No abstract

Key Points C1q can form a multimolecular signaling complex with HMGB1, RAGE, and LAIR-1 in lipid rafts. C1q and HMGB1 together promote monocytes to differentiate to an anti-inflammatory phenotype.

Plasma cells (PCs) are responsible for the production of protective antibodies against infectious agents but they also produce pathogenic antibodies in autoimmune diseases, such as systemic lupus erythematosus (SLE). Traditionally, high affinity IgG autoantibodies are thought to arise through germinal center (GC) responses. However, class switching and somatic hypermutation can occur in extrafollicular (EF) locations, and this pathway has also been implicated in SLE. The pathway from which PCs originate may determine several characteristics, such as PC lifespan and sensitivity to therapeutics. Although both GC and EF responses have been implicated in SLE, we hypothesize that one of these pathways dominates in each individual patient and genetic risk factors may drive this predominance. While it will be important to distinguish polymorphisms that contribute to a GC-driven or EF B cell response to develop targeted treatments, the challenge will be not only to identify the differentiation pathway but the molecular mechanisms involved. In B cells, this task is complicated by the cross-talk between the B cell receptor, toll-like receptors (TLR), and cytokine signaling molecules, which contribute to both GC and EF responses. While risk variants that affect the function of dendritic cells and T follicular helper cells are likely to primarily influence GC responses, it will be important to discover whether some risk variants in the interferon and TLR pathways preferentially influence EF responses. Identifying the pathways of autoreactive PC differentiation in SLE may help us to understand patient heterogeneity and thereby guide precision therapy.

High-grade osteosarcoma occurs predominantly in adolescents and young adults and has an overall survival rate of about 60%, despite chemotherapy and surgery. Therefore, novel treatment modalities are needed to prevent or treat recurrent disease. Natural killer (NK) cells are lymphocytes with cytotoxic activity toward virus-infected or malignant cells. We explored the feasibility of autologous and allogeneic NK cell–mediated therapies for chemotherapy-resistant and chemotherapy-sensitive high-grade osteosarcoma. The expression by osteosarcoma cells of ligands for activating NK cell receptors was studied in vitro and in vivo, and their contribution to NK cell–mediated cytolysis was studied by specific antibody blockade. Chromium release cytotoxicity assays revealed chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines and osteosarcoma primary cultures to be sensitive to NK cell–mediated cytolysis. Cytolytic activity was strongly enhanced by IL-15 activation and was dependent on DNAM-1 and NKG2D pathways. Autologous and allogeneic activated NK cells lysed osteosarcoma primary cultures equally well. Osteosarcoma patient–derived NK cells were functionally and phenotypically unimpaired. In conclusion, osteosarcoma cells, including chemoresistant variants, are highly susceptible to lysis by IL-15-induced NK cells from both allogeneic and autologous origin. Our data support the exploitation of NK cells or NK cell–activating agents in patients with high-grade osteosarcoma.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-010-0965-3) contains supplementary material, which is available to authorized users.

IntroductionMast cells have been implicated to play a functional role in arthritis, especially in autoantibody-positive disease. Among the cytokines involved in rheumatoid arthritis (RA), IL-17 is an important inflammatory mediator. Recent data suggest that the synovial mast cell is a main producer of IL-17, although T cells have also been implicated as prominent IL-17 producers as well. We aimed to identify IL-17 expression by mast cells and T cells in synovium of arthritis patients.MethodsSynovial samples of anticitrullinated protein antibody-positive (ACPA+) and ACPA-negative (ACPA-) RA and osteoarthritis (OA) patients were stained for IL-17 in combination with CD117 (mast cells), CD3 (T cells) and CD68 (macrophages). Concentrations of IL-17 in synovial fluid were determined by ELISA.ResultsThe number of IL-17+ cells in synovium was comparable in all groups. Although the vast majority of IL-17+ cells are mast cells, no difference in the percentage of IL-17+ mast cells was observed. Nonetheless, levels of IL-17 in synovial fluid were increased in ACPA+ RA patients compared to ACPA- RA and OA patients.ConclusionsThe synovial mast cell is the main IL-17+ cell in all three arthritis groups analyzed. These data are relevant for studies aimed at blocking IL-17 in the treatment of arthritis.

Objective Mast cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). In particular, their activation by interleukin‐33 (IL‐33) has been linked to the development of arthritis in animal models. The aim of this study was to evaluate the functional responses of human mast cells to IL‐33 in the context of RA. Methods Human mast cells were stimulated with IL‐33 combined with plate‐bound IgG or IgG anti–citrullinated protein antibodies (ACPAs), and their effects on monocyte activation were evaluated. Cellular interactions of mast cells in RA synovium were assessed by immunofluorescence analysis, and the expression of messenger RNA (mRNA) for mast cell–specific genes was evaluated in synovial biopsy tissue from patients with early RA who were naive to treatment with disease‐modifying antirheumatic drugs. Results IL‐33 induced the up‐regulation of Fcγ receptor type IIa and enhanced the activation of mast cells by IgG, including IgG ACPAs, as indicated by the production of CXCL8/IL‐8. Intriguingly, mast cell activation triggered with IL‐33 and IgG led to the release of mediators such as histamine and IL‐10, which inhibited monocyte activation. Synovial mast cells were found in contact with CD14+ monocyte/macrophages. Finally, mRNA levels of mast cell–specific genes were inversely associated with disease severity, and IL‐33 mRNA levels showed an inverse correlation with the levels of proinflammatory markers. Conclusion When human mast cells are activated by IL‐33, an immunomodulatory phenotype develops, with human mast cells gaining the ability to suppress monocyte activation via the release of IL‐10 and histamine. These findings, together with the presence of synovial mast cell–monocyte interactions and the inverse association between the expression of mast cell genes at the synovial level and disease activity, suggest that these newly described mast cell–mediated inhibitory pathways might have a functional relevance in the pathogenesis of RA.

Our data show that synovial mast cells express FcγRIIA and that mast cells can be activated by IgG-ACPA and TLR ligands. Importantly, combined stimulation via TLRs and immune complexes leads to synergy in cytokine production. These findings suggest mast cells are important targets for TLR ligands and immune complexes, and that combined activation of mast cells via these pathways greatly enhances inflammation in synovial tissue of RA patients.

Mast cells (MCs) are immune cells residing in tissues where pathogens are first encountered. It has been indicated that MCs might also be involved in setting the outcome of T-cell responses. However, little is known about the capacity of human MCs to express MHC class II and/or to capture and present antigens to CD4(+) T cells. To study the T-cell stimulatory potential of human MCs, CD34(+) stem cell derived MCs were generated. These cells expressed HLA-DR when stimulated with IFN-γ, and, importantly, presented peptide and protein for activation of antigen-specific CD4(+) T cells. The interplay between MC and T cell led to increased HLA-DR expression on MCs. MCs were present in close proximity to T cells in tonsil and expressed HLA-DR and CD80, indicating their ability to present antigens to CD4(+) T cells in T-cell areas of human LNs. Our data show that MCs can present native antigens to human CD4(+) T cells and that HLA-DR expressing MCs are present in tonsil tissue, indicating that human MCs can directly activate T cells and provide a rationale to study the potential of MCs to prime and/or skew human T-cell responses.