Systemic autoimmune disease are a heterogenous and complex group of disorders of unknown etiology,? characterized by the production of high titer autoantibodies directed against a variety of self-antigens. In? many cases, specific autoantibodies are associated with unique phenotypes. Recent studies have? demonstrated that the majority of autoantigens targeted across the spectrum of autoimmune diseases are? cleaved efficiently by granzyme B (GrB) during cytotoxic lymphocyte granule-induced cell death, generating? unqiue forms of these molecules not observed during other forms of apoptosis. Taken together with the? numerous observations that cytotoxic lymphocytes are active in several autoimmune phenotypes, including? scleroderma, lupus, polymyositis, and Sjogren's syndrome, these findings suggest that GrB may play a role? in the generation and propagation of rheumatic diseases. It remains unknown whether differences in the? expression and/or function of GrB influence the development or expression of any autoimmune disease.? In this pilot proposal, we will address this question in a population of well-characterized and? phenotypieally diverse scleroderma patients from the Johns Hopkins Scleroderma Center and controls? matched for age, sex, and ethnicity from genetic studies ongoing at our institution. Scleroderma patients will? include those with either the limited or diffuse form of the disease. These patients have been followed? longitudinally and phenotyped thoroughly with respect to the presence or absence of overt (?) vascular? disease, ischemic digital loss, interstitial lung disease, renal crisis, and pulmonary hypertension. DMA? samples on these patients have been saved in the Bioassay Core. In order to define SNP haplotypes in Aim? 1, we will sequence the entire GrB gene in 25 patients and 25 controls, including 1000 bp from the 5' and 3'? UTRs. We will then perform SNP genotyping on 200 scleroderma and 200 control subjects, to define the? allelic frequencies for GrB.
In Aim 2, we will test for association between SNPs in the GrB gene and distinct? clinical phenotypes and/or serological subsets of scleroderma.
|Bartlett, S J; Gutierrez, A K; Butanis, A et al. (2018) Combining online and in-person methods to evaluate the content validity of PROMIS fatigue short forms in rheumatoid arthritis. Qual Life Res 27:2443-2451|
|Darrah, Erika; Yu, Fang; Cappelli, Laura C et al. (2018) Association of baseline peptidylarginine deiminase 4 autoantibodies with favorable response to treatment escalation in rheumatoid arthritis. Arthritis Rheumatol :|
|Cappelli, Laura C; Konig, Maximilian F; Gelber, Allan C et al. (2018) Smoking is not linked to the development of anti-peptidylarginine deiminase 4 autoantibodies in rheumatoid arthritis. Arthritis Res Ther 20:59|
|Igusa, Takeru; Hummers, Laura K; Visvanathan, Kala et al. (2018) Autoantibodies and scleroderma phenotype define subgroups at high-risk and low-risk for cancer. Ann Rheum Dis 77:1179-1186|
|McGrath-Morrow, Sharon A; Ndeh, Roland; Helmin, Kathryn A et al. (2018) DNA methylation regulates the neonatal CD4+ T-cell response to pneumonia in mice. J Biol Chem 293:11772-11783|
|Shi, Jing; Darrah, Erika; Sims, Gary P et al. (2018) Affinity maturation shapes the function of agonistic antibodies to peptidylarginine deiminase type 4 in rheumatoid arthritis. Ann Rheum Dis 77:141-148|
|Lee, Yvonne C; Bingham 3rd, Clifton O; Edwards, Robert R et al. (2018) Association Between Pain Sensitization and Disease Activity in Patients With Rheumatoid Arthritis: A Cross-Sectional Study. Arthritis Care Res (Hoboken) 70:197-204|
|Wohlfahrt, Alyssa; Bingham 3rd, Clifton O; Marder, Wendy et al. (2018) Responsiveness of Patient Reported Outcomes Measurement Information System (PROMIS) Measures in RA Patients Starting or Switching a DMARD. Arthritis Care Res (Hoboken) :|
|Leung, Ying Ying; Ogdie, Alexis; Orbai, Ana-Maria et al. (2018) Classification and Outcome Measures for Psoriatic Arthritis. Front Med (Lausanne) 5:246|
|Cohen, Ezra M; Edwards, Robert R; Bingham 3rd, Clifton O et al. (2018) Pain and Catastrophizing in Patients With Rheumatoid Arthritis: A Prospective Observational Cohort Study. J Clin Rheumatol :|
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