B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2

Abstract

Autoantibodies to transglutaminase 2 (TG2) are hallmarks of celiac disease. To address B cell tolerance and autoantibody formation to TG2, we generated immunoglobulin knock-in (Ig KI) mice that express a prototypical celiac patient–derived anti-TG2 B cell receptor equally reactive to human and mouse TG2. We studied B cell development in the presence/absence of autoantigen by crossing the Ig KI mice to Tgm2−/− mice. Autoreactive B cells in Tgm2+/+ mice were indistinguishable from their naive counterparts in Tgm2−/− mice with no signs of clonal deletion, receptor editing, or B cell anergy. The autoreactive B cells appeared ignorant to their antigen, and they produced autoantibodies when provided T cell help. The findings lend credence to a model of celiac disease where gluten-reactive T cells provide help to autoreactive TG2-specific B cells by involvement of gluten–TG2 complexes, and they outline a general mechanism of autoimmunity with autoantibodies being produced by ignorant B cells on provision of T cell help.

Association Between Celiac Disease and Cancer

“…The highest relative risks are for T cell NHL, but also B cell NHL are described in CD. This is in accordance with the relevance of B cells in CD-pathogenesis, as antigen-presenting cells and immunoglobulin producers [43]. The most likely explanation for this association between lymphoma and CD is chronic inflammation.…”

Gliadin Sequestration as a Novel Therapy for Celiac Disease: A Prospective Application for Polyphenols

“…Early studies implicating TG2 in celiac disease pathogenesis showed that jejunal tissue samples taken from individuals with treated and untreated celiac disease demonstrated increased TG2 activity compared to healthy controls [ 47 ]. While the prevailing hypothesis has been that TG2 activity occurs in the lamina propria [ 48 ], recent studies have shown that active TG2 can also be released into the lumen as a result of standard shedding of the gut epithelium [ 49 ], where anti-TG2 B cells may develop to produce autoantibodies against TG2 [ 49 , 50 ]. Catalytically active TG2 plays an important role in the presentation of gliadin as an antigen; it catalyzes the deamidation of glutamine to glutamic acid within gliadin peptides [ 48 ], resulting in a change in charge of the peptide from neutral to negative [ 48 , 51 ].…”

Dietary Gluten and Neurodegeneration: A Case for Preclinical Studies

“…It was established that increased tTG2 activity leads to autoimmune reaction and GSE, i.e., CD in genetically-predisposed individuals [34][35][36]. Besides gluten digestion, tTG-mediated glutamine deamidation can, in some celiac patients, lead to the aggregation of cerebral β-amyloid, one of the hallmarks of neurodegeneration in people with PD, HD, and AD [37][38][39][40][41][42].…”