Rheumatoid Arthritis: Pawelec G

Larbi A, Fülöp T, Pawelec G. · Center for Medical Research (ZMF), Tübingen Aging and Tumour Immunology Group, Section for Transplantation Immunology and Immunohematology, University of Tübingen, Waldhörnlestrasse 22, D-72072 Tübingen, Germany. · Adv Exp Med Biol. · Pubmed #19065799 No free full text.

Abstract: Aging is associated with a myriad of changes including alterations in glucose metabolism, brain function, hormonal regulation, muscle homeostasis and the immune system. Aged dividuals, generally still defined as over 65 years old, differ from middle-aged or young donors in many features of the immune system. The major observation is that the elderly population is not able to cope with infections as well as younger adults and recovery generally takes longer. Moreover, some diseases first appear with advancing age and are likely associated with dysfunction of the immune system. Thus, Alzheimer's disease, atherosclerosis, type II diabetes and some autoimmune disorders are linked to changes in immune function. One major immune cell population implicated as being responsible for the initiation and chronicity of immune dysfunction leading to diseases or immunosuppression is the T-cell. Although many changes in B-cell and innate immune function in aging are associated with the appearance of disease, they are not as well studied and clearly demarcated as changes in the T-cell compartment. The adaptive immune system is coordinated by T-cells, the activation of which is required for the initiation, maintenance and termination of responses against pathogens. Changes in the expression and functions of the T-cell receptor (TCR) for antigen and its co-receptors are closely associated with immunosenescence. Certain similar changes have also been found in some other disease states, e.g., rheumatoid arthritis, systemic lupus erythematosus and cancer. In this chapter, we will summarize our knowledge about multichain immune recognition receptor signaling, mainly the TCR, in aging and autoimmune diseases.

Fülöp T, Larbi A, Dupuis G, Pawelec G. · Research Center on Ageing, Sherbrooke Geriatric University Institute, University of Sherbrooke, Quebec, Canada. · Arthritis Res Ther. · Pubmed #14680505 links to  free full text

Abstract: It is widely accepted that cell-mediated immune functions decline with age, rendering an individual more susceptible to infection and possibly cancer, as well as to age-associated autoimmune diseases. The exact causes of T-cell functional decline are not known. One possible cause could be the development of defects in the transduction of mitogenic signals following TCR stimulation. This T-cell hyporesponsiveness due to defects of signalling through the TCR either from healthy elderly subjects or from individuals with autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus results in an impaired ability to mount efficient immune responses and to maintain responsiveness to foreign antigens. This implies that a high proportion of autoreactive T cells might accumulate either intrathymically or in the periphery. T-cell anergy and differential TCR signalling could thus also be key players in the disruption of tolerance and the onset of autoimmune diseases. The increasing number of the elderly may lead to an increase of clinically important autoimmune diseases. We will review the signal transduction changes through the TCR-CD3 complex in T lymphocytes from healthy elderly subjects, which result in a modification of the activation of transcription factors involved in IL-2 gene expression leading to decreased IL-2 production. The putative contribution of altered T-cell signalling with ageing in the development of autoimmune diseases will be also discussed.

Klatt T, Ouyang Q, Flad T, Koetter I, Bühring HJ, Kalbacher H, Pawelec G, Müller CA. · Section for Transplantation-Immunology and Immunohematology, University Clinics, Tuebingen, Germany. · J Rheumatol. · Pubmed #15693083 No free full text.

Abstract: OBJECTIVE: To investigate control of Epstein-Barr virus (EBV) infection in rheumatoid arthritis (RA) by comparing the frequency phenotypes and function of peripheral CD8+ EBV-peptide antigen-specific T cells in patients with RA and healthy longterm carriers of EBV. METHODS: The frequency of interferon-g (IFN-g)-producing HLA-A2 or HLA-B8-restricted EBV-reactive CD8+ T cells in peripheral blood mononuclear cells (PBMC) from 49 RA patients and 26 healthy EBV carriers was evaluated in Elispot assays with 12 lytic/latent peptide epitopes. Direct staining with HLA-peptide tetramers containing 3 of these peptides was performed for comparison. The phenotype and function of these T cells was determined by FACS and cytotoxicity testing. RESULTS: IFN-g production patterns in Elispot assays revealed that EBV-specific CD8+ T cells were directed predominantly against the lytic epitopes A2/GLC and B8/RAK and to a minor extent to all the other lytic and latent epitopes tested, with no significant differences of the frequencies in patients and controls. However, although similar frequencies of CD8+ T cells stained with A2/GLC or B8/RAK tetramers in both groups, the fraction of A2/GLC or B8/RAK-reactive T cells producing IFN-g in response to specific peptide antigen was significantly lower in RA patients than controls. The A2/GLC or B8/RAK tetramer-positive T cells were also substantially enriched in CD28-CD27- T cells of a late-differentiated phenotype in RA patients but not in controls. CONCLUSION: RA patients show clonal expansion of dysfunctional, terminally differentiated CD8+ EBV-specific T cells in their T cell responses to immunodominant lytic peptide EBV epitopes, which could be a sign of specific impairment of virus-host interactions in RA.