Association of FCGR3A and FCGR3B Haplotypes with Rheumatoid Arthritis and Primary Sjögren's Syndrome [POSTER PRESENTATION]

This is a repository copy of Association of FCGR3A and FCGR3B haplotypes with rheumatoid arthritis and primary Sjögren's syndrome [POSTER PRESENTATION] . White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/1054/ Article: Mackie, S., Robinson, J.I., Barrett, J.H. et al. (12 more authors) (2005) Association of FCGR3A and FCGR3B haplotypes with rheumatoid arthritis and primary Sjögren's syndrome [POSTER PRESENTATION]. Arthritis Research and Therapy, 7 (Suppl ). p. 121. ISSN 1478-6362 https://doi.org/10.1186/ar1642 Reuse See Attached Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Available online http://arthritis-research.com/supplements/7/S1 Arthritis Research & Therapy Volume 7 Supplement 1, February 2005 Meeting abstracts 25th European Workshop for Rheumatology Research Glasgow, UK 24–27 February 2005 Received: 11 January 2005 Published: 17 February 2005 © 2005 BioMed Central Ltd Speaker abstracts S3 Autoimmune diabetes: mechanisms S1 A Cooke Stem cells now and in the future in medicine University of Cambridge, UK A Smith Arthritis Res Ther 2005, 7(Suppl 1):S3 (DOI 10.1186/ar1508) MRC Centre Development in Stem Cell Biology, Institute for Stem Cell Type 1 diabetes is an autoimmune disease that is increasing dramatically in inci- Research, University of Edinburgh, UK dence in the developed world. Explanations for this increase in incidence include Arthritis Res Ther 2005, 7(Suppl 1):S1 (DOI 10.1186/ar1506) viral precipitation of disease and the so-called ‘hygiene hypothesis’. Abstract not submitted. In Type 1 diabetes the insulin-producing beta cells of the pancreas are selectively S2 destroyed by the immune system. Type 1 diabetes is generally recognised as a T- cell-mediated autoimmune disease with the autoantibody response to islet anti- Chaperonins and the regulation of immunity gens serving as markers of ongoing beta cell destruction. GS Panayi, VC Corrigall Studies in spontaneous animal models of this human condition suggest that it is a + Academic Department of Rheumatology, King’s College London, Guy’s Hospital, Th1-mediated autoimmune disease with an involvement of both CD8 T cells and London, UK macrophages in pathology. There are multiple ways in which the beta cell could be destroyed including a Class I restricted killing by CD8+ T cells, proinflamma- Arthritis Res Ther 2005, 7(Suppl 1):S2 (DOI 10.1186/ar1507) tory cytokine-mediated cell death and death induced by Fas/FasL interactions. Chaperonins have classically been thought of as intracellular molecules involved At the time of clinical diagnosis it is possible that the patient will have destroyed 70% in the correct folding of proteins. Their expression is upregulated during times of of their beta cell mass and exogenous insulin is required to maintain glucose home- stress such as heat (hence their common nomenclature as heat shock proteins ostasis. There is currently much interest in the development of tolerogenic strategies [HSP]), anoxia, hypoglycaemia and reactive oxygen species [1]. These are condi- to inhibit and halt beta destruction. This coupled with strategies to facilitate the tions found in infected tissues or in tissues with chronic inflammation such as the replacement of the destroyed beta cells would constitute a cure for this disease. rheumatoid synovium. In their intracellular location they protect the cell from apoptotic death due to stress. Increasingly chaperonins have been recognised to S4 subserve extracellular functions for which they have received the name ‘chaper- Autoimmunity or immune deficiency? On the role and okines’ since they bind to specific receptors on the cell surface and activate cells function of regulatory T cells in chronic arthritis of the innate immune system to secrete inflammatory cytokines, chemokines and BJ Prakken, I de Kleer small molecular weight mediators such as prostaglandins [2]. Indeed, an early Department of Paediatric Immunology, University Medical Centre Utrecht, event in inflammation is cell stress/necrosis leading to the release of HSP60 and The Netherlands HSP70 that binds via a CD14-mediated mechanism to Toll-like receptors 2 and 4 7(Suppl 1): [2] as part of the ‘danger’ signal [3]. The secretion of tumour necrosis factor Arthritis Res Ther 2005, S4 (DOI 10.1186/ar1509) alpha, IL-1, IL-12 and other chemokines prepares the environment for a TH1 Human autoimmune diseases are characterized by chronic, non-remitting inflamma- adaptive immune response. It is now recognised that some chaperonins, such as tion. In the early phase of chronic arthritis auto-reactive T cells initiate a cascade of BiP and HSP27, may activate the innate immune system to secrete anti-inflamma- events that leads to chronic inflammation. Following the initial phase of the disease, tory cytokines, such as IL-10 [4,5] that may skew the adaptive immune response other cells such as macrophages and monocytes mainly mediate the ongoing non- to TH2. Recent work by our group has shown that BiP can not only prevent but specific inflammation. At this later stage, auto reactive T cells presumably do not also treat ongoing collagen-induced arthritis in DBA/1 mice [6], suggesting that play an important role in sustaining the chronic inflammation. Mechanisms underly- chaperonins may down modulate ongoing TH1 responses. Thus, it may be possi- ing the perpetuation of this cascade of non-specific inflammation are still poorly ble to suppress rheumatoid inflammation by administration of appropriate chaper- understood. As a consequence, treatment of the disease until now has been mainly onins such as BiP. Finally, chaperonins may be important system regulators focused on non-specific suppression of inflammation. In patients with chronic arthri- determining the outcome between TH1 and Th2 immune responses. tis, such juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA) blockade of References the tumour necrosis factor alpha pathway has proven to be a very potent treatment 1. Pockley AG: Heat shock proteins as regulators of the immune response. option. On the other hand, such treatment is costly and fails to induce a long-lasting Lancet 2003, 362:469-476. remission of the disease. As a consequence long-term treatment with immune sup- 2. Asea A: Chaperokine-induced signal transduction pathways. Exerc pressive agents is necessary, which increases not only the costs of the treatment Immunol Rev 2003, 9:25-33. but also harbours considerable risk for long-term side effects. Thus, the need for 3. Matzinger P: The danger model: a renewed sense of self. Science 2002, additive and/or alternative strategies is growing. Ideally such alternative treatment 296:301-305. should be safe, not expensive and specifically modulate cells that are responsible 4. De AK, Kodys KM, Yeh BS, Miller-Graziano C: Exaggerated human for the inflammation and/or counter-regulation. Lately, a lot of attention has focused monocyte IL-10 concomitant to minimal TNF-alpha induction by heat- on the role of regulatory T cells for the control of autoimmunity. There are currently shock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflam- two well-characterized types of regulatory T cells, Tr1 cells and CD4+CD25+ T reg- matory stimulus. J Immunol 2000, 165:3951-3958. ulatory cells. The CD4+CD25+ T regulatory cells are a heterogeneous group of 5. Corrigall VM, Bodman-Smith MD, Brunst M, Cornell H, Panayi GS: Inhibi- cells identified by the expression of CD25 and the transcription factor foxP3. We tion of antigen-presenting cell function and stimulation of human recently showed that these so-called naturally occurring T regulatory cells and regu- peripheral blood mononuclear cells to express an antiinflammatory latory T cells with specificity towards heat shock proteins may play a role in deter- cytokine profile by the stress protein BiP: relevance to the treatment of mining disease outcome in JIA [1,2]. Following autologous stem cell transplantation inflammatory arthritis. Arthritis Rheum 2004, 50:1164-1171. for arthritis T regulatory cell function is restored coinciding with a remission of the 6. Panayi G, Brownlie R, Corrigall V, Bodman-Smith M, Thompson S: arthritis (de Kleer et al., submitted). Moreover, oral treatment with a peptide Immunotherapy of collagen induced arthritis with the stress protein (dnaJP1), derived from heat shock protein dnaJ, restored T regulatory cells in BiP. FASEB J 2004, 18(suppl S):A1174. peripheral blood mononuclear cells from patients with RA [3]. Acknowledgements GSP and VCC are shareholders in Immune Regulation Ltd Thus, due to insufficient numbers of regulatory T cells, feedback mechanisms fail, that is investigating the potential of BiP as an immunotherapeutic agent for the resulting in an unrestrained proinflammatory immune response and severe tissue treatment of rheumatoid arthritis. damage in RA and JIA. A lack of a counter-regulatory mechanism based by regu- S1 Arthritis Research & Therapy Vol 7 Suppl 1 Abstracts of the 25th European Workshop for Rheumatology Research latory T cells is at least in part responsible for the perpetuation of inflammation processes and biomarkers in patients suffering from RA, we searched for con- [4]. Heat shock proteins may be instrumental in restoring the immunological spicuous differences in the abundance of soluble proteins between synovial balance and thus contribute to a long-lasting disease remission. fluids (SF) and plasmas of patients. Detailed analysis of two-dimensional gel elec- References trophoresis-separated protein spots by means of MALDI-MS and MALDI-QIT- 1. de Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M, de Jager ToF-MSn sequencing [1,2] revealed that the haptoglobin α-chain is present in W, Pugayung G, Giannoni F, Rijkers G, et al.: CD4+CD25(bright) regulatory T both body fluids in at least four variants.

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