We have proposed that significant subsets of individuals with IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) may represent polar ends of a clinical spectrum reflecting a single underlying genetic defect. This proposal was supported by our finding that individuals with these immunodeficiencies have in common a high incidence of C4A gene deletions and C2 rare gene alleles. Here we present our analysis of the MHC haplotypes of 12 IgA-D and 19 CVID individuals from 21 families and of 79 of their immediate relatives. MHC haplotypes were defined by analyzing polymorphic markers for 11 genes or their products between the HLA-DQB1 and the HLA-A genes. Five of the families investigated contained more than one immunodeficient individual and all of these included both IgA-D and CVID members. Analysis of the data indicated that a small number of MHC haplotypes were shared by the majority of immunodeficient individuals. At least one of two of these haplotypes was present in 24 ofthe 31 (77%) immunodeficient individuals. No differences in the distribution of these haplotypes were observed between IgA-D and CVID individuals. Detailed analysis of these haplotypes suggests that a susceptibility gene or genes for both immunodeficiencies are located within the class III region of the MHC, possibly between the C4B and C2 genes. (J. Clin. Invest. 1992.89:1914-1922

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.

We have reported previously that a retroposon, containing a variable number of tandemly repeated nucleotide sequences, is present in the third intron of the human C2 gene. This element, termed SINE-R.C2, is a member of a large retroposon family derived from the endogenous retrovirus HERV-K10 and estimated to include a few thousand copies per haploid human genome. In the present study we analyzed genomic DNA from 175 humans from several ethnic groups including Americans of European and African descent, Chinese, Africans, Australians, Pacific Islanders, Japanese, and Koreans. They all contained SINE-R.C2, as indicated by Southern blotting. However, SINE-R.C2 was absent from the genome of nonhuman primates, although SINE-R-type elements were present in chimpanzees and gorillas and the HERV-K10 genome was apparently present in all primates except for New World monkeys. These results indicate that HERV-K10 was inserted into the genome after the divergence of New World monkeys; the prototype SINE-R element, after divergence of orangutans; and SINE-R.C2, after the split between humans and chimpanzees.

The concentration of serum immunoglobulins in individuals with IgA deficiency (IgAD) and CVID can vary with age to have practical implications for evaluation, therapy, and genetic analysis. Most IgAD and CVID patients in our clinic population in the Southeastern United States have inherited part or all of two extended MHC haplotypes, referred to as haplotype 1 (HLA‐DQB1 0201, HLA‐DR3, C4B‐Sf, C4A‐0, G1‐15, Bf‐0.4, C2‐a, HSP‐7.5, TNFα‐5, HLA‐B8, HLA‐A1) and haplotype 2 (HLA‐DQB1 0201, HLA‐DR‐7, C4B‐S, C4A‐L, G11‐4.5, Bf‐0.6, C2‐b, HSP‐9, TNFα‐9, HLA‐B44, HLA‐A29). In the present study, the clinic records of 68 CVID patients and 73 IgAD patients were reviewed to determine whether patients with familial or MHC‐associated IgAD or CVID experience changes in serum immunoglobulin concentrations. An increase in serum immunoglobulin to the normal range was associated with clinical improvement in one patient with CVID and haplotype 2, two patients with IgAD and haplotype 2, and one IgAD patient whose haplotype was not determined. Two patients with haplotype 1 and one with haplotype 2 had a significant decline in serum immunoglobulin: one progressed from normal to IgAD associated with IgG subclass deficiencies, and two progressed from IgAD to CVID. Five of the seven patients with notable changing serum immunoglobulin levels have a family member with either IgAD or CVID. The findings suggest that familial, MHC‐associated IgAD and CVID may be either progressive or reversible disorders, and emphasize the value of monitoring immunoglobulin levels in affected individuals and their family members.

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