We report here that B lymphocytes from SLE-afflicted mice express relatively elevated levels of CD74, compared with B cells

from healthy mice. CD74 is a receptor found in complex with CD44, and it binds the pro-inflammatory cytokine MIF. The latter components were also up-regulated in B cells from the diseased mice, and treatment with hCDR1 resulted in their down-regulation and in reduced B-cell survival. Furthermore, up-regulation of CD74 and Venetoclax concentration CD44 expression was detected in brain hippocampi and kidneys, two target organs in SLE. Treatment with hCDR1 diminished the expression of those molecules to the levels determined for young healthy mice. These results suggest that the CD74/MIF pathway plays an important role in lupus pathology. Systemic lupus

erythematosus (SLE) is an autoimmune disease characterized by impaired B-cell and T-cell functions and it is associated with serological and clinical manifestations that involve multiple organ systems.1 Because B and T cells play a pivotal role in SLE pathogenesis, successful treatment strategies for the disease should optimally target both cell types. For a specific treatment of SLE, a peptide designated hCDR1,2 which is based on the sequence of the complementarity-determining region (CDR) -1 of an autoantibody,3 was designed and shown to ameliorate lupus manifestations in both spontaneous and induced models of SLE.4,5 The mechanisms underlying the beneficial effects of hCDR1 are manifested through the induction of CD4+ CD25+6 MK-1775 chemical structure and CD8+ CD28−7 regulatory T cells, immunomodulation of cytokines,4 Ribose-5-phosphate isomerase apoptosis8 and induction of regulatory molecules.9–11 Serologically, SLE is characterized by the presence of high titres of autoantibodies and abnormal B-cell activation and differentiation.12 The regulation of mature B-cell survival involves multiple mechanisms. The B-cell receptor provides survival

signals essential for maintaining the mature B-cell pool. In addition, the B-cell activating factor (BAFF) is required for successful survival and maturation of splenic B cells.13 We demonstrated that BAFF, which was found to be elevated in sera from patients with SLE and lupus-prone mice,14,15 was down-regulated following treatment with hCDR1 in SLE-afflicted mice.16 Recently, we described an additional mechanism that regulates B-cell survival, which depends on CD74 (the cell surface form of invariant chain, li).17–19 CD74 is a type II integral membrane protein containing a transmembrane region and a luminal domain that functions as a MHC class II chaperone.20 Part of the CD74 molecule, modified by the addition of chondroitin sulphate, is expressed on antigen-presenting cells, monocytes and B cells, and interacts with CD44.21,22 Macrophage migration inhibitory factor (MIF) binds to the CD74 extracellular domain on macrophages, consequently initiating a signalling pathway.