Immunoglobulin A Deficiency 1

Description

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.

Clinical Features

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.

Inheritance

The pedigrees of IgA-deficient individuals show familial clustering with no distinct mendelian inheritance pattern. Autosomal recessive, autosomal dominant, and sporadic transmission patterns have all been observed (review by Yel, 2010).

In a Swiss kindred, Stocker et al. (1968) described selective complete deficiency of IgA in 2 sisters, the son and daughter of one and the son of the other. Both parents of the 2 sisters had normal serum globulin. They suggested autosomal dominant inheritance, but the evidence was meager. Goldberg et al. (1968) reported a kindred in which inheritance seemed to be autosomal recessive. Huntley and Stephenson (1968) reported 1 large kindred suggesting autosomal recessive inheritance, but other families in which dominant inheritance seemed likely. In addition, they presented identical twins who were discordant for the trait. The frequency of isolated IgA deficiency in their study was 0.2%. Out of 24 deficient persons, 4 had rheumatoid arthritis and 2 had severe sinopulmonary disease. Hilman et al. (1969) found low IgA in a mother and 2 daughters.

Ammann and Hong (1971) found inheritance patterns suggesting autosomal inheritance of IgA deficiency in 5 families, although 4 were consistent with dominant and 1 with recessive inheritance. Nell et al. (1972) observed selective deficiency in 13 persons in 5 kindreds. Father and son and mother and daughter were affected in 2 of the families; in the other 3, recessive inheritance was suggested by the occurrence in double cousins and in multiple sibs.

Grundbacher (1972) concluded that selective immunoglobulin A deficiency is probably multifactorial.

Webb and Condemi (1974) found selective IgA deficiency in a 43-year-old woman, offspring of an uncle-niece mating, with advanced chronic obstructive pulmonary disease. Other immunoglobulins and alpha-1-antitrypsin were normal. Among her relatives several had either definite or borderline IgA deficiency. Her mother, aged 71, and 2 brothers, aged 48 and 44, had emphysema. Buckley (1975) observed familial cases including 1 family with affected persons in 3 generations.

Waldmann et al. (1976) found evidence of genetic heterogeneity. Some cases showed an apparent defect in secretion of IgA from the B cell despite presumptively normal synthesis. Other cases showed suppression by IgA-specific T cells. Such heterogeneity was consistent with the known modes of inheritance.

Mapping

By HLA typing of 62 unrelated IgA-deficient blood donors, Oen et al. (1982) showed a significant increase in the prevalence of HLA-B8.

In the family of a 57-year-old woman with IgA deficiency and Still disease, Lakhanpal et al. (1988) found a suggestion of linkage to the HLA haplotype A1-B8. The maternal HLA-A1-B8 haplotype was associated with IgA deficiency in all 3 of her children, whereas all 5 family members with exclusively paternally derived A1-B8 haplotype had normal IgA levels. In a third generation, of 3 family members whose A1-B8 haplotype was of indeterminate origin--that is, potentially either maternally or paternally derived--2 had IgA deficiency and 1 did not.

Olerup et al. (1990) found that the amino acid at codon 57 of the HLA-DQ beta chain (146880) could be implicated in susceptibility to selective immunoglobulin A deficiency. The 'protective' allele had the negatively charged aspartic acid at position 57, whereas 'susceptibility' alleles had a neutral alanine or valine at this position. Codon 57 of this gene has been implicated also in the susceptibility to insulin-dependent diabetes mellitus (222100).

In an analysis of the MHC haplotypes of 12 IgA-deficient persons and 19 CVID persons from 21 families and of 79 of their immediate relatives, Volanakis et al. (1992) found that a small number of MHC haplotypes were shared by the majority of immunodeficient persons. Five of the families contained more than 1 immunodeficient individual and all of these 5 families included both IgA-deficient and CVID members. At least 1 of 2 MHC haplotypes was present in 24 of the 31 (77%) immunodeficient persons. No differences in the distribution of these haplotypes were observed between IgA-deficient and CVID persons. The analysis suggested that a susceptibility gene (or genes) for both immunodeficiencies is located within the class III region of MHC, possibly between the C4B and C2 genes.

Vorechovsky et al. (1999) showed an increased allele sharing at chromosome 6p21 in affected members of 83 multiplex families with either IGAD or CVID, both of which can occur in the same family. Using transmission/disequilibrium tests, the authors demonstrated family-based associations indicating the presence of a predisposing locus, designated IGAD1, in the proximal part of the major histocompatibility complex. The recurrence risk of IGAD was found to depend on the sex of the parents transmitting the defect; affected mothers were more likely to produce offspring with IGAD than were affected fathers. Carrier mothers but not carrier fathers transmitted IGAD1 alleles more frequently to the affected offspring than would be expected under random segregation. Vorechovsky et al. (1999) proposed that the differential parent-of-origin penetrance reflected a maternal effect mediated by the production of anti-IgA antibodies tentatively linked to IGAD1. This was supported by a higher frequency of anti-IgA-positive females transmitting the disorder to children, in comparison with female IGAD nontransmitters, and by linkage data in the former group. Such pathogenic mechanisms may be shared by other MHC-linked complex traits associated with the production of specific autoantibodies, parental effects, and a particular MHC haplotype.

Vorechovsky et al. (2000) haplotyped 554 members of 101 multiple-case European families using microsatellite markers placed onto the physical map of the IGAD1 locus. Linkage analysis provided additional support for a strong susceptibility locus at IGAD1. The maternal transmission effect was in excess in families with unaffected heterozygous parents but not in multiple-case families with a predominance of affected mothers. Of 110 haplotypes shared by 258 affected family members, haplotype H1 was found in 44 pairs of affected relatives. The authors identified 2 families carrying a crossover event in the IGAD1 candidate region in informative meioses. The results suggested that IGAD1 is most likely located at the telomeric part of the class II region or the centromeric part of the class III region of the MHC.

Associations Pending Confirmation

Ferreira et al. (2010) performed a genomewide association study in 430 Swedish and Icelandic patients with selective IgA deficiency and 1,090 ethnically matched controls, with replication studies in 2 independent European cohorts. In addition to the known association of HLA with IGAD, they identified association with a nonsynonymous variant in the IFIH1 gene (606951) on chromosome 2q24, rs1990760 (p = 7.3 x 10(-10)), which had previously been associated with type 1 diabetes (IDDM19; 610155) and systemic lupus erythematosus (see 152700). Consistent with previous results, the minor 'G' allele conferred protection against IGAD (odds ratio = 0.67). Variants in CLEC16A (611303) on chromosome 16p13 showed suggestive evidence for association (e.g., rs6498142; p = 1.8 x 10(-7)), and 29 additional loci were identified with p less than 5 x 10(-5).

Molecular Genetics

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 (rs28381349 and 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.

Pathogenesis

Hammarstrom et al. (1985) observed transfer of IgA deficiency from a sister to a brother who received bone marrow transplant for aplastic anemia. Southern blot analysis showed the presence of the IgA genes in both children; hence, the defect may be in lymphocyte stem cell differentiation. Both the recipient and the donor were homozygous HLA-A1, B8, DR3, a haplotype associated with selective IgA deficiency. Despite normal serum levels of IgG subclasses, both children showed a relative lack of specific IgG2 anticarbohydrate antibodies. Thus, their IgA deficiency may be part of a more fundamental problem.

In a study involving a total of 772 patients with IGAD and 1,976 controls, Ferreira et al. (2010) surveyed 118 validated non-HLA autoimmunity loci and found significant enrichment of association with autoimmunity loci as compared to nonautoimmunity loci (p = 9.0 x 10(-4)) or random SNPs across the genome (p less than 0.0001), supporting the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IGAD.

Population Genetics

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.