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Kanneboyina Nagaraju, M.D.and Antony Rosen, M.D. (The following abstracts were written by Kanneboyina Nagaraju, M.D.) Abstract 766 Neopterin and Quinolinic Acid Are Surrogate Measures of Disease Activity in the Juvenile Idiopathic Inflammatory Myopathies In this abstract, Neopterin and Quinolinic acid (QUIN) concentrations were correlated with disease activity in juvenile idiopathic inflammatory myopathies (IIM). Neopterin and QUIN concentrations were measured in plasma and first morning void urine samples of 45 juvenile IIM patients and 79 healthy controls by ELISA and chromatography/mass spectrometry techniques. Disease activity measures were assessed by physicians blinded to the laboratory results. Results: Plasma and urine neopterin and QUIN concentrations were significantly elevated in juvenile IIM patients compared to healthy controls (P < 0.017). Urine neopterin and QUIN correlated moderately with myositis disease activity assessments (rs = 0.43 - 0.62, P < 0.05). Urine neopterin or QUIN, in combination with either serum lactate dehydrogenase (LD) or aspartate aminotransferase (AST), significantly predicted physician global disease activity (R2 = 0.40 and 0.56, P < 0.002), better than LD or AST alone (R2 = 0.16 and 0.21). Urinary neopterin and QUIN appear to be sensitive measures of disease activity in juvenile IIM patients. Editorial Comments: Both humoral and cell-mediated components are activated in juvenile IIM. Measuring activation markers such as neopterin and QUIN which are predominantly produced by IFN-a?activated macrophages will help to monitor the effector phases of the immune response. This study suggests that measurement of the immune activation markers (Neopterin and QUIN) along with markers of tissue damage (AST and LD) will significantly help to accurately predict the disease activity. The value of these markers in adult IIM remains to be explored. Additional studies are needed to confirm these interesting preliminary findings. Abstract 518 The Granzyme B Cleavage Site in Histidyl-tRNA Synthetase is a Critical Component of its B Cell Epitope in Myositis This study elegantly demonstrates that Histidiyl-tRNA synthetase (Jo-1), a frequently targeted myositis-specific autoantigen, is efficiently cleaved only by Granzyme B but not by caspases 2,3,7,8, and 9. Mutation analysis was performed to confirm that a tetrapeptide sequence (LGPD48) in the N-terminal regulatory domain is the granzyme B site. Results: Incubation of radiolabelled Jo-1 antigen with anti-Jo-1 serum greatly reduced the granzyme B mediated cleavage of the antigen suggesting that the immunodominant epitope recognized by the anti-Jo-1 serum is located in and around the granzyme B site. Preliminary immunoprecipitation analysis further suggests that anti-Jo-1 positive patient sera recognized wild type LGPD antigen more efficiently than the LGPA mutant antigen indicating that the granzyme B cleavage site is an integral part of an immunodominant epitope in this antigen. Editorial Comments: Autoantibodies are the hallmark of systemic and organ-specific autoimmune diseases, but the mechanisms responsible for the initiation and propagation of the immune response to autoantigens remain unclear. These investigators have previously shown that a majority of autoantigens targeted across the spectrum of human systemic autoimmune diseases are efficiently cleaved by granzyme B, in vitro and during cytotoxic lymphocyte granule induced death, generating unique autoantigenic fragments not observed during any other form of apoptosis. The current study strongly suggests a critical role for the granzyme B pathway in the initiation of an autoimmune response against the Jo-1 antigen in myositis. Futher experiments may be needed to address why only Jo-1, and not other synthetases, is preferentially targeted in myositis. This is an exciting and evolving area of investigation. Abstract 1034 Anatomic Localization of Immature and Mature Dendritic Cells Subsets, Th1 T Lymphocytes, and CCL20/CCR6 in Polymyositis and Dermatomyositis This study investigated the presence of immature and mature dendritic cell subtypes in five polymyositis (PM) and four dermatomyositis (DM) biopsies using immunohistochemistry. Anti-CD1a and anti-DC-LAMP antibodies were used to detect immature and mature dendritic cells respectively. Results: Th1 cytokine producing T cells were detected by anti-IL-17 and anti-IFN-aantibodies. Th1 lymphocytes were demonstrated near the dendritic cells in perivascular and perifascicular areas of PM and DM biopsies suggesting an active interaction between the powerful antigen presenting dendritic cells and T lymphocytes. This study also demonstrates the upregulation of molecules involved in DC homing (CCL20/CCR6). The authors speculate a role for chemokines in the pathogenesis of myositis. Editorial Comments: The presence of professional APCs in myositis biopsies suggests that these cells may initiate an autoimmune response by cross-priming and cross-presenting autoantigens to T cells. The cytokine-rich muscle microenvironment facilitates the maturation of dendritic cells in the milieu. These preliminary studies suggest that dendritic cells may play an important role in eliciting immune activation during muscle inflammation. Systematic double labeling studies are needed to address the DC-T cell interactions in myositis. Recent experiments from Dr. Plotzs group at the NIH (Howard et al., 2002) also suggest a critical role for chemokines and their receptors in myositis. Abstract 1033 Comparison of IL1alpha Expression in Symptomatic and Asymptomatic Muscle Tissue in Dermatomyositis and Polymyositis Patients This group has published several papers addressing the role of IL-1alpha in the immunopathogenesis of dermatomyositis (DM) and polymyositis (PM). This study was designed a) to determine the differences in IL-1alpha expression between asymptomatic and symptomatic muscles in the same patient, and b) to investigate whether there is a correlation between muscle weakness and IL-1alpha expression. Eleven patients (3 DM and 8 PM) and six normal control biopsies were used for immunohistochemistry. Both manual and computerized image analysis was performed to determine the percentage positive staining areas for IL-1alpha in relation to the total area of the muscle section. Results: Seven patients showed higher IL-1alpha expression in symptomatic muscle. Control biopsies showed very little IL-1alpha> expression. The authors suggest that microvessels of the muscle tissue may have a role in causing muscle weakness and decreased muscle endurance in PM and DM patients. Editorial Comments: It is generally thought that blood vessels play a major role in the pathogenesis of DM. Interesting observations made by this group suggest a critical role for blood vessels in the pathogenesis of not only DM but also PM patients. Further studies are needed to address the exact molecular mechanisms by which increased IL-1 expression in blood vessels cause muscle weakness in myositis. Abstract 1030 Induction of Autoantibodies by Myopathic Virus in a Model of Coxsackievirus-Induced Chronic Inflammatory Myopathy This study investigated the presence of autoantibodies in myopathic coxsackievirus B1 induced chronic inflammatory myopathy in CD1 mice. The mice were infected for one month with two myopathic (pMP1.23 and pMP1.24) and one amyopathic clone (pAMP2.17) of CVB1 virus. Serum samples were collected after one month and tested for anti-nuclear antibodies (ANA) using HEp-2 cells. Results: ANA were found only in mice infected with myopathic CVB1 virus clones (pMP1.23:10/20 and pMP1.24:5/33), whereas uninfected mice (1/19) or mice infected with amyopathic clone (pAMP2.17: 0/18) did not show ANA positivity (chi-square P < 0.0001). The ANA-positive sera exhibited patterns of fine and/or coarse nuclear staining associated with virus infection. The mice infected with myopathic but not amyopathic virus produced anti-muscle antibodies. These experiments suggest that CVB1 infection triggers autoantibodies in this mouse model. Editorial Comments: This preliminary report suggests the presence of autoantibodies in this model. However they could not detect anti-Jo-1 antibodies. It is not surprising because they did not detect a cytoplasmic staining pattern characteristic of anti-Jo-1 positive sera. It will be interesting to see whether any of the other myositis specific antibodies are present in this model. (The following abstracts were written by Antony Rosen, M.D.) Abstract 441 Persistence of Chlamydia in reactive arthritis: Via evasion of the apoptotic pathway? In this plenary abstract, Grinstein and colleagues from Toronto present a provocative proposal - that protein kinase C delta (PKCd) is recruited to the phagocytic vacuole which encloses Chlamydial organisms, and that this novel subcellular distribution of PKCdalters in some way the initiation of the apoptotic pathway in infected cells. Such prevention of cell death may allow persistence of the organisms in reactive arthritis. The authors speculate that interference with the ability of the pathogen to inhibit apoptosis may have therapeutic use in reactive arthritis. Editorial Comments: While consistent with their proposal, these studies do not definitively establish a role for altered distribution of PKCdin the inhibition of apoptosis in infected cells. It is also interesting to consider whether the inhibition of apoptosis by chlamydia varies in different individuals, which might influence whether organisms are cleared effectively or not. Further studies to more fully define the effects of many different pathogens on the apoptotic pathway may also provide important insights into the applicability of such a mechanism to other autoimmune diseases. Abstract 662 Adult dermatomyositis and subacute cutaneous LE are oligogenic disorders associated with specific polymorphisms of mannose-binding lectin (MBL) and TNF-alpha. Werth, Sullivan and colleagues perform an interesting study on the potential role of MBL in photosensitive skin diseases. The role of apoptosis of keratinocytes in photosensitive skin diseases has previously been emphasized. Since MBL has been postulated to play a role in the clearance of apoptotic cells, the authors examined whether any polymorphisms in MBL that are associated with decreased expression of the MBL protein are associated with photosensitive skin diseases. 2 alleles (Asp54 and Glu57) were strongly positively associated with dermatomyositis, but not with SLE. The authors postulate that impaired clearance of apoptotic cells generated by irradiation in the skin may play an important role in generating the ongoing immune response and inflammatory damage in dermatomyositis. Editorial Comments: Clearly, the studies suggest that additional expression and functional studies be performed on MBL in the skin (particularly after irradiation), and the inflammatory consequences of decreased expression in patients.
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