Immunoglobulin (Ig) A deficiency (IGAD) is characterized by decreased or absent levels of serum IgA in the presence of normal serum levels of IgG and IgM in a patient older than 4 years of age in whom other ... Immunoglobulin (Ig) A deficiency (IGAD) is characterized by decreased or absent levels of serum IgA in the presence of normal serum levels of IgG and IgM in a patient older than 4 years of age in whom other causes of hypogammaglobulinemia have been excluded. IgA in the dimeric form is the dominant immunoglobulin in luminal secretions, such as saliva, tears, bronchial secretions, nasal mucosal secretions, and mucous secretions of the small intestine. Individuals with selective IgA deficiency may be asymptomatic or have recurrent sinopulmonary and gastrointestinal infections, allergic disorders, and autoimmune disorders. The diagnosis of IgA deficiency depends on the measurement of monomeric IgA concentrations in serum; thus individuals with IgA deficiency may have IgA in mucosal systems, which may offer some protection (review by Yel, 2010). - Genetic Heterogeneity of IgA Deficiency The IGAD1 locus maps to chromosome 6p21. See also IGAD2 (609529), which is caused by mutation in the TNFRSF13B gene (604907) on chromosome 17p11.
Oxelius et al. (1981) concluded that deficiency of IgG2 in combination with IgA deficiency is a critical factor in whether or not IgA-deficient persons have illness, such as frequent infections, autoimmune disorders, atopy, or malabsorption.
Schaffer ... Oxelius et al. (1981) concluded that deficiency of IgG2 in combination with IgA deficiency is a critical factor in whether or not IgA-deficient persons have illness, such as frequent infections, autoimmune disorders, atopy, or malabsorption. Schaffer et al. (1989) noted that the clinical consequences of IgA deficiency are highly variable. Many affected persons have no obvious health problems, whereas others may have recurrent infections, gastrointestinal disorders, autoimmune diseases, allergies, or malignancies. A central feature in the pathogenesis of IgA deficiency is an arrest of B-cell differentiation. Affected individuals have a normal number of IgA-bearing B-cell precursors, but a profound deficit in the terminal differentiation of IgA-secreting plasma cells. Schaffer et al. (1989) proposed that selective IgA deficiency and common variable immunodeficiency (CVID; see, e. g., 607594), which is characterized by reduced levels of 1 or more Ig classes, may represent polar ends of a spectrum reflecting a common underlying genetic defect. Hammarstrom and Smith (1999) stated that in about two-thirds of cases, selective IgA deficiency does not lead to an increased occurrence of infections, whereas the remaining patients suffer from bacterial infections in both the upper and lower respiratory tract. The defect is manifested already at the stem cell level, and transfer of bone marrow from an IgA-deficient donor to a normal recipient can result in IgA deficiency in the recipient (Hammarstrom et al., 1985), whereas transfer of bone marrow from a normal individual to an IgA-deficient patient will correct the defect (Kurobane et al., 1991). Some patients with IgA deficiency develop anti-IgA antibodies. Van Loghem (1974) reported 2 families with isolated IgA deficiency associated with antibodies to IgA. Anti-IgA antibodies of different specificities were encountered in 8 of 15 IgA-deficient family members; sometimes more than one specificity was observed in the same individual. Several members of the family were found to be deficient for IgA1 (146900) as well as for IgA2 (147000). However, by means of typing with the closely linked Gm markers, van Loghem (1974) excluded a defect in the structural IGHA1 and IGHA2 genes. An autosomal recessive mode of inheritance of genes concerned with the synthesis of IgA was thought to best account for the observations. In 2 families, de Laat et al. (1991) found that the mothers had selective IgA deficiency with circulating class-specific anti-IgA antibodies. Each gave birth to 2 children who were found to be IgA deficient. Three of these children developed anti-IgA antibodies before puberty. In all 4 children, in vitro immunoglobulin production studies showed an IgA B-cell defect combined with IgA-specific excessive T-suppressor function. Maturation of their IgA system seemed to have been influenced in the perinatal period by the maternal anti-IgA antibodies.
Sekine et al. (2007) identified 5 nonsynonymous polymorphisms and numerous SNPs in noncoding regions of the MSH5 gene (603382) on chromosome 6p22.1-p21.3 in Swedish patients with IgA deficiency or common variable immunodeficiency (CVID). Two nonsynonymous SNPs leading to ... Sekine et al. (2007) identified 5 nonsynonymous polymorphisms and numerous SNPs in noncoding regions of the MSH5 gene (603382) on chromosome 6p22.1-p21.3 in Swedish patients with IgA deficiency or common variable immunodeficiency (CVID). Two nonsynonymous SNPs leading to leu85-to-phe (L85F) and pro786-to-ser (P786S) changes (dbSNP rs28381349 and dbSNP rs28399984, respectively) were always found together. In a combined analysis of Swedish and U.S. patients, Sekine et al. (2007) found that the L85F/P786S allele showed a significant association with IGAD and a borderline significant association with CVID. Yeast 2-hybrid analysis showed that the variant MSH5 protein encoded by the L85F/P786S allele had diminished capacity to bind MSH4. Control subjects heterozygous for the L85F/P786S allele had normal IgA levels, suggesting incomplete penetrance for the Ig deficiency phenotype. IGAD and CVID patients carrying disease-associated MSH5 alleles had long microhomologies at Ig switch (S) joints, as seen in mice with low or no Msh5. Sekine et al. (2007) proposed that MSH4/MSH5 heterodimers contribute to class-switch recombination and promote resolution of DNA breaks, supporting the notion that the immunodeficiency states result from complex interactions.
Oen et al. (1982) found IgA deficiency, defined as less than 0.01 mg/ml, in 155 of 72,296 blood donors.
With a prevalence of about 1 in 800 Caucasians, selective IgA deficiency is the most frequently recognized ... Oen et al. (1982) found IgA deficiency, defined as less than 0.01 mg/ml, in 155 of 72,296 blood donors. With a prevalence of about 1 in 800 Caucasians, selective IgA deficiency is the most frequently recognized primary immunodeficiency (Schaffer et al., 1989). Smith et al. (1994) reviewed the genetics of selective IgA deficiency, which they suggested is the most prevalent immunodeficiency, with a frequency of 1 in 500 in Caucasoids. Hammarstrom and Smith (1999) stated that selective IgA deficiency is the most common form of immunodeficiency in the Western world, affecting approximately 1 in 600 individuals. Great variability in the prevalence is found in different ethnic groups, and a markedly lower frequency has been reported in mongoloid populations, suggesting a genetic influence.