Roshini Fernando1, Andrew Vonberg, Stephen J Atkins, Susan Pietropaolo, Massimo Pietropaolo, Terry J Smith. 1. Department of Ophthalmology and Visual Sciences (R.F., S.J.A., T.J.S.), Kellogg Eye Center and Division of Metabolism, Endocrinology, and Diabetes (A.V., S.P., M.P., T.J.S.), Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105.
Abstract
CONTEXT: Factors common to multiple autoimmune diseases have been sought vigorously. Graves' disease (GD) and type 1 diabetes mellitus (T1DM) involve end-organ remodeling. Fibrocytes participate in inflammatory diseases and were recently shown to express thyroid-specific proteins such as the thyrotropin receptor and thyroglobulin. OBJECTIVE: The objective of the study was to determine whether a broader repertoire of autoantigen expression, such as proteins associated with T1DM, can be ascribed to fibrocytes. DESIGN, SETTING, AND PARTICIPANTS: Fibrocytes and fibroblasts were collected and analyzed from healthy individuals and those with autoimmune diseases in an academic clinical practice. MAIN OUTCOME MEASURES: Real-time PCR, Western blot analysis, gene promoter analysis, cell transfections, and flow cytometric cell sorting were performed. RESULTS: Islet cell antigen ICA512 (IA-2) and islet cell autoantigen of 69 kDa (ICA69), two islet-specific proteins implicated in T1DM, are expressed by fibrocytes from healthy donors and those with T1DM, GD, and multiple sclerosis. Both transcripts are detected by PCR, the proteins are resolved on Western blots, and both gene promoters are active in fibrocytes. Levels of ICA69 are substantially higher than those of IA-2 in fibrocytes. ICA69 localizes to CD34(+) GD orbital fibroblasts putatively derived from fibrocytes, whereas higher levels of IA-2 are found in CD34(-) fibroblasts. CONCLUSIONS: In addition to autoantigens implicated in thyroid autoimmunity, fibrocytes and derivative fibroblasts express multiple autoantigens associated with T1DM. This expression results from active gene promoters and abundant steady-state mRNA encoding ICA69 and IA-2. These latest findings demonstrate that fibrocytes express antigens relevant to multiple forms of endocrine autoimmunity. They suggest the potential for these cells playing a direct role in immune reactivity directed at the thyroid and pancreatic islets.
CONTEXT: Factors common to multiple autoimmune diseases have been sought vigorously. Graves' disease (GD) and type 1 diabetes mellitus (T1DM) involve end-organ remodeling. Fibrocytes participate in inflammatory diseases and were recently shown to express thyroid-specific proteins such as the thyrotropin receptor and thyroglobulin. OBJECTIVE: The objective of the study was to determine whether a broader repertoire of autoantigen expression, such as proteins associated with T1DM, can be ascribed to fibrocytes. DESIGN, SETTING, AND PARTICIPANTS: Fibrocytes and fibroblasts were collected and analyzed from healthy individuals and those with autoimmune diseases in an academic clinical practice. MAIN OUTCOME MEASURES: Real-time PCR, Western blot analysis, gene promoter analysis, cell transfections, and flow cytometric cell sorting were performed. RESULTS: Islet cell antigen ICA512 (IA-2) and islet cell autoantigen of 69 kDa (ICA69), two islet-specific proteins implicated in T1DM, are expressed by fibrocytes from healthy donors and those with T1DM, GD, and multiple sclerosis. Both transcripts are detected by PCR, the proteins are resolved on Western blots, and both gene promoters are active in fibrocytes. Levels of ICA69 are substantially higher than those of IA-2 in fibrocytes. ICA69 localizes to CD34(+) GD orbital fibroblasts putatively derived from fibrocytes, whereas higher levels of IA-2 are found in CD34(-) fibroblasts. CONCLUSIONS: In addition to autoantigens implicated in thyroid autoimmunity, fibrocytes and derivative fibroblasts express multiple autoantigens associated with T1DM. This expression results from active gene promoters and abundant steady-state mRNA encoding ICA69 and IA-2. These latest findings demonstrate that fibrocytes express antigens relevant to multiple forms of endocrine autoimmunity. They suggest the potential for these cells playing a direct role in immune reactivity directed at the thyroid and pancreatic islets.
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