Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The long-lived plasma cells, which develop after alloantigen sensitization, produce donor specific alloantibodies (DSAs) that generate a positive serum cross-match and preclude transplantation. Bortezomib, a proteasome inhibitor, is being investigated in clinical desensitization protocols, however preclinical studies in a transplant model are nonexistent. We hypothesized that sustained treatment with only a proteasome inhibitor would eliminate plasma cells and reduce DSA over time. Cardiac allografts were transplanted into murine recipients. Eight weeks after allograft rejection the proteasome inhibitor, bortezomib, was injected intravenously twice weekly for 60 days. Serum alloantibody responses were assayed using flow cross-match. Total and alloreactive plasma cell numbers were enumerated using flow cytometry and ELISPOT. All recipients of cardiac allografts rejected their graft promptly within 16 days and demonstrated alloantibody by flow cross-match. DSA was sustained in the control mice while mice treated with bortezomib had sustained elimination of DSA and a marked reduction in plasma cell population. Also, bortezomib was associated with an increased level of BLyS. Within a murine model, proteasome inhibition can eliminate alloantibody secreting plasma cells, and reduce alloantibody. Cessation of bortezomib is not associated with return of DSA.
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PMID:Sustained reduction of alloantibody secreting plasma cells and donor specific antibody with proteasome inhibition in mice. 2410 31

B lymphocytes are crucial mediators of systemic immune responses and are known to be substantial in the pathogenesis of autoimmune diseases with cutaneous manifestations. Amongst them are lupus erythematosus, dermatomyositis, systemic sclerosis and psoriasis, and particularly those driven by autoantibodies such as pemphigus and pemphigoid. However, the concept of autoreactive skin-associated B cells, which may reside in the skin and locally contribute to chronic inflammation, is gradually evolving. These cells are believed to differ from B cells of primary and secondary lymphoid organs and may provide additional features besides autoantibody production, including cytokine expression and crosstalk to autoreactive T cells in an antigen-presenting manner. In chronically inflamed skin, B cells may appear in tertiary lymphoid structures. Those abnormal lymph node-like structures comprise a network of immune and stromal cells possibly enriched by vascular structures and thus constitute an ideal niche for local autoimmune responses. In this review, we describe current considerations of different B cell subsets and their assumed role in skin autoimmunity. Moreover, we discuss traditional and B cell-associated approaches for the treatment of autoimmune skin diseases, including drugs targeting B cells (e.g., CD19- and CD20-antibodies), plasma cells (e.g., proteasome inhibitors, CXCR4 antagonists), activated pathways (such as BTK- and PI3K-inhibitors) and associated activator molecules (BLyS, APRIL).
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PMID:Skin-Associated B Cells in the Pathogenesis of Cutaneous Autoimmune Diseases-Implications for Therapeutic Approaches. 3329 81