A GPI-linked isoform of the IgD receptor regulates resting B cell activation

Autoantibodies specific for the enzyme transglutaminase 2 (TG2) are a hallmark of the gluten-sensitive enteropathy celiac disease. Production of the Abs is strictly dependent on exposure to dietary gluten proteins, thus raising the question how a foreign Ag (gluten) can induce an autoimmune response. It has been suggested that TG2-reactive B cells are activated by gluten-reactive T cells following receptor-mediated uptake of TG2–gluten complexes. In this study, we propose a revised model that is based on the ability of the BCR to serve as a substrate to TG2 and become cross-linked to gluten-derived peptides. We show that TG2-specific IgD molecules are preferred in the reaction and that binding of TG2 via a common epitope targeted by cells using the IgH variable gene segment (IGHV)5–51 results in more efficient cross-linking. Based on these findings we hypothesize that IgD-expressing B cells using IGHV5–51 are preferentially activated, and we suggest that this property can explain the previously reported low number of somatic mutations as well as the overrepresentation of IGHV5–51 among TG2-specific plasma cells in the celiac lesion. The model also couples gluten peptide uptake by TG2-reactive B cells directly to peptide deamidation, which is necessary for the activation of gluten-reactive T cells. It thereby provides a link between gluten deamidation, T cell activation, and the production of TG2-specific Abs. These are all key events in the development of celiac disease, and by connecting them the model may explain why the same enzyme that catalyzes gluten deamidation is also an autoantigen, something that is hardly coincidental.

Section: Discussionmentioning

confidence: 99%

Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease

Iversen

Pré

Niro

et al. 2015

“…The number of known GPIlinked B cell surface Ags is limited (38). Other than CD48, those expressed on B cells include CD24 and CD14, the LPS receptor, and a minor subset of IgD (39). Fig.…”

Section: Induction Of I␥2a Requires the Presence Of Cd48 On B Cellsmentioning

confidence: 99%

Receptors and Counterreceptors Involved in NK-B Cell Interactions

Gao

Dang

Dunnick

et al. 2005

In addition to the well-documented effect of NK cells on B cell differentiation via their ability to secrete IFN-γ, NK cells can also induce, via direct cell-cell interactions, germline transcripts (Iγ2a) necessary for switch recombination to IgG2a. Analysis of the ligand-receptor pairs that could be involved in this induction revealed that the expression of CD48 on B cells is crucial for the induction. NK cells from mice with targeted deletions of either the CD2 or the CD244 gene, both of which encode ligands for CD48, are compromised in their ability to induce B cell Iγ2a expression. Interestingly, although CD244 can bind to CD48 with a higher affinity, the ability of NK cells from CD244−/− mice to stimulate Iγ2a is not as compromised as NK cells from CD2−/− mice. Despite the difference between cell surface receptors that are stimulated by NK cells vs those stimulated by the combination of LPS and IFN-γ, we show in this study that the initiation of γ2a germline transcription is regulated by similar cis-acting elements located at the 3′ end of the IgH locus. However, NK cells cannot induce the final steps of switch recombination resulting in the production of mature mRNA from recombined DNA. Our findings suggest that these different signaling pathways converge on regulatory elements that are common to germline transcription; however, because NK induction does not result in the final steps of switch recombination, some signals initiated by LPS plus IFN-γ are not induced by NK cells.

“…Potential Ags for IgM a B cells should be no different between 3H9-and 3H9R Tg BWF 1 mice; however, IgM a B cells in 3H9R but not 3H9-Tg BWF 1 mice expressed IgD and could switch V H 3H9 or a different V H generated by editing on the Tg allele to IgG or other constant regions. Recently reported results have indicated that IgD may be important for B cell activation and germinal center formation (37,38). Likewise, signaling through B cell surface IgG is more effective for signaling activation, and consequently, the induction of more clonal expansion than signaling through IgM (39).…”

Section: Anergy In Igm Aϩ B Cells In Conventional 3⌯9-and Knock-in 3hmentioning

confidence: 99%

Tolerance to DNA in (NZB × NZW)F1 Mice That Inherit an Anti-DNA VH as a Conventional μ H Chain Transgene but Not as a VH Knock-in Transgene

Steeves

Marion

2004

Lupus-prone (NZB × NZW)F1 (BWF1) mice were made transgenic (Tg) for an anti-DNA Ab inherited either as a conventional VH3H9-μ H chain Tg (3H9-μ) with or without a conventional Vκ8-κ Tg, or a VH3H9 VH knock-in Tg allele (3H9R) with or without a Vκ4 Vκ knock-in Tg allele (Vκ4R). VH3H9 yields an anti-DNA Ab with most L chains including an anti-ssDNA with the Vκ8 Tg and an anti-dsDNA with the Vκ4 Tg. BWF1 mice that inherited the conventional 3H9-μ had normal serum IgM, little to none of which was encoded by 3H9-μ, and only a small percentage of those mice had serum anti-DNA, none of which was transgene encoded. B cells expressing the conventional 3H9-μ Tg were anergic. BWF1 mice that inherited the knock-in 3H9R Tg allele also had normal serum IgM, one-half of which was encoded by 3H9R, and produced anti-DNA encoded by the Tg allele. Most B cells expressing the knock-in 3H9R Tg also had an anergic phenotype. The results indicate that autoimmune-prone BWF1 mice initially develop effective B cell tolerance to DNA through anergy, and anergy was sustained in 3H9-μ Tg peripheral B cells but not in 3H9R Tg B cells. B cells expressing the 3H9R knock-in Tg allele were able to achieve an activation threshold that B cells expressing the 3H9-μ conventional Tg could not. The maintenance of B cell tolerance to DNA in autoimmune-prone BWF1 mice appears to differ from both normal mice and autoimmune-prone MRLlpr/lpr mice.