Celiac disease (CD) is an immune mediated disorder in which there is an immune response to the exogenous antigen gluten (from wheat, rye, and barley) in individuals who are HLA restricted. The disease causes duodenal inflammation but can be reversed by withdrawal from gluten. Patients experience loss of oral tolerance (LOT) to gluten, with T cells and B cells reactive. Patients also produce mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) which is involved in gluten metabolism. We previously found that TG2- specific plasma represent 10% of antibody-secreting cells (ASCs) within the duodenal mucosa of patients with active CD. These anti-TG2 B cells and antibodies are believed to enhance or perpetuate disease either directly through antibody-mediated effector mechanisms, such as compliment deposition, or by presentation of gluten peptides, perpetuating the LOT by T cells. It is therefore important to understand the origin of anti-TG2 autoantibody responses. We also previously found that anti-TG2 antibodies were encoded by a highly restricted repertoire of Ig genes, consisting predominantly of VH5-51 and two other VH genes. Repertoire restrictions such as this are often reminiscent of a distinct subset of B cells, predominantly expressing Ig encoded by VH5-51. We now have preliminary data identifying a recirculating subset of IgA+ B cells that exhibit the same repertoire restrictions as the anti-TG2 antibodies but found in the blood of all healthy subjects. Notably, the recirculating population of IgA+ B cells and antibody-secreting cells (ASCs) in particular, has been associated with microbiota interactions. We hypothesize that these cells represent a distinct functional subset of the IgA peripheral blood repertoire that normally provides mucosal protection, but that can be induced to secrete anti-TG2 autoantibodies in susceptible individuals upon gluten exposure.
In aim 1 we will characterize the functional phenotype and transcriptome of this subset and we will determine if the subset is clonally linked to anti-TG2 mucosal ASCs in patients.
In aim 2 we will characterize the microbiota specificity of these blood- borne IgA ASCs from the blood and biopsied mucosal ASCs from patients with active disease and from control subjects at the monoclonal level. Finally, in aim 3 we will explore the origin of the TG2 autoantibody response in mucosal tissues. Particular cellular functions or distinct targeting of particular microbes, plus differences from control subject cells could provide important insight into the etiology of celiac disease. A novel cell-surface phenotype, such as expression of a particular CD marker, for example, or a particular cytokine receptor, could provide distinct targets useful for therapeutic intervention into disease.
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