title: Rheumatoid arthritis.
abstract: Therapeutic efficacy of depleting B cells or blocking T-cell costimulation in rheumatoid arthritis (RA) has confirmed the critical pathogenic role of adaptive immune responses. Yet, RA preferentially affects elderly individuals, in whom adaptive immunity to exogenous antigens begins to fail. Here, we propose that senescence of the immune system is a risk factor for RA, with chronic inflammation resulting from the accumulation of degenerate T cells that have a low threshold for activation and utilize a spectrum of novel receptors to respond to microenvironmental cues. The process of immunosenescence is accelerated in RA and precedes the onset of disease, the acceleration, in part, being conferred by the HLA-DR4 haplotype. Naive CD4(+) T cells in RA are contracted in diversity and restricted in clonal burst. Senescence of effector CD4(+) T cells is associated with the loss of CD28 and the de novo expression of KIR2DS2, NKG2D, and CX(3)CR1, all of which function as costimulatory molecules and reduce the threshold for T-cell activation. The synovial microenvironment promotes chronic persistent immune responses by facilitating ectopic lymphoid neogenesis, such as the formation of aberrant germinal centers. With the propensity to develop complex lymphoid architectures and to provide optimal activation conditions for senescent CD4(+) T cells, the synovium becomes a natural target for pathogenic immune responses in prematurely aged individuals.
authors.affiliation: Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory School of Medicine, Atlanta, GA 30322, USA. jgoronz@emory.edu
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology*; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D015398:Signal Transduction; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology
chemical_list: D001324:Autoantigens