Immunity is based on self/nonself discrimination. In vertebrates, two major systems, innate and adaptive immune systems, constitute host defense against invading microbes. Adaptive immunity is characterized by specific immune responses through B- or T-cell antigen receptors that are generated by somatic recombination, whereas nonspecific responses to microbes had been accentuated in innate immunity. However, the discovery of pattern recognition receptors (PRRs) that are encoded in the germ-line, including Toll-like receptors, RIG-I-like receptors, NOD-like receptors and AIM2-like receptors, advanced our understanding of a mechanism for innate immune recognition. These types of PRR recognize pathogen- or damage-associated molecular patterns (PAMPs or DAMPs) during infection or tissue damage, and commonly evoke the downstream gene induction programme, such as expression of type I interferons, inflammatory cytokines and chemokines. Dysregulation of PRR-triggered signal activation leads to pathologic inflammatory responses. In this regard, it has been shown that many of “autoinflammatory diseases”, recently defined clinical entity, have putatively causative mutations in the genes that encode PRRs or their signaling mediators. In this review article, we describe recent overview of PRRs as innate sensors and update knowledge of “autoinflammatory diseases” particularly by focusing on their association with innate signaling.

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  Inflammation is a host adaptational response to cell injury caused by various exogenous and endogenous stimuli. IL-1β, which is an important proinflammatory cytokine secreted at the site of cellular injury, plays an important role in inflammation. Inflammasome is an intracellular multi-protein complex that mediates caspase-1-dependent processing of IL-1β. In this review, inflammasome function and its dysregulation are discussed in relation to autoinflammatory diseases.

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  Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent and short duration (1-3 days) of fever, and serositis. Based on the nationwide survey of FMF in Japan, the estimated number of Japanese FMF patients is about three hundred. High grade fever was observed in 95.5%, chest pain in 35.8% abdominal pain in 62.7% and arthritis in 31.3% among Japanese FMF patients. AA amyloidosis was confirmed in 5 patients (3.7%). Colchicine was effective in 91.8% of Japanese FMF patients. A significant number of FMF patients exist in Japan, and early diagnosis and treatments should be required to prevent AA amyloidosis.

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  TNF receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder characterized by recurrent febrile attacks. TRAPS is associated with mutation in the gene encoding TNF Receptor I (TNFRI) and seven mutations have been reported in Japan. Molecular modeling experiments indicate that the mutant TNFRI accumulates intracellularly in the endoplasmic reticulum due to misfolding and activates MAP kinase (MAPK) through induction of mitochondrial reactive oxygen species production. MAPK activation is further enhanced by the stimulation through toll-like receptor, resulting in the enhanced proinflammatory cytokine production. Febrile attacks last 21 days on average and occur every one to several months. Myalgia, erythematous macular rash, abdominal pain, conjunctivitis, periorbital edema, chest pain and arthralgia are commonly seen during the attacks. Glucocorticoid is effective in decreasing the severity and duration of the febrile attacks. Soluble TNF receptor etanercept, IL-1 receptor antagonist Anakinra^TM and IL-6 receptor antagonist tocilizumab are effective in some patients. Japanese study group of TRAPS conducted national survey to make new diagnostic criteria in 2010.

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  Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by heterozygous mutations of NLRP3 gene. CAPS consists of three phenotypically similar but distinct syndromes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome and CINCA syndrome. Among them, FCAS shows the mildest phenotype while CINCA is the severest. Common symptoms include sporadic or cold-induced nonpruritic urticarial rash and fever. Severe cases suffers from deafness, meningitis, articular contracture and secondary amyloidosis. Gain-of-function mutations of NLRP3 causes excessive production of a potent proinflammatory cytokine IL-1β, thereby evokes autoinflammatory symptoms of CAPS. Recent advances of anti-IL-1 therapy dramatically improved the prognosis of CAPS. Currently three anti-IL-1 medicines are available, and all of them significantly improved clinical symptoms of CAPS patients. Although long-term observation is still needed, the molecular-targeted therapy has opened up a new opportunity for managing CAPS.

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  Familial Blau syndrome and sporadic early-onset sarcoidosis (EOS) are both systemic granulomatous diseases evoked by the spontaneous activation of mutated NOD2. In Japan, the R334W amino acid substitution is more frequently identified, whereas the R334Q mutation is rare and, in contrast to western countries where disease causing mutations are typically hereditary, most Japanese cases derive from sporadic mutations. Recently, a case with a six-base deletion in the NOD2 gene was reported. This Blau syndrome/EOS patient presented with the unpainful soft swelling of the dorsal side of the wrist and ankles, as well as flexion contracture at the proximal interphalangeal joint that gradually appeared during their clinical course. These features are useful for the differential diagnosis of Blau syndrome/EOS from juvenile idiopathic arthritis. Owing to their characteristic clinical symptoms, Blau and EOS patients can be identified earlier if medical experts become more acquainted with these distinctions. Even though specific treatment based on pathophysiologic mechanism has not been explored yet, early diagnosis will prevent the progression to severe impairment, which can severely affect patients' lives.

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  Hyperimmunogloblinemia D and periodic fever syndrome (HIDS) is inherited autoinflammatory syndrome caused by deficiency of the mevalonate kinase (MK), which is involved in metabolism of cholesterol. The disease is characterized as periodic fever from early infancy accompanied by elevated serum C-reactive protein. Since clinical symptoms such as abdominal symptom, skin rash, and arthritis are common to other autoinflammatory disease, the diagnosis of HIDS during clinical work is difficult for the physicians without suspicion of HIDS for infants suffering from fever of unknown origin. Moreover, serum IgD levels are not high during infancy conflicting to the name of the disease, which is often misunderstood in the clinicians. Thus, the diagnosis of HIDS in Japan is bothering, depending on the lack of correct recognition of the disease and on the lack of commercially available examination for the disease. It is important for clinicians, especially pediatricians to update current knowledge about HIDS and to learn the appropriate way to the definitive diagnosis of HIDS, because HIDS patients exist also in Japan and the specific therapies for HIDS would be developed in the near future.

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  Nakajo-Nishimura syndrome (NNS) (MIM256040, ORPHA2615) is a distinct inherited inflammatory and wasting disease, which usually begins in early infancy with a pernio-like rash. The patients develop periodic high fever and nodular erythema-like eruptions, and gradually progress lipomuscular atrophy in the upper body, mainly the face and the upper extremities, to show the characteristic long clubbed fingers with joint contractures. So far about 30 cases have been reported from Kansai, especially Wakayama and Osaka, Tohoku and Kanto areas. In addition to 10 cases in Kansai area, which have been confirmed to be alive by national surveillance, an infant case has newly been discovered in Wakayama and more cases will be added. Although cause of the disease has long been undefined, a homozygous mutation of the PSMB8 gene, which encodes the β5i subunit of immunoproteasome, has been identified by homozygosity mapping. By analyses of the patients-derived cells and tissues, it has been suggested that accumulation of ubiquitinated and oxidated proteins due to deficiency of proteasome activities cause hyperactivation of p38 MAPK and overproduction of IL-6. Similar diseases with PSMB8 mutations have recently been reported from Europe and the U.S.A., and therefore, it is becoming clear that proteasome deficiency syndromes are globally distributed as a new category of the autoinflammatory diseases.

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  Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is a non-hereditary autoinflammatory disease, characterized by relatively regular recurrence of febrile episodes of 3-6 days duration, accompanied by aphthous stomatitis, pharyngitis/tonsillitis, and/or cervical adenititis. It is considered to be the most common periodic fever syndrome in Japan. Although no responsible gene is identified, some genetic factors may confer the predisposition toward this disorder. Important differential diagnosis includes hereditary periodic syndromes and cyclic neutropenia. Although its etiology is still to be elucidated, a recent study suggested an environmentally triggered activation of complement and IL-1β/IL-18 during PFAPA syndrome flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. This study also demonstrated the possibility that IP-10/CXCL10 might serve as a potential biomarker to differentiate PFAPA syndrome from other periodic fever syndromes. Therapeutic strategy for PFAPA syndrome has not been well established. Recent advances in the understating of etiology and pathophysiology might lead to re-evaluation of recent therapeutic options and/or development of new treatment.

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  Behçet's disease is a systemic inflammatory disease presented with recurrent oral aphtha, cutaneous manifestations, uveitis, and genital ulcer. The etiology of Behçet's disease is still unknown, but both genetic background and environmental factors are thought to be important in the pathogenesis of Behçet's disease. Behçet's disease has long been regarded as a Th1 type autoimmune disease, because of the association with HLA-B51 and hyperreactivity against streptococcal antigen. However, it was recently found that Behçet's disease and autoinflammatory diseases share several clinical features. Furthermore, increased activity of neutrophils and elevated levels of interleukin-1β are observed in both Behçet's disease and autoinflammatory diseases. The relationship between Behçet's disease and autoinflammatory diseases, especially Familial Mediterranean fever, is speculated, because both diseases are prevalent in the Mediterranean basin and treated with colchicine. Genetic researches on Behçet's disease and FMF suggest that the MEFV gene mutated in Familial Mediterranean fever is a probable susceptibility gene for Behçet's disease. Although many observations suggest that Behçet's disease might be autoinflammatory, there is evidence implying autoimmune pathogenesis of Behçet's disease. For example, some symptoms of Behçet's disease is treated with T cell suppressing agents. Recent data suggest that a novel subset of T cells, Th17, plays a crucial role in pathogenesis of Behçet's disease, and genome-wide association researches verified it. IL-17, which is the secreted from of Th17 activates neutrophils. Hence, IL-17 might cause the symptoms resembling autoinflammatory diseases. Recently, Anti-IL-1 treatment proved to be effective and other susceptibility genes are being investigated. These new findings will shed light on the long-sought pathogenesis of Behçet's disease.

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  While tumor necrosis factor (TNF) inhibitors have dramatically improved the clinical outcomes of rheumatoid arthritis (RA) in recent years, infectious complications are a serious concern. Adalimumab (ADA) is a newly-developed human monoclonal antibody against TNF-alpha. Here we report 2 cases of pneumocystis pneumonia (PCP) which developed in RA patients during ADA therapy. One patient is a 66-year-old woman who had a history of RA for 6 months. The patient was given ADA at 40 mg biweekly for her active arthritis which had been refractory to 6 mg/week of methotrexate (MTX), and 5 mg/day of prednisolone (PSL). One hundred and six days later, she was admitted to our hospital because of fever, cough, and dyspnea. Another patient is a 62-year-old man who had a history of RA for 3 years. Since his arthritis was so active even under the treatment with MTX (8 mg/week) and PSL (15 mg/day), the patient started to be given ADA at 40 mg biweekly. After 28 days, the patient was admitted to the hospital because of dyspnea. Chest roentgenogram and computed tomography revealed interstitial pneumonia in both patients. Beta-D-glucan levels were so high in their serum suggesting the diagnosis of PCP, which was confirmed by the detection of Pneumocystis jirovecii DNA in the sputa by polymerase chain reaction. The patients were immediately treated with sulfamethoxazole/trimethoprim and high-dose prednisolone, which successfully improved pneumonia, and they were discharged from the hospital on the 8^th and 16^th day, respectively. PCR and β-D-glucan were useful for the early diagnosis of PCP and lead to the timely induction of adequate treatment and the rescue of these patients.

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  This report describes a 50-year-old woman with coexisting Basedow's disease and adult-onset Still's disease (AOSD) that relapsed simultaneously. She was diagnosed with Basedow's disease in 1999, and treatment with antithyroid agents was started. However, the treatment was soon stopped because of severe side effects. A partial thyroidectomy was performed and the thyroid function stayed well-controlled after the surgery. In August 2007, she was admitted to our hospital with fever, a sore throat, skin rashes, arthritis and leukocytosis, and was diagnosed with AOSD. At the same time, her laboratory data revealed decreased serum TSH and elevated serum free T4, suggesting a relapse of Basedow's disease. After initiation of steroid pulse therapy accompanied by oral prednisolone, both diseases improved significantly. Prednisolone was gradually reduced, and the disease activity remained in remission. Immediately after prednisolone reached 3 mg/day in November 2009, both diseases relapsed. Prednisolone was increased to 30 mg/day, and the diseases became well-controlled again. In this case, Basedow's disease was aggravated when AOSD was in the active stage. Literature searches revealed five previously reported cases with coexisting Basedow's disease and AOSD. In four of the six cases, including our case, both diseases were activated simultaneously. AOSD in the active stage is known to cause hypercytokinemia and immunological derangement. Our case indicated that the pathogenesis of AOSD might lead to relapse of coexisting Basedow's disease.

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  The present article documents a case of Fusobacterium sepsis with a transient anticardiolipin antibody increase in an otherwise healthy 24-year-old patient. He was presented to the emergency room with headache and fever. His temperature was 39.5°C, laboratory results revealed a white blood count of 15.2×10³/μl and C reactive protein 22.6 mg/dl. The patient was admitted. Chest X-ray showed the infiltrate in bilateral lower lung area. He received 400 mg of clarithromycin per day. His all symptoms did not change. On the 8^th day in the hospital, the patient's antibiotics were switched to pazufloxacin. Chest and abdominal CT scan showed some irregular patchy nodules of around 1 cm in diameter in the bilateral lower lung fields and a round low density lesion 3 cm in diameter in the right upper segment (S8) in the liver. Blood culture revealed Fusobacterium necrophorum. On the 10^th day, the antibacterial agent was changed from pazufloxacin to ampicillin sulbactam. On the 17^th day, we added clindamycin. As a result his temperature gradually returned to normal. It is reported that the titer of anticardiolipin antibody increases in the sepsis patients caused by Fusobacterium necrophorum. As his symptoms disappeared, his titer of anticardiolipin antibody also decreased. So we considered he had a transient anticardiolipin titer increase.

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