Separate Gut Plasma Cell Populations Produce Auto‐Antibodies against Transglutaminase 2 and Transglutaminase 3 in Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto‐antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto‐antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto‐antibodies are specific for either TG2 or TG3 with no TG2–TG3 cross reactivity. By generating monoclonal antibodies from TG3‐specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2‐specific and TG3‐specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase‐reactive populations show distinct selection of certain heavy and light chain V‐genes. Mass spectrometry analysis of TG3‐specific serum IgA corroborates preferential usage of IGHV2‐5 in combination with IGKV4‐1. Collectively, these results demonstrate parallel induction of anti‐TG2 and anti‐TG3 auto‐antibody responses involving separate B‐cell populations in DH patients. Patients with dermatitis herpetiformis (DH) make auto‐antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3). By assessing serum immunoglobulin A (IgA) reactivity and by generating monoclonal antibodies from duodenal plasma cells, it is demonstrated that the auto‐antibodies show no sign of TG2‐TG3 cross reactivity. The findings indicate that the anti‐TG2 and anti‐TG3 responses are induced in parallel through similar mechanisms.