Osteoclasts, cells of myeloid lineage, play a unique role in bone resorption, maintaining skeletal homeostasis in concert with boneproducing osteoblasts. Osteoclast development and maturation (osteoclastogenesis) is driven by receptor activator of NF-B ligand and macrophage-colony stimulating factor and invariably requires a signal initiated by immunoreceptor tyrosine-based activation motif (ITAM)-harboring Fc receptor common ␥ chain or DNAX-activating protein (DAP)12 (also referred to as KARAP or TYROBP) that associates with the cognate immunoreceptors. Here, we show that a third adaptor, YINM costimulatory motif-harboring DAP10, triggers osteoclastogenesis and bone remodeling. DAP10-deficient (DAP10 ؊/؊ ) mice become osteopetrotic with age, concomitant with a reduction in osteoclasts. The DAP10-associating receptor was identified as myeloid DAP12-associating lectin-1 (MDL-1), whose physiologic function has not been found. MDL-1-mediated stimulation of osteoclast precursor cells resulted in augmented osteoclastogenesis in vitro. MDL-1 associates with both DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages, where DAP10 association depends almost entirely on DAP12, suggesting a formation of MDL-1-DAP12/ DAP10 trimolecular complexes harboring ITAM/YINM stimulatory/ costimulatory motifs within a complex that could be a novel therapeutic target for skeletal and inflammatory diseases.immunoreceptor tyrosine-based activation motif-harboring adaptor ͉ osteoclast development ͉ synergistic signal

Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that TLR7 is present on the cell surface of immune cells and that TLR7 responses can be inhibited by an anti-TLR7 antibody. The anti-TLR7 antibody is internalized with TLR7 and accumulates in endolysosomes as an immune complex. TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-TLR7 antibody. Furthermore, the anti-TLR7 antibody inhibits in vivo cytokine production induced by a TLR7 ligand. Spontaneous TLR7 activation in Unc93b1 D34A/D34A mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-TLR7 antibody treatment. These results demonstrate that cell surface TLR7 is a promising target for therapeutic intervention in autoimmune diseases.

Type 1 diabetes mellitus (T1D) in humans is an organ-specific autoimmune disease in which pancreatic islet β cells are ruptured by autoreactive T cells. NOD mice, the most commonly used animal model of T1D, show early infiltration of leukocytes in the islets (insulitis), resulting in islet destruction and diabetes later. NOD mice produce various islet β cell-specific autoantibodies, although it remains a subject of debate regarding whether these autoantibodies contribute to the development of T1D. FcγRs are multipotent molecules that play important roles in Ab-mediated regulatory as well as effector functions in autoimmune diseases. To investigate the possible role of FcγRs in NOD mice, we generated several FcγR-less NOD lines, namely FcR common γ-chain (FcRγ)-deficient (NOD.γ−/−), FcγRIII-deficient (NOD.III−/−), FcγRIIB-deficient (NOD.IIB−/−), and both FcRγ and FcγRIIB-deficient NOD (NOD.null) mice. In this study, we show significant protection from diabetes in NOD.γ−/−, NOD.III−/−, and NOD.null, but not in NOD.IIB−/− mice even with grossly comparable production of autoantibodies among them. Insulitis in NOD.γ−/− mice was also alleviated. Adoptive transfer of bone marrow-derived dendritic cells or NK cells from NOD mice rendered NOD.γ−/− animals more susceptible to diabetes, suggesting a possible scenario in which activating FcγRs on dendritic cells enhance autoantigen presentation leading to the activation of autoreactive T cells, and FcγRIII on NK cells trigger Ab-dependent effector functions and inflammation. These findings highlight the critical roles of activating FcγRs in the development of T1D, and indicate that FcγRs are novel targets for therapies for T1D.

The Runx1 transcription factor is abundantly expressed in naive T cells but rapidly downregulated in activated T cells, suggesting that it plays an important role in a naive stage. In the current study, Runx1−/−Bcl2tg mice harboring Runx1-deleted CD4+ T cells developed a fatal autoimmune lung disease. CD4+ T cells from these mice were spontaneously activated, preferentially homed to the lung, and expressed various cytokines, including IL-17 and IL-21. Among these, the deregulation of IL-21 transcription was likely to be associated with Runx binding sites located in an IL-21 intron. IL-17 produced in Runx1-deleted cells mobilized innate immune responses, such as those promoted by neutrophils and monocytes, whereas IL-21 triggered humoral responses, such as plasma cells. Thus, at an initial stage, peribronchovascular regions in the lung were infiltrated by CD4+ lymphocytes, whereas at a terminal stage, interstitial regions were massively occupied by immune cells, and alveolar spaces were filled with granular exudates that resembled pulmonary alveolar proteinosis in humans. Mice suffered from respiratory failure, as well as systemic inflammatory responses. Our data indicate that Runx1 plays an essential role in repressing the transcription of cytokine genes in naive CD4+ T cells and, thereby, maintains cell quiescence.