The pathological findings in collagen disease, which was originally proposed by Klemperer et al. in 1942, show complex lesions with glomerulonephritis, vasculitis, polyarthritis and/or sialoadenitis etc. It is still controversial whether such diversity and similarity of the lesions among collagen diseases depend on an ambiguity in diagnosis or an intrinsic quality of the diseases. In the study of susceptibility loci to collagen disease in MRL mouse models, we learned that several lesions such as glomerulonephritis, vasculitis, arthritis and sialoadenitis developed in a cumulative effect of multiple gene loci, each of which by itself did not have a significant effect to induce the related phenotype, thus indicating a polygenic system. The mice developed each lesion in an additive manner with a hierarchical effect. Some of the susceptibility loci seemed to be common to those in other collagen diseases as well. Some of the positional candidate genes showed an allelic polymorphism in the coding region, possibly causing a qualitative difference in their function. As a result, a particular combination of polygenes with such an allelic polymorphism may thus play a critical role in leading the cascade reaction to develop lesions, and also a regular variation of collagen disease. This is designated as the polygene network in collagen disease.

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  Rheumatoid arthritis (RA) is a complex mutifactorial autoimmune disease. As anti-citrullinated peptide antibodies (ACPA) exhibit unique specificity for RA, breakdown of immunological tolerance to citrullinated self-proteins is considered to be a key feature of RA pathogenesis. While environmental factors such as smoking and viral infections have been implicated in the pathogenesis, recent genome-scans for RA have unraveled multiple genetic factors involved in RA. Some of these genetic factors may specifically contribute to the tolerance breakdown of RA. For instance, PADI4 gene encoding an enzyme that converts arginine residues to citrullines may enhance the production of auto-antigens. These citrullinated proteins are then presented to helper T-cells via HL-DR molecule on the antigen presenting cells, where specific HLA-DRB1 alleles encoding “shared-epitope” have significant relevance to RA. On the other hand, genes regulating the activity of lymphocytes such as PTPN22 and FCRL3 may influence auto-reactivity of individual lymphocytes. Taken together, combination of these genetic factors accelerates autoimmune response in RA.

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  Recent large-scale studies in the Caucasian populations identified many new susceptibility genes to systemic lupus erythematosus (SLE). In this review, we discuss our findings on some of such genes, interferon regulatory factor 5 (IRF5), signal transducer and activator of transcription 4 (STAT4) and B lymphoid tyrosine kinase (BLK), in the Japanese population. All of these genes were associated with SLE also in Japanese; however, there are notable differences. In IRF5, the risk haplotype in Caucasians was not present in Japanese. Instead, a SNP that does not exist in Caucasians defined a protective haplotype in Japanese. In STAT4 and especially in BLK, the risk allele frequency was substantially larger in the Japanese population than in Caucasians; as a result, the genetic contribution of these genes in the population is considered to be greater in the Japanese. Presence of susceptibility genes shared by the Caucasian and Asian populations as well as population-specific susceptibility genes was supported by the first genome-wide association study in the Asians published from China in 2009.
  We and other investigators also found that IRF5, STAT4 and BLK are associated not only with SLE, but also rheumatoid arthritis and systemic sclerosis. Thus, a substantial proportion of susceptibility genes are shared by multiple autoimmune rheumatic diseases.

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  Autoimmune thyroid disease (AITD), including Graves'disease (GD) and Hashimoto's thyroiditis (HT), is caused by immune response to self-thyroid antigens, and affects up to 2-5% of the general population. Twin studies and familial aggregation have clearly indicated the involvement of genetic factors with AITD in addition to environmental factors. Known AITD-susceptibility genes are classified into three categories: HLA genes, non-HLA immune-related genes, and thyroid-specific genes. A comprehensive catalogue of AITD-susceptibility genes with major effects will facilitates elucidating the molecular mechanisms underlying the initiation of AITD. Genome-wide association studies conducted for autoimmune diseases in the last few years have identified a significant number of novel loci contributing disease risk. In this review, we describe the current status of genome-wide association studies for GD and the recent advances in the functional characterization of ZFAT, an AITD-related transcription factor previously identified by our genetic analyses for the Japanese GD population.

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  Kawasaki disease is an acute febrile illness of infants and children with unknown etiology. Coronary artery lesions occurring in 20-25% of untreated patients of KD has made KD a leading cause of acquired heart diseases of childhood in developed countries. High prevalence in East Asian countries is one of the epidemiological features of KD and has suggested genetic factors underlying the disease pathogenesis. We tried to identify genetic variants relevant to KD susceptibility by sibpair linkage study and linkage diseuilibrium mapping with SNPs and found that inositol 1,4,5-trisphosphate 3-kianse C gene is a susceptibility gene for KD. We also found the negative regulatory role of ITPKC in TCR signaling and the mechanism by which the responsible SNP in intron 1 of the gene affects transcripts level of ITPKC. Our findings highlighted the importance of Ca²⁺/NFAT pathway in the pathogenesis of KD and shed light on the possibility of immuno-suppressants targeting the pathway as a therapeutic strategy for KD.

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  Systemic sclerosis is characterized by tissue fibrosis, obliterative microangiopathy and immune abnormalities. The etiology of SSc is largely unknown and is known to be resistant to existing corticosteroid and immunosuppressive drugs. Therefore, establishment of a treatment strategy especially for SSc patients with organ involvement is strongly desired. Mast cells are widely recognized as effector cells in allergic disorders and other IgE-mediated immune responses. However, recently, mast cells have become known to play a role in bridging innate immunity and adaptive immunity. Additionally, there is growing evidence of mast cell to be involved in pathogenesis of rheumatoid arthritis, and is expected as a novel therapeutic target. We describe here the role of mast cell in SSc pathology and suggest as a novel therapeutic target.

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  Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of salivary glands, in which CD4⁺ T cells are predominant. These infiltrating T cells play a crucial role in the generation of SS. Previous studies showed that autoantibodies and auto-reactive T cells against M3 muscarinic acethylcholine receptor (M3R) were detected in patients with SS. In this study, to reveal the pathological mechanisms underlying immune response against M3R, we tried to induce SS like sialoadenitis. M3R knockout (M3R^−/−) mice were immunized with murine M3R peptides. Their splenocytes were isolated and transferred into Rag1 knockout (Rag1^−/−) mice. Mononuclear cells infiltration was detected in salivary glands of Rag1^−/− mice inoculated splenocytes of M3R^−/− mice immunized with M3R peptides. Moreover we transferred CD3⁺ cells from splenocytes of M3R^−/− mice immunized with M3R peptides into Rag1^−/− mice. In their salivary glands, mononuclear infiltration was also detected. These findings suggest that the immune response to M3R plays a crucial role in the generation of SS like sialoadenitis.

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  We have recently reported a murine novel regulatory T cell population, CD4⁺CD25⁻LAG-3⁺ regulatory T cells (Tregs). Microarray analysis revealed that CD4⁺CD25⁻LAG-3⁺ Tregs had a unique mRNA expression profile that was different from the conventional CD4⁺CD25⁺ regulatory T cells. In particular, CD4⁺CD25⁻LAG-3⁺ Tregs characteristically expressed early growth response gene 2 (Egr-2) that was reported to be associated with the induction of anergy. CD4⁺CD25⁻LAG-3⁺ Tregs produced high-amount of IL-10 in response to TCR stimulation and showed immunosuppressive activity in vitro and in vivo. Retroviral gene transfer of Eg-2 converted naïve CD4⁺ T cells into IL-10-secreting and LAG-3-expressing T cells, and Egr-2 transduced CD4⁺ T cells exhibited antigen-specific immunosuppressive capacity in vivo.
  On the basis of these observations, we have attempted to identify a human counterpart of murine CD4⁺CD25⁻LAG-3⁺ Tregs in human. CD4⁺CD25⁻LAG-3⁺ T cells were found in human in similar pattern as murine CD4⁺CD25⁻LAG-3⁺ Tregs. In the quantitative PCR, human CD4⁺CD25⁻LAG-3⁺ T cells expressed high levels of IL-10. From the microarray analysis, we found the close similarity between human CD4⁺CD25⁻LAG-3⁺ T cells and murine CD4⁺CD25⁻LAG-3⁺ Tregs. Therefore, human CD4⁺CD25⁻LAG-3⁺ T cells might be a human counterpart of murine CD4⁺CD25⁻LAG-3⁺ Tregs.

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  A 56-year-old-woman presented a local otolaryngologist with a complaint of hearing loss. She was treated with antibiotics as acute otitis media, however her symptom did not improved. She admitted to our hospital because of hearing loss on both sides, fever, otorrhea and vertigo. On admission, an audiogram showed bilateral mixed conductive-sensorineural hearing loss, and CT image revealed the exudates in bilateral middle ear cavities and mastoid air cells. Moreover, serum level of myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) elevated (133EU). Although pulmonary, renal and cutaneous involvements were not noted and the histopathological examination of operated specimen taken from otitis media revealed non-specific inflammatory changes, in the absence of any other obvious causes of otitis media, these findings might be associated with positive serum MPO-ANCA value itself. After the initiation of therapy with methylprednisolone and azathioprine, her symptoms and hearing ability ameliorated and both CRP value and the titer of ANCA became normalized. But, after the improvement by the immunosuppressive treatment, MRSA in the otorrhea persisted. This case suggests that otitis media may be one of the symptoms of vasculitis, and some previous cases described otitis media or hearing loss as rare manifestations of vasculitis. It is important to make an early diagnosis for good prognosis of hearing ability, and we have to consider the differential diagnosis including of ANCA-related vasculitis.

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  A 63-year-old-man was diagnosed in March 2002 with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis because of mononeuritis multiplex, interstitial pneumonia and a positive finding for myeloperoxidase (MPO)-ANCA. Although treated with prednisolone and oral cyclophosphamide, he suffered repeated remission and deterioration of his conditon, which was complicated by hypertrophic pachymeningitis and sinusitis. In July 2006, he was diagnosed with an exacerbation of ANCA-associated vasculitis because of pyrexia, general malaise, numbness in his face and legs, and elevated serum CRP level. Steroid pulse therapy was thus initiated and the patient's clinical symptoms improved. However, serum CRP levels elevated again (5.18 mg/dl) in September 2006. We began administration of rituximab (500 mg/body×4 times) in November 2006 and his symptom and laboratory data significantly improved. The dose of prednisolone was slowly decreased without suffering a relapse. Rituximab has been administered every one year, and good disease control has been achieved. Diagnosis of Wegener's granulomatosis was made from the findings of a nodular lesion in the left lung. Rituximab should be considered for patients with refractory ANCA-associated vasculitis.

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  We report a case of MPA with cerebral infarction and hemorrhage. A 72-year-old man was admitted to our hospital because of high fever, speech failure, and weakness of the left limbs in April 2008. Magnetic resonance imaging of the head showed cerebral infarction at the right corona radiata. Mononeuropathy multiplex and renal dysfunction (Cr 1.46 mg/dl) were noted. Urinalysis revealed occult blood, proteinuria and granular casts. White blood cell count was 11960/ul, CRP concentration was 12.9 mg/dl, and the MPO-ANCA titer was 330 EU. Computed tomography of the abdomen revealed arterial aneurysms in the kidney. The patient was diagnosed with microscopic polyangiitis (MPA). On the 8th day after hospital admission, a new cerebral hemorrhage occurred at the right thalamus. Prednisolone (1 mg/kg/day) and intravenous pulse cyclophosphamide (200 mg) were initiated. Because the patient's MPA was refractory, methylprednisolone pulse therapy (1000 mg/day×3 days) was added to his treatment regimen, and he received plasma exchange (20 U/day) and double filtration plasmapheresis twice each ; after this, his MPA recovered. Cerebral infarction and hemorrhage are rare complications in MPA and are associated with poor prognosis. Published literature on these complications is reviewed.

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