Key Roles of B Cells and B‐Cell Receptors in <scp>HLA</scp> Class <scp>II</scp> ‐Associated Diseases: Insights From Coeliac Disease

When an HLA association is observed for a disease, it is typically to one or a few HLA class II allotypes. Considering that the HLA association is mechanistically tied to a preferential presentation of antigenic peptides to T cells, its presence suggests that only one or a few HLA-binding peptides are likely to contribute to the pathogenesis. By contrast, if many antigenic peptides are involved, the likelihood for involvement of several HLA allotypes increases and, consequently, the disease will not appear as an HLA associated disease even though T cells could play equally important roles. With B cells serving as antigen-presenting cells, the B-cell receptor will improve antigen uptake and, at the same time, serve as a pruning filter for antigen thus giving rise to the above-described scenario of few antigenic peptides being preferred for presentation to CD4+ T cells. This notion of B cells as key antigen presenting cells in HLA class II-associated diseases is supported by recent results from coeliac disease. This paper, written on the occasion of deliverance of the Ceppellini Award Lecture in 2025, reviews the HLA association of coeliac disease and presents the experimental data obtained for this disorder which demonstrate how disease-specific autoantibodies are connected to disease-associated HLA-DQ allotypes via involvement of the antigen-presenting capacity of B cells. The view of B cells as key antigen-presenting cells should be reconciled with the impressive effectiveness of B-cell-targeting therapies for the treatment of HLA class II-associated diseases.