Publications & Reports

Transgenic mice expressing human FcgammaRIIa have enhanced sensitivity to induced autoimmune arthritis as well as elevated Th17 cells.

Van de Velde NC, Mottram PL, Powell MS, Lim B, Holmdahl R, Hogarth PM
Helen Macpherson Smith Laboratory, Burnet Institute, Melbourne, VIC, Australia.

Abstract

The major human Fc receptor, huFcgammaRIIa, is implicated in the development of autoimmune arthritis in humans but until recently has not been studied in mouse models. We evaluated potential roles of FcgammaRIIa by using transgenic mice expressing the receptor. We examined two models of induced autoimmune arthritis pristane-induced arthritis (PIA) and collagen-induced arthritis (CIA) as well as the anti-collagen-II antibody-induced arthritis (CAIA) model. In the induced arthritis models PIA and CIA, the transgenic mice developed a more severe arthritis than the other arthritis-prone SJL or DBA1 mice. Interestingly, anti-collagen-II antibodies were elevated in PIA in the susceptible mice. In the CIA model, the highly susceptible transgenic mouse had IgG subclass levels equivalent to the unaffected and disease resistant C57BL/6 mouse strain implying that the FcgammaRIIa lowers the threshold of IgG dependent leukocyte activation. This is consistent with the greatly enhanced sensitivity of the FcgammaRIIa transgenic mice to CAIA which clearly indicates a role for the receptor at least at the inflammatory effector cell level. Other roles for huFcgammaRIIa or other gene products in the development of autoimmunity cannot be ruled out however, especially as the mice exhibited elevated Th1 or Th17 CD4 T cells in the draining lymph nodes.

Projects

  • Characterising the cause of human inflammation in autoimmune disease using transgenic mouse models
    Antibodies activate and modulate normal immunity but in certain inflammatory conditions (especially autoimmunity), antibodies trigger destructive information through Fc receptors and in particular through the FcgRIIa. By blocking this receptor, destructive inflammation can be completely inhibited. This has broad implications for other related diseases including lupus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, vitiligo and vasculitis, including Wegener's granulomatosis.
  • New approaches to the treatment of lupus
    Lupus is a neglected severe chronic disease primarily affecting women. We discover the receptor that triggers inflammation caused by immune complexes (ab and antibodies produced in lupus and related diseases like rheumatoid arthritis). Antiphospholipid syndrome a particular complication of lupus but one also found in the broader community also involves immune complex activation of life-threatening blood clotting. We are researching potential new diagnostic and therapeutic approaches targeting the cause of the disease.

Publication

  • Journal: Immunology Letters
  • Published: 04/05/2010
  • Volume: 130
  • Issue: 1-2
  • Pagination: 82-88

Authors