IgA deficiency and the MHC: assessment of relative risk and microheterogeneity within the HLA A1 B8, DR3 (8.1) haplotype.

INTRODUCTION: Selective IgA deficiency (IgAD; serum IgA concentration of <0.07 g/l) is the most common primary immunodeficiency in Caucasians with an estimated prevalence of 1/600. The frequency of the extended major histocompatibility complex haplotype HLA A1, B8, DR3, DQ2 (the "8.1" haplotype) is increased among patients with IgAD. MATERIALS AND METHODS: We carried out a direct measurement of the relative risk of homozygosity of the 8.1 haplotype for IgA deficiency in a population-based sample of 117 B8, DR3 homozygous individuals. RESULTS AND DISCUSSION: IgA deficiency was found to be present in 2 of 117 (1.7%) of these subjects, a figure that is concordant with estimates of relative risk from large case-control studies in the Swedish population. These data are consistent with a multiplicative model for the 8.1 haplotype contribution to IgA deficiency and contrasts with prior studies, suggesting a much higher risk for 8.1 homozygosity. Using a dense single nucleotide polymorphism marker analysis of the MHC region in HLA B8, DR3, DQ2 homozygous individuals, we did not observe consistent differences between cases (n = 26) and controls (n = 24). Overall, our results do not support the hypothesis that IgA deficiency is associated with a distinct subgroup of 8.1 related haplotypes, but rather indicate that risk is conferred by the common 8.1 haplotype acting in multiplicative manner.

Genetic influence on the shaping of the human T-cell receptor repertoire: quantitative assessment by competitive polymerase chain reaction.

It has been difficult to define the different factors which contribute to the shaping of the human T-cell receptor (TCR) repertoire. In this study, the influence of the polymorphic human leucocyte antigen (HLA) genes and non-HLA genes on the phenotype of the TCRBV segment repertoire was assessed in a population of HLA class I-matched individuals including three pairs of siblings. The gene expression levels of 24 TCRBV families were evaluated in the CD4+ and CD8+ T-cell subsets of unstimulated peripheral blood mononuclear cells (PBMC) by reverse transcription (RT) and a newly developed competitive polymerase chain reaction (cPCR) assay. Titration experiments demonstrated that the RT-cPCR assay was suitable for an accurate quantification of the relative TCRBV segment expression levels. The T-cell repertoires of HLA-identical siblings were found to be more similar than the repertoires of unrelated individuals. On the other hand, there was no difference in the degree of similarity between the TCRBV repertoires of CD4+ T-cells of HLA class II identical or non-identical unrelated individuals. Furthermore, although most of these individuals had identical HLA class I genes and non-identical HLA class II genes, the TCRBV repertoires of the CD4+ T cells exhibited significantly lower variabilities than the repertoires of the CD8+ T cells. The results of the RT-cPCR assay were supported by flow cytometric analysis of the CD4+ and CD8+ T-cell subsets of the same eight individuals employing 10 different TCRBV segment-specific monoclonal antibodies. These observations argue for a predominant role of non-HLA or non-polymorphic HLA determinants for the shaping of the TCRBV repertoire.