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Finnegan
Alison
PhD
Professor of Medicine
Immunology-Microbiology, Internal Medicine
GME, Graduate College, Rush Medical College
1735 W. Harrison St.
Room 726
Chicago, IL 60612

1735 W. Harrison St.
Room 726
Chicago, IL 60612

(312) 942-7847
(312) 942-2808
Alison_Finnegan@rush.edu
PhD, Immunology
Animal Diseases, Biological Phenomena Cell Phenomena and Immunity, Biological Sciences, Genetic Processes, Immune System Diseases, Musculoskeletal Diseases
Animal surgery/Modeling, Cytokine Assessment, ELISA Development, Flow Cytometry, PCR, Real-time PCR, si RNA, Western Northern Southern Blotting

Professor of Medicine, Section of Rheumatology

Professor of Immunology/Microbiology

Research Description

My laboratory investigates the cellular and molecule mechanism of several aspects of the immunopathogenesis of experimental autoimmune arthritis. In this model immunization with human proteoglycan (PG) in adjuvant induces a robust disease similar to rheumatoid arthritis PG-induced arthritis (PGIA) displaying many of the clinical, histolopathogical and immunolopathogical as well as genetic susceptibility and inheritance characteristics of human RA.?? PGIA develops in older female BALB/c and C3H mice and requires both T and B cells; autoantibodies or arthritic serum alone is not sufficient for the induction of arthritis.??

The role of T cell cytokines and transcription factors in PGIA. Our studies in T cells are currently focused on the role of T cell cytokines and transcription factors in development of PGIA. CD4 T cells produce a robust IFN gamma??response and IFN gamma is critically involved in the pathogenesis of PGIA.?? We utilize gene deficient mice to identify genes that control disease. We found that IL-12, STAT4, and IFNg??are required for the development of disease.?? IL-12, STAT4, and IFNg??are all classical cytokines and transcriptional factors that participate in Th-1 mediated responses.?? However, the transcription factor T-bet, which also belongs to the Th1-differentiation pathway, is not required for induction of arthritis.???? Our present studies involve understanding the role of T-bet in PGIA.?? In PGIA the role of Th17 cells is complex.?? In the absence of IL-17 there is no alteration in development of arthritis, however, in the absence of IFN-g, IL-17 now is important for disease.?? These results suggest that both Th1 and Th17 play a role in disease and that IFN-g may regulate the requirement for Th17 cells.

Th-1- responses in PGIA are regulated by IL-4. We have demonstrated that systemic administration of IL-4???? effectively suppresses disease. We further showed that arthritis is exacerbated in IL-4-/- mice and IL-4 mediates this effect through activation of STAT6.?? Aggravated arthritis in IL-4-/- mice is associated with an increase in chemokine (MIP-1b, MIP-1a, MIP-2, and MCP-1) and cytokine (IL-12p35, IL-1b, IL-6, and TNF-a) transcripts in joints before development of any signs of inflammation or cellular infiltration.?? Thus, IL-4 may regulate the activation of resident synovial macrophages reducing infiltration of other leukocytes into the joint.

B cells are required for the development of PGIA.???????? B cell depletion dramatically affects clinical symptoms in RA patients, this observation suggests that B cells are involved in the pathogenesis of the disease. B cell may perform multiple functions in the development of arthritis.?? Autoantibodies produced by B cells form immune complexes.?? These immune complexes can function through several different pathways to induce inflammation.?? Immune complexes bind to FcgR on macrophages and neutrophils activating proinflammatory chemokines and cytokines directing cells to sites of inflammation.?? Immune complexes can also activate the complement system. In PGIA, both FcgR and complement are involved in the development of disease.???? B cells may also function as antigen-presenting cells for T cell activation.?? Our current work is focus on costimulatory molecules and cytokines expressed by B cells and how they maintain T cell activation. Our overall hypothesis is that B cells are able to control the development of arthritis through stimulatory and inhibitory interactions that principally affect T cell activation. This is an important area of investigation, which is expected to shed new light on the mechanisms of B cell function in RA, and more generally in autoimmune disease, and thereby provide novel potential targets for the development of therapeutic strategies to selectively block or enhance immune responses. ??????

??

References

O???Neill, S.K., Glant, T.T., Finnegan, A. The role of B cells in animal models of rheumatoid arthritis. Front Biosci 12:1722- 36, 2007.

??

Cao, Y., Brombacher, F., Tunyogi-Csapo, M., Glant, T.T., Finnegan, A. Interleukin-4 regulates proteoglycan-induced arthritis by specifically suppressing the innate immune response. Arthritis Rheum. 56:861-70, 2007.

??

O???Neill, S.K., Cao, Y., Hamel, K.M., Doodes, P.D., Hutas, G., and Finnegan, A. Expression of CD80/86 on????B cells is essential for autoreactive T cell activation and the development of arthritis. J. Immunol.??179:5109, 2007.

??

Cao, Y., Doodes, P.D., Glant, T.T., and Finnegan, A. IL-27 induces a Th1 immune response and

susceptibility to experimental arthritis. J. Immunol. 180:922, 2008.

??

Hamel, K., Doodes, P., Cao, Y., Wang, Y., Martinson, J., Dunn, R., Kehry, M.R., Farkas, B., and

Finnegan,??A. Suppression of proteoglycan-induced arthritis by anti-CD20 B cell depletion therapy is mediated by??reduction in autoantibodies and CD4+ T cell reactivity. J. Immunol. 180:4994, 2008.

??

Doodes, P.D., Cao, Y., Hamel, K., Wang, Y., Farkas, B., Iwakura, Y., and Finnegan, A., Development of Proteoglycan-Induced Arthritis is Independent of IL-17. J. Immunol.181:329, 2008.

??

Tunyogi-Csapo, M., Kis-Toth, K., Radacs, M., Farkas, B., Jacobs, J.J., Finnegan, A., Mikecz,K., and Glant, T.T. Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial

fibroblasts. Arthritis Rheum 58:2397-2408, 2008.

??

Hutas, G., Bajnok, E., Gal, I., Finnegan, A., Glant, T.T., and Mikecz, K. CD44-specific antibody treatment??and CD44deficiency exert distinct effects on Leukocyte recruitment in experimental arthritis. Blood?? 12:4999, 2008.

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Finnegan, A., and Doodes, P.D. Pathways for interleukin-1-driven arthritis. Arthritis Rheum. 58:3283,

2008.

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O???Neill, S.K, Veselits, M.L, Zhang, M., Labno, C., Cao, Y., Finnegan, A., Uccellini, M., Alegre, M-L.,

Cambier, J.C., and Clark, M.R. Endocytic sequestration of the B cell antigen receptor and toll-like receptor??9 in anergic cells. PNAS 106:6262, 2009.

??

Doodes, P.D. Cao, T., Hamel, K.M., Wang, Y., Rodeghero,?? Finnegan, A. CCR5 is involved in resolution of inflammation in proteoglycan-induced arthritis. Arthritis Rheum 60:2945, 2009.

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Grant support

??

1R01AR056999-01 ( PI Finnegan)????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

NIH/NIAMS????????????????????????????????????????????????????????????????????????????

Cytokine Regulation in Experimental Arthritis

????

R01 AR047657-07 (PI Finnegan)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? ??????????

NIH/NIAMS????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

B Cell Function in Autoimmune Arthritis

??

1. Cao, Y., Brombacher, F., Tunyogi-Csapo, M., Glant, T.T., Finnegan, A. Interleukin-4 regulates proteoglycan-induced arthritis by specifically suppressing the innate immune response. Arthritis Rheum. 56:861-70, 2007.

??

??2. O???Neill, S.K., Cao, Y., Hamel, K.M., Doodes, P.D., Hutas, G., and Finnegan, A. Expression of CD80/86 on ??B cells is essential for autoreactive T cell activation and the development of arthritis. J. Immunol. 179:5109, 2007.

??

??3.Cao, Y., Doodes, P.D., Glant, T.T., and Finnegan, A. IL-27 induces a Th1 immune response and susceptibility to experimental arthritis. J. Immunol. 180:922, 2008.

??

??4. Hamel, K., Doodes, P., Cao, Y., Wang, Y., Martinson, J., Dunn, R., Kehry, M.R., Farkas, B., and Finnegan, A. Suppression of proteoglycan-induced arthritis by anti-CD20 B cell depletion therapy is mediated by reduction in autoantibodies and CD4+ T cell reactivity. J. Immunol. 180:4994, 2008.

??

5. Doodes, P.D., Cao, Y., Hamel, K., Wang, Y., Farkas, B., Iwakura, Y., and Finnegan, A., Development of Proteoglycan-Induced Arthritis is Independent of IL-17. J. Immunol.181:329, 2008.

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