Immune System Diseases Commons^™

Impacts Of Population Level Environmental Contaminants, Sex Hormones, And Fibroblast Cell Subsets On Systemic Sclerosis (Ssc), Noelle N. Kosarek

Dartmouth College Ph.D Dissertations

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by fibrosis of the skin and internal organs, vascular abnormalities, and autoantibody formation. The etiology of SSc is unknown, though the disease is thought to arise in genetically predisposed individuals after exposure to an environmental factor. There are few FDA approved disease modifying medications available to treat SSc.

The express aims of this dissertation are tripart. First, we aimed to validate a 3D tissue model known as the self-assembled skin equivalent (saSE) model. Second, we sought to describe the geographic distribution of SSc in a US Medicare population to better understand …

Vista Deficiency Attenuates Antibody-Induced Arthritis And Alters Macrophage Gene Expression In Response To Simulated Immune Complexes, Sabrina Ceeraz, Susan K. Eszterhas, Petra Sergent, David A. Armstrong, Alix Ashare, Thomas Broughton, Li Wang, Dov Pechenick, Christopher M. Burns, Randolph J. Noelle, Matthew P. Vincenti, Roy A. Fava

Dartmouth Scholarship

In addition to activated T cells, the immune checkpoint inhibitor “V domain-containing Ig suppressor of T-cell activation” (VISTA) is expressed by myeloid cell types, including macrophages and neutrophils. The importance of VISTA expression by myeloid cells to antibody-induced arthritis and its potential for relevance in human disease was evaluated. Methods: VISTA was immunolocalized in normal and arthritic human synovial tissue sections and synovial tissue lysates were subjected to western blot analysis. The collagen antibody-induced arthritis model (CAIA) was performed with DBA/1 J mice treated with antibodies against VISTA and with VISTA-deficient mice (V-KO). Total mRNA from arthritic joints, spleens, and …

Suppression Of Systemic Autoimmunity By The Innate Immune Adaptor Sting, Shrutie Sharma, Allison M. Campbell, Jennie Chan, Stefan A. Schattgen, Gregory M. Orlowski, Ribhu Nayar, Annie H. Huyler, Kerstin Nundel, Chandra Mohan, Leslie J. Berg, Mark J. Shlomchik, Ann Marshak-Rothstein, Katherine A. Fitzgerald

Katherine A. Fitzgerald

Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to …

The Anti-Inflammatory Caspase-12 Gene Does Not Influence Sle Phenotype In African-Americans, Trista Fuchs, Jennifer A. Kelly, Emily Simon, Kathy L. Sivils, Evan Hermel

Faculty Publications & Research of the TUC College of Osteopathic Medicine

No abstract provided.

Caspase-12 And Lupus: The Curious Case Of The Dog That Didn’T Bark, Evan Hermel

Faculty Publications & Research of the TUC College of Osteopathic Medicine

CASPASE-12 (CASP12) has an anti-inflammatory function during infection, and is a risk factor for sepsis in African-Americans (AA). To determine if CASP12 could be protective for systemic lupus erythematosus (SLE) in AA, we genotyped AA SLE patients and controls. We found that, at best, there was a weak association between CASP12 genotype with the absence of anti-dsDNA autoantibodies in SLE patients. No effect was seen upon serum interleukin-1 beta levels, nor was any other protective effect noted for the CASP12 genotype, whether upon association with SLE, or any of the 11 American College of Rheumatology classification criteria. We concluded that …

Autoimmune Susceptibility Imposed By Public Tcrβ Chains, Yunqian Zhao

Theses and Dissertations (ETD)

The major histocompatibility complex (MHC) is the strongest genetic risk factor for autoimmunity. It acts together with a corresponding TCR repertoire, yet, considering the extent of the repertoire's diversity, how this imposes disease susceptibility on a population is not well understood. We address the hypothesis that shared or public TCR, those present in most individuals, modulate autoimmune risk. High resolution analyses of autoimmune encephalomyelitis-associated T-cell receptor β chain (TCRβ) showed preferential utilization of public TCR sequences, implicating them in pathogenesis. Disease-associated public TCRβ, when transgenically expressed in association with endogenously rearranged T-cell receptor α chain (TCRα), could further endow unprimed …

Humanized Chimeric Receptors In The Therapy Of Multiple Sclerosis, Ioana Moisini

Theses and Dissertations (ETD)

The role of autoreactive, antigen-specific T-cells in the development of autoimmunity has long been documented. T-cells expressing chimeric receptors are specifically redirected against such cells and have been proven to suppress autoimmune encephalomyelitis, the murine model of multiple sclerosis. We here demonstrate the ability of humanized chimeric receptors to suppress experimental autoimmune encephalomyelitis (EAE) in a humanized mouse model by redirecting T lymphocytes against autoreactive T-cells. The receptors were synthesized by linking the 84-102 epitope of human myelin basic protein (MBP) to the extracellular and transmembrane domains of the beta chain of human major histocompatibility complex (MHC) class II molecule …

Modified Amino Acid Copolymers Suppress Myelin Basic Protein 85–99-Induced Encephalomyelitis In Humanized Mice Through Different Effects On T Cells, Zsolt Illés, Joel N.H. Stern, Jay Reddy, Hanspeter Waldner, Marcin P. Mycko, Celia F. Brosnan, Stephan Ellmerich, Daniel M. Altmann, Laura Santambrogio, Jack L. Strominger, Vijay K. Kuchroo

Jay Reddy Publications

A humanized mouse bearing the HLA-DR2 (DRA/DRB1*1501) pro- tein associated with multiple sclerosis (MS) and the myelin basic protein (MBP) 85–99-specific HLA-DR2-restricted T cell receptor from an MS patient has been used to examine the effectiveness of modified amino acid copolymers poly(F,Y,A,K)n and poly- (V,W,A,K)n in therapy of MBP 85–99-induced experimental auto-immune encephalomyelitis (EAE) in comparison to Copolymer 1 [Copaxone, poly(Y,E,A,K)n]. The copolymers were designed to optimize binding to HLA-DR2. Vaccination, prevention, and treatment of MBP-induced EAE in the humanized mice with copolymers FYAK and VWAK ameliorated EAE more effectively than Copolymer 1, reduced the number of pathological lesions, and …

Amelioration Of Proteolipid Protein 139–151-Induced Encephalomyelitis In Sjl Mice By Modified Amino Acid Copolymers And Their Mechanisms, Joel N.H. Stern, Zsolt Illés, Jay Reddy, Derin B. Keskin, Eric Sheu, Masha Fridkis-Hareli, Hiroyuki Nishimura, Celia F. Brosnan, Laura Santambrogio, Vijay K. Kuchroo, Jack L. Strominger

Jay Reddy Publications

Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by ≈30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85–99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139–151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (ii) …