Familial IgA Defects

A survey of 28,000 pregnant women revealed an incidence of IgA deficiency (serum IgA less than 1 mg per deciliter) of 1 in 450, which is identical to that in a normal blood-donor population of both sexes. Using an enzyme-linked immunosorbent assay (ELISA) in a study of 61 serum samples from IgA-deficient pregnant women, we observed antibodies to IgA2 alone in 20 per cent, as compared with 7.5 per cent of pregnant women not deficient in IgA and no IgA-deficient blood donors. Antibodies reacting with IgA1 alone were present in occasional serum samples (2 to 7 per cent) from all groups studied, and class-specific anti-IgA antibodies were present in 17 per cent of IgA-deficient blood donors and in 16 per cent of IgA-deficient pregnant women. Blocking experiments showed that some serum samples contained an antibody that reacted with both IgA1 and IgA2, whereas others contained two antibodies, one reacting with IgA1 and the other with IgA2. The anti-IgA2 antibodies tended to diminish in titer after delivery. The ELISA was, as expected, more sensitive than the hemagglutination assay. The offspring of IgA-deficient mothers (but not of IgA-deficient fathers) had levels of serum IgA below the normal mean (21 of 27); 12 had levels more than 1 S.D., and seven had levels more than 2 S.D., below the normal mean. Of the seven infants with serum IgA levels more than 2 S.D. below the normal age-related mean, five had mothers with anti-IgA antibodies during gestation. It is possible that maternal anti-IgA exerts a transplacental effect on the fetal immune system, causing IgA deficiency in some instances.

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Genetic Linkage of IgA Deficiency to the Major Histocompatibility Complex: Evidence for Allele Segregation Distortion, Parent-of-Origin Penetrance Differences, and the Role of Anti-IgA Antibodies in Disease Predisposition

Vořechovský

Webster

Plebani

et al. 1999

The American Journal of Human Genetics

110

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Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of terminal lymphocyte differentiation, leading to a lack of IgA in serum and mucosal secretions. Familial clustering, variable population prevalence in different ethnic groups, and a predominant inheritance pattern suggest a strong genetic predisposition to IgAD. The genetic susceptibility to IgAD is shared with a less prevalent, but more profound, defect called "common variable immunodeficiency" (CVID). Here we show an increased allele sharing at 6p21 in affected members of 83 multiplex IgAD/CVID pedigrees and demonstrate, using transmission/diseqilibrium tests, family-based associations indicating the presence of a predisposing locus, designated "IGAD1," in the proximal part of the major histocompatibility complex (MHC). The recurrence risk of IgAD was found to depend on the sex of 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. The differential parent-of-origin penetrance is proposed to reflect a maternal effect mediated by the production of anti-IgA antibodies tentatively linked to IGAD1. This is supported by 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.

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Familial IgA Defects

Cited by 5 publications

References 7 publications

Genetic Aspects of Immunoglobulin A Deficiency

Genetic Aspects of Immunoglobulin A Deficiency

Anti-IgA Antibodies in Pregnancy

Genetic Linkage of IgA Deficiency to the Major Histocompatibility Complex: Evidence for Allele Segregation Distortion, Parent-of-Origin Penetrance Differences, and the Role of Anti-IgA Antibodies in Disease Predisposition

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