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AB0054 No evidence for premature immunosenescence in newly diagnosed, non treated, shared epitope-positive patients with rheumatoid arthritis
  1. P. Chalan1,
  2. B.-J. Kroesen2,
  3. K.S.M. van der Geest1,
  4. M.G. Huitema1,
  5. W.H. Abdulahad1,
  6. B. Hepkema3,
  7. E. Brouwer1,
  8. A. Boots1
  9. on behalf of Groningen Research initiative on healthy Ageing and Immune Longevity (GRAIL), the Netherlands
  1. 1Rheumatology and Clinical Immunology
  2. 2Medical Biology
  3. 3Laboratory Medicine, Transplantation Immunology, University Medical Center Groningen, Groningen, Netherlands

Abstract

Background The peripheral T-cell pool in chronic autoimmune syndromes, such as Rheumatoid Arthritis (RA) displays features associated with senescence of the immune system. Immunosenescence is characterized by increased frequencies of terminally differentiated T lymphocytes defined as CD45RO-CCR7- (TEMRA) or CD28null (and/or CD27null) cells. In addition, aged T cells produce pro-inflammatory cytokines (IFN-γ and TNF-α) (1,2) and show an increased expression of NK receptors which is speculated to compensate for the loss of CD28 co-stimulatory signal (3). Previously, it has been suggested that carriers of the RA-associated HLA-DRB1 alleles containing the shared epitope (SE) sequence show signs of premature T-cell immunosenescence and that this is causally linked to the development of autoimmune pathology, as seen in RA (4).

Objectives 1) To elucidate if T-cell ageing is a feature of early RA; 2) to assess the relation between the presence of the RA-associated HLA-DRB1 shared epitope alleles and the number of TEMRA cells.

Methods PBMCs from recently diagnosed, non-treated RA patients (n=35) and age-/sex–/HLA-DRB1-matched healthy controls (HC, n=20) were stained with antibodies against CD4, CD8, CD45RO, CCR7. In addition, an extended phenotypic and functional analysis of T cells from 5 RA patients and 5 HC was performed by staining of senescence-associated surface markers (CD28, CD27, CD57, KLRG1, NKG2D, CD56, NKG2A and, CD94), intracellular cytokines (IFN-γ, TNF-α) and cytotoxic effector molecules (perforin, granzyme B). The presence of the SE+ HLA-DRB1 alleles was assessed by low-resolution PCR-SSOP typing for all the subjects included in the study.

Results The frequencies of CD4+ and CD8+ TEMRA lymphocytes (CD45RO-CCR7-) were not different between early-stage RA patients and HC. SE positivity was not associated with an increase of TEMRA in any of the studied groups. RA patients and HC showed similar frequencies of T cells with senescent phenotype defined based on CD28, CD27, CD57, KLRG1, CD56, CD94/NKG2A expression. Furthermore, T cells (both CD28+ and CD28-) from RA expressed IFN-γ, TNF-α, perforin and granzymeB at the same level as T cells from HC. Interestingly, CD8+CD28- T cells from RA patients showed increased expression of NK receptor NKG2D (median 96,8% vs 74,2% of NKG2D+ within CD8+CD28- in RA and HC, respectively).

Conclusions 1) The number of TEMRA lymphocytes is not altered in early-stage RA patients and is not dependent on the presence of the SE. Thus, the previously observed premature immune aging in RA is not causal to the disease but rather a consequence of the chronic inflammatory process. 2) The increased frequency of CD8+CD28-NKG2D+ T cells in early RA might be involved in the breakdown of immune tolerance.

  1. Thewissen M et al. Clin Immunol 2007, 123: 209-218.

  2. Fasth A.E.R. et al. Scand J Immunol 2004, 60: 199-208.

  3. Fasth A.E.R. et al. Eur J Immunol 2010.

  4. Schönland S.O. et al. PNAS 2003, 100: 13471-76.

Disclosure of Interest None Declared

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