Dataset Information

Role of Cell Division Autoantigen 1 (CDA1) in Cell Proliferation and Fibrosis.

ABSTRACT: Cell Division Autoantigen 1 (CDA1) was discovered following screening a human expression library with serum from a patient with Discoid Lupus Erythematosus. CDA1, encoded by TSPYL2 on the X chromosome, shares anti-proliferative and pro?fibrotic properties with TGF-b. It inhibits cell growth through p53, pERK1/2 and p21?mediated pathways and is implicated in tumorigenesis and the DNA damage response. Its pro-fibrotic property is mediated through cross-talk with TGF-b that results in upregulation of extracellular matrix proteins. The latter properties have identified a key role for CDA1 in diabetes associated atherosclerosis. These dual properties place CDA1 as an attractive molecular target for treating tumors and vascular fibrosis including atherosclerosis and other vascular disorders associated with enhanced TGF-? action and tissue scarring.

SUBMITTER: Toh BH

PROVIDER: S-EPMC3966230 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Publications

Role of Cell Division Autoantigen 1 (CDA1) in Cell Proliferation and Fibrosis.

Toh Ban-Hock BH Tu Yugang Y Cao Zemin Z Cooper Mark E ME Chai Zhonglin Z

Genes 20100930 3

Cell Division Autoantigen 1 (CDA1) was discovered following screening a human expression library with serum from a patient with Discoid Lupus Erythematosus. CDA1, encoded by TSPYL2 on the X chromosome, shares anti-proliferative and pro‑fibrotic properties with TGF-b. It inhibits cell growth through p53, pERK1/2 and p21‑mediated pathways and is implicated in tumorigenesis and the DNA damage response. Its pro-fibrotic property is mediated through cross-talk with TGF-b that results in upregulation ...[more]

PMID: 24710090

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Project description:Antigen-specific tolerance induction using autologous B-cell gene therapy is a potential treatment to eliminate undesirable immune responses. For example, we have shown that experimental autoimmune encephalomyelitis (EAE) and type 1 diabetes in NOD mice can be ameliorated using antigen-Ig fusion protein transduced B cells. However, it is well established that auto-reactive antigen-specific B cells are activated in many autoimmune diseases and can contribute to pathogenesis. While syngeneic B cells from immunized or autoimmune mice can serve as tolerogenic antigen-presenting cells (APC), this observation begs the question of whether the antigen-specific B cells per se can be transduced as tolerogenic APC. To test this, we employed two model systems employing B cell receptor (BCR) transgenic or wild type (wt) mice as B-cell donors. While adoptively transferred MOG-Ig transduced wt C57Bl/6 B cells were highly tolerogenic and ameliorated EAE, MOG-Ig transduced anti-MOG B cells from BCR transgenic mice were not. This phenomenon was reproduced in the NOD diabetes model in which pro-insulin-Ig transduced polyclonal wt NOD B cells were protective, whereas similarly transduced anti-insulin BCR B cells were not. Since the frequency of antigen-specific B cells in an immunized animal is quite low, we wished to determine the threshold numbers of BCR transgenic B cells that could be present in an effective transduced population. Therefore, we "spiked" polyclonal wt C57Bl/6 B cells with different numbers of anti-MOG BCR transgenic B cells. In the EAE model, we found protection when BCR B cells were present at 1%, but they prevented tolerance induction at 10%. Antigen-specific B cells expressed normal levels of co-stimulatory molecules and were tolerogenic when transduced with an irrelevant antigen (OVA). Thus, the presence of a BCR specific for the target autoantigen may interfere with the tolerogenic process to that antigen, but BCR-specific B cells are not intrinsically defective as tolerogenic APC. Taken together, these data suggest that antigen-specific tolerance induction can be achieved in the presence of a limited number of antigen-specific B cells, but higher numbers of pathogenic B cells may mask this induction. This observation should guide future development of therapies using autologous B cells to treat patients with autoimmune diseases.

Dataset Information

Role of Cell Division Autoantigen 1 (CDA1) in Cell Proliferation and Fibrosis.

Publications

Role of Cell Division Autoantigen 1 (CDA1) in Cell Proliferation and Fibrosis.

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