Multidisciplinary studies - including clinical, immunologic, pathologic, epidemiologic and molecular genetic investigations - are being used to complement findings in each area and overcome limitations inherent in each approach. Current studies are focusing on: exploring possible environmental risk and protective factors;identifying genetic risk and protective factors by candidate gene and whole genome SNP analyses;defining the associations among clinical, laboratory and immunologic features of autoimmune diseases for diagnostic, prognostic and pathogenic purposes;and understanding differences in epigenetics, gene expression and proteomic patterns between monozygotic twins discordant for disease. Evaluation of exposures to silica, organic solvents, ultraviolet light, vaccinations, selected drugs and dietary supplements, hormones and pregnancy, tobacco smoke, stressful life events and infectious agents in the development of systemic autoimmune diseases are being conducted via a study of twins and close siblings discordant for systemic autoimmune disease. A group of poorly-understood, life-threatening autoimmune muscle diseases called the myositis syndromes are defined by chronic muscle inflammation and weakness and associated with specific autoantibodies. The major forms of myositis are polymyositis, in which multiple muscles are affected by inflammation, and dermatomyositis, in which patients also develop skin inflammation. Yet there appear to be other types of myositis based on the clinical presentations, pathology and autoantibodies. Our worldwide studies suggested that ultraviolet radiation exposure may modulate the clinical and immunologic expression of myositis in different populations and studies in the United States this year demonstrated similar findings. Ultraviolet radiation exposure strongly correlated with the prevalence of dermatomyositis and the associated anti-Mi-2 autoantibodies directed against a 220 KD member of the SNF2/RAD54 helicase family, which is a major component of the nucleosome remodeling and histone deacetylase (NuRD) complex. Studies are ongoing to understand the molecular effects of ultraviolet radiation and estrogen on the expression and function of the Mi-2 target autoantigen. Because studies suggest that ultraviolet (UV) radiation modulates the myositis phenotype and Mi-2 autoantigen expression, we conducted a retrospective investigation to determine whether UV radiation may influence the relative prevalence of dermatomyositis and anti-Mi-2 autoantibodies in the US. We assessed the relationship between surface UV radiation intensity in the state of residence at the time of onset with the relative prevalence of dermatomyositis and myositis autoantibodies in patients with myositis from referral centers. We found that UV radiation intensity was associated with the relative proportion of patients with dermatomyositis and with the proportion of patients expressing anti-Mi-2 autoantibodies. Modeling of these data showed that these associations were confined to women and suggests that sex influences the effects of UV radiation on autoimmune disorders. This first study of the distribution of myositis phenotypes and UV radiation exposure in the US showed that UV radiation may modulate the clinical and immunologic expression of autoimmune disease in women. Further investigation of the mechanisms by which these effects are produced may provide insights into pathogenesis and suggest therapeutic or preventative strategies. We are also assessing the pathogenesis of certain disease features that result in poor clinical outcomes. For example, inflammation of subcutaneous tissue, called panniculitis, and the loss of fat in the subcutaneous tissue, called lipodystrophy, are major problems for some patients with myositis, especially children. To understand possible risk factors for their development, we performed extensive clinical, laboratory and genetic assessments on subjects with these disorders. Panniculitis was associated with focal lipoatrophy, while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more commonly associated with generalized lipodystrophy. Metabolic studies revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial lipodystrophy. We conclude that lipodystrophy is an under-recognized complication of juvenile dermatomyositis, and certain patients with a severe, prolonged clinical course and a high frequency of subcutaneous calcinosis appear to be at greater risk for the development of this problem. Regarding our genetic studies, we have defined new genetic risk and protective factors for myositis in adults and children. To study tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1) cytokine polymorphisms as possible risk and protective factors, define their relative importance, and examine these as severity factors in patients with juvenile dermatomyositis (DM), TNFalpha and IL-1 cytokine polymorphism typing were performed in Caucasian patients with juvenile DM, and the results were compared with those in ethnically matched healthy volunteers. We found that TNFalpha and IL-1 genetic polymorphisms contribute to the development of juvenile DM and may also be indicators of disease severity. We extended these studies to polymorphic determinants of genes encoding regions of immunoglobulin gamma heavy and kappa light chains (GM and KM loci on chromosomes 14q32.33 and 2p12, respectively), which have been associated with different immune responses in a variety of infectious and autoimmune diseases. In European American dermatomyositis patients the GM 3 23 5,13 phenotype was a risk factor for both adults and children. Among the myositis autoantibody groups, GM 3 23 5,13 was a risk factor for adults with anti-Jo-1 autoantibodies, while the GM 3 allotype was protective for adults with anti-threonyl-tRNA synthetase or anti-RNP autoantibodies. In contrast, GM 6 was a risk factor for African American adults with autoantibodies to the signal recognition particle. These data, taken together, suggest that polymorphic alleles of MHC genes, pro-inflammatory cytokines, as well as the GM and KM loci for immunoglobulin genes, are differentially associated with myositis subgroups defined by age, ethnicity, clinical features and autoantibodies, and expand the list of immune response genes possibly important in the pathogenesis of myositis. Our findings, obtained from the largest cohort of patients with myositis studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms as a result of different gene-environment interactions. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. We reported the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2010
Total Cost
$1,446,418
Indirect Cost
City
State
Country
Zip Code
Yeker, Richard M; Pinal-Fernandez, Iago; Kishi, Takayuki et al. (2018) Anti-NT5C1A autoantibodies are associated with more severe disease in patients with juvenile myositis. Ann Rheum Dis 77:714-719
Dinse, Gregg E; Parks, Christine G; Meier, Helen C S et al. (2018) Prescription medication use and antinuclear antibodies in the United States, 1999-2004. J Autoimmun 92:93-103
Miller, Frederick W; Lamb, Janine A; Schmidt, Jens et al. (2018) Risk factors and disease mechanisms in myositis. Nat Rev Rheumatol 14:255-268
Parkes, Joanna E; Rothwell, Simon; Oldroyd, Alexander et al. (2018) Genetic background may contribute to the latitude-dependent prevalence of dermatomyositis and anti-TIF1-? autoantibodies in adult patients with myositis. Arthritis Res Ther 20:117
Feldon, Michal; Farhadi, Payam Noroozi; Brunner, Hermine I et al. (2017) Predictors of Reduced Health-Related Quality of Life in Adult Patients With Idiopathic Inflammatory Myopathies. Arthritis Care Res (Hoboken) 69:1743-1750
Grau-PĂ©rez, Maria; Kuo, Chin-Chi; Spratlen, Miranda et al. (2017) The Association of Arsenic Exposure and Metabolism With Type 1 and Type 2 Diabetes in Youth: The SEARCH Case-Control Study. Diabetes Care 40:46-53
Dinse, Gregg E; Parks, Christine G; Weinberg, Clarice R et al. (2017) Antinuclear antibodies and mortality in the National Health and Nutrition Examination Survey (1999-2004). PLoS One 12:e0185977
Mamyrova, Gulnara; Rider, Lisa G; Ehrlich, Alison et al. (2017) Environmental factors associated with disease flare in juvenile and adult dermatomyositis. Rheumatology (Oxford) :
Kishi, Takayuki; Rider, Lisa G; Pak, Katherine et al. (2017) Association of Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Autoantibodies With DRB1*07:01 and Severe Myositis in Juvenile Myositis Patients. Arthritis Care Res (Hoboken) 69:1088-1094
Hong, Kyeong-Man; Kim, Hyun-Kyoung; Park, Seong-Yeol et al. (2017) CD3Z hypermethylation is associated with severe clinical manifestations in systemic lupus erythematosus and reduces CD3?-chain expression in T cells. Rheumatology (Oxford) 56:467-476

Showing the most recent 10 out of 63 publications