X-Linked Agammaglobulinemia

Ogden Bruton published the classic description of this disorder in 1952; therefore this condition is often called ‘Bruton’s agammaglobulinemia’. It is caused by a defect in a signal transducing protein known as Bruton’s tyrosine kinase (BTK). BTK is expressed in B cells, monocytes, macrophages, mast cells, erythroid cells and platelets; it transduces signals from the B cell immunoglobulin receptor. Without BTK, B cell development is impeded at an early stage.

Only males are affected, and they are often asymptomatic during infancy. In this period, they are protected by maternal antibodies acquired during gestation. After birth, maternal IgG gradually disappears, and infectious complications usually begin by the age of 9 to 18 months. The absence of tonsils or palpable lymph nodes is notable on examination. Laboratory investigation reveals absent or very low serum levels of immunoglobulins and B cells.

Despite normal cellular immunity, patients with X-linked agammaglobulinemia (XLA) are prone to certain viral infections, including chronic enteroviral meningoencephalitis and vaccine-associated paralytic poliomyelitis. Additional infections described in these patients include mycoplasma or ureaplasma arthritis. Opportunistic infections such as Pneumocystis jiroveci pneumonia are rare.

About half of XLA patients have a family history of affected male relatives on the maternal side. Autosomal forms of agammaglobulinemia must be distinguished in males without such a history. It is desirable to confirm the diagnosis at the molecular level whenever possible. BTK is expressed in platelets and monocytes and may be detected by flow cytometry. These tests are useful for screening males and detecting carrier females who have two populations (BTK ⁺ and BTK ⁻ ) of monocytes or platelets as a result of random X chromosome inactivation. Female carriers of XLA show nonrandom X chromosome inactivation in their B cells, and this can also be used for carrier detection.

Some patients with BTK mutations have an ‘atypical’ phenotype with low numbers of B cells and low-level antibody production. In general, mutations that permit low-level function of BTK are more often associated with higher B cell numbers, immunoglobulin levels and antibody formation. Some of these atypical XLA cases may be misdiagnosed as having common variable immunodeficiency (see below). However, even siblings with identical mutations may show divergent clinical features.

Autosomal Agammaglobulinemia

A few patients have agammaglobulinemia (AGAM) with autosomal (mostly recessive) patterns of inheritance. Mutations of the immunoglobulin (Ig)µ heavy chain locus (IGHM) , and defects of λ5 (surrogate light chain), Igα (CD79a) and Igβ (CD79b), all prevent formation of the pre-B cell Ig receptor. Mutations in BLNK (encoding B cell linker protein) and in PIK3R1 (encoding regulatory subunit 1 of phosphoinositol-3′ kinase) disrupt B cell signaling and lead to agammaglobulinemia. All of these disorders have recessive inheritance. The only defined autosomal dominant monogenic agammaglobulinemia is due to defects of transcription factor 3 (TC3 ). Finally, a single female patient has been described with a translocation interrupting the gene encoding leucine rich repeat containing 8 (LRRC8). All of these autosomal defects arrest B cell development at early stages within the bone marrow.

Common Variable Immunodeficiency

The diagnosis of common variable immunodeficiency (CVID) encompasses an unknown number of genetically and etiologically distinct conditions having in common a (relatively) late-onset humoral immunodeficiency, most often in the first or third decade of life. Due to rapid development of the immune system in childhood, and frequent resolution of hypogammaglobulinemia in young children, it is not considered appropriate to confer a diagnosis of CVID under 4 years of age.

CVID is defined by laboratory and clinical criteria; there is no universal consensus on the necessary elements establishing the diagnosis. All patients have low IgG and impaired antibody response. Some authorities require that IgA also be low to establish the diagnosis, while others accept that IgA and/or IgM may be normal or low. Not all patients with CVID have infections, nor are symptoms a component of the definition (i.e. one may have ‘asymptomatic’ CVID).

Many CVID patients have recurrent sinopulmonary bacterial infections. Additional manifestations include asthma, chronic rhinosinusitis, inflammatory bowel disease, and recurrent or chronic arthropathy. The apparent ‘atopic’ symptoms mimicking asthma and chronic rhinosinusitis found in about 10% of patients do not involve allergen-specific IgE. Autoimmune cytopenias also occur with increased frequency. In addition, noncaseating granulomatous disease resembling sarcoidosis may involve the skin or viscera, even in children.

Lymphoproliferation may cause splenomegaly, adenopathy and intestinal lymphonodular hyperplasia, and CVID patients also have a higher incidence of lymphoid and gastrointestinal malignancy. The relative risk of lymphoma is estimated to be 10–20-fold greater than in the general population. Most of these are B cell non-Hodgkin’s lymphomas not associated with Epstein-Barr virus (EBV).

Numbers of peripheral B and T cells are variable in CVID; particular abnormalities may correlate with phenotype. After activation, B cells may ‘switch’ isotype production from IgM and IgD to IgG, IgA or IgE (see section on hyper-IgM syndromes ). Memory B cells express the surface marker CD27. Levels of ‘switched’ (IgM ⁻ IgD ⁻ ) memory (CD27 ⁺ ) cells correlate with disease phenotype. Levels below 1–2% of B cells are associated with a higher rate of severe infection, autoimmune disease, lymphoproliferation and lymphoma. The T cell phenotype is also variable. Low levels of naïve (CD45RA ⁺ ) CD4 T cells correlate with these complications.

Causative genetic lesions have been identified in about 1% of patients with CVID or CVID-like syndromes. These include defects of inducible T cell co-stimulator (ICOS) and several surface glycoproteins important for B cell activation including CD19, CD20, CD21 and CD81. Other monogenic forms of CVID-like hypogammaglobulinemia include defects of protein kinase C δ, NF-κB2 and the lipopolysaccharide responsive beige like anchor protein (LRBA).

Additional genetic associations occur in subgroups of CVID patients. Some functionally important polymorphisms of the transmembrane activator and calcium mobilizing ligand interactor (TACI) are found in a higher proportion of CVID patients (5–10%) in comparison to the general population (1%). This molecule, also called tumor necrosis factor receptor superfamily member 5 (TNFRSF5), is expressed on activated B cells. Patients with CVID may be homozygous or heterozygous for polymorphisms in TACI. However, these alterations in TACI are not disease-causing; some healthy individuals harbor the same genetic changes.

X-linked lymphoproliferative disease (XLP) arises from defects in the SLAM (signaling lymphocytic activation molecule)-associated protein (SAP) signal transducing molecule. Some of these patients have dysgammaglobulinemias of various types, and a few had been classified as having CVID before the discovery of the genetic basis of XLP. It is important to rule out XLP in males with a CVID phenotype because prognosis and therapy are distinct for these disorders. Rarely, patients with XLA may be misdiagnosed as having CVID.

The occurrence of thymoma and hypogammaglobulinemia with low B cell numbers has been designated Good’s syndrome. It is unknown if these patients have genetic or immunologic distinctions from CVID. Disseminated and opportunistic infections (such as P. jiroveci pneumonia) occur more frequently in Good’s syndrome and prognosis is worse than that for most CVID patients. Approximately 10% of CVID patients have severe CD4 lymphocytopenia (<200 cells/µL) and/or an opportunistic infection. Several complications (intestinal disease, splenomegaly, lymphomas and granulomas) are more frequent in this subset. This has been called ‘late onset combined immunodeficiency’ (LOCID) and is similar to Good’s syndrome, with the exception of thymoma.

IgA Deficiency

Human IgA is divided into two subclasses – IgA1 and IgA2 – encoded by separate genes. IgA1 constitutes 80% to 90% of serum IgA; both contribute equally to secretory IgA. Both subclasses are affected in IgA deficiency (IGAD). Very low levels of IgA (<7 mg/dL) are found in about 1 : 500–700 Caucasians. This is called selective IgA deficiency (IGAD). Clinical associations with levels of IgA above this threshold but below the normal range (‘low’ IgA) are not well established. As with CVID, due to rapid immune system development in children and wider normal ranges of immunoglobulin levels in early childhood, it is not appropriate to confer a diagnosis of IGAD below the age of 4 years. Many individuals with IGAD are asymptomatic. However, more than 80% have clinical manifestations similar to CVID or IgG subclass deficiency including viral and bacterial upper and lower respiratory tract infections, atopic disease and autoimmunity.

Autoimmune syndromes in IGAD include rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, insulin-dependent diabetes mellitus and other endocrinopathies, pernicious anemia, hemolytic anemia, Crohn’s disease and autoimmune hepatitis. The forms of malignancy associated with CVID do not appear to occur with greater frequency in IGAD in comparison to the general population. Rare cases of IGAD may evolve into CVID or improve over time. About one third of IGAD patients have a concomitant IgG subclass deficiency (see below). This association is more frequently accompanied by deficits in specific antibody production and significant infectious complications in comparison to the absence of IgA alone. The same T and B cell abnormalities found in CVID patients are observed in those with IGAD, albeit in a smaller proportion in comparison to controls.

No disease-causing single gene defects underlying IGAD have been defined. The polymorphisms of MSH5 described above are associated with the A1-B8-DR3 extended HLA haplotype and have also been found in individuals with IGAD. IGAD has been reported in patients after chemotherapy or treatment with anticonvulsants such as phenytoin. In the latter case, the effect was reversible with drug discontinuation.

IgG Subclass Deficiency

Human IgG is divided into four subclasses designated IgG1, IgG2, IgG3 and IgG4, each encoded by different Ig constant region genes. Each represents approximately 67%, 23%, 7% and 3% of the total, respectively. IgG subclasses are produced in different relative amounts depending on the antigenic stimulus. For example, IgG1 predominates in responses to soluble protein antigens, and responses to pneumococcal capsular polysaccharides consist almost entirely of the IgG2 subclass.

A consensus definition of IgG subclass deficiency does not exist. In contrast to CVID or IGAD, a clinical significance of abnormal IgG subclass levels has not been established outside the context of recurrent infections. Thus, this should be considered an element of the definition. In a patient with recurrent infections, a disproportionately low level (<2 SD below the mean or <5th percentile) of one or more IgG subclasses with a normal total serum IgG may constitute an IgG subclass deficiency (IGGSD). Levels should be abnormal on at least two measurements more than 1 month apart. Many authorities insist that impaired vaccine response (usually to polysaccharide antigens) also be included in the definition. In one recent case-control study of patients with recurrent respiratory infections, pneumococcal polysaccharide responses did not correlate with IgG2 or IgG3 serum levels. This emphasizes the importance of direct assessment of vaccine response in patient evaluation, rather than relying on subclass measurement alone.

Diagnostic controversy arises due to interlaboratory variation in immunoglobulin subclass determinations and differences in normal ranges depending on age and ethnicity. As with CVID and IGAD, caution should be exercised when conferring this diagnosis in patients less than 4 years of age. Furthermore, since low subclass levels are defined based on population statistics, most individuals with isolated low IgG subclass levels are asymptomatic, rendering its significance questionable in patients with recurrent infections. However, some studies show a higher prevalence of subclass deficiency in groups of patients with chronic or recurrent sinopulmonary bacterial infections. Not all of these patients have impaired specific antibody responses. Thus, the connection between IgG subclass deficiency and susceptibility to infection or other disease may be difficult to demonstrate.

Individuals with IGGSD most often present with recurrent sinopulmonary infections of varying severity caused by common respiratory bacterial pathogens. Additional manifestations include frequent viral infections, recurrent diarrhea (infectious or allergic) and atopic diseases such as asthma and allergic rhinitis, and autoimmunity. Lymphoproliferative disease has been reported in association with IGGSD, although its significance is unknown.

IgG subclass deficiencies occur in various patterns. Low IgG2 is most common in children (male > female). It may occur in isolation but is also frequently associated with IgG4 and/or IgA deficiency. Selective IgG3 deficiency is found more commonly in women and may be associated with low levels of IgG1. Recurrent infections have also been reported in association with only low IgG4. Young children with IGGSD often improve with time: 50% to 70% (depending on the pattern of Ig abnormalities) achieve normal serum levels by age 6.

Abnormalities of lymphocyte populations have not been established in IGGSD. Some have found low levels of switched memory B cells (as in CVID) in some individuals with IGGSD. IGGSD is not commonly the result of genetic lesions in the human Ig heavy-chain locus. In fact, most individuals with deletions in this locus with restricted IgG subclass expression are asymptomatic. Mutations preventing expression of cell surface IgG2 have been found in a few reported cases of IgG2 deficiency.

Specific Antibody Deficiency With Normal Immunoglobulins

Some patients with recurrent infections and poor antibody responses (mainly to polysaccharide antigens) have normal levels of antibody classes and subclasses. This is called ‘specific antibody deficiency with normal immunoglobulins’ (SADNI) or ‘functional antibody deficiency’. In one tertiary care center, SADNI was the most frequent diagnosis among patients evaluated for immunodeficiency (23%). In another recent study, poor response to pneumococcal polysaccharides was found in 58% of 24 children evaluated for chronic productive cough. In a larger cohort of 129 adult patients with chronic rhinosinusitis, more than 11% had a diagnosis of SADNI. In one retrospective study of 72 patients, approximately 8% exhibited autoimmunity and 5% had chronic enteropathy. Abnormalities of lymphocyte populations are not well described, though low levels of switched memory B cells are found in some patients.

Transient Hypogammaglobulinemia of Infancy

In humans, IgG is transported from the mother to the fetus during gestation. Maternal antibody has a half-life in the infant between 20 and 30 days. A nadir of IgG occurs at 3 to 9 months of age as maternal IgG is cleared and newborn production begins. Transient hypogammaglobulinemia of infancy (THI) is an IgG deficiency that begins in infancy and resolves spontaneously by 5 years of age. Thus, the diagnosis can be confirmed only after IgG levels normalize. By definition, IgG is lower than normal for age. Many of these children are asymptomatic. Beginning at about 6 months of age, many (>90%) of these IgG-deficient children manifest the types of recurrent infections associated with hypogammaglobulinemia. Severe infections are not often seen, but vaccine strain polio meningoencephalitis has been reported in one case of THI. Fifty to eighty per cent of patients are atopic and autoimmunity may be seen in a small fraction (4%).

Patients with higher initial IgG levels and males normalize more rapidly. High total B cells, low memory B cells and reduced CD19 on B cells have been described in patients with THI.

Many studies indicate mainly normal vaccine responses in THI, but one study documented poor responses to Hib vaccine in a majority and to tetanus in one third of patients. Those with low levels of IgA and IgM and poor vaccine responses had longer time to resolution and a higher rate of persistent hypogammaglobulinemia.

Hyper-IgM Syndromes

The eponym ‘hyper-IgM syndrome’ is applied to immunodeficiency with defective Ig class switching. In primary antibody responses, IgM is produced initially; IgG and other isotypes are produced later. This is called class switching and requires genetic rearrangement to juxtapose the Ig variable region gene with a new heavy-chain gene. If this process fails, IgM predominates in antibody responses without other isotypes being produced . The X-linked hyper-IgM syndrome (abbreviated XHIM or HIM1) is an immunodeficiency resulting from defects in TNFSF5 (tumor necrosis factor superfamily member 5). This is also called CD154 or CD40 ligand (CD40L). This is truly a combined immunodeficiency because the interactions of T cells with antigen-presenting cells and mononuclear cells are impaired. However, HIM1 is often classified with antibody deficiencies because hypogammaglobulinemia is such a prominent feature.

Usually within the first 2 years of life, patients with HIM1 develop recurrent bacterial infections generally seen in hypogammaglobulinemia. They also have opportunistic infections from fungal pathogens such as Pneumocystis , Histoplasma and others. Additional infections include erythrovirus and sclerosing cholangitis due to Cryptosporidium. Noninfectious complications include neutropenia and hepatic and hematologic malignancies.

In HIM1, IgG is low and IgM is normal or high; more than half of patients lack IgA. Specific antibody formation is often impaired. Patients make IgM antibody in response to immunization or infection but little IgG. Antibody levels wane rapidly, and there are no memory responses. Secondary lymphoid tissues are poorly developed and do not contain germinal centers. The diagnosis is established by demonstrating a failure of T cells to express CD40L after stimulation. The diagnosis should be confirmed with molecular genetic study.

Forms of hyper-IgM syndrome with autosomal (mostly recessive) inheritance have also been described. ‘Hyper-IgM syndrome type 3’ (HIM3) results from mutations in the gene encoding tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40. Because this is the ligand for TNFSF5 (HIM1), the same cellular interactions are affected.

Two additional forms of autosomal hyper-IgM syndrome are due to mutations of the genes encoding activation-induced cytidine deaminase (AID) and uracil nucleoside glycosylase (UNG). These are called HIM2 and HIM5, respectively. Bacterial sinopulmonary infections occur in these patients along with diarrhea, failure to thrive and lymphadenopathy. These defects affect only class-switch machinery in B cells; T cell function is completely intact and opportunistic infections are not observed.

Another form of hyper-IgM syndrome (unknown defect) has been designated ‘hyper-IgM syndrome type 4’. This is a milder antibody deficiency with residual IgG production and an intrinsic B cell class-switch defect with normal T cell function. Immune function may normalize over time in some patients.

A few patients have been described with a hyper-IgM phenotype and defects of PI3 kinase catalytic subunit δ (PI3KCD).

Differential Diagnosis

Clinical entities that mimic antibody deficiency are listed in Box 8-1 . The most frequent presentation of antibody deficiency includes recurrent, frequent and severe respiratory tract infections with encapsulated bacteria. Additional bacterial infections may occur in other sites, along with frequent viral infections and noninfectious complications. Of course, antibody deficiency may accompany cellular immunodeficiency (i.e. combined immunodeficiency). Normal cellular immune function should be confirmed in all cases of abnormal humoral immunity ( Figure 8-1 ).

Box 8-1

Differential Diagnosis of Recurrent Respiratory Tract Bacterial Infections

• 
  

  Primary humoral immunodeficiency

  
  
• 
  

  Secondary or acquired humoral immunodeficiency

  
  
• 
  

  Primary combined immunodeficiency

  
  
  
  
  • 
    

    Severe combined immunodeficiency

    
    
  • 
    

    Wiskott-Aldrich syndrome

    
    
  • 
    

    DiGeorge syndrome

    
    
  • 
    

    Ataxia-telangiectasia

    
    
  • 
    

    Many others

  
  
  
  
• 
  

  Secondary or acquired combined immunodeficiency

  
  
• 
  

  Complement deficiency

  
  
• 
  

  Phagocytic cell defect

  
  
  
  
  • 
    

    Chronic granulomatous disease

    
    
  • 
    

    Leukocyte adhesion defect

    
    
  • 
    

    Chédiak-Higashi syndrome

    
    
  • 
    

    Neutropenia

  
  
  
  
• 
  

  Allergic rhinosinusitis

  
  
• 
  

  Anatomic obstruction of Eustachian tube or sinus ostia (tumor, foreign body, lymphoid hyperplasia)

  
  
• 
  

  Cystic fibrosis

  
  
• 
  

  Ciliary dysfunction

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