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Purpose: Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature., Methods: The type I IFN signature was measured in patients' whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature., Results: A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling., Conclusions: Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miyamoto, Honda, Izawa, Kanazawa, Kadowaki, Ohnishi, Fujimoto, Kambe, Kase, Shiba, Nakagishi, Akizuki, Murakami, Bamba, Nishida, Inui, Fujisawa, Nishida, Iwata, Otsubo, Ishimori, Nishikori, Tanizawa, Nakamura, Ueda, Ohwada, Tsuyusaki, Shimizu, Ebato, Iwao, Kubo, Kawai, Matsubayashi, Miyazaki, Kanayama, Nishitani-Isa, Nihira, Abe, Tanaka, Hiejima, Okada, Ohara, Saito, Takita, Nishikomori and Yasumi.)

Nakajo-Nishimura syndrome (ORPHA2615; also registered as Nakajo syndrome in OMIM#256040) is a distinct inherited inflammatory and wasting disease, originally reported from Japan. This disease usually begins in early infancy with a pernio-like rash, especially in winter. 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 thin facial appearance and long clubbed fingers with joint contractures. So far about 30 cases have been reported from Kansai, especially Wakayama and Osaka, Tohoku and Kanto areas. At present, about 10 cases are confirmed to be alive only in the Kansai area, including one infant case in Wakayama. However, more cases are expected to be added in the near future. 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 to be responsible in 2011. By analyses of the patients-derived cells and tissues, it has been suggested that accumulation of ubiquitinated and oxidated proteins due to immunoproteasome dysfunction causes hyperactivation of p38 mitogen-activated protein kinase and interleukin-6 overproduction. Since similar diseases with PSMB8 mutations have recently been reported from Europe and the United States, it is becoming clear that Nakajo-Nishimura syndrome and related disorders form proteasome disability syndromes, a new category of autoinflammatory diseases distributed globally.

Objective: Recent genome-wide association studies have identified polymorphisms of lymphotoxin-α (LTA), galectin-2 (LGALS2), and proteasome subunit a type 6 (PSMA6) genes as genetic risk factors for myocardial infarction (MI). However, their effects on coronary atherosclerosis, an intermediate phenotype of MI, remain largely unknown., Methods: We investigated the correlation between polymorphisms of the LTA, LGALS2, and PSMA6 genes and the severity of pathological coronary stenosis index (CSI) and MI in 1503 consecutive autopsy cases of Japanese elderly patients., Results: The polymorphisms LTA rs1041981 and LGALS2 rs7291467 were associated with CSI with odds ratios of 1.54 (95% CI, 1.17-2.01; AA+CA over CC) and 1.62 (95% CI, 1.11-2.37; TT over CC+CT), respectively. PSMA6 rs1048990 was not associated with CSI. None of the SNPs was associated with MI in our sample., Conclusion: Our findings indicate that the LTA and LGALS2 polymorphisms affect the subclinical phenotype of the coronary artery, which predisposes to the incidence of MI., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

Coronary artery disease (CAD) has become a major health problem in many countries because of its increasing prevalence and high mortality. Recently, an association of a functional sequence variation, -8C>G, in the human proteasome subunit alpha type 6 gene (PSMA6) with the susceptibility to CAD was reported. To validate the association, we investigated a total of 1330 cases and 2554 controls from Japanese and Korean populations for PSMA6 genotypes, and no evidence of the association was obtained in both Japanese (odds ratio (OR)=1.03, 95% confidence interval (CI); 0.90-1.19, P=0.66, allele count model) and Korean populations (OR=1.00, 95% CI; 0.86-1.17, P=0.95, allele count model). However, when a meta-analysis of data from this study and previously reported six replication studies was done, OR was 1.08 for the G allele (95% CI; 1.02-1.14, P=0.0057), suggesting that the contribution of PSMA6 to CAD was not large enough to be readily replicated. Further studies are required to establish the contribution of this variant in the susceptibility to CAD.

Background: Recently, a large case-control study (2,851 cases and 2,592 controls) reported that a functional single nuclear polymorphism (SNP) in the proteasome subunit alpha type 6 gene (PSMA6) conferred a risk of myocardial infarction (MI) in a Japanese population. The SNP (exon 1, -8C/G) is located in the 5' untranslated region of exon 1, and the risk-conferring allele G appears to enhance the transcription of PSMA6, which may exaggerate inflammation through activation of nuclear factor-kappa beta protein. The frequency of the risk conferring genotype (GG) in cases was reported to be greater than that in controls (12.4% vs 8.9%). The purpose of the present study was to validate this observation in our study population., Methods and Results: Subjects with MI (n=433) were recruited from the outpatient clinic of the National Cardiovascular Center. Control subjects (n=2,186) were recruited from the Suita study. The frequencies of the GG genotype did not significantly differ between the control (9.8%) and MI groups (10.6%). Moreover, this genotype was not associated with C reactive protein levels in the Suita study. However, the GG genotype was significantly associated with greater intima-media thickness (n=2,051, p=0.015) after adjusting for blood pressure, sex, body mass index and age in the Suita study., Conclusion: The reported genotype in PSMA6 appears not to contribute appreciably to MI, but may contribute slightly to atherosclerosis in the present study population.