Altered VH6-D-JH repertoire in human insulin-dependent diabetes mellitus and autoimmune idiopathic thrombocytopenic purpura

Abstract

We have characterized the peripheral B cell repertoire in T cell-mediated insulin-dependent diabetes mellitus (IDMM) and in B cell-mediated autoimmune idiopathic thrombocytopenic purpura (AITP). The VH6-containing repertoire in adult patients with IDDM or AITP and healthy control subjects was investigated by PCR amplification using VH6- and JH-specific primers. Nucleotide sequence analysis of VH6-D-JH rearrangements showed an abnormally high frequency of somatic mutations in non-functional rearrangements from diabetic (3. 58 %) as well as AITP patients (3.18 %), compared to controls (0.4 % and 1.43 %, respectively; p < 0.05). In contrast, the mutation frequency among functional rearrangements was 2.4 - 3 times lower in patients compared to controls ( p < 0.05). Detailed analysis of the VH6 genes carrying mutations showed that the underlying mechanism for this observation is probably different for the two diseases. Analysis of D- and JH gene usage revealed additional deviations from the normal pattern. Taken together, these results suggest defects in the mechanisms controlling selection of the B cell repertoire in patients with IDDM or AITP.

B cells in autoimmune diseases: Insights from analyses of immunoglobulin variable (Ig V) gene usage

“…In an analysis of VH6 rearrangements in peripheral B cells of T1D patients and in splenocytes of AITP patients, the frequency of somatic mutations was found to be significantly increased in the non-functional VH6 repertoire, but markedly decreased in the functional repertoire from both patient groups compared to healthy controls [48]. However, T1D patients exhibited an increased number of mutations per gene in the functional rearrangements of VH6, whereas the number of mutated genes, but not the number of mutations per gene, was increased in AITP patients in this family of VH genes.…”