Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory disease resulting from an autoimmune response to self-antigens, leading to inflammation of synovial tissue of joints and subsequent cartilage and bone erosion. Current disease-modifying anti-rheumatic drugs and biologic inhibitors of TNF, IL-6, T cells and B cells block inflammation nonspecifically, which may lead to adverse effects, including infection. They do not generally induce long-term drug-free remission or restoration of immune tolerance to self-antigens, and lifelong treatment is usual. The development of antigen-specific strategies in RA has so far been limited by insufficient knowledge of autoantigens, of the autoimmune pathogenesis of RA and of the mechanisms of immune tolerance in man. Effective tolerance-inducing antigen-specific immunotherapeutic strategies hold promise of greater specificity, of lower toxicity and of a longer-term solution for controlling or even preventing RA. This paper reviews current understanding of autoantigens and their relationship to immunopathogenesis of RA, and emerging therapeutics that aim to leverage normal tolerance mechanisms for implementation of antigen-specific therapy in RA.
Highlights
Rheumatoid arthritis (RA) is a systemic inflammatory disease resulting from an autoimmune response to self-antigens, leading to inflammation of synovial tissue of joints and subsequent cartilage and bone erosion
We found that proinflammatory cytokines were secreted by peripheral blood (PB) CD4+ T cells of RA patients and healthy controls, in response to citrullinated but not unmodified peptides in the context of the human leukocyte antigen (HLA)-shared epitope (SE) sequence
Given the potential for development of antigen-specific autoimmune immunotherapy using dendritic cell (DC) treated with soluble inhibitors of nuclear factor (NF)-κB, such as Bay11-7082 (Bay-DCs) [94], we translated this concept to a phase I clinical trial of autologous BayDCs exposed to citrullinated peptides in HLA-DRSE+a variety of citrullinated peptide antigens (ACPA)+ RA patients
Summary
Rheumatoid arthritis (RA) is a systemic inflammatory disease resulting from an autoimmune response to self-antigens, leading to inflammation of synovial tissue of joints and subsequent cartilage and bone erosion. Post-translational modifications are likely to represent a general mechanism for immune priming to neoself-antigens for which T cells potentially reactive with the native self-antigen were poorly deleted in the thymus, if at all, due to insufficient binding strength of the native peptide to the susceptibility HLA allele.
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