Susceptibility Locus for IgA Deficiency and Common Variable Immunodeficiency in the HLA-DR3, -B8, -A1 Haplotypes

Abstract

Crossover events within the MHC indicated a susceptibility locus for IgAD/CVID between the class III markers D821/D823 and HLA-B8, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CVID in this family.

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

“…It has been estimated that ϳ70% of the human haplotypes are conserved, extended haplotypes or recombinants of no more than two of them (17,32,33). It is generally accepted that a small number of these MHC conserved haplotypes are found in the majority of IgAD patients (5,7,8,10,11,13,19) and that these haplotypes share a susceptibility locus designated IGAD1. To track down this MHC susceptibility locus, most studies have either focused on the B8-DR3 haplotype (13,14) or looked for a shared feature between different haplotypes associated with the disease (8, 10 -12, 15, 18, 19).…”

“…It is generally accepted that a small number of these MHC conserved haplotypes are found in the majority of IgAD patients (5,7,8,10,11,13,19) and that these haplotypes share a susceptibility locus designated IGAD1. To track down this MHC susceptibility locus, most studies have either focused on the B8-DR3 haplotype (13,14) or looked for a shared feature between different haplotypes associated with the disease (8, 10 -12, 15, 18, 19). Conclusions from different groups map the susceptibility locus either to the telomeric class III region (8,(11)(12)(13)15) or to the telomeric class II region (10,18,19).…”

“…To track down this MHC susceptibility locus, most studies have either focused on the B8-DR3 haplotype (13,14) or looked for a shared feature between different haplotypes associated with the disease (8, 10 -12, 15, 18, 19). Conclusions from different groups map the susceptibility locus either to the telomeric class III region (8,(11)(12)(13)15) or to the telomeric class II region (10,18,19).…”

“…In recent years, despite the development of high-density genetic maps and large kindred studies, the point has not been completely settled; although the telomeric part of the MHC class III region is usually favored (13,15), a report points to the telomeric part of the MHC class II region (19). Most studies published in recent years (13,14,19,20) have focused on IgAD patients bearing the B8-DR3 haplotype, because this is the most common haplotype associated with IgAD in Caucasians. However, in Spanish white IgAD patients, HLA-DR1 and HLA-DR7 are even more frequent than HLA-DR3 (21), reflecting the distribution of HLA-DR alleles and extended haplotypes in southern Europe, where HLA-DRB1*0102 (carried on the B14-DR1 haplotype) and DR7 are more frequent than in northern Europe and the U.S. (22).…”

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

“…6,7 No primary genetic factor has been identified and variation in familial inheritance patterns suggests that IgAD may be due to multiple genetic defects. Several studies have shown association of HLA alleles with IgAD, [8][9][10][11] and the extended haplotype HLA-A1-B8-DR3 occurs more frequently in individuals with IgAD than it does in the general population. This haplotype is known as an autoimmunity risk haplotype as it is associated with several autoimmune pathologies.…”