B Lymphocytes Contribute to Celiac Disease Pathogenesis

Abstract

Celiac disease (CD) is a complex intestinal disorder with autoimmune features that develops in genetically susceptible individuals expressing HLA-DQ8 or HLA-DQ2 molecules. 1 Abadie V. Sollid L.M. Barreiro L.B. et al. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol. 2011; 29: 493-525 Crossref PubMed Scopus (351) Google Scholar The presence of anti–tissue transglutaminase 2 (TG2) and anti–deamidated gluten peptide antibodies represent strong disease markers. 2 Husby S. Koletzko S. Korponay-Szabo I. et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020; 70: 141-156 Crossref PubMed Scopus (231) Google Scholar Inflammation and villous blunting in the small intestine result from an abnormal immune response to gluten proteins. CD is characterized by the loss of oral tolerance to gluten manifested by HLA-DQ2– or HLA-DQ8–restricted antigluten inflammatory CD4 T cells and a massive expansion of cytotoxic CD8+ intraepithelial lymphocytes (IELs) that mediate the killing of intestinal epithelial cells (IECs). 3 Abadie V. Kim S.M. Lejeune T. et al. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature. 2020; 578: 600-604 Crossref PubMed Scopus (49) Google Scholar These observations have led to the general idea that CD is primarily a T-cell–mediated immune disorder. However, studies in human suggest that B cells could play a central role in CD pathogenesis. 4 Iversen R. Sollid L.M. Autoimmunity provoked by foreign antigens. Science. 2020; 368: 132-133 Crossref PubMed Scopus (11) Google Scholar We have recently engineered a mouse model of CD that develops villous atrophy (VA) in a gluten, HLA-DQ8, and TG2-dependent manner. Intestinal tissue destruction in this model is also dependent on CD4+ and CD8+ T cells and requires interferon-γ. We now demonstrate that B cells are required for the development of VA and the associated full licensing of cytotoxic IELs in this pathophysiologically relevant mouse model of CD, providing support for the exploration of B-cell–directed therapies for the treatment of CD.