The ability to generate inducible pluripotent stem cells (iPSCs) and the potential for their use in treatment of human disease is of immense interest. Autoimmune diseases, with their limited treatment choices are a potential target for the clinical application of stem cell and iPSC technology. IPSCs provide three potential ways of treating autoimmune disease; (i) providing pure replacement of lost cells (immuno-reconstitution); (ii) through immune-modulation of the disease process in vivo; and (iii) for the purposes of disease modeling in vitro. In this review, we will use examples of systemic, system-specific and organ-specific autoimmunity to explore the potential applications of iPSCs for treatment of autoimmune diseases and review the evidence of iPSC technology in auto-immunity to date.
Inclusion body myositis (IBM) belongs to a group of muscle diseases known as the inflammatory myopathies. The disease is viewed to be T cell mediated. However, emerging data suggests that B cells may play a role in IBM. To further the understanding of IBM immunopathology and explore the role of the humoral autoimmune response in IBM, we searched for autoantibodies both in the periphery and at the site of tissue damage. Peripheral autoantibodies that recognized muscle-derived cells were demonstrated in IBM serum using both immunohistochemistry and flowcytometry. To focus on the site of tissue injury, we examined the immunoglobulin-secreting plasma cells that infiltrate IBM muscle. A series of single, tissue-associated plasma cells were isolated from IBM muscle. Recombinant immunoglobulins (rIgG) produced from these cells were used as molecular tools to search for autoantigens. Flow cytometry and immunoblotting revealed that these tissue-derived rIgGs recognized human muscle tissue-associated antigens. To identify the target of the rIgGs, a multi-step protein separation scheme and mass spectrometry were employed. Desmin, a major intermediate filament protein expressed in muscle, was identified as a candidate autoantigen for one IBM rIgG. Specificity to desmin was confirmed with a solid-phase assay. Collectively, these data indicate that IBM autoimmunity includes a humoral component.
Meningiomas are among the most common adult neoplasms of the central nervous system. Like several other tumor types, these intracranial tumors often harbor an immune cell infiltrate that can include substantial numbers of B cells. Characteristic details of the B cell infiltrate remain undefined. To gain a deeper understanding of both the B cell repertoire and insight into the role they play in this tumor, we characterized the immune infiltrate of resected meningiomas. Immunohistochemistry revealed a conspicuous B cell infiltrate in the microenvironment of most tumors examined. Flow cytometry of tissue homogenate showed that the infiltrate included naïve and memory B cells and differentiated plasma cells. Molecular characterization of the immunoglobulin variable regions expressed by tumor-infiltrating B cells revealed clear evidence of antigen experience, in that the cardinal features of an antigen-driven B cell response were present: significant somatic mutation, isotype switching and codon insertion/deletion. This characterization also revealed the presence of B cell clonal expansion and intraclonal variation. Testing the specificity of recombinant immunoglobulin derived from single, dissected, intra-tumoral B cells revealed that tumor antigens were recognized. These data indicate that an adaptive and specific humoral immune response exists within meningiomas, further suggesting that tumor antigens may drive B cell maturation within the tumor microenvironment.
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