HLA‐A, B, C and DR antigens in immunoglobulin A deficiency

Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/lpr mice carrying a congenic H-2 b/b MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long microhomologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the H-2 b haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway.immunoglobulin subclass deficiency ͉ mismatch repair ͉ Msh4 A fter appropriate stimulation, B cells undergo class switch recombination (CSR), whereby the functionally rearranged V(D)J DNA segment is recombined with a downstream Ig constant region segment. The biochemistry of CSR is complex and involves the B cell-specific gene activation-induced cytidine deaminase, which initiates both CSR and somatic hypermutation (1). CSR also requires many ubiquitously expressed genes important for detecting DNA mismatches and breaks and regulating DNA repair (2). CSR occurs at specific DNA segments called switch (S) regions, which lie upstream of each constant region and contain hotspots for activation-induced cytidine deaminase-mediated cytosine deamination. The ligation of the S region with the downstream S regions is carried out by protein factors that comprise the nonhomologous end joining machinery for DNA repair (1, 2).Mismatch repair proteins play a critical role in safeguarding genetic stability. The key proteins for initiation of eukaryotic mismatch repair are homologues of bacterial MutS and MutL. In mammals, there are five MutS (Msh2, Msh3, Msh4, Msh5, and Msh6) and four MutL (Mlh1, Mlh3, Pms1, and Pms2) homologues. Each Mut homologue acts at the DNA repair or recombination site by forming heterodimers; Msh2-Msh6 (MutS␣), Msh2-Msh3 (MutS␤), M...

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“…Haplotypes of the MHC show genetic association with IgAD, notably HLA (HLA) A1-B8-DR3 and B14-DR1 (15)(16)(17).…”

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confidence: 99%

Role for Msh5 in the regulation of Ig class switch recombination

Sekine

Ferreira

Pan‐Hammarström

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

141

100

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“…However, a variety of putatively predisposing HLA antigens, including HLA-A1, A2, A19, A28; B.5, B8. B14, B40 and DR3, have been found by different investigators (Ambrus et al 1977, Cobain et al 1983, Fontana et al 1978, Gilhus et al 1982, Hammarstrom & Smith 1983, Jersild et al 1983, Oen et al 1982, Seignalet et al 1978, Shakir et al 1978. In addition, a number of negative associations (HLA-A3, A l l and B7) have also been suggested (Cobain et al 1983, Seignalet et al 1978).…”

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confidence: 87%

HLA antigens in selective IgA deficiency: Distribution in healthy donors and patients with recurrent respiratory tract infections

et al. 1984

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HLA‐A, B, C and DR typing was performed in healthy IgA deficient donors and in IgA deficient patients with recurrent respiratory tract infections. In healthy donors, a strong association with HLA B8 and DR3 was observed. In the patient group however, no statistically significant association with these antigens could be found. In contrast, an increased frequency of HLA B40 was noted. The preference for HLA B8/DR3 in healthy donors could not be attributed to higher levels of serum immunoglobulins since no major differences in the concentrations of IgM, IgG or the IgG subclasses were seen between the two groups.

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“…Ferreira and associates found that 39% of their IgA-deficient patients had anti-IgA antibodies 195 ; 22% of those in the antibodypositive group had IgA levels between 1.1 and 5 mg/dl, and the remaining 78% had IgA levels lower than 1.1 mg/ dl. Anti-IgA antibodies are usually of the IgG1 class, 196 and are more common in IgA-deficient subjects who are also IgG2 deficient. 195,197 Anti-IgA antibodies may be of the IgE isotype, leading to true anaphylactic reactions 115 ; however, the actual incidence of such antibodies is unknown, and some studies have not found them.…”

Section: Sigad and Malignancymentioning

confidence: 99%