Genetics of primary immunodeficiency diseases

University dissertation from Stockholm : Karolinska Institutet, Department of Laboratory Medicine

Abstract: 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. There are strong indications for involvement of genetic factors in the development of the disease and the frequency of several extended major histocompatibility complex haplotypes (including HLA B8, DR3; DR1, DQ5; DR7, DQ2) have previously been shown to be increased in Caucasian patients with IgAD. Based on our study, there is a strong association with the HLA B14, DR1 alleles in Iranian subjects and HLA B8, B12, B13, B14, B40, DR1, DR3, DR7, DQ2 and DQ5 alleles in Swedish subjects. We also carried out a direct measurement of the relative risk of homozygosity of the B8, DR3 (8.1 haplotype) for IgA deficiency in a population-based sample of 117 B8-DR3 homozygous individuals. IgA deficiency was found to be present in 2/117 (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 much higher risk for 8.1 homozygosity. In order to address the hypothesis that microheterogeneity within particular subsets of the 8.1 haplotype might contribute to risk for development of IgAD, we also carried out dense marker analysis of 8.1 homozygous cases and controls. We utilized 1,738 and 4,867 SNP markers within the MHC region for these studies. We did not observe consistent differences between cases (n=18 and 8, respectively) and controls (n=9 and 15, respectively). 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. Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and co-occurrence of autoimmune, lymphoproliferative and granulomatous diseases. Genes within the MHC region have previously been shown to be involved in the pathogenesis of the disease and a genetic relationship between CVID and IgA deficiency (IgAD) has previously been suggested. We observed no HLA association neither in Swedish nor Iranian patients with sporadic CVID. However, Swedish patients with a familial form of CVID and IgAD display a similar HLA association pattern. Using 15 informative multiplex familieswith patients affected by CVID and IgAD, shared haplotypes such as HLA B8, DR3, DQ2; HLA DR1, DQ5 and HLA, DR7, DQ2 were observed. Based on our findings, we hypothesize that only the familial form of CVID/IgAD may have a common, HLA associated, genetic background whereas sporadic CVID cases show no HLA association. Mutations in the gene encoding TACI (Transmembrane Activator and CAML Interactor), were previously found tobe associated with CVID. In a cohort of 47 Iranian CVID patients, we identified one patient with a homozygous G to T substitution in the TNFRSF13B gene at the splice site of intron 1 (c.61+1G>T), which abolished expression of the TACI molecule. In addition, we found the previously recognized C104R and C172Y mutations in a heterozygous form in 2 patients with CVID and one, novel, heterozygous P42T mutation. These missense mutations resided in the extracellular or transmembrane regions of TACI and are all predicted to impair the function of the protein.

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