We established a large cohort of incident cases of PM/DM-associated ILD, and successfully identified independent predictors of short-term ILD mortality.

Objective. To examine the physiologic role of natural killer T (NKT) cells bearing V ␣ 14 T cell receptor (TCR) in the pathogenesis of collagen-induced arthritis (CIA) and antibody-induced arthritis in mice.Methods. NKT cells were stained with ␣-galactosylceramide-loaded CD1 dimer, and then assessed using flow cytometry. CIA was induced in mice by immunization on days 0 and 21 with type II collagen (CII) emulsified with an equal volume of Freund's complete adjuvant. Anti-CII antibodies were measured by enzyme-linked immunosorbent assay. For antibodyinduced arthritis, mice were injected with anti-CII monoclonal antibodies (mAb) followed by lipopolysaccharide, or with serum from KRN TCR-transgenic mice crossed with nonobese diabetic mice (K/BxN). The severity of arthritis was monitored with a macroscopic scoring system.Results. The number of NKT cells increased in the liver at the peak of the clinical course of CIA. Administration of anti-CD1 mAb inhibited development of CIA. The severity of CIA in NKT cell-deficient mice was reduced compared with that in wild-type mice. The IgG1:IgG2a ratio of anti-CII was elevated and production of interleukin-10 from draining lymph node cells was increased in NKT cell-deficient mice. NKT celldeficient mice were significantly less susceptible to antibody-induced arthritis.Conclusion. NKT cells contribute to the pathogenesis of arthritis by enhancing autoantibodymediated inflammation. NKT cells also contribute to the disease process in a deleterious way, due, at least in part, to the alteration of the Th1/Th2 balance in T cell response to CII.Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent inflammation of the joints. Affected joints display hyperplasia of the synovia with large cellular infiltrates of several cell types, including neutrophils, macrophages, T cells, B cells, dendritic cells, and fibroblasts. Complement deposition and high levels of proinflammatory cytokine expression are found in the synovial and periarticular regions, and the perpetuation of synovitis results in destruction of the cartilage and bone of the affected joints. Although the etiology of RA remains controversial, cumulative evidence suggests that T cell-mediated autoimmune responses play an important role, and the ensuing inflammation is a critical component in the processes leading to damage of joint cartilage and bone (1).Natural killer T (NKT) cells are a unique subset of T cells that coexpress receptors of the NK lineage and ␣/␤ T cell receptor (TCR). A majority of NKT cells express an invariant TCR␣ chain (encoded by a V ␣ 14-J ␣ 281 rearrangement in mice and a homologous V ␣ 24-J ␣ Q rearrangement in humans). Unlike conventional T cells that recognize peptides in association with the major histocompatibility complex (MHC), V ␣ 14 NKT cells recognize glycolipid antigens such as ␣-galactosylceramide (␣-GC) presented by the nonpolymorphic MHC class I-like protein, CD1d. V ␣ 14 NKT cells have been demonstrated to regulate a variety of immune responses through their...

The newly characterized cytokine IL-38 (IL-1F10) belongs to the IL-1 family of cytokines. Previous work has demonstrated that IL-38 inhibited Candida albicans-induced IL-17 production from peripheral blood mononuclear cells. However, it is still unclear whether IL-38 is an inflammatory or an anti-inflammatory cytokine. We generated anti-human IL-38 monoclonal antibodies in order to perform immunohistochemical staining and an enzyme-linked immunosorbent assay. While human recombinant IL-38 protein was not cleaved by recombinant caspase-1, chymase, or PR3 in vitro, overexpression of IL-38 cDNA produced a soluble form of IL-38 protein. Furthermore, immunohistochemical analysis showed that synovial tissues obtained from RA patients strongly expressed IL-38 protein. To investigate the biological role of IL-38, C57BL/6 IL-38 gene-deficient (−/−) mice were used in an autoantibody-induced rheumatoid arthritis (RA) mouse model. As compared with control mice, IL-38 (−/−) mice showed greater disease severity, accompanied by higher IL-1β and IL-6 gene expression in the joints. Therefore, IL-38 acts as an inhibitor of the pathogenesis of autoantibody-induced arthritis in mice and may have a role in the development or progression of RA in humans.

A characteristic feature of tissue resident human mast cells (MCs) is their hTryptase-␤-rich cytoplasmic granules. Mouse MC protease-6 (mMCP-6) is the ortholog of hTryptase-␤, and we have shown that this tetramer-forming tryptase has beneficial roles in innate immunity but adverse roles in inflammatory disorders like experimental arthritis. Because the key tissue factors that control tryptase expression in MCs have not been identified, we investigated the mechanisms by which fibroblasts mediate the expression and granule accumulation of mMCP-6. Immature mouse bone marrow-derived MCs (mBMMCs) cocultured with fibroblast-like synoviocytes (FLS) or mouse 3T3 fibroblasts markedly increased their levels of mMCP-6. This effect was caused by an undefined soluble factor whose levels could be increased by exposing FLS to tumor necrosis factor-␣ or interleukin (IL)-1␤. Gene expression profiling of mBMMCs and FLS for receptor⅐ligand pairs of potential relevance raised the possibility that IL-33 was a sought after fibroblast-derived factor that promotes tryptase expression and granule maturation via its receptor IL1RL1/ST2. MCs lacking IL1RL1 exhibited defective fibroblast-driven tryptase accumulation, whereas recombinant IL-33 induced mMCP-6 mRNA and protein accumulation in wild-type mBMMCs. In agreement with these data, synovial MCs from IL1RL1-null mice exhibited a marked reduction in mMCP-6 expression. IL-33 is the first factor shown to modulate tryptase expression in MCs at the mRNA and protein levels. We therefore have identified a novel pathway by which mesenchymal cells exposed to inflammatory cytokines modulate the phenotype of local MCs to shape their immune responses. Mast cells (MCs)2 are granulated cells of the myeloid lineage that reside within connective tissues (1). Although it has been known for some time that MCs complete their differentiation and granule maturation after they exit the bone marrow (2-4), the factors and mechanisms governing the final stages of their development remain poorly understood at the molecular level. Although it was originally proposed that the phenotype of a mature MC was irreversibly determined before its progenitor exits the bone marrow, it is now known that human and mouse MCs exhibit substantial plasticity in their development and that MCs can quickly alter the expression of their granule mediators in a cytokine-dependent manner (2, 5-9).All human MCs contain abundant amounts of hTryptase-␤ (10 -12), which is a tetramer-forming serine protease with tryptic-like substrate specificity (13). The ortholog of hTryptase-␤ is mouse MC protease (mMCP)-6 (14, 15). No human has been identified who lacks MCs, in part, because their tryptase-serglycin proteoglycan complexes are essential for combating bacterial and helminthic infections efficiently (16 -18).In the context of inflammatory arthritis, the number of MCs often increases Ͼ10-fold in the chronically inflamed joint (19). Their prominent roles in experimental arthritis and other MCdependent inflammatory disorders have heightened i...