complicated by a high mortality rate.50 54 Progressive neurological symptoms in XLA patients, such as ataxia, paresthesias, loss of cognitive skills, and neurosensorial hearing loss, should always raise the suspicion of enteroviral infection. Enteroviral

Chapter | 13

Agammaglobulinemia

meningoencephalitis in XLA patients tends to manifest slowly throughout the years, although fulminating infection with fever, headache, and seizures has also been reported.55 The difficulty in isolating the enterovirus from the CSF may be overcome by using PCR techniques; however, this method does not always detect the enterovirus. CSF features of a viral infection are pleocytosis, elevated protein content, and in some cases hypoglycorrhachia, but some patients with symptoms of encephalitis may have normal or near-normal CSF findings. Enteroviral CNS infections were frequent before the introduction of IVIG, and were one of the major causes of death. However, these infections may still occur even while on immunoglobulin substitution therapy. It has been suggested that high-dose IVIG treatment may be efficient in controlling this type of infection, but the limited number of patients studied does not allow statistical conclusions.12,13,56 Intrathecal delivery of IVIG has also been used in some cases for a more prompt and direct effect. An anti-inflammatory effect of high-dose IVIG has been proposed, although it is difficult to demonstrate. Combined treatment with immunoglobulin replacement therapy and pleconaril has been shown to be effective in controlling enteroviral infection. Furthermore, pleconaril treatment was found to be effective in controlling lifethreatening enterovirus infections in almost 80% of cases.57 59 Nonetheless, pleconaril is no longer available for compassionate use in chronic enteroviral meningoencephalitis. It has also been postulated that high Ig levels in patients under regular Ig replacement treatment may play a protective role against enteroviral infection, especially when Ig replacement treatment is initiated at high doses before the age of 5 years.55 However, there are still no clear indications regarding the most effective therapeutic approach to better prevent enteroviral infection in XLA or treat life-threatening enteroviral infections in XLA. An MRI or CT scan is usually normal at the onset of symptoms, and therefore has limited diagnostic value. Chronic enteroviral infection eventually results in cerebral edema, diffuse inflammation, and progressive cerebral atrophy.55 59 Chronic leptomeningitis has been reported in some cases instead of the “classic” findings of encephalitis. CNS enteroviral infection may also present with peripheral edema and erythematous rash mimicking a dermatomyositis-like syndrome; affected patients usually present with “woody” edema of their extremities (see also Box 13.3). Biopsy specimens from skin and muscle evidence inflammation, suggestive of fasciitis and myositis.

Box 13.3 CNS enteroviral infections in XLA may still occur even when under regular Ig replacement treatment.

333

Such manifestations may follow the CNS involvement and demonstrate a disseminated enteroviral infection.60 Involvement of the liver, with an enteroviral hepatitis, ALT increase, and hepatomegaly, has also been reported, usually associated with rash and fever. Recently, the first case of astrovirus encephalitis in a patient with agammaglobulinemia was reported.61

Other Infections Hepatitis C infection from contaminated IVIG preparations was reported in the early 1990s. XLA patients seem to tolerate HCV infection better than CVID patients.62 More than one-third of the reported patients cleared the infection or remained asymptomatic, whereas only one patient developed hepatic failure, but was co-infected with hepatitis B virus. Pneumocystis has been documented as a rare cause of pneumonia in XLA patients, mainly debilitated ones.38 40 Recurrent pyoderma was recently shown to be the only clinical manifestation of an XLA patient.63 Chronic gingivitis has also been reported as the only clinical finding in a single XLA patient.64

Arthritis Up to 20% of XLA patients may develop arthritis. Clinical findings are indistinguishable from rheumatoid arthritis (RA), including motion limitation, effusion, pain, and destructive pannus formation.65 71 In some cases a pyogenic cause has been isolated, although in the majority of cases no isolates are found. These manifestations tend to respond to IVIG therapy, sometimes at increased doses, indicating a potential infectious cause. Antibiotics are usually administered with the IVIG treatment. In many reported cases, an enteroviral or Mycoplasma infection has been associated with the rheumatic manifestations. Interestingly, although B cells have been proposed to be involved in the pathogenesis of RA, it appears evident that RA pathogenesis involves other cell types besides B cells; in an XLA patient reported to be affected with RA, no B cell infiltrates were found in the synovium.65 71

Neutropenia Neutropenia has been reported in XLA.72 77 A recent Japanese nationwide study showed that 18% of XLA patients presented with neutropenia before IVIG treatment was initiated.76 Neutropenia in most reported cases is found at diagnosis and usually resolves after regular Ig replacement therapy is initiated. In different studies, neutropenia has been reported in 10 25% of patients, although the mechanism has not yet been elucidated.72 77 Pseudomonas ecthyma is typically only seen in neutropenic XLA patients.

334

Other Manifestations Other rare manifestations include glomerulonephritis,78 membranous glomerulopathy,79,80 alopecia,81 amyloidosis,82,83 and von Recklinghausen disease.84 Conjunctivitis is rather frequent, mainly in adult patients, and some report a benefit from IVIG treatment. Gastric adenocarcinomas85 87 and cutaneous T cell lymphomas88 have been reported in XLA patients as well. Figure 13.9 shows the histological findings from a patient with XLA and gastric adenocarcinoma. Sensorineural hearing loss (SNHL) has also been reported in XLA patients, although the underlying pathogenic mechanism is still not clear.89 In a limited number of cases, gross deletions encompassing BTK and TIMM8A have been implicated in the combination of immunodeficiency and sensorineural hearing loss.90 All reported patients presented recurrent

FIGURE 13.9 Histological findings in a patient with XLA and diffuse cell gastric adenocarcinoma.

PART | 2

Primary Immune Deficiencies

respiratory infections, such as pneumonia and bronchitis, even when under replacement treatment. The immunological presentation was typical of X-linked agammaglobulinemia with absent peripheral B cells and very low to undetectable serum immunoglobulin levels of all classes. Neurological manifestations, including sensorineural hearing loss (SNHL), presented at variable age of onset, but always within the first years of life. Besides SNHL, other neurological symptoms have been reported, including abnormal speech, aggressive behavior, muscle wasting, progressive dystonia, and spasticity. Clinical presentation did not depend on the type and/or extension of the deletion involving TIMM8A. Children with recurrent respiratory infections and neurological symptoms such as speech and motor delay should be evaluated for this rare combination of XLA and TIMM8A deletion. Besides cutaneous T cell lymphomas, XLA patients may present with skin lesions due to granulomatous vasculitis (Figure 13.10). Growth hormone deficiency with agammaglobulinemia was initially reported in four male family members.91 All patients presented with short stature and an isolated growth hormone deficiency. All patients showed hypogammaglobulinemia. Peripheral B cells were absent in three out of four, although tonsillar tissue was present. Molecular analysis of these four patients did not evidence any defect in the BTK gene and protein expression,92 suggesting that a different genetic etiology may be responsible for this disorder. Recent findings suggest that the ELF4 gene may be involved in the pathogenesis of this disorder, although the data are not yet conclusive.93 Mutations in BTK have been reported in additional patients with agammaglobulinemia and isolated growth hormone deficiency,94,95 although the same mutations have also been

FIGURE 13.10 Extensive papular and itchy dermatitis in a patient with X-linked agammaglobulinemia (left panel). The right panel depicts the histological findings from the skin biopsy, showing granulomatous vasculitis with a lympho-histiocytic infiltrate.

Chapter | 13

Agammaglobulinemia

335

Monocytes

100

100

80

80 % of max

Healthy control

% of max

B lymphocytes

60 40

101

102

103

0 100

104

100

100

80

80 % of max

% of max

XLA patient

60 40

101

102

103

103

104

101

102

103

104

101

102

103

104

40

100

100

80

80

60 40

60 40 20

20 0 100

102

60

0 100

104

% of max

% of max

0 100

101

20

20

Healthy carrier (mother of XLA patient)

40 20

20 0 100

60

101

102

103

104

0 100

BTK FIGURE 13.11 Histograms showing BTK protein expression in B cells and monocytes from a healthy control, a patient with XLA, and his healthy mother (carrier).

reported in classical XLA patients without growth hormone deficiency96 arguing therefore that a different X-linked gene may be involved in the pathogenesis of this disorder.

Laboratory Findings The typical laboratory findings of XLA consist of low to undetectable immunoglobulin serum levels and the almost complete absence of peripheral B cells (,2% of lymphocytes), reflecting the early block in B cell development.7 9,12,13 However, there have been case reports of XLA patients with low IgG levels and near normal IgA or IgM serum levels adding variability to the immunological presentation of XLA. Rare cases of patients with peripheral B cells and/or near normal Ig levels have been reported. In such cases, specific antibody response to

vaccines is used for further characterization. T cell numbers and function are typically normal, although the former may be slightly high. Once the clinical suspicion is supported by laboratory findings, molecular analysis of the BTK gene should be performed in order to define the mutation. If molecular analysis is not available, evaluation of the expression of BTK protein by means of flow cytometry in monocytes is an alternative valuable and rapid diagnostic tool (Figure 13.11). If the protein is not expressed, a definite diagnosis of XLA is made, and genetic analysis can be done sequentially in order to define the causative mutation.7 9 Cytofluorimetric analysis of BTK expression can also be used for the carrier detection state. Once the mutation is defined, carrier diagnosis and prenatal diagnosis can also be performed where necessary.

336

Management Immunoglobulin replacement therapy is fundamental in XLA, as in other humoral immunodeficiencies, such as common variable immunodeficiency (CVID). The first cases of agammaglobulinemia1,97 were treated with both intramuscular and subcutaneous preparations. Although the subcutaneous route was preferred by several physicians, the intramuscular one became the gold standard for decades. However, it was painful for the patients receiving the treatment, especially considering the volume necessary to reach an acceptable trough level, and the availability of the product, once administered, was rather limited. Still, it was used for at least two decades.98,99 The superiority of the intravenous preparations when compared to the intramuscular ones was demonstrated by direct comparison.100 In fact, starting from 1981, intravenous immunoglobulins became the routine treatment for all patients with humoral immune deficiencies.10 13,33 36 In parallel, the original subcutaneous route of administration was still used in several clinical studies101 104 demonstrating similar efficacy in preventing infectious episodes in patients with antibody deficiency. The numerous advantages of the subcutaneous route and the availability of different commercial subcutaneous products led to wide use of subcutaneous immunoglobulin preparations. In fact, in many countries subcutaneous preparations are currently preferred by patients affected with humoral defects.105 It has been widely accepted, based on different international studies, that maintaining pre-infusion IgG levels of .500 mg/dl assures a notable reduction in the number of infections, reducing the necessity for hospitalizations. A dose of 400 mg/kg per dose every 3 to 4 weeks (in the case of IVIG) or 100 mg/kg per dose every week (in the case of SCIG) is usually sufficient to maintain such levels. However, several studies have disputed the cut-off level that should be considered protective.106 109 In fact, long-term follow-up in numerous cohorts of patients has demonstrated that in many cases the trough level of 500 mg/dl (which was once considered protective) is not fully protective. It appears that certain affected patients may require higher doses of immunoglobulins in order to control infectious episodes. This should always be taken into consideration when offering clinical assistance to affected patients who have infectious episodes even under regular replacement therapy. Immunoglobulin replacement therapy, however, has certain limitations. On one hand, it contains only IgG, which is not selected on antigen specificity. On the other hand, secreted antibody (IgA) is not replaceable. In addition, different studies have shown that after almost two decades of follow-up, patients regularly on IVIG therapy may develop chronic lung disease (CLD). Therefore, the optimal therapy is still to be determined.108 The

PART | 2

Primary Immune Deficiencies

development of CLD is a factor that compromises both the quality of life and prognosis in XLA.12,13,110,111 Since replacement treatment and antibiotics are not apparently sufficient to prevent the development of this complication, it is evident that respiratory physiotherapy should be considered as a supportive therapeutic measure.13,110,111

Antibiotics Any infectious episode in XLA should be immediately treated with antibiotics. In XLA, patients may require frequent treatment with antibiotics, often for long periods.10 13,33 36 In addition, the infectious agent is not always eradicated even though antibiotics may be used for months. Frequently, antibiotic prophylaxis is necessary in order to control the number of infections even when IVIG therapy is adequate.

Gene Therapy Considering the specificity of the defect in XLA, where BTK is defective in the B cell lineage, the gene therapy approach has been strongly considered. Following complications (leukemia) in patients treated with gene therapy, the risks and benefits have been reassessed. However, recent advances in the field have demonstrated that gene therapy is possible for XLA in the murine model, and will probably soon become a therapeutic option for affected patients as well.112 116 Bone marrow transplantation has been reported to be successful in the mouse model of XLA (xid mice) but not in humans.117,118

Complications and Prognosis The introduction of antibiotics and immunoglobulin replacement therapy has completely changed the prognosis for XLA patients. Before the introduction of appropriate therapy, patients would die before the age of 10 years. The main causes of death in the past were invasive infections such as sepsis and meningitis. This was particularly the case when intramuscular immunoglobulin replacement treatment was applied and when diagnosis of XLA was delayed.119 121 Now, invasive infections are rarely part of the clinical history of XLA once early diagnosis is established and appropriate treatment is initiated.12,13 In fact, the increased awareness regarding XLA over recent decades has led to a significant improvement in patients’ clinical management, which, together with improved socio-economic conditions, has contributed to assure a longer lifespan with fewer complications, ultimately leading to a better quality of life for affected patients. Nonetheless, although invasive infections represent a rarity in the modern era of XLA, lung complications are becoming the main cause of morbidity and mortality, and CLD is now considered the major cause of death in these

Chapter | 13

Agammaglobulinemia

patients.12,13 This is likely due to different variables, such as the inability of immunoglobulin substitution to reach the mucosal surface where it is expected to play a crucial protective role, and the absence of the IgA at the mucosal surfaces. On the other hand, the longer clinical follow-up of affected patients is making it clear that complications such as CLD, even under appropriate treatment, do occur. In this context, respiratory physiotherapy should be considered as an important supportive preventive measure. Recently, lung transplantation was performed in a limited number of XLA patients with very good results, a positive follow-up for the first year, and significant improvement of the respiratory function.122 Malignancy has also been reported in XLA. The percentage is variable between different studies. Colorectal cancer has been reported in several patients, although the underlying association with XLA is not yet well defined. Gastric adenocarcinoma has been observed in XLA patients with underlying chronic gastritis. Lymphoid malignancies have been reported, but percentages vary in the different cohorts of patients.10 13,33 36

AUTOSOMAL RECESSIVE AGAMMAGLOBULINEMIA Autosomal recessive agammaglobulinemia (AAR) is a rare form of primary immunodeficiency characterized by severe reduction of all of immunoglobulin classes and the absence of peripheral B cells, in the absence of BTK mutations. It affects both males and females. Table 13.1 demonstrates similarities and differences between the agammaglobulinemias. The underlying genetic defect is known in only a limited number of patients. T cell counts and function are usually normal.

Mu (μ Heavy Chain) (OMIM #601495) Genetics The gene encoding for the μ heavy chain is the second most frequently mutated gene (after BTK) in patients with agammaglobulinemia, and the most frequently mutated gene in patients with autosomal recessive agammaglobulinemia (AAR). The μ heavy chain gene encodes for the heavy chain of the IgM immunoglobulin class. The protein is expressed on the B cell surface within a receptor complex: pre-BCR during initial stages of B cell development in the bone marrow, and BCR in the later ones and in the periphery. Mutations in the gene encoding for the μ heavy chain were first described in 1996 in patients affected with autosomal recessive agammaglobulinemia.123 Since then, additional patients with agammaglobulinemia and mutations in the μ heavy chain have been identified.124,125

337

Pathogenesis B cell development takes place in the bone marrow, where the sequential expression of specific gene products promotes B cell differentiation from the pro-B to pre-B to immature B to mature B cell that enters the periphery126 (Figure 13.2). Pre-B cells express the pre-BCR, a receptor complex formed by the μ heavy chain, VpreB, [γ]5/14.1, Igα, and Igβ that initiates downstream signaling necessary for B cell differentiation through kinases such as Btk (Figure 13.12). Animal models and in vitro studies have elucidated the importance of each of the pre-BCR components for the transition from the pro-B to pre-B stage of maturation,127 and consequently become candidates for the cause of agammaglobulinemia of unknown genetic origin. Mutations in the gene encoding for the μ heavy chain lead to the absence of a functional pre-BCR complex, leading therefore to the arrest of B cell development in the bone marrow at the pro-B to pre-B stage.123,124

Clinical Presentation The first patients with mutations in the μ heavy chain were described in 1996.123 An extensive investigation including large numbers of agammaglobulinemic patients was undertaken by Conley and colleagues in the United States, and by Plebani and colleagues in Italy, in order to define the exact incidence of μ heavy chain mutations within the cohort of patients with agammaglobulinemia of non-defined genetic origin.122,124 Approximately 40 50% of patients without mutations in BTK had mutations in the μ heavy chain locus, in both cohorts of patients. Clinical symptoms were similar to those of XLA, although more severe. In fact, the age at diagnosis was younger for this disorder when compared to XLA. Chronic enteroviral encephalitis, recurrent bronchitis, pneumonia, Pseudomonas aeruginosa sepsis, otitis media, and other severe infections characterized the onset of the disease. The infections ameliorated after immunoglobulin replacement therapy was initiated on a regular basis. Chronic infection by Giardia lamblia, resistant to therapy, resulting in anemia and malabsorption, was present in one female patient with μ heavy chain deficiency (A. Plebani, personal communication). Neutropenia has also been reported in almost one-third of patients with this disorder.123,124 Bone marrow analysis from μ heavy chaindeficient patients evidenced an early arrest of B cell development (even earlier than that seen in Btk-deficient individuals) with almost complete absence of peripheral B cells.

L5 (λ5/14.1) (OMIM #613500) Genetics The λ5/14.1 gene encodes for the surrogate light chain expressed on the pre-B cell surface during bone marrow

TABLE 13.1 Clinical and Immunological Findings in Patients Affected with Agammaglobulinemia Gene

Frequency (%)

B cells

IgG

IgA

IgM

T Cells

Bacterial Infections

Viral Infections

LRTI

GI Involvement

Neutropenia

Arthritis

Tumors

Btk

85

,2%

Low

Low

Low

Normal

Yes

Yes

Yes

Yes

Yes (10 25%)

Yes

Yes

Mu

,10

,1 2%

Low

Low

Low

Normal

Yes

Yes

Yes

Yes

Yes

Yes

No

L5

,1

,1%

Low

Low

Low

Normal

Yes

No

Yes

No

No

Yes

No

IgA

,1

,1%

Low

Low

Low

Normal

Yes

No

Yes

Yes

Yes

No

No

IgB

,1

,1%

Low

Low

Low

Normal

Yes

No

Yes

Yes

No

No

No

BLNK

,1

,1%

Low

Low

Low

Normal

Yes

No

Yes

Yes

No

No

No

PI3K

,1

,1%

Low

Low

Low

Normal

Yes

No

Yes

Yes

Yes

Yes

No

LRRC8

,1

,1%

Low

Low

Low

Normal

Chapter | 13

Agammaglobulinemia

VpreB

339

μHC

μHC VpreB λ5/14.1

λ5/14.1

pre-B cell Igα Igβ

L;n

Syk

FIGURE 13.12 The pre-BCR receptor complex is expressed during the early stages of B cell development in the bone marrow, and is required for the maturation of B lymphocytes from the pro-B to the pre-B stage.

Btk PLCγ2 BLNK

pro-B cell

development.128 It was found to be mutated in one male patient129: the maternal allele had a premature stop codon, and the paternal allele had three base-pair substitutions resulting in an amino acid substitution at an invariant proline.

Pathogenesis The λ5/14.1 together with VpreB comprise the surrogate light chains that are part of the pre-BCR receptor complex (Figure 13.12), which is essential for early B cell development. Conley and colleagues129 reported on the first male patient with mutations in the λ5/14.1 gene causing autosomal recessive agammaglobulinemia. Bone marrow analysis of the affected patient showed a block at the transition from the pro-B to the pre-B stage, although a small number of mature CD19 1 Surface Ig 1 B cells were detected. This maturational block resembled the one observed in the λ5/ 14.1 knockout animal model. Furthermore, in vitro transfection experiments in COS cells demonstrated that the mutant λ5/14.1 resulted in impaired protein folding and secretion, underscoring the importance of a wild type λ5/14.1 protein for normal B cell development in the bone marrow.

Clinical Presentation The patient’s clinical history started at the age of 2 months with recurrent otitis media, and he was found to be hypogammaglobulinemic with absence of peripheral B cells at the age of 5 years, when he was hospitalized for Haemophilus influenzae meningitis.129 Peripheral blood B cell analysis demonstrated less than 0.06% of B cells. Bone marrow studies showed a specific block at the proB to pre-B stage of differentiation.

CD79A (Igα) (OMIM #613501) Genetics Igα, along with Igβ, is part of the signaling transducing elements that associate with the pre-BCR during bone marrow B cell development. The first patient identified with a defect in Igα had a homozygous mutation resulting in alternative exon splicing of the gene product, which abolished the expression of the protein on the cell surface.130 The second reported patient had a homozygous alteration at an invariant splice donor site of intron 2, which presumably resulted in truncation of the protein.131

Pathogenesis Igα and Igβ form the signaling components that associate with the pre-BCR and allow initiation of the downstream signaling cascade, rendering both valid candidates for AR agammaglobulinemia132 (Figure 13.12). Mice models lacking the COOH-terminal part of Igα have low immunoglobulin serum levels with a mild block at the pro-B to pre-B stage during B cell development in the bone marrow.133,134 Igα is in particular essential for transduction of the pre-BCR signal,135 therefore suggesting that its absence should significantly alter B cell development in the bone marrow. In fact, its lack due to the mutations identified in humans leads to almost complete abrogation of pre-BCR expression, leading to a maturational arrest of B cells at the pro-B to pre-B stage.

Clinical Presentation Minegishi and colleagues reported on the first patient with a homozygous mutation in the Igα gene.130 This female patient had chronic diarrhea with failure to thrive within the first month of life. At 1 year of age, she was hospitalized for bronchitis and neutropenia. Immunological work-up showed severely reduced levels

340

of all immunoglobulin classes, and the absence of peripheral B cells. Bone marrow analysis identified a specific block at the transition from pro-B to pre-B cell. Interestingly, no lymph nodes were detectable during clinical examination. The second patient was a male with a history of respiratory infections, diarrhea, and a dermatomyositis-like phenotype.131 He died of a pulmonary infection.

PART | 2

Primary Immune Deficiencies

immunological work-up evidenced severe hypogammaglobulinemia and the absence of peripheral B cells. The patient was put on regular replacement treatment; nonetheless, even under replacement therapy, his clinical history was complicated by recurrent respiratory infections such as sinusitis, otitis media, and bronchitis.

BLNK (OMIM #613502)

CD79B (Igβ) (OMIM #612692)

Genetics

Genetics

BLNK (B cell linker protein also called SLP-65) is a cytoplasmic adapter protein important for BCR downstream signaling.138 Since mutations in pre-BCR components have been found to cause agammaglobulinemia and BLNK acts downstream of this complex, it was evaluated as a candidate gene. The only reported patient had a homozygous splice defect in intron 1, leading to absent BLNK transcript in the bone marrow.139

Igβ, together with Igα, represents essential signaling components of the pre-BCR required for bone marrow B cell development.132 Mutations in Igβ in patients affected with agammaglobulinemia were recently described.136,137 The first reported patient was female, and presented with a hypomorhic mutation in Igβ leading to the substitution of a glycine with a serine.136 The second patient described was male, and had a history of repiratory and gastrointestinal infections. A homozygous nonsense mutation leading to a stop codon in Igβ was identified. The patient had a maturational block at the pro-B to pre-B stage in the bone marrow. Furthermore, the mutant form of Igβ abrogated the expression of a functional pre-BCR on the cell surface, as shown with in vitro experiments using Schneider S2 cells.137

Pathogenesis Igβ and Igα are essential for normal expression of the pre-BCR and BCR complex on healthy B cells.132 134 Igα and Igβ form the signal transduction complex that associates with the pre-BCR and allows initiation of the downstream signaling cascade (Figure 13.12). The reported mutations in Igβ abrogate the expression of the pre-BCR during B cell development in the bone marrow, thereby establishing a block at the pro-B to pre-B stage, leading to the absence of peripheral B cells and lack of immunoglobulins.

Clinical Presentation The first reported patient was female136; her infectious history started at the age of 5 months with bronchitis. At the age of 15 months, during an admission for pneumonia, hypogammaglobulinemia in the absence of peripheral B cells was diagnosed and she started regular replacement therapy with resolution of infectious episodes. The second patient described was male, and had a history of respiratory and gastrointestinal infections.137 His clinical history started at the age of 8 months of age, when the patient was admitted for pneumonia and salmonella infection of the gastrointestinal tract. His

Pathogenesis BLNK is activated after BCR crosslinking and initiates the downstream signaling cascade.138 Once phosphorylated by Syk, it acts as a scaffold to assemble downstream targets of antigen activation, such as Grb2, phospholipase C-gamma (PLCγ), and others.140 The absence of a functional BLNK product in the presence of the reported intronic mutation abrogates B cell development in the bone marrow, leading to a block at the pro-B to pre-B stage as shown by bone marrow analysis.139 Additional experiments concluded that BLNK is essential for B cell development once the pre-BCR is expressed (Figure 13.12).

Clinical Presentation The male patient with BLNK deficiency presented with infections at the age of 8 months, with recurrent otitis media.139 After two episodes of pneumonia, an immunological work-up was performed leading to the diagnosis of panhypogammaglobulinemia with the absence of peripheral B cells. Despite immunoglobulin replacement treatment, his clinical history was complicated by chronic otitis media, sinusitis, and protein-losing enteropathy.

PI3K (OMIM #615214) Genetics PI3Ks are a broadly expressed group of cytoplasmic enzymes that respond to a variety of extracellular signals to influence cell cycle progression, cell growth and survival, cell migration, and metabolic control.141 There are multiple isoforms of PI3K, all of which function as heterodimers. The gene that encodes for p85α, PI3KR1, also

Chapter | 13

Agammaglobulinemia

341

encodes for two additional isoforms, p55α and p50α.142 The single reported patient, identified by whole exome sequencing, had a homozygous nonsense mutation leading to the substitution of a tryptophan with a premature stop codon in exon 6 of p85α.143 This mutation abrogates the expression of p85α in a patient’s T cells, neutrophils, or dendritic cells. The amount of p50α was normal/slightly increased in T cells, normal in dendritic cells, and reduced in neutrophils.

The protein consists of 810 amino acids, and showed a higher expression in the bone marrow than in peripheral blood. LRRC8 is expressed on a variety of tissues and cell types. The reported patient presented a chromosomal translocation t(9;20)(q33.2;q12) resulting in the deletion of the eighth, ninth, and half of the seventh LLR domains located close to the C-terminal. The patient’s parents showed no chromosomal abnormalities.

Pathogenesis

Pathogenesis

A B cell defect similar to that seen in btk-deficient mice was observed in mice that are deficient in the p85α or p110δ subunit of class I PI3K.144 146 The patient’ s bone marrow analysis revealed an early block in B cell development before the expression of CD19 1 cells, and the presence of minimal V(D)J rearrangement. This block is earlier than that observed in other types of agammaglobulinemia due to mutations in btk or components of the pre-BCR. Surprisingly, although PI3K is widely expressed, the immunological phenotype of the patient is restricted to the B cell compartment, with minor additional alterations in PI3K-deficient DC responses to LPS stimulation.143 T cells, on the other hand, did not exhibit any alterations in terms of maturation or activation.

LRRC8 is a novel family of proteins with unknown function.148 The reported female patient had a deletion in almost three LRRs in the C-terminal of the protein, leading to the expression of two isoforms, wild type and mutant. Experiments with retroviral overexpression of wild type and mutant LRRC8 in mice showed that LRRC8 plays an important role in the early stages of B cell development, especially at the pro-B to pre-B transition, thereby explaining the causative link between mutations in LRRC8 and the agammaglobulinemia found in the patient.147 The wide expression of LRRC8 in diverse tissues such as brain, heart, liver, and kidney, may explain, at least partially, the dysmorphic features described in the reported female patient.

Clinical Presentation

Clinical Presentation

The female patient with p85α deficiency, born to consanguineous parents, was evaluated at the age of 3.5 months for neutropenia, interstitial pneumonia, and gastroenteritis.143 Her initial immunological work-up demonstrated ,1% B cells and agammaglobulinemia. She was put on immunoglobulin replacement therapy, with progressive resolution of the neutropenia and the clinical manifestations. At the age of 12 she developed erythema nodosum. At the age of 15, she was treated with TNF antagonists and methothrexate for juvenile idiopathic arthritis. At 17 years of age, the patient was diagnosed with campylobacter bacteremia and inflammatory bowel disease. No alteration in growth or insulin metabolism was noted, even though the mutated gene is involved in cell growth and metabolic control.

The reported patient with mutations in LRRC8 is a female with agammaglobulinemia and 0.6% of CD20 1 B cells in the periphery. She presented with epicantic folds, mild hypertelorism, a high-arched palate, and low-set ears.

LRRC8 (OMIM #613506) Genetics The leucine-rich repeat-containing 8 (LRRC8) is a novel gene that was identified in a female patient with agammaglobulinemia and minor dysmorphic features.147 It consists of four transmembrane helixes with one isolated and eight sequentially located leucine-rich repeats (LRRs).

Laboratory Findings The typical laboratory findings of autosomal recessive agammaglobulinemia consist of low to undetectable immunoglobulin serum levels and the almost complete absence of peripheral B cells (,1%), reflecting the early block in B cell development. In the case of male patients, btk deficiency is the first diagnostic option; once BTK is excluded as the causative gene, the gene encoding for the μ heavy chain should be analyzed for disease-causing mutations, since it is the most frequently mutated gene in the autosomal recessive forms of agammaglobulinemia. In the case of female patients, the genes responsible for AAR should be investigated, starting with the gene encoding for the μ heavy chain. Flow cytometric analysis of the early stages of B cell development in the bone marrow may be of diagnostic help, especially when mutations in the known genes are not identified.

342

Management and Prognosis The introduction of antibiotics and immunoglobulin replacement therapy has completely changed the prognosis of agammaglobulinemic patients. Nowadays, the prompt use of antibiotics, regular replacement therapy, and an early diagnosis can assure a longer lifespan with fewer complications. The clinical history of affected patients may include diverse complications such as chronic lung disease and malabsorption due to gastrointestinal infections. However, considering the limited number of patients affected with the autosomal recessive forms of agammaglobulinemia and the limited (in most cases) follow-up period, it is not feasible, at least for the moment, to provide comparative data for known complications in XLA, such as incidence of tumors, autoimmune phenomena, and similar complications.

ACKNOWLEDGMENTS The authors would like to thank the members of the Italian Network for primary Immunodeficiencies (IPINET) for the IPINET data included in this chapter.

REFERENCES 1. Bruton OC. Agammaglobulinemia. Pediatrics 1952;9:722 8. 2. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993;72:279 80. 3. Vetrie D, Vorechovski I, Sideras P, et al. The gene involved in X-linked agammmaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature 1993;361:226 33. 4. Block H, Zarbock A. The role of the tec kinase Bruton’s tyrosine kinase (Btk) in leukocyte recruitment. Int Rev Immunol 2012; 31(2):104 18. 5. Hussain A, Yu L, Faryal R, et al. TEC family kinases in health and disease loss-of-function of BTK and ITK and the gain-offunction fusions ITK SYK and BTK SYK. FEBS J 2011; 278(12):2001 10. 6. Mohamed AJ, Yu L, Ba¨ckesjo¨ CM, et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev 2009;228(1):58 73. 7. Va¨liaho J, Smith CI, Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Hum Mutat 2006;27(12):1209 17. 8. Lindvall JM, Blomberg KE, Va¨liaho J, et al. Bruton’s tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling. Immunol Rev 2005;203:200 15 [Review]. 9. Ochs HD, Smith CI. X-linked agammaglobulinemia. A clinical and molecular analysis. Medicine (Baltimore) 1996;75:287 99. 10. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Medicine (Baltimore) 1985;64:145 56. 11. Moin M, Aghamohammadi A, Farhoudi A, et al. X-linked agammaglobulinemia: a survey of 33 Iranian patients. Immunol Invest 2004;33:81 93.

PART | 2

Primary Immune Deficiencies

12. Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological and molecular analysis of a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol 2002;104:221 30. 13. Winkelstein JA, Marino MC, Lederman HM, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 2006;85(4):193 202. 14. Takada H, Kanegane H, Nomura A, et al. Female agammaglobulinemia due to the Bruton tyrosine kinase deficiency caused by extremely skewed X-chromosome inactivation. Blood 2004; 103(1):185 7. 15. Lee PP, Chen TX, Jiang LP, et al. Clinical characteristics and genotype-phenotype correlation in 62 patients with X-linked agammaglobulinemia. J Clin Immunol 2010;30(1):121 31. 16. Teimourian S, Nasseri S, Pouladi N, et al. Genotype phenotype correlation in Bruton’s tyrosine kinase deficiency. Pediatr Hematol Oncol 2008;30(9):679 83. 17. Broides A, Yang W, Conley ME. Genotype/phenotype correlations in X-linked agammaglobulinemia. Clin Immunol 2006;118 (2 3):195 200. 18. Cancro MP, Sah AP, Levy SL, et al. xid mice reveal the interplay of homeostasis and Bruton’ s tyrosine kinase-mediated selection at multiple stages of B cell development. Int Immunol 2001;13 (12):1501 14. 19. Maas A, Hendriks RW. Role of Bruton’s tyrosine kinase in B cell development. Dev Immunol 2001;8(3 4):171 81. 20. Santos P, Arumemi F, Park KS, et al. Transcriptional and epigenetic regulation of B cell development. Immunol Res 2011; 50(2 3):105 12. 21. Ye M, Graf T. Early decisions in lymphoid development. Curr Opin Immunol 2007;19(2):123 8. 22. Rolink AG, Massa S, Balciunaite G, et al. Early lymphocyte development in bone marrow and thymus. Swiss Med Wkly 2006; 136(43 44):679 83. 23. Espeli M, Rossi B, Mancini SJ, et al. Initiation of pre-B cell receptor signaling: common and distinctive features in human and mouse. Semin Immunol 2006;18(1):56 66. 24. Hoffmann R. Gene expression patterns in human and mouse B cell development. Curr Top Microbiol Immunol 2005;294:19 29 [Review]. 25. Zhang M, Srivastava G, Lu L. The pre-B cell receptor and its function during B cell development. Cell Mol Immunol 2004;1(2):89 94 [Review]. 26. Noordzij JG, de Bruin-Versteeg S, Comans-Bitter WM, et al. Composition of precursor B-cell compartment in bone marrow from patients with X-linked agammaglobulinemia compared with healthy children. Pediatr Res 2002;51(2):159 68. 27. Nomura K, Kanegane H, Karasuyama H , et al. Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway. Blood 2000;96(2):610 17. 28. Maas A, Hendriks RW. Role of bruton’ s tyrosine kinase in B cell development. Dev Immunol 2001;8(3 4):171 81. 29. Ochs HD, Smith CI. X-linked agammaglobulinemia. A clinical and molecular analysis. Medicine (Baltimore) 1996; 75:287 99. 30. Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol 2000;19:183 204.

Chapter | 13

Agammaglobulinemia

31. Hashimoto S, Miyawaki T, Futatani T, et al. Atypical X-linked agammaglobulinemia diagnosed in three adults. Intern Med 1999;38:722 5. 32. Stewart DM, Tian L, Nelson DL. A case of X-linked agammaglobulinemia diagnosed in adulthood. Clin Immunol 2001;99:94 9. 33. Sigmon JR, Kasasbeh E, Krishnaswamy G. X-linked agammaglobulinemia diagnosed late in life: case report and review of the literature. Clin Mol Allergy 2008;6:5. 34. Qin X, Jiang LP, Tang XM, et al. Clinical features and mutation analysis of X-linked agammaglobulinemia in 20 chinese patients. World J Pediatr 2013;9(3):273 7. 35. Wang Y, Kanegane H, Wang X, et al. Mutation of the BTK gene and clinical feature of X-linked agammaglobulinemia in mainland China. J Clin Immunol 2009;29(3):352 6. 36. Aghamohammadi A, Fiorini M, Moin M, et al. Clinical, immunological and molecular characteristics of 37 Iranian patients with X-linked agammaglobulinemia. Int Arch Allergy Immunol 2006;141(4):408 14. 37. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr 2002;141(4):566 7. 38. Alibrahim A, Lepore M, Lierl M, et al. Pneumocystis carinii pneumonia in an infant with X-linked agammaglobulinemia. J Allergy Clin Immunol 1998;101:552 3. 39. Dittrich AM, Schulse I, Magdorf K, et al. X-linked agammaglobulinaemia and Pneumocystis carinii pneumonia an unusual coincidence. Eur J Pediatr 2003;162:432 3. 40. Saulsbury FT, Bernstein MT, Winkelstein JA. Pneumocystis carinii pneumonia as the presenting infection in congenital hypogammaglobulinemia. J Pediatr 1979;95:559 65. 41. van den Bruele T, Mourad-Baars PE, Claas EC, et al. Campylobacter jejuni bacteremia and Helicobacter pylori in a patient with X-linked agammaglobulinemia. Eur J Clin Microbiol Infect Dis 2010;29(11):1315 19. 42. Autenrieth IB, Schuster V, Ewald J, et al. An unusual case of refractory Campylobacter jejuni infection in a patient with X-linked agammaglobulinemia: successful combined therapy with maternal plasma and ciprofloxacin. Clin Infect Dis 1996;23(3):526 31. 43. Dua J, Elliot E, Bright P, et al. Pyoderma gangrenosum-like ulcer caused by Helicobacter cinaedi in a patient with X-linked agammaglobulinaemia. Clin Exp Dermatol 2012;37(6):642 5. 44. Simons E, Spacek LA, Lederman HM, et al. Helicobacter cinaedi bacteremia presenting as macules in an afebrile patient with X-linked agammaglobulinemia. Infection 2004;32(6):367 8. 45. Cuccherini B, Chua K, Gill V, et al. Bacteremia and skin/bone infections in two patients with X-linked agammaglobulinemia caused by an unusual organism related to Flexispira/Helicobacter species. Clin Immunol 2000;97(2):121 9. 46. Turvey SE, Leo SH, Boos A, et al. Successful approach to treatment of Helicobacter bilis infection in X-linked agammaglobulinemia. J Clin Immunol 2012;32(6):1404 8. 47. Murray PR, Jain A, Uzel G, et al. Pyoderma gangrenosum-like ulcer in a patient with X-linked agammaglobulinemia: identification of Helicobacte rbilis by mass spectrometry analysis. Arch Dermatol 2010;146(5):523 6. 48. Funato M, Kaneko H, Ohkusu K, et al. Refractory chronic pleurisy caused by Helicobacter equorum-like bacterium in a patient with X-linked agammaglobulinemia. J Clin Microbiol 2011;49(9): 3432 5.

343

49. Cho YK, Kook H, Woo YJ, et al. Morganella morganii pericarditis in a child with X-linked agammaglobulinemia. Pediatr Int 2010; 52(3):489 91. 50. Mamishi S, Shahmahmoudi S, Tabatabaie H, et al. Novel BTK mutation presenting with vaccine-associated paralytic poliomyelitis. Eur J Pediatr 2008;167(11):1335 8. 51. Fiore L, Plebani A, Buttinelli G, et al. Search for poliovirus longterm excretors among patients affected by agammaglobulinemia. Clin Immunol 2004;111(1):98 102. 52. Andronikou S, Siamopoulou-Mavridou A, Pontikaki M, et al. Poliovirus vaccination in an infant with hypogammaglobulinaemia. Lancet 1998;351(9103):674. 53. Hara M, Saito Y, Komatsu T, et al. Antigenic analysis of polioviruses isolated from a child with agammaglobulinemia and paralytic poliomyelitis after sabin vaccine administration. Microbiol Immunol 1981;25(9):905 13. 54. Wilfert CM, Buckley RH, Mohanakumar T, et al. Persistent and fatal central-nervous-system ECHOvirus infections in patients with agammaglobulinemia. N Engl J Med 1977;296(26):1485 9. 55. Quartier P, Foray S, Casanova JL, et al. Enteroviral meningoencephalitis in X-linked agammaglobulinemia: intensive immunoglobulin therapy and sequential viral detection in cerebrospinal fluid by polymerase chain reaction. Pediatr Infect Dis J 2000; 19(11):1106 8. 56. Misbah SA, Spickett GP, Ryba PC, et al. Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. J Clin Immunol 1992;12:266 70. 57. Wildenbeest JG, van den Broek PJ, Benschop KS, et al. Pleconaril revisited: clinical course of chronic enteroviral meningoencephalitis after treatment correlates with in vitro susceptibility. Antivir Ther 2012;17(3):459 66. 58. van de Ven AA, Douma JW, Rademaker C, et al. Pleconarilresistant chronic parechovirus-associated enteropathy in agammaglobulinaemia. Antivir Ther 2011;16(4):611 14. 59. Schmugge M, Lauener R, Bossart W, et al. Chronic enteroviral meningo-encephalitis in X-linked agammaglobulinaemia: favourable response to anti-enteroviral treatment. Eur J Pediatr 1999; 158(12):1010 11. 60. Bardelas JA, Winkelstein JA, Seto DS, et al. Fatal ECHO 24 infection in a patient with hypogammaglobulinemia: relationship to dermatomyositis-like syndrome. J Pediatr 1977;90(3):396 9. 61. Quan PL, Wagner TA, Briese T, et al. Astrovirus encephalitis in boy with X-linked agammaglobulinemia. Emerg Infect Dis 2010;16(6):918 25. 62. Quinti I, Pierdominici M, Marziali M, et al. European surveillance of immunoglobulin safety results of initial survey of 1243 patients with primary immunodeficiencies in 16 countries. Clin Immunol 2002;104(3):231 6. 63. Lin MT, Chien YH, Shyur SD, et al. De novo mutation in the BTK gene of atypical X-linked agammaglobulinemia in a patient with recurrent pyoderma. Ann Allergy Asthma Immunol 2006;96 (5):744 8. 64. Liu AJ, Dao-Ung LP, McDonald D, et al. Chronic gingivitis in a new BTK mutation. Eur J Haematol 2006;76(2):171 5. 65. Va´ncsa A, To´th B, Szekanecz Z. BTK gene mutation in two nonidentical twins with X-linked agammaglobulinemia associated with polyarticular juvenile idiopathic arthritis. Isr Med Assoc J 2011; 13(9):579 80.

344

66. Sukumaran S, Marzan K, Shaham B, et al. A child with X-linked agammaglobulinemia and enthesitis-related arthritis. Int J Rheumatol 2011;175973. 67. Machado P, Santos A, Faria E, et al. Arthritis and X-linked agammaglobulinemia. Acta Rheumatol Port 2008;33(4):464 7. 68. Bloom KA, Chung D, Cunningham-Rundles C. Osteoarticular infectious complications in patients with primary immunodeficiencies. Curr Opin Rheumatol 2008;20(4):480 5. 69. Baeten D, Kruithof E, Breban M, et al. Spondylarthritis in the absence of B lymphocytes. Arthritis Rheum 2008;58(3):730 3. 70. Arai A, Kitano A, Sawabe E, et al. Relapsing Campylobacter coli bacteremia with reactive arthritis in a patient with X-linked agammaglobulinemia. Intern Med 2007;46(9):605 9. 71. Verbruggen G, De Backer S, Deforce D, et al. X linked agammaglobulinaemia and rheumatoid arthritis. Ann Rheum Dis 2005; 64(7):1075 8. 72. Kawakami C, Inoue A, Koh M, et al. Three brothers of X-linked agammaglobulinemia: the relation between phenotype and neutropenia. Int J Hematol 2009;90(1):117 19. 73. Aghamohammadi A, Cheraghi T, Rezaei N, et al. Neutropenia associated with X-linked agammaglobulinemia in an Iranian referral center. Iran J Allergy Asthma Immunol 2009;8(1):43 7. 74. Jacobs ZD, Guajardo JR, Anderson KM. XLA-associated neutropenia treatment: a case report and review of the literature. J Pediatr Hematol Oncol 2008;30(8):631 4. 75. Rezaei N, Farhoudi A, Pourpak Z, et al. Neutropenia in patients with primary antibody deficiency disorders. Iran J Allergy Asthma Immunol 2004;3(2):77 81. 76. Kanegane H, Taneichi H, Nomura K, et al. Severe neutropenia in Japanese patients with X-linked agammaglobulinemia. J Clin Immunol 2005;25(5):491 5. 77. Cham B, Bonilla MA, Winkelstein J. Neutropenia associated with primary immunodeficiency syndromes. Semin Hematol 2002; 39(2):107 12 [Review]. 78. Avasthi PS, Avasthi P, Tung KS. Glomerulonephritis in agammaglobulinaemia. Br Med J. 1975;2(5969):478. 79. Yoshino A, Honda M, Kanegane H, et al. Membranoproliferative glomerulonephritis in a patient with X-linked agammaglobulinemia. Pediatr Nephrol 2006;21(1):36 8. 80. Endo LM, Giannobile JV, Dobbs AK, et al. Membranous glomerulopathy in an adult patient with X-linked agammaglobulinemia receiving intravenous gammaglobulin. J Investig Allergol Clin Immunol 2011;21(5):405 9. 81. Garcı´a MC, Fonseca E, Pascual D, et al. [Primary hypogammaglobulinemia and alopecia areata]. Med Clin (Barc) 1983;80 (16):717 19. 82. Tezcan I, Ersoy F, Sanal O, et al. A case of X-linked agammaglobulinaemia complicated with systemic amyloidosis. Arch Dis Child 1998;79(1):94. 83. Lo´pez J, Rodrı´guez JM, Ramos J, et al. [Amyloid goiter as the beginning symptom of amyloidosis in a patient with sex-linked agammaglobulinemia]. Rev Clin Esp 1999;199(7):481. 84. Hirata D, Nara H, Inaba T, et al. Von Recklinghausen disease in a patient with X-linked agammaglobulinemia. Intern Med 2002; 41(11):1039 43. 85. Bachmeyer C, Monge M, Cazier A, et al. Gastric adenocarcinoma in a patient with X-linked agammaglobulinaemia. Eur J Gastroenterol Hepatol 2000;12(9):1033 5.

PART | 2

Primary Immune Deficiencies

86. Lavilla P, Gil A, Rodriquez MC, et al. X-linked agammaglobulinemia and gastric adenocarcinoma. Cancer 1993;72:1528 31. 87. Van de Meer JW, Weening RS, Schellekens PT, et al. Colorectal cancer in patients with X-linked agammaglobulinemia. Lancet 1993;341:1439 40. 88. Park JY, Kim YS, Shin DH, et al. Primary cutaneous peripheral T-cell lymphoma in a patient with X-linked agammaglobulinaemia. Br J Dermatol 2011;164(3):677 9. 89. Berlucchi M, Soresina A, Redaelli De Zinis LO, et al. Sensorineural hearing loss in primary antibody deficiency disorders. J Pediatr 2008;153(2):293 6. 90. Sediva´ A, Smith CI, Asplund AC, et al. Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. J Clin Immunol 2007;27(6):640 6. 91. Fleisher TA, White RM, Broder S, et al. X-linked hypogammaglobulinemia and isolated growth hormone deficiency. N Engl J Med 1980;302(26):1429 34. 92. Stewart DM, Notarangelo LD, Kurman CC, et al. Molecular genetic analysis of X-linked hypogammaglobulinemia and isolated growth hormone deficiency. J Immunol 1995;155(5):2770 4. 93. Stewart DM, Tian L, Notarangelo LD, et al. Update on X-linked hypogammaglobulinemia with isolated growth hormone deficiency. Curr Opin Allergy Clin Immunol 2005;5(6):510 12. 94. Abo K, Nishio H, Lee MJ, et al. A novel single base-pair insertion in exon 6 of the Bruton’s tyrosine kinase (Btk) gene from a Japanese X-linked agammaglobulinemia patient with growth hormone insufficiency. Hum Mutat 1998;11(4):336. 95. Duriez B, Duquesnoy P, Dastot F, et al. An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Lett 1994;346(2-3):165 70. 96. Va¨liaho J, Smith CI, Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Hum Mutat 2006;27(12): 1209 17. 97. Janeway CA. The Development of Clinical Uses of Immunoglobulins: A Review. Washington, DC: National Academy of Science; 1970. pp. 3 14. 98. Gitlin D, Janeway DC. Agammaglobulinemia: congenital, acquired and transient forms. Prog Hematol 1956;1:318 29. 99. Barandun S. Die gammaglobulin-therapie: chemische, immunologische und klinische grundlagen. Bibl Haematol 1964;17:1 138. 100. Garbett ND, Currie DC, Cole PJ. Comparison of the clinical efficacy and safety of an intramuscular and an intravenous immunoglobulin preparation for replacement therapy in idiopathic adult onset panhypogammaglobulinaemia. Clin Exp Immunol 1989; 76:1 7. 101. Berger M, Cupps TR, Fauci AS. Immunoglobulin replacement therapy by slow subcutaneous infusion. Ann Intern Med 1980;93:55 6. 102. Roord JJ, van der Meer JW, Kuis W, et al. Home treatment in patients with antibody deficiency by slow subcutaneous infusion of gammaglobulin. Lancet 1982;1:689 90. 103. Gardulf A, Hammarstrom L, Smith CI. Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet 1991;338:162 6. 104. Gardulf A, Andersen V, Bjorkander J, et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 1995;345:365 9.

Chapter | 13

Agammaglobulinemia

105. Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies a prospective, multi-national study. J Clin Immunol 2006;26:177 85. 106. Berger M. Incidence of infection is inversely related to steadystate (trough) serum IgG level in studies of subcutaneous IgG in PIDD. J Clin Immunol 2011;31(5):924 6. 107. Orange JS, Belohradsky BH, Berger M, et al. Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy. Clin Exp Immunol 2012; 169(2):172 81. 108. Quinti I, Soresina A, Guerra A, et al. Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: results from a multicenter prospective cohort study. J Clin Immunol 2011;31(3):315 22. 109. Misbah S, Kuijpers T, van der Heijden J, et al. Bringing immunoglobulin knowledge up to date: how should we treat today? Clin Exp Immunol 2011;166(1):16 25. 110. Buckley RH. Pulmonary complications of primary immunodeficiencies. Paediatr Respir Rev 2004;5(Suppl. A):S225 33. 111. Rusconi F, Panisi C, Dellepiane RM, et al. Pulmonary and sinus diseases in primary humoral immunodeficiencies with chronic productive cough. Arch Dis Child 2003;88(12):1101 5. 112. Hendriks RW, Bredius RG, Pike-Overzet K, et al. Biology and novel treatment options for XLA, the most common monogenetic immunodeficiency in man. Expert Opin Ther Targets 2011; 15(8):1003 21. 113. Ng YY, Baert MR, Pike-Overzet K, et al. Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK. Leukemia 2010;24(9):1617 30. 114. Kerns HM, Ryu BY, Stirling BV, et al. B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia. Blood 2010; 115(11):2146 55. 115. Moreau T, Barlogis V, Bardin F, et al. Development of an enhanced B-specific lentiviral vector expressing BTK: a tool for gene therapy of XLA. Gene Ther 2008;15(12):942 52. 116. Yu PW, Tabuchi RS, Kato RM, et al. Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer. Blood 2004;104(5):1281 90. 117. Rohrer J, Conley ME. Correction of X-linked immunodeficient mice by competitive reconstitution with limiting numbers of normal bone marrow cells. Blood 1999;94(10):3358 65. 118. Howard V, Myers LA, Williams DA, et al. Stem cell transplants for patients with X-linked agammaglobulinemia. Clin Immunol 2003;107(2):98 102. 119. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Medicine (Baltimore) 1985;64(3): 145 56 [Review]. 120. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 1993;86(1):31 42. 121. Sideras P, Smith CI. Molecular and cellular aspects of X-linked agammaglobulinemia. Adv Immunol 1995;59:135 223. 122. Morales P, Herna´ndez D, Vicente R, et al. Lung transplantation in patients with X-linked agammaglobulinemia. Transplant Proc 2003;35(5):1942 3.

345

123. Yel L, Minegishi Y, Coustan-Smith E, et al. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N Engl J Med 1996;335(20):1486 93. 124. Ferrari S, Zuntini R, Lougaris V, et al. Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia. Genes Immun 2007; 8(4):325 33. 125. Mohammadzadeh I, Yeganeh M, Aghamohammadi A, et al. Severe primary antibody deficiency due to a novel mutation of mu heavy chain. J Investig Allergol Clin Immunol 2012;22(1):78 9. 126. Conley ME, Broides A, Hernandez-Trujillo V, et al. Genetic analysis of patients with defects in early B-cell development. Immunol Rev 2005;203:216 34. 127. Kitamura D, Roes J, Ku¨hn R, et al. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 1991;350(6317):423 6. 128. Minegishi Y, Hendershot LM, Conley ME. Novel mechanisms control the folding and assembly of lambda5/14.1 and VpreB to produce an intact surrogate light chain. Proc Natl Acad Sci USA 1999;96(6):3041 6. 129. Minegishi Y, Coustan-Smith E, Wang YH, et al. Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia. J Exp Med 1998;187(1):71 7. 130. Minegishi Y, Coustan-Smith E, Rapalus L, et al. Mutations in Igalpha (CD79a) result in a complete block in B-cell development. J Clin Invest 1999;104(8):1115 21. 131. Wang Y, Kanegane H, Sanal O, et al. Novel Igalpha (CD79a) gene mutation in a Turkish patient with B cell-deficient agammaglobulinemia. Am J Med Genet 2002;108(4):333 6. 132. Ma˚rtensson IL, Almqvist N, Grimsholm O, et al. The pre-B cell receptor checkpoint. FEBS Lett 2010;584(12):2572 9. 133. Pelanda R, Braun U, Hobeika E, et al. B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta. J Immunol 2002;169(2):865 72. 134. Storch B, Meixlsperger S, Jumaa H. The Ig-alpha ITAM is required for efficient differentiation but not proliferation of pre-B cells. Eur J Immunol 2007;37(1):252 60. 135. Fuentes-Panana´ EM, Bannish G, Karnell FG, et al. Analysis of the individual contributions of Igalpha (CD79a)- and Igbeta (CD79b)-mediated tonic signaling for bone marrow B cell development and peripheral B cell maturation. J Immunol 2006;177(11):7913 22. 136. Dobbs AK, Yang T, Farmer D, et al. Cutting edge: a hypomorphic mutation in Igbeta (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development. J Immunol 2007;179(4):2055 9. 137. Ferrari S, Lougaris V, Caraffi S, et al. Mutations of the Igbeta gene cause agammaglobulinemia in man. J Exp Med 2007; 204(9):2047 51. 138. Tsukada S, Baba Y, Watanabe D. Btk and BLNK in B cell development. Adv Immunol 2001;77:123 62 [Review]. 139. Minegishi Y, Rohrer J, Coustan-Smith E, et al. An essential role for BLNK in human B cell development. Science 1999; 286(5446):1954 7. 140. Schebesta M, Pfeffer PL, Busslinger M. Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene. Immunity 2002;17(4):473 85.

346

141. Pauls SD, Lafarge ST, Landego I, et al. The phosphoinositide 3-kinase signaling pathway in normal and malignant B cells: activation mechanisms, regulation and impact on cellular functions. Front Immunol 2012;3:224. 142. So L, Fruman DA. PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances. Biochem J. 2012; 442(3):465 81. 143. Conley ME, Dobbs AK, Quintana AM, et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J Exp Med 2012;209(3):463 70. 144. Fruman DA, Snapper SB, Yballe CM, et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science 1999;283:393 7.

PART | 2

Primary Immune Deficiencies

145. Suzuki H, Terauchi Y, Fujiwara M, et al. Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. Science 1999;283:390 2. 146. Jou ST, Carpino N, Takahashi Y, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol 2002;22:8580 91. 147. Sawada A, Takihara Y, Kim JY, et al. A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest 2003;112(11):1707 13. 148. Kubota K, Kim JY, Sawada A, et al. LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins. FEBS Lett 2004;564(1-2):147 52.