Thymic Hassall's Corpuscles, Regulatory T-Cells, and Rheumatoid Arthritis

ObjectiveTo review evidence for the involvement of thymic Hassall's corpuscles (HC) in the pathogenesis of rheumatoid arthritis (RA).MethodsWe used PubMed to search for articles dedicated to the involvement of HC and regulatory T-cells (Tregs) in the pathogenesis of RA, and articles on thymic B-cells.ResultsTregs are central players mediating tolerance to self. The functional defects in Tregs observed in patients with active RA may contribute to RA pathogenesis, promoting the premature immunosenescence of T-cells. This may partly explain the persisting expansion of CD4+ effector T-cell clones in peripheral blood, as well as the parallel improvement of RA activity and numbers of Tregs observed in the third trimester of pregnancy. HC play a major role in the selection of natural Tregs in the thymus, potentially altering the peripheral Tregs repertoire. The promiscuous expression of tissue-specific antigens by thymic medullary epithelial cells shapes the repertoire of natural Tregs. Thus, the presence of 2 major RA autoantigens (immunoglobulins and filaggrin) in the cytoplasm of normal human HC is puzzling, particularly given that thymic B-cells are also concentrated around HC, where CD55 (DAF) and CD59 are strongly expressed. Defects in HC could alter the repertoire of thymic B-cells and Tregs in RA patients, promoting the onset of this disorder.ConclusionThe identification of other joint-specific antigens, like gp-39, in HC and medullary epithelial cells, would provide new insights into the mechanisms of RA pathogenesis and may lead to more specific and physiologic methods of immunomodulation.