High abundance of plasma cells secreting transglutaminase 2–specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions

Abstract

Celiac disease (CD) is an immune mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2)1 are generated in response to the exogenous antigen gluten2 in individuals who are HLA-DQ2 or HLA-DQ83. We assessed in a comprehensive and non-biased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire on ex vivo isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are hugely expanded in patients with active CD, representing on average 10% of ASCs within the duodenal mucosa. Surprisingly, anti-TG2 antibodies were of high affinity and yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts4, the TG2-specific ASCs had neither recently proliferated nor were they short-lived ex vivo. Altogether these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favour massive generation of autoreactive B cells. Anti-TG2 antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM, but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naïve IgD/IgM-expressing B cells, thus possibly explaining why the anti-TG2 response bears signs of a primary immune response despite the disease chronicity.

Dietary gluten triggers concomitant activation of CD4 + and CD8 + αβ T cells and γδ T cells in celiac disease

“…Also, although plasma cells secreting anti-gluten and autoantibodies are present in celiac intestinal lesions (17-19), we did not detect a similar increase in intestinal-homing B cells (not shown). This is consistent with reports indicating that tissue transglutaminasespecific B cells were undetectable in the peripheral blood of celiac patients (19,20). In summary, dietary gluten induces the activation and concomitant peripheral blood presence of CD4 + and CD8 + αβ T cells and γδ T cells with gut-homing potential in celiac patients who have been on a gluten-free diet ( Fig.…”

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

“…That all 19 mAbs generated were genetically unrelated and used multiple V genes in each patient shows that there was not preferred V-gene use like those seen in autoantibodies against TG2 (7). The fact that the autoantibodies were polyclonal excludes a single forbidden clonotype of pathogenic autoantibodies in each patient.…”

“…Thus, one notion for the origin of pathogenic autoantibodies is the propensity of certain V genes or alleles or preferred combinations of H and L chains to give rise to high-affinity autoantibodies against self-antigens (6). An elegant study showed that authentic human monoclonal autoantibodies (mAbs) against transglutinaminase 2 (TG2) in celiac disease used preferred V genes (7). There were few somatic mutations in the mAbs so that germ-line V genes could produce high-affinity autoantibodies against TG2, but whether the autoantibodies against TG2 are pathogenic for celiac disease is unclear (7).…”

“…An elegant study showed that authentic human monoclonal autoantibodies (mAbs) against transglutinaminase 2 (TG2) in celiac disease used preferred V genes (7). There were few somatic mutations in the mAbs so that germ-line V genes could produce high-affinity autoantibodies against TG2, but whether the autoantibodies against TG2 are pathogenic for celiac disease is unclear (7). Conversely, an alternative origin of pathogenic autoantibodies is that the autoantibodies arise in response to a pathogen antigen that mimics a selfantigen (8).…”

Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/deuterium exchange

“…The panel of TG2-specific mAbs described above was generated from small intestinal biopsies of celiac disease patients (23). Based on competitive ELISA experiments, we recently showed that 49 of 57 mAbs could be placed into one of four distinct epitope groups (epitope 1-4, targeted by 30, 6, 11, and 2 mAbs, respectively), which correlated with mAb VH-segment use.…”