Overview
Our laboratory is part of the William S. Rowe Division of Rheumatology at the Cincinnati Children's Hospital Medical Center. Our focus is on the role of angiogenesis in juvenile inflammatory diseases. Our major long-term goals are to:
- Identify differential gene regulatory patterns specific to systemic JRA.
- Determine the molecular mechanism of angiogenic factors on inflammation in juvenile dermatomyositis.
- Determine the molecular basis of effects of angiogenic factors on inflammation in a mouse model of rheumatoid arthritis and in human juvenile rheumatoid arthritis.
What are our major projects?
To identify the differential gene regulatory patterns associated with systemic JRA.
Systemic Onset Juvenile Rheumatoid Arthritis and an associated condition known as Macrophage Activation Syndrome are severe and often devastating illnesses. The pathological mechanisms are not known but Dr. Alexei Grom has focused his research on NK and cytotoxic cell function in this disease. The rationale for this approach has been based on the strong clinical similarities between MAS and the better understood autosomal recessive disorder familial hemophagocytic lymphohistiocytosis, in which the uncontrolled proliferation of T cells and macrophages has been recently associated with decreased NK cell and cytotoxic cell functions secondary to mutations in the gene encoding perforin. Recent observations suggest as in FHLH, MAS patients also have profoundly depressed NK function. Moreover, a large subgroup of systemic JRA patients has very similar immunologic abnormalities. Combined with the evidence of the immunoregulatory role of NK cells in many immune responses, this suggests that NK dysfunction is relevant to the pathogenesis of MAS. New directions have thus been established for research in this poorly understood disease.
To determine the molecular mechanism of angiogenic factors on inflammation in juvenile dermatomyositis.
Juvenile Dermatomyositis is a chronic inflammatory condition involving primarily muscles and skin. The most characteristic feature of JDM is vascular damage associated with the capillary necrosis that eventually leads to capillary loss and tissue ischemia. The project is based on the hypothesis that capillary loss in this condition may be caused by angiostatic chemokines that are prominent in the inflammatory response in the affected muscles.
To determine the molecular basis of effects of angiogenic factors on inflammation in arthritis.
Angiogenesis plays a major role in autoimmune arthritis. Cellular proliferation within the synovium results in tissue starvation and subsequent angiogenesis to maintain nutrient delivery and gas exchange to the growing pannus tissue. Within this growing pannus are also activated cells that secrete chemokines for recruitment of inflammatory cells into the joint. Activated endothelium within blood vessels also secretes inflammatory cytokines and allows infiltration of inflammatory cells, both of which contribute to disease processes. Therefore, the angiogenic process itself augments the inflammatory response. Certain molecules have been identified that can stabilize the vasculature, such as Angiopoietin-1 (Ang1).
Our recent microarray analysis identified the increased expression of a molecule homologous to Ang1, angiopoietin like 4 (Angptl4), which is anti-apoptotic for endothelial cells. Expression of Angptl4 correlates with arthritic disease in both humans and a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA), suggesting a novel role for this protein in arthritis. Our long-term goal is to determine the role of Angptl4 in angiogenic processes related to arthritic disease. Our studies address the hypothesis that Angptl4 inhibits apoptosis of vascular endothelial cells in the arthritic joint by acting through an endothelial cell specific receptor, resulting in the increase or stabilization of newly formed vasculature and subsequent enhancement of inflammatory responses. Targeting angiogenesis either by itself or in combination with other therapies has great potential for therapy of autoimmune arthritis.
Publications, Most Recent
Thornton, S, KA Kuhn, FD Finkelman and R Hirsch. 2001. NK cells secrete high levels of IFN-gamma in response to in vivo administration of IL-2. Eur J Immunol 31:3355-3360.
Scola MP, Thompson SD, Brunner HI, Tsoras MK, Witte D, van Dijk MA, Grom AA, Passo MH, and Glass DN. IFN-:IL4 ratios and associated type 1 cytokine expression in juvenile rheumatoid arthritis synovial tissue. J Rheumatol, 2002;29:369-78.
L Zuo, CM Cullen, ML DeLay, S Thornton, LK Myers, EF Rosloniec, G.P. Boivin, and R Hirsch. 2002. A single-chain class II MHC-IgG3 fusion protein inhibits autoimmune arthritis by induction of antigen specific hyporesponsiveness. J. Immunol. 168:2554-2559.
Yang L, Thornton S, and Grom AA. 2002. IL-15 inhibits SNP-induced apoptosis of synovial fibroblasts and vascular endothelial cells. Arthritis Rheum, 46:3010-3014.
Thornton, S. D Sowders, B Aronow, DP Witte, HI Brunner, EH Giannini and R Hirsch. 2002. DNA Microarray analysis Reveals Novel Gene Expression Profiles in Collagen Induced Arthritis. Clinical Immunology. 105:155-168.
Yang L, Thornton S, Grom AA: IL-15 inhibits SNP-induced apoptosis of synovial fibroblasts and vascular endothelial cells. Arthritis Rheum 2002;46:3010-14.
Grom AA, Villanueva J, Lee S, Goldmuntz EA, Passo MH, Filipovich A: Natural Killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J Pediatr 2003;142:292-6.
Barnes M, Aronow B, Luyrink L, Moroldo M, Pavlidis P, Passo MH, Grom AA, Hirsch R, Giannini EH, Colbert R, Glass DN, and Thompson S. Gene Expression in Juvenile Arthritis and Spondyloarthropathy: Pro-angiogenic ELR+ Chemokine Genes Relate to Course of Arthritis. Rheumatology (Oxford) 2004, (in press).
Grom AA. NK dysfunction: a common pathway in systemic onset juvenile rheumatoid arthritis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Arthritis Rheum 2004:50;689-98.
Katakura, S, K Jennings, S, Watanabe, E Adachi, S Thornton, G Gao, JM Wilson, H Burstein, B Trapnell, and R Hirsch. 2004. Recombinant adeno-associated virus preferentially transduces human, compared to mouse, synovium: implications for arthritis therapy. Mod. Rheumatol. 14: 18-24.
Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich AH, and Grom AA: Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Research & Therapy, 2004 (pre-published online Arthritis Res Ther; 7:R30-37).
Hermann, LM, L Yang, M. Pinkerton, A Grom, D Sowders, DP Witte, R Hirsch, and S Thornton. 2005. Angiopoietin-Like-4 is a Potential Angiogenic Mediator in Arthritis. Clinical Immunology. (115(1):93-101).
Carey, B, M DeLay, JE Strasser, C Chalk, K Dudley-McClain, GG Milligan, HI Brunner, S Thornton, and R Hirsch. 2005. A Soluble Divalent Class I MHC/IgG1 Fusion Protein Activates CD8+ T Cells. Clinical Immunology (116: 65-76).
Fall, N, KE Bove, K Stringer, DJ Lovell, HI Brunner, NT Ilowite, GC Higgins, SL Bowyer, TB Graham, S Thornton, and AA Grom. 2005. Lack of Angiogenic Response in Muscle Tissues from Patients with Juvenile Dermatomyositis is Associated with High Expression of Angiostatic ELR-negative CXC-Chemokines: Possible Link to Vasculopathy. Arthritis and Rheumatism. (in press).
