IgA and IgG Subclass Deficiencies Clinical Presentation

• As many as 80% of patients with immunoglobulin (Ig)A deficiency are asymptomatic. A compensatory increase in IgM production and subsequent increase in secretary IgM in the mucosal lumen may account for lack of clinical symptoms, but the data are conflicting. Another explanation for lack of clinical symptoms is normal levels of secretary IgA despite decreased serum IgA levels. However, patients with IgA deficiency can present with broad spectrum of medical conditions, including recurrent sinopulmonary infections, atopic disorders (atopic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergy), GI disease (especially celiac disease), neurologic diseases, autoimmunity, and malignancy.

  • Gastric carcinomas or lymphomas are malignancies frequently associated with IgA deficiency.
  • Various autoimmune diseases are associated with IgA deficiency. These include rheumatoid arthritis, systemic lupus erythematosus, pernicious anemia, and immune thrombocytopenic purpura (ITP). Even in absence of overt clinical symptoms, the sera of patients of IgA deficiency often reveal a wide spectrum of autoantibodies. In 1981, Cunningham-Rundles et al reported that patients with IgA deficiency are most likely to have high titers of IgG antibodies to cow's milk and that these patients were most likely to develop various autoantibodies.^[10]
  • Various GI diseases also are associated with IgA deficiency. These diseases often cause chronic diarrhea with or without malabsorption. Persistent and recurrent infection with Giardia lamblia, and autoimmune GI diseases (eg, celiac, ulcerative colitis, regional enteritis) must be considered and ruled out in patients with IgA deficiency and GI symptoms. Biopsy specimens may show nodular lymphoid hyperplasia with flattened villi.
  • Recurrent sinopulmonary infection is the illness most frequently encountered in patients with selective IgA deficiency. These infections often alert the clinician to order a test of serum Ig levels. Reduced IgA levels establish the diagnosis. Most upper and lower respiratory tract infections are caused by relatively less virulent microbes, or patients present without overt causative pathogens. Patients with a concomitant IgM or IgG subclass deficiency present with recurrent infection more frequently than patients with isolated IgA deficiency.
  • IgA deficiency is also frequently detected in patients with various neurologic disorders. Genetic defects that affect DNA repair enzymes cause ataxia telangiectasia and Nijmegan breakage syndrome. These lead to progressive neurodegenerative disorders. They are also associated with declining IgA levels with age. Anti-convulsants can cause hypogammaglobulinemia or selective IgA deficiency.
  • Food allergy and other atopic disorders (eg, allergic conjunctivitis, rhinitis, allergic urticaria, atopic dermatitis, asthma) are more common in patients with IgA deficiency than in the general population.
• Controversy surrounds the clinical relevance of IgG subclass deficiency because many patients with IgG2 subclass deficiency (level of 0) can be asymptomatic. Therefore, the patient's ability to produce specific antibodies against polysaccharide antigens is important in determining the need for therapeutic intervention. One report indicated that as many as 20% of children with recurrent or chronic infections due to encapsulated bacteria have IgG subclass deficiency.
• Although the IgG2 isotype is generally thought to dominate the antibody responses to polysaccharide antigens, a direct causal relationship between decreased serum IgG2 and infection with encapsulated organisms has not been definitively shown. The concept that antibodies against polysaccharide antigens are mainly IgG2 (with some IgG4) and that most antibodies against protein antigens are predominantly IgG1 and IgG3 does not appear to be universally valid. Notable crossover among IgG isotypes appears to occur with both protein and polysaccharide antigens.
• In contrast, antibody deficiency against microbial polysaccharide antigens is a well-established clinical entity and has been referred to as either antigen specific antibody deficiency (ASAD) or specific antibody deficiency (SAD). These patients generally present with recurrent upper and/or lower respiratory infections due to an encapsulated organism (Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, or Staphylococcus aureus). Examining patients with increased susceptibility to airway infections show 8-15% with SPAD.^{[11, 12, 13]} The latter authors suggest a particular high association with a history of otitis media and chronic otorrhea.
• Patients may also present with concomitant atopic disorders (eg, asthma, atopic dermatitis). Authors have indicated a need to assess antibody responses to polysaccharide vaccines (eg, Pneumovax) in patients with bronchiectasis of unknown etiology.^[14] This is strongly indicated for IgA deficiency patients with a history of recurrent or chronic otitis media and/or sinusitis, IgG2 subclass deficiency, and low levels of baseline specific antibodies.^{[15, 7, 8]}

  • Frequent, recurrent episodes of otitis media are most commonly observed in patients with selective IgA deficiency and decreased IgA or IgG subclass levels (especially IgG2).^[16] These patients also frequently have specific antibody deficiency due to bacterial polysaccharide antigens. Frequent infections were reported in 92% of patients with SAD (sinusitis, 77%; pneumonia, 42%; otitis media, 25%; bronchitis, 28%).^[17]
  • As many as 50% of patients with idiopathic bronchiectasis have an absence of antipolysaccharide IgA or IgG2 antibodies.^[14] Although others find such a defect only in 11%.^[15] However, laboratory measures of IgA-IgG subclass antibodies against pneumococcal antigens are not readily available. Costa Carvalho et al (2005) also reported the absence of a positive association between unresponsiveness to unconjugated pneumococcal vaccines (for polysaccharide antigens [Pneumovax]) and IgA and/or IgG subclass deficiencies in children with recurrent sinusitis.^[18]
• Deficiency of antibodies of certain IgG subclasses may have clinical relevance in identifying patients with relatively severe atopic dermatitis.^[19] It may also be associated with nonresponsiveness to interferon alfa in patients with hepatitis B viral infection.^[20]

• Patients appear to be healthy between infections.
• Any abnormal physical findings may indicate various diseases to which patients with selective IgA deficiency have an increased susceptibility.
• Patients with IgA deficiency and abnormalities of chromosome 18 may present with the following:

  • Facial abnormalities
  • Ear abnormalities
  • Hand abnormalities
  • Growth retardation
  • Muscular hypotonia
  • Mental retardation

In most cases, IgA-deficiency appears to occur in a sporadic fashion, but familial inheritance is described in a mode of autosomal-recessive or autosomal-dominant pattern with variable or incomplete expression. IgA deficiency is also most commonly found in family members with common variable immunodeficiency (CVID).

• Transplacental passage of anti-IgA antibodies also can cause IgA deficiency in an offspring by inducing IgA-specific T-cell suppressor activity. This was suggested in a report of 2 mothers with IgA deficiency whose infants had excessive T-cell suppressor function specific for IgA and IgA deficiency.^[21]
• IgA deficiency is also reported in individuals with various chromosomal abnormalities, particularly those with chromosome 18 abnormalities. Decreased or absent IgA is described in 2 of 6 patients with ring 18, in 5 of 15 patients with deletion of the long arm of 18 (18p-), and in 2 of 5 patients with deletion of the short arm (18q-). Patients with 18p- also have an increased incidence of autoimmune diseases. The actual mechanism is not known because no specific area in chromosome 18 has been consistently associated with IgA deficiency. Partial deletions of chromosome 4 (Wolf-Hirschhorn syndrome) have also resulted in immune defects, including CVID, IgA and IgG2 subclass deficiency, IgA deficiency, and impaired antibody responses to polysaccharide antigens.
• Other data indicate an association with certain major histocompatibility complex (MHC) haplotypes, suggesting a role with another gene located in chromosome 6 that may explain the high prevalence of autoimmune diseases with IgA deficiency. Certain MHC haplotypes, such as human leukocyte antigen (HLA)-A1, HLA-B8, HLA-DR3; HLA-B57, HLA-SC61, HLA-DR7; and HLA-B44, HLA-FC31, HLA-DR7, have been associated with primary IgA deficiency. Linkage with other haplotypes, eg, HLA-A1, HLA-B8, HLS-DR3, HLA-DQB1*0201, C4B-Sf, C4A-null, G11-15, Bf-0.4, C2a, HSP70-7.5, and tumor necrosis factor (TNF)-a5 is described in a family with IgA deficiency or CVID.
• Certain drugs can induce transient IgA deficiency which resolve after the causative drugs are removed. This is implicated with induction of suppressor T-cell activity specific for IgA. Agents that can cause IgA deficiency with such mechanisms include sulfasalazine, hydantoin, cyclosporine, gold, fenclofenac, sodium valproate, and captopril. Indeed, 20-40% of patients treated with phenytoin may develop IgA deficiency.^[22]
• Certain viral infections, such as congenital rubella infection or Epstein-Barr virus (EBV) infection, may result in persistent IgA deficiency.

  • Ig heavy-chain genes are located on chromosome 14 in the following order: 3'-V-D-J–mu-delta-gamma1-psi/epsilon1-alpha1-psi/gamma1-gamma2-gamma4-epsilon1-alpha2. Therefore, deletions of the 1 result in absent IgA1 and also may involve IgE, IgG4, and IgG2, or deletions of the 2 may result in absent IgE, IgG2, and IgG4. No individuals have been described with both IgA1 and IgA2 gene deletions. Individuals with a selective IgA subclass deficiency are usually asymptomatic.
  • Patients in whom homozygous deletions have resulted in absent IgG2, IgG4, IgA1, and IgE Igs appear to be healthy and have normal responses to protein and polysaccharide antigens. Therefore, the most valid indication of immunodeficiency may be the child's ability to make specific antibody.
  • During normal development, synthesis of IgG2 and IgG4 lags that of IgG1 and IgG3. Measurement of IgG subclass levels in children younger than 4 years may simply reflect maturational delay. In 1999, Lawton did not consider a diagnosis of IgG subclass deficiency in young patients before excluding a long list of conditions that might contribute to recurrent respiratory diseases.
• IgG subclass levels can be affected by placental passage, maturational age, presence of infection, protein loss, or the use of drugs, such as corticosteroids. An example of the differential response can be found in measles. In children younger than 3 years, measles IgG antibodies are predominantly IgG3 in isotype whereas those older than 4 years of age, IgG2 antibodies are predominant.^[23]