Large granular lymphocyte (LGL) leukemia, a rare hematologic malignancy, has long been associated with rheumatoid arthritis (RA), and the diseases share numerous common features. This review aims to outline the parallels and comparisons between the diseases as well as discuss the potential mechanisms for the relationship between LGL leukemia and RA. RA alone and in conjunction with LGL leukemia exhibits cytotoxic T-cell (CTL) expansions, HLA-DR4 enrichment, RA-associated autoantibodies, female bias, and unknown antigen specificity of associated T-cell expansions. Three possible mechanistic links between the pathogenesis of LGL leukemia and RA have been proposed, including LGL leukemia a) as a result of longstanding RA, b) as a consequence of RA treatment, or c) as a driver of RA. Several lines of evidence point towards LGL as a driver of RA. CTL involvement in RA pathogenesis is evidenced by citrullination and granzyme B cleavage that modifies the repertoire of self-protein antigens in target cells, particularly neutrophils, killed by the CTLs. Further investigations of the relationship between LGL leukemia and RA are warranted to better understand causal pathways and target antigens in order to improve the mechanistic understanding and to devise targeted therapeutic approaches for both disorders.
PURPOSE: We have recently identified a previously unknown lymphocyte that is a dual expresser (DE) of productively rearranged and surface-expressed TCRαβ and BCR (surface immunoglobulin, Ig) (Ahmed et al, Cell, 2019: 177:11583). Importantly, a single immunoglobulin heavy-chain, IGHV clonotype (clone-x) predominates DEs that encodes a potent autoantigen (x-autoantigen) in its CDR3 region. The x-autoantigen (as a soluble intact x-mAb) cross-activate autoreactive T cells. The goal of this study is to investigate the properties of x-mAb reactive T cells and examining the mechanisms of how x-mAb recognizes and activates the tolerant autoreactive T cells in autoimmune diseases particularly in T1D. METHODS: We used EBV immortalized DE clone as a source of x-mAb and FACS-based protocols to identify x-mAb-responsive autoreactive T cells and their functional properties. ImmunoSEQ assay used to characterize TCR repertoires. RESULTS: Preliminary data show that x-mAb potentially binds and activates a subset of autoreactive T cells in T1D compared to HC subjects. Additionally, x-mAb-reactive T cells exhibits an activated and antigen experienced phenotype, including expression of CD45RO, CD44, and CD69. TCRVβ repertoire analysis shows that x-mAb reactive T cells are enriched for public clonally expanded TCRs in T1D patients. Further, x-mAb activates the autoreactive T cell through by crosslinking directly to their T cell receptor (TCR). CONCLUSIONS: DE cells in T1D patients secretes a public x-mAb that binds and activate specific subset of autoreactive T cells predominated by few clonotypes that express public TCRs. Our results are revealing previously unknown mechanism that appears to be a play critical role in pathogenesis of T1D.
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