Biomedical subjects

Kutty S Nandakumar

Publications and source records attributed to Kutty S Nandakumar.

4 recordsLinked to original sources

PubMed2006

Backcross and partial advanced intercross analysis of nonobese diabetic gene-mediated effects on collagen-induced arthritis reveals an interactive effect by two major loci.

Genetic segregation analysis between NOD and C57BL strains have been used to identify loci associated with autoimmune disease. Only two loci (Cia2 and Cia9) had earlier been found to control development of arthritis, whereas none of the previously identified diabetes loci was of significance for arthritis. We have now made a high-powered analysis of a backcross of NOD genes on to the B10.Q strain for association with collagen-induced arthritis. We could confirm relevance of both Cia2 and Cia9 as well as the interaction between them, but we did not identify any other significant arthritis loci. Immune cellular subtyping revealed that Cia2 was also associated with the number of blood macrophages. Congenic strains of the Cia2 and Cia9 loci on the B10.Q background were made and used to establish a partial advanced intercross (PAI). Testing the PAI mice for development of collagen-induced arthritis confirmed the loci and the interactions and also indicated that at least two genes contribute to the Cia9 locus. Furthermore, it clearly showed that Cia2 is dominant protective but that the protection is not complete. Because these results may indicate that the Cia2 effect on arthritis is not only due to the deficiency of the complement C5, we analyzed complement functions in the Cia2 congenics as well as the PAI mice. These data show that not only arthritis but also C5-dependent complement activity is dominantly suppressed, confirming that C5 is one of the major genes explaining the Cia2 effect.

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PubMed2005

Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen.

Antibodies against type II collagen (CII) are important in the development of collagen-induced arthritis (CIA) and possibly also in rheumatoid arthritis. We have determined the fine specificity and arthritogenicity of the antibody response to CII in chronic relapsing variants of CIA. Immunization with rat CII in B10.Q or B10.Q(BALB/cxB10.Q)F2 mice induces a chronic relapsing CIA. The antibody response to CII was determined by using triple-helical peptides of the major B cell epitopes. Each individual mouse had a unique epitope-specific response and this epitope predominance shifted distinctly during the course of the disease. In the B10.Q mice the antibodies specific for C1 and U1, and in the B10.Q(BALB/cxB10.Q)F2 mice the antibodies specific for C1, U1 and J1, correlated with the development of chronic arthritis. Injection of monoclonal antibodies against these epitopes induced relapses in chronic arthritic mice. The development of chronic relapsing arthritis, initially induced by CII immunization, is associated with an arthritogenic antibody response to certain CII epitopes.

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PubMed2005

Stromal cells and osteoclasts are responsible for exacerbated collagen-induced arthritis in interferon-beta-deficient mice.

OBJECTIVE: Clinical trials using interferon-beta (IFNbeta) in the treatment of rheumatoid arthritis have shown conflicting results. We undertook this study to understand the mechanisms of IFNbeta in arthritis at a physiologic level. METHODS: Collagen-induced arthritis (CIA) was induced in IFNbeta-deficient and control mice. The role of IFNbeta was investigated in both the priming and effector phases of the disease. The effect of IFNbeta deficiency on synovial cells, macrophages, and fibroblasts from preimmunized mice was analyzed by flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. Differences in osteoclast maturation were determined in situ by histology of arthritic and naive paws and by in vitro maturation studies of naive bone marrow cells. The importance of IFNbeta-producing fibroblasts was determined by transferring fibroblasts into mice at the time of CIA immunization. RESULTS: Mice lacking IFNbeta had a prolonged disease with a higher incidence compared with control mice. IFNbeta deficiency was found to influence the effector phase, but not the priming phase, of arthritis. Compared with control mice, IFNbeta-deficient mice had greater infiltration of CD11b+ cells and greater production of tumor necrosis factor alpha in vivo, and their macrophages and fibroblasts were both more activated in vitro. Moreover, IFNbeta-deficient mice generated a greater number of osteoclasts in vitro, and mice immunized to induce arthritis, but not naive mice, had a greater number of osteoclasts in vivo compared with control mice. Importantly, IFNbeta-competent fibroblasts were able to ameliorate arthritis in IFNbeta-deficient recipients. CONCLUSION: Our data indicate that IFNbeta is involved in regulating the activation state of osteoclasts and stromal cells, including macrophages and fibroblasts, but that it has little effect on T cells.

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PubMed2004

Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis.

To analyze the role of the classical and alternative pathways of complement activation in the effector phase of arthritis, we have induced arthritis in C3- and factor B (FB)-deficient (C3(-/-) and FB(-/-)) DBA/1J mice using well-defined monoclonal IgG2b and IgG2a antibodies to type II collagen. In control DBA/1J mice, severe swelling of the joints, destruction of cartilage and erosion of bone developed very rapidly with a 100% incidence and a peak on days 7-10. Although 75% of C3(-/-) mice developed arthritis, the clinical severity was very mild and the onset was delayed. Severity of arthritis in FB(-/-) mice ranked intermediate in comparison with C3(-/-) and control mice with an incidence of 100%. Immunohistochemical analysis of the inflamed joints demonstrated substantial reduction in macrophage and neutrophilic leukocyte infiltration in both C3(-/-) and FB(-/-) mice, thereby confirming the clinical findings. We conclude that both the classical and the alternative pathways of complement activation are involved in the effector phase of arthritis.

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