Mouse models are similar but not identical to human diseases. However, they are important for research into the pathogenesis underlying autoimmune diseases because they allow us to evaluate similarities and differences between human diseases and mouse models. There are many inbred strains of systemic lupus erythematosus (SLE)-prone mice including New Zealand Black (NZB), F1 hybrids of NZB x New Zealand White (NZW) (B/W F1), MRL/Mp-lpr/lpr (MRL/lpr), and BXSB mice. The postulated etiology of these murine diseases includes many genetic and extrinsic factors such as retroviruses, an impaired balance of T cell interaction, ultraviolet irradiation, etc. For examples, genetic studies of MRL/lpr mice revealed that the appearance of macroscopic LE-like skin lesions needs the lpr mutation plus an additional factor in an autosomal dominant fashion. The candidate is ultraviolet (UV) B light, the susceptibility to which is regulated by the genetic background. Such abnormalities described in SLE now span the spectrum from innate immunity to acquired immunity. In this review, based on historical review, we focus on skin lesions from the well-studied MRL/lpr and B/W F1 mouse and discuss how SLE-prone mice can contribute to a better understanding of cutaneous LE pathogenesis.

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  Dendritic cells are one of antigen presenting cells and are thought to play an important role in the establishment of immune responses. However, recent advances in immunology have revealed that there exist several dendritic cell subsets in the skin. In addition, a certain dendritic cell subset is able to regulate cutaneous immune responses. We used contact hypersensitivity as a cutaneous immune response model and review the recent advances in the roles of dendritic cells in contact hypersensitivity.

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  A recent proteomics study of multiple sclerosis (MS) brain lesion-specific proteome profiling clearly revealed a pivotal role of coagulation cascade proteins in chronic active demyelination (Han MH et al. Nature 451 : 1076-1081, 2008). However, among thousands of proteins identified, nearly all of remaining proteins were left behind to be characterized in terms of their implications in MS brain lesion development. By the systems biology approach using four different pathway analysis tools of bioinformatics, we studied molecular networks and pathways of the proteome dataset of acute plaque (AP), chronic active plaque (CAP), and chronic plaque (CP). The database search on KEGG and PANTHER indicated the relevance of extracellular matrix (ECM)-mediated focal adhesion and integrin signaling to CAP and CP proteome. IPA identified the network constructed with a wide range of ECM components as one of the networks highly relevant to CAP proteome. KeyMolnet disclosed a central role of the complex interaction among diverse cytokine signaling pathways in brain lesion development at all disease stages, as well as a role of integrin signaling in CAP and CP. Although four distinct platforms produced diverse results, they commonly suggested a role of ECM and integrin signaling in development of chronic lesions of MS. These observations indicate that the selective blockade of the interaction between ECM and integrins would be a rational approach for designing inhibitors of chronic inflammatory demyelination in MS brain lesions.

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  CD69 is a type II membrane protein expressed as a homodimer composed of heavily glycosylated subunits. CD69 is known as an early activation marker antigen of lymphocytes,and its selective expression in inflammatory infiltrates suggests that it plays a role in the pathogenesis of inflammatory diseases. In order to address the role of CD69 in the pathogenesis of arthritis and allergic airway inflammation, we established CD69-deficient mice. CD69-deficient mice displayed a markedly attenuated arthritic inflammatory response and airway inflammation. The administration of anti-CD69 antibody inhibited the induction of the antigen-induced airway inflammation and hyperresponsiveness. These results indicate that CD69 plays a crucial role in the pathogenesis of arthritis and allergic airway inflammation and that CD69 could be a possible therapeutic target for arthritis and asthma in human patients.

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  CD4⁺CD25⁺ T cells which have also been described as regulatory T cells (Treg), have immune inhibitory functions in the immune system. This population inhibits excessive immune responses, such as those present in patients with autoimmune disease, allergy and inflammation, and plays an important role in maintenance of immunological homeostasis. It has been demonstrated that the FOXP3 gene is a master gene for a transcriptional factor of Tregs. This finding has led to the elucidation of the Treg functions during development, differentiation and immune suppression.
  Either a deficiency or dysfunction of Tregs results in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked) syndrome. The clinical features of IPEX syndrome include chronic dermatitis, enteropathy characterized by severe and refractory diarrhea, and autoimmune endocrinopathy, such as early-onset insulin-dependent diabetes mellitus, thyroiditis, or both. This syndrome is also associated with various symptoms such as anemia, thrombocytopenia and nephritis which may be caused by an autoimmune response.
  We herein describe the clinical and molecular characteristics of patients with IPEX syndrome and also elucidate the function of human Treg cells.

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  Anti-endothelial cell antibodies (AECA) were antibodies targeting the antigens expressed on the endothelial cell surface. It has been reported that AECA were detected frequently in patients with vasculitis and were associated with disease activity and vasculitis symptoms. Consequently, AECA are thought to be involved in pathophysiology of vasculitis, including Kawasaki disease (KD) ; however, the role of AECA is not clear yet. One of the causes is that target proteins of AECA have been poorly identified. Therefore, we try to detect new target proteins of AECA in patients with vasculitis using proteomics. We have identified 63 proteins out of about 150 endothelial cell-specific candidate target proteins of AECA in patients with vasculitis so far. One of the identified proteins was peroxiredoxin2 (Prx2), an antioxidant enzyme. Our research suggests that the anti-Prx2 antibodies are detected frequently in patients with vasculitis and may have pathogenic roles in vasculitis via inflammatory cytokines/chemokines production and inhibition of anti-oxidative activity of Prx2. In this paper, we overview our study of the autoantigens detected by AECA in patients with vasculitis, and will provide some data on clinical significance of autoantibodies to Prx2, a target protein of AECA, in patients with KD.

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  Th17 cells, though having been discovered just few years ago, is believed as the pathogenic T cells in many autoimmune diseases and chronic inflammatory diseases, such as rheumatoid arthritis (RA). Biologics targeting IL-17 have already been on clinical trial, and the results were recently reported. Although the importance of Th17 cells in animal models of arthritis is unquestionable, it is not recognized that there are only limited data on the role of Th17 cells and related cytokines in human arthritic diseases. In addition, the characteristics of human Th17 cells have not been fully defined, and there seem to be substantial differences between human and mouse Th17 cells. In this review, I will introduce and discuss about updated findings on human Th17 cells and its relation with human arthritic diseases.

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  Sjögren's syndrome (SS) is an autoimmune disease that affects exocrine glands including salivary and lacrimal glands. It is characterized by lymphocytic infiltration into exocrine glands, leading to dry mouth and eyes. A number of auto-antibodies, such as anti-SS-A and SS-B antibodies, are detected in patients with SS. However, no SS-specific pathologic auto-antibodies have yet been found in this condition. M3 muscarinic acetylcholine receptor (M3R) plays a crucial role in the secretion of saliva from salivary glands. It is reported that some patients with SS carried inhibitory auto-antibodies against M3R. To clarify the epitopes and function of anti-M3R antibodies in SS, we examined antibodies to the extracellular domains (N terminal region, the first, second, and third extracellular loop) of M3R by ELISA using synthesized peptide antigens encoding these domains in 42 SS and 42 healthy controls (HC). Titers and positivity of anti-M3R antibodies to every extracellular domain of M3R were significantly higher in SS than in HC. For functional analysis, human salivary gland (HSG) cells were pre-cultured with IgG from anti-M3R antibodies positive SS, negative SS, and HC. HSG cells were stimulated with cevimeline hydrochloride and intracellular calcium concentration ([Ca²⁺]_i) was measured. IgG from anti-M3R antibodies to the second loop positive SS inhibited the increase of [Ca²⁺]_i, but IgG from antibodies to the N terminal or the first loop positive SS enhanced it, while IgG from antibodies to the third loop positive SS showed no effect on [Ca²⁺]_i as well as IgG from anti-M3R antibodies negative SS and HC. These findings indicated the presence of several B cell epitopes on M3R in SS and effect of anti-M3R antibodies on the salivary secretion might differ with these epitopes.

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