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RISS 인기검색어
- 검색키워드
- 저자 : Shrestha Lekha (검색결과 2 건)
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Shrestha, Lekha University of Massachusetts Lowell ProQuest Disser 2020 해외박사(DDOD)
소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.
Immune tolerance – defined as a state of unresponsiveness of the immune system to self-antigens and other immune activating triggers - is a critical defense mechanism against autoimmune disorders. A compromise in the body’s immune tolerance has been implicated in autoimmune diseases like Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). The production of autoantibodies in autoimmune diseases suggests a vital role for B cell in immune tolerance. About 70% of newly generated B cells have autoreactive B Cell Receptors (BCR). In order to minimize potential autoreactivity caused by the production of self-reactive B cells, B cell development is regulated through important mechanisms that involve tolerance checkpoints, mainly via clonal deletion, receptor editing, and anergy. Growing evidence suggests that anergy is the principal mechanism of B cell immune tolerance. Animal models and human studies have demonstrated a loss of peripheral anergic B cell tolerance during RA. However, the exact mechanism for altered signaling events in anergic B cells in RA or other autoimmune diseases is not fully understood. The main objective of this thesis is to understand how peripheral B cell tolerance by autoreactive anergic B cells towards self-antigens is disrupted in conditions like RA and Inflammatory Bowel Disease (IBD). Understanding and investigating mechanistic factors in the disruption of B cell-mediated peripheral immune tolerance will open more avenues towards identification of new targets for therapeutic intervention in autoimmunity. Nineteen patients with a clinical diagnosis of RA and twenty age and gender matched controls were recruited for the study. The lymphocytes were isolated from freshly collected blood. The Phosphoflow assay was performed on the lymphocytes to determine the phosphorylation response of signaling proteins involved in anergic B cell receptor-mediated signal transduction following B cell stimulation using anti-BCR antibody. Lymphocytes were further challenged with a range of doses of BCR stimulants, over variable time intervals. Furthermore, in an animal model of chemically-induced IBD, we investigated the additional role of high-fat diet and anergic B cell involvement in IBD. Splenocytes and colon tissues were isolated and were assessed via histology, immunofluorescence, and biochemical assays. We found that RA subjects showed heterogeneity in anergic BCR signaling features specifically by PTEN protein in response to changes in the BCR stimulation dose and stimulation period. An increase in the phosphorylation response by PTEN protein, a negative signal regulator in the signaling pathway, can be one of the factors associated with loss of anergy in RA. In the colitis mouse model taking high-fat diet, pronounced anergic B cell signaling activity was seen with increased phosphorylation response in Syk, CD19, PI3K, and PTEN signaling proteins. These results reveal previously unknown involvement of anergic B cells in exacerbation of IBD by high-fat diet, manifested by characteristic alterations in signaling mechanisms. Overall, the findings of this work highlight the importance of anergic B cell signaling proteins in disrupting peripheral anergic B cell tolerance in RA and IBD. The functional role of specific signaling intermediaries in the loss of B cell anergy in RA and IBD should be further validated with pharmacological inhibitors and siRNA knockdown methods.
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