Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Arthritogenic T Cells Regulate the Homeostatic Expansion of Antigen-Specific B Cells, and These B Cells or Antibodies Are Essential for the Development of Arthritis.
Kis-Toth1, Katalin, Radacs2, Marianna, Kobezda3, Tamas, van Eden4, Willem, Mikecz3, Katalin, Glant3, Tibor T.
The original goals of this study were to prove whether the arthritogenic epitope-specific T cell receptor transgenic (TCR-Tg) CD4+ T cell can transfer arthritis, and if so, what other 'costimulatory' components (e.g., B cells or antibodies) can contribute to an earlier onset or more severe arthritis. Unexpectedly, these highly specific arthritogenic TCR-Tg CD4+ T cells were unable to transfer the disease alone, but supported the reconstitution of arthritogenic proteoglycan (PG)-specific B cell homeostasis, which appeared to be critical for arthritis induction.
PG (arthritogenic epitope)-specific TCR-Tg mice were generated earlier and their basic functions tested both in vitro and in vivo. CD4+ T cells were separated from spleen of wild-type (WT) and TCR-Tg BALB/c (arthritic or non-arthritic) mice using the Pan T Cell Isolation Kit and B Cell Isolation Kit for negative selection. The purity and viability of CD3+/CD4+ T cells and CD19+/B220+ B cells were at least 98%. CD4+ T cells (5×106 cells in 200 ml PBS) were injected intraperitoneally into syngeneic BALB/cSCID mice without or with PG antigen (100 mg with the first transfer), followed by a second transfer of (i) T cells from arthritic or non-arthritic WT or TCR-Tg mice, (ii) B cells from naïve, non-arthritic or arthritic BALB/c mice, or (iii) with IgGs purified from sera of arthritic or naïve animals. Two transfers were given at 710-day intervals. In reciprocal experiments, (i-iii) were injected first, which was followed by purified CD4+ T cells from naïve or arthritic WT or TCR-Tg mice. Mice were scored for arthritis, and sacrificed 2124 days after the second transfer for characterization of T and B cell markers, antigen-specific T cell responses, serum auto-antibodies (Abs) and cytokines.
Neither PG-specific T or B cells, nor anti-PG Abs alone were sufficient for arthritis induction. In contrast, purified CD4+ T cells (>98% purity) from TCR-Tg mice, if injected together with arthritogenic epitope-containing PG, induced arthritis in recipient SCID mice, but the onset and severity seemed to be dependent on selective proliferation of PG-specific autoAb-producing B cells. To further analyze the critical role of autoAbs in the development of arthritis, T cell transfer was followed by transfers of autoAb-producing B cells or autoAbs. TCR-Tg CD4+ T cells controlled a highly selective homeostatic proliferation of autoAb-producing B cells, which their presence was critical for disease induction.
Anti-PG autoAbs bound to cartilage surface and co-localized with complement C3, might thus activate the complement cascade. They might also react with either intact or citrullinated G1 domain of PG, a domain structure which contains 12 potential sites of citrullination, and the G1 domain of human PG (injected together with the first transfer) heavily citrullinated in an age-dependent manner in human cartilage. At this moment, it remains an open question whether the homeostatic anti-PG B cell proliferation has been controlled primarily by highly specific TCR-Tg CD4+ T cells, or the citrullinated G1 domain injected together with the first cell transfer, or both.
To cite this abstract, please use the following information:
Kis-Toth, Katalin, Radacs, Marianna, Kobezda, Tamas, van Eden, Willem, Mikecz, Katalin, Glant, Tibor T.; Arthritogenic T Cells Regulate the Homeostatic Expansion of Antigen-Specific B Cells, and These B Cells or Antibodies Are Essential for the Development of Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1755