Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) have been characterized in the context of malignancies. Here we show that PMN-MDSCs can restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G+ cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and interleukin-6 (IL-6), and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G+ cells or dysfunction of Ly6G+ cells through conditional ablation of STAT3 led to the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and lack of recovery from EAE. The frequency of CD138+ B cells in the cerebrospinal fluid (CSF) of human subjects with multiple sclerosis was negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells in the inflamed CNS.

Antigen processing and presentation in human muscle: cathepsin S is critical for MHC class II expression and upregulated in inflammatory myopathies.

The immunological properties of muscle cells are of critical importance for both the pathogenesis of inflammatory muscle disorders as well as for understanding and controlling novel therapeutic strategies. Muscle cells can present antigens to both CD4 and CD8 cells. However, the cellular biochemistry of antigen processing and presentation by muscle cells is not clear. Cathepsins play a central role in the generation of antigenic peptide and control transport and maturation of MHC class II molecules. To further elucidate the molecular basis for the MHC class II-mediated antigen presentation by muscle cells, we here analyzed cultured human myoblasts and biopsies from inflammatory myopathies with respect to the expression and function of the constituents of the MHC class II antigen presentation machinery. We identified cathepsin S (CatS) as the dominant endocytic protease that is specifically upregulated under inflammatory conditions to significant mRNA levels, synchronously with HLA-DR, -DM and the class II invariant chain (Ii), both in muscle biopsies from affected individuals with inflammatory myopathies and in human myoblasts cultured in the presence of IFN-gamma. This led to translation of the mature CatS polypeptide that was enzymatically active in human myoblasts under inflammatory conditions. By contrast, expression of CatL and CatB was unaffected by IFN-gamma at both the expression and activity levels. CatS activity is required for efficient surface display of MHC class II in this cell type: functional inhibition of CatS using a CatS-selective inhibitor reduced the levels of surface class II alphabeta:peptide complexes on stimulated myoblasts by almost 50%. Surprisingly, and in contrast to B cells and dendritic cells, this was not due to inefficient processing of Ii in the absence of CatS, which was unaffected by the elimination of CatS activity. We therefore conclude that CatS is involved in the regulation of class II expression in human myoblasts independently from Ii processing.