ORCID Profile
0000-0001-7790-8197
Current Organisations
Karolinska Institutet
,
Madurai kamaraj university
,
Lunds Universitet
,
University of Madras
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Publisher: SPIE-Intl Soc Optical Eng
Date: 2011
DOI: 10.1117/1.3585680
Abstract: Collagen antibody-induced arthritis develops in mice following passive transfer of monoclonal antibodies (mAbs) to type II collagen (CII) and is attributed to effects of proinflammatory immune complexes, but transferred mAbs may react directly and damagingly with CII. To determine whether such mAbs cause cartilage damage in vivo in the absence of inflammation, mice lacking complement factor 5 that do not develop joint inflammation were injected intravenously with two arthritogenic mAbs to CII, M2139 and CIIC1. Paws were collected at day 3, decalcified, paraffin embedded, and 5-μm sections were examined using standard histology and synchrotron Fourier-transform infrared microspectroscopy (FTIRM). None of the mice injected with mAb showed visual or histological evidence of inflammation but there were histological changes in the articular cartilage including loss of proteoglycan and altered chondrocyte morphology. Findings using FTIRM at high lateral resolution revealed loss of collagen and the appearance of a new peak at 1635 cm(-1) at the surface of the cartilage interpreted as cellular activation. Thus, we demonstrate the utility of synchrotron FTIRM for examining chemical changes in diseased cartilage at the microscopic level and establish that arthritogenic mAbs to CII do cause cartilage damage in vivo in the absence of inflammation.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-08-2014
Abstract: We identified a previously undescribed disease mechanism for psoriasis (Ps) and psoriasis arthritis (PsA)-like disease by developing a new mouse model having characteristic features similar to those of Ps and PsA in human patients. Mannan-induced activation of tissue macrophages triggers IL-17A secretion from γδ T cells, causing Ps-like inflammation. Such inflammation was significantly increased under a reduced oxidative environment. Increased frequency of monocytes/macrophages, depletion experiments, and the disease suppressor function of macrophage-derived reactive oxygen species clearly argue in favor of a role for monocytes/macrophages in this disease model, which is in accordance with the findings in patients with the psoriatic form of skin lesions and arthritis. This novel PsA model could be immensely useful to test new therapeutics for patients with Ps and PsA.
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.MOLIMM.2011.04.014
Abstract: Activation of the complement system is a major pathogenic event that drives various inflammatory responses in numerous diseases. All pathways of complement activation lead to cleavage of the C5 molecule generating the anaphylatoxin C5a and, C5b that subsequently forms the terminal complement complex (C5b-9). C5a exerts a predominant pro-inflammatory activity through interactions with the classical G-protein coupled receptor C5aR (CD88) as well as with the non-G protein coupled receptor C5L2 (GPR77), expressed on various immune and non-immune cells. C5b-9 causes cytolysis through the formation of the membrane attack complex (MAC), and sub-lytic MAC and soluble C5b-9 also possess a multitude of non-cytolytic immune functions. These two complement effectors, C5a and C5b-9, generated from C5 cleavage, are key components of the complement system responsible for propagating and/or initiating pathology in different diseases, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries and neurodegenerative diseases. Thus, the C5-C5a receptor axis represents an attractive target for drug development. This review provides a comprehensive analysis of different methods of inhibiting the generation of C5a and C5b-9 as well as the signalling cascade of C5a via its receptors. These include the inhibition of C5 cleavage through targeting of C5 convertases or via the C5 molecule itself, as well as blocking the activity of C5a by neutralizing antibodies and pharmacological inhibitors, or by targeting C5a receptors per se. Ex les of drugs and naturally occurring compounds used are discussed in relation to disease models and clinical trials. To date, only one such compound has thus far made it to clinical medicine: the anti-C5 antibody eculizumab, for treating paroxysmal nocturnal hemoglobinuria. However, a number of drug candidates are rapidly emerging that are currently in early-phase clinical trials. The C5-C5a axis as a target for drug development is highly promising for the treatment of currently intractable major human diseases.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2005
Abstract: Identification of genes controlling complex diseases has proven to be difficult however, animal models may pave the way to determine how low penetrant genes interact to promote disease development. We have dissected the Cia5/Eae3 susceptibility locus on mouse chromosome 3 previously identified to control disease in experimental models of multiple sclerosis and rheumatoid arthritis. Congenic strains showed significant but small effects on severity of both diseases. To improve the penetrance, we have now used a new strategy that defines the genetic interactions. The QTL interacted with another locus on chromosome 15 and a partial advanced intercross breeding of the two congenic strains for eight generations accumulated enough statistical power to identify interactions with several loci on chromosome 15. Thereby, three separate loci within the original QTL could be identified Cia5 affected the onset of arthritis by an additive interaction with Cia31 on chromosome 15, whereas the Cia21 and Cia22 affected severity during the chronic phase of the disease through an epistatic interaction with Cia32 on chromosome 15. The definition of genetic interactions was a prerequisite to dissect the Cia5 QTL and we suggest the partial advanced intercross strategy to be helpful also for dissecting other QTL controlling complex phenotypes.
Publisher: Elsevier BV
Date: 06-2004
Publisher: American Society for Clinical Investigation
Date: 10-2007
DOI: 10.1172/JCI31935
No related grants have been discovered for Kutty Selva Nandakumar.