RESEARCH - Senescence of the immune system is a risk factor for RA?

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Immunological Reviews

Volume 204 Page 55 - April 2005

doi:10.1111/j.0105-2896.2005.00245.x

Volume 204 Issue 1

Rheumatoid arthritis

Jörg J. Goronzy, Cornelia M. Weyand

Summary:

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 CX3CR1, 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.

http://www.blackwell-synergy.com/doi/abs/10.1111/j.0105-2896.2005.00245.x

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