Immunodeficiency with Low IgG and Normal or High IgM Levels (Class Switch Recombination Defects)
The term hyper-IgM has been used to describe a group of disorders of CSR with characteristically elevated IgM levels and low levels of switched isotypes (IgG, IgA, and IgE). In the past decade, the molecular defects for the majority of these disorders have been identified, and their characterization has been instrumental in elucidating some of the central mechanisms of antibody isotype switching and SHM (Fig. ).
X-linked hyper-IgM is caused by mutations of the gene encoding CD40L (TNFSF5). A very rare autosomal-recessive form with an identical phenotype is due to mutations in the gene encoding CD40 (TNFRSF5). Defective CD40L or CD40 expression results in a combined humoral and cellular immunodeficiency with absent or abortive germinal center formation as well as impaired interactions of T cells with dendritic cells. Patients usually present in infancy with severe and/or recurrent bacterial respiratory and gastrointestinal infections as well as opportunistic infections such as Pneumocystis jirovecii
pneumonia, disseminated fungal infections, disseminated cytomegalovirus (CMV) and herpes simplex virus infections, and cholangitis due to Cryptosporidium parvum
. Other clinical features are neutropenia, chronic anemia associated with erythrovirus (parvovirus B19) infections, and an increased incidence of gastrointestinal tumors (77
Two forms of hyper-IgM with autosomal-recessive inheritance are caused by deficiencies of AID or UNG, both resulting in profoundly defective CSR. Patients present with recurrent or severe infections of the type classically associated with profound antibody deficiency. Lymphoid hyperplasia is present in about two-thirds of patients due to massive germinal center enlargement, which often manifests as prominent cervical lymphadenopathy and tonsillar hypertrophy. Patients have an increased incidence of autoimmune disease such as autoimmune hemolytic anemia and autoimmune thrombocytopenia (62
Mutations in the genes encoding the I-κB kinase γ chain (also called NF-κB essential modulator [NEMO]) or I-κB kinase α chain result in a distinct phenotype characterized by variable manifestations of ectodermal dysplasia (conical or absent teeth, sparse hair, frontal bossing, and decreased eccrine sweat glands) and susceptibility to mycobacterial infections in addition to antibody deficiency with often high serum IgM or IgA levels (63
). These disorders are sometimes classified as hyper-IgM syndromes. However, these defects include significant elements of T-cell and NK cell dysfunction and are best classified among the combined (cellular and humoral) immunodeficiencies.
Patients with a CD40L or CD40 deficiency have markedly reduced IgG levels (IgG levels of <250 mg/dl), often low IgA levels, and normal to elevated IgM levels (142
). Among those patients with AID and UNG deficiency, IgG and IgA levels are generally profoundly decreased (IgG levels of <200 mg/dl and IgA levels of <20 mg/dl), and IgM levels are normal to increased (100 to 3,700 mg/dl) (105
). Specific IgG responses are poor for all subtypes of CSR defects. Lymphocyte subset composition is normal. T-cell proliferative responses are normal except for patients with CD40L and CD40 deficiencies, who have impaired responses to recall antigens. CD40 and CD40L expression can be evaluated by flow cytometric analysis. Gene testing for mutations in CD40, CD40L, AID, UNG, and NEMO is available (14
Common Variable Immunodeficiency
CVID is a heterogeneous disorder of B-cell differentiation and maturation with dysfunctional antibody production. Patients have markedly reduced serum concentrations of IgG, impaired specific antibody responses, and recurrent infections. With an estimated prevalence of 1 in 25,000 to 1 in 75,000 individuals, it is the most common of the more severe primary immunodeficiencies that come to medical attention (41
). A familial pattern of inheritance has been demonstrated for approximately 10 to 20% of patients with CVID (54
). The variability of its phenotype and the incomplete penetrance of some of its associated molecular defects suggest that the etiology of CVID is multifactorial, with a combination of defects of B-cell differentiation resulting in antibody deficiency.
While the etiology remains unknown for the majority of patients, gene defects have been revealed for approximately 10 to 15% of CVID patients in recent years. Thus far, mutations or polymorphisms in four genes, two of which appear to affect only very few patients, have been described. Mutations in the gene encoding TACI have been identified for 8 to 10% of patients with CVID (24
). Two TACI sequence variants, Cys104Arg and Ala181Glu, have shown a significant association with CVID even in a heterozygous state. However, these TACI mutations are also present in some healthy individuals; hence, it has been proposed that additional genetic and/or environmental factors are needed to develop disease (76
Several single nucleotide polymorphisms in the gene encoding Msh5, an MMR protein with likely involvement in CSR, have recently been reported to occur more frequently in patients with CVID and IgA deficiency in a combined analysis of U.S. and Swedish cohorts (126
). Again, these polymorphisms are also found in healthy individuals, and other potentially disease-modifying factors are yet to be determined.
The other two recently identified monogenetic defects are very rare causes for CVID but may be exemplary of how defects affecting different stages of antigen-dependent B-cell maturation can result in primary antibody production failure. Nine individuals with CVID due to ICOS deficiency have been reported. They all carry an identical large homozygous deletion in the ICOS gene and likely descend from a common ancestor (121
). Four patients from two unrelated families who developed CVID due to homozygous mutations in the gene encoding the B-cell surface protein CD19 have been described. Their phenotype was characterized by normal total peripheral B-cell numbers but severely reduced numbers of memory B cells (135
The age of presentation of CVID varies widely. According to a recent large European registry study of 334 patients, the most common age at the onset of symptoms was in the third decade, with a mean of 26.3 years and a median of 24 years. The mean age at diagnosis was 35.3 years, with a median of 33 years (26
). This indicates that many patients suffer from their disease for many years before their immunodeficiency is recognized.
Patients often come to medical attention due to acute or chronic bacterial and, less frequently, viral infections. Noninfectious complications are also frequent, encompassing autoimmune diseases, lymphoproliferative disease, granulomatous disease, a spectrum of gastrointestinal disorders, as well as malignancies. Significant morbidity and mortality arise from chronic lung disease as a consequence of recurrent and chronic infections as well as granulomatous and lymphoid interstitial pneumonitis (32
). Granulomatous disease is present in 5 to 10% of patients with CVID. Granulomas are of the noncaseating type and resemble those found in sarcoidosis. In many cases, patients are misdiagnosed with sarcoidosis before their antibody deficiency is detected and the diagnosis of CVID is made (40
). Although granulomas most commonly affect the lungs, they are also found in almost any other organ including skin, liver, spleen, bone marrow, and the gastrointestinal tract of patients (85
). Hypertrophy of lymphoid tissue is common in CVID. Splenomegaly has been reported for 26% of patients according to one study (111
The overall prevalence of autoimmune disease is estimated to be 20 to 30% and includes a wide spectrum of disorders. The most frequently encountered are idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, rheumatoid arthritis, and pernicious anemia (32
). Both hematologic malignancies and solid tumors have an increased prevalence in patients with CVID. Particularly common are non-Hodgkin B-cell lymphoma and gastric cancer, with reported prevalences of approximately 2 to 8% and 1 to 2%, respectively (14
). Studies have found no increased risk of malignancies among relatives of patients with CVID, suggesting that the immunodeficiency itself predisposes one to cancer (87
For patients with CVID, IgG levels are reduced by greater than 2 standard deviations (SDs) below the mean for age. An associated reduction in either the IgA or IgM level has been included as part of the diagnostic criteria by some authors. Also essential for establishing the diagnosis is evidence of impaired specific antibody responses to infection or vaccine challenge. Peripheral B-cell numbers can be either normal or reduced. T-cell numbers and function are also reduced in some patients.
CVID remains predominantly a diagnosis of exclusion. Other specific immunodeficiency diagnoses have to be ruled out by careful evaluation of clinical features and laboratory phenotypes. In some cases, molecular testing may be required to distinguish other diseases with similar phenotypes, including CSR defects, agammaglobulinemia, and X-linked lymphoproliferative syndrome (caused by mutations in SH2D1A) (37
). ICOS expression on T cells can be assessed by flow cytometric analysis; however, it is not routinely done due to the extraordinarily rare occurrence of this mutation. It may be considered for individuals who can trace their ancestry to the Black Forest region of Germany. The expression of CD19 is routinely assessed as part of the lymphocyte subset evaluation. In a rare individual with other clinical and laboratory features of CVID in whom no B cells are detected after staining for CD19, the presence of measurable numbers of B cells with analysis of another marker, such as CD20, may suggest the defect. TACI gene sequence analysis is commercially available.
The number of isotype-switched memory B cells in the peripheral blood has been found to be one of several useful parameters to distinguish distinct phenotypes of CVID. Reduced numbers of switched memory B cells (<2% of total B cells) have been shown to correlate with disease-associated complications such as splenomegaly and granulomatous disease (140
). One study reported a significant correlation with autoimmune disease if the cutoff level for switched memory B cells was lowered to <0.55% of total B cells (122
). A low percentage of naïve CD4 T cells also correlates with overall disease severity and splenomegaly (50
Selective IgA deficiency is a common immunological variant with a prevalence of 1:400 to 1:600 in the healthy U.S. population. Affected individuals are asymptomatic in up to 90% of cases (28
). There is familial clustering of IgA deficiency with CVID, with 20 to 25% of individuals having a positive family history of either IgA deficiency or CVID. Some IgA-deficient patients progress over time to CVID. The pattern of inheritance of selective IgA deficiency is unclear (54
). The underlying defect has also not been determined for the majority of patients. Patients with associated chromosomal abnormalities, particularly on chromosome 18, have been described. Acquired IgA deficiency has been associated with a relatively large number of medications (see above) (14
Despite its association with a benign clinical course in most patients, a subgroup of IgA-deficient patients develops recurrent sinopulmonary and gastrointestinal infections typical of antibody deficiency, yet invasive infections such as meningitis or sepsis generally do not occur. IgA-deficient individuals are at an increased risk of developing autoimmune disease, particularly systemic lupus erythematosus and rheumatoid arthritis, and gastrointestinal disease such as inflammatory bowel disease and celiac disease (2
). A higher prevalence of asthma and allergies has also been reported.
Selective IgA deficiency is defined as a serum IgA level below 7 mg/dl in the presence of normal serum IgG and IgM levels for a patient older than 4 years of age after other causes for hypogammaglobulinemia have been excluded. Young children can have a physiological delay in IgA production that they will outgrow and therefore are not considered deficient. The clinical presentation together with an evaluation of specific antibody responses should determine further management (14
IgG Subclass Deficiency
IgG subclass deficiency is defined as an abnormally low level of one or more IgG subclasses (IgG1, IgG2, IgG3, or IgG4) with normal levels of total IgG and normal levels of the other immunoglobulin isotypes. It is sometimes associated with IgA deficiency (14
The diagnosis of IgG subclass deficiency is controversial, since low levels of one or more IgG subclasses can be found in 2 to 20% of healthy individuals. Diagnosis is further complicated by the variation of IgG subclass levels with age and by different methods used in individual laboratories for determining the serum levels (17
). The sequence of appearance of the different subclasses throughout childhood reflects the order of the respective heavy-chain constant-region genes on chromosome 14 (Fig. ). Levels of IgG3 and IgG1 rise quickly during infancy, followed by delayed increases in IgG2 and IgG4 levels, with adult levels often not being reached before puberty. Since IgG2 is the isotype that is primarily responsible for responses against polysaccharides, it was postulated that a deficiency of this subclass in children would predispose patients to infections with encapsulated bacteria. However, some studies identified children with low IgG2 levels in the healthy population without evidence of increased susceptibility to infections (127
). Another study revealed a resolution of IgG2 deficiency in all children observed over a time period of 6 years (6
). The presence of symptoms seems to correlate rather with an impairment of specific antibody responses to vaccines or to natural exposure to pathogens (21
). If patients are symptomatic, they present with recurrent sinopulmonary bacterial infections. Association with atopy and autoimmune disease has been reported, similarly to IgA deficiencies (14
IgG subclass deficiency can be established if one or more IgG subclasses are 2 SDs below the age-adjusted norm, with normal total serum IgG levels. Only if associated infections are present is further immunological workup warranted, including evaluation of specific antigen responses to protein and polysaccharide antigens (21
Specific Antibody Deficiency
Specific antibody deficiency (SAD) is characterized by impaired IgG responses to polysaccharides in the presence of normal serum concentrations of IgG, IgM, and IgA. It is therefore also called selective antibody deficiency with normal immunoglobulin. Patients have poor responses to polysaccharide antigens such as pneumococcal polysaccharide and Haemophilus influenzae
type b capsular polysaccharide. The underlying molecular defect is not known. The prevalence of SAD is also unknown but is estimated to be high, with a few studies reporting 5 to 10% of children who are evaluated for recurrent infections being affected (61
). Patients present with infections characteristic of PAD, with a predominance of recurrent upper and lower respiratory tract bacterial infections.
A diagnosis of SAD requires a demonstration of poor responses to polysaccharide vaccines in the context of normal serum immunoglobulin concentrations. It may be difficult to establish the diagnosis with confidence for young children below the age of 2 years, as they have less consistent responses to polysaccharide vaccine challenge. Abnormal responses to protein vaccines or evidence of further abnormal laboratory findings can be indicative of a more extensive defect and should prompt evaluation for other immunodeficiencies.
Transient Hypogammaglobulinemia of Infancy
Transplacentally acquired maternal antibodies protect the infant against pathogens until his or her own antibody production has reached sufficient levels. The hiatus between the loss of maternal antibodies and the onset of a robust antibody synthesis represents a physiological period of hypogammaglobulinemia, usually lasting from 3 months to about 6 months of age. Prolongation and accentuation of this phase with decreased levels of IgG and, in some cases, also IgA and IgM production until early childhood are considered to account for cases of transient hypogammaglobulinemia of infancy (THI). The term is somewhat misleading given that hypogammaglobulinemia persists until childhood in most cases and may not be transient in other cases but rather represents an early presentation of a more profound antibody deficiency such as CVID (33
). The delay in antibody production is sometimes associated with recurrent infections. Infectious manifestations include mostly upper respiratory tract infections and, less commonly, pneumonia. Rarely, invasive infections such as sepsis or meningitis have been reported (14
Laboratory evaluation reveals serum IgG levels 2 SDs below the mean for age-matched controls. Serum levels of IgA and, less frequently, IgM can also be decreased. Evaluation should include specific antibody responses to vaccines and also flow cytometric quantitation of lymphocyte subsets to rule out more substantial defects. Specific antibody responses are most often normal in patients with transient hypogammaglobulinemia. Patients should be monitored over time until levels have normalized. The disease is self-limited by definition; however, medical intervention is indicated for some patients, and the diagnosis has to be revised for others (91