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Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.

ObjectivesTo collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis.MethodsFifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians.ResultsThe study population comprised 26 males and 24 females aged 0–61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment.ConclusionsIn patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

Blau syndrome is a rare autosomal dominant autoinflammatory granulomatous disease caused by a mutation in the gene. It is characterized by a clinical trial of granulomatous dermatitis, arthritis, and uveitis. Tofacitinib is a pan Janus kinase (JAK) inhibitor used for treatment of Blau syndrome and idiopathic sarcoidosis. Here, we evaluated its effect on inflammatory pathways associated with Blau syndrome. The effect of tofacitinib on downstream pathways regulated by mutant was analyzed using luciferase assays with overexpression of mutants. The effect of tofacitinib on the upstream pathway for the induction of expression and proinflammatory cytokine production was assessed using monocytic cell lines differentiated from Blau syndrome patient-derived induced pluripotent stem cells. Tofacitinib did not suppress the increased spontaneous transcriptional activity of NF-κB by mutant . In addition, mutant was not involved in the transcription of ISRE and GAS, which are activated by type 1 and type 2 interferons (IFN), respectively. On the other hand, IFNγ induced the expression of , which led to the production of inflammatory cytokines by an autoinflammatory mechanism only in cells with mutant . Tofacitinib suppressed the induction of by IFNγ, thereby inhibiting the production of pro-inflammatory cytokines. Thus, tofacitinib showed anti-inflammatory effects through suppression of expression. The JAK inhibitor tofacitinib is a potential therapeutic agent for Blau syndrome because it suppresses the autoinflammation seen in Blau syndrome by inhibiting the expression of .

Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 ( NOD2 ) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.

A decrease in the number of basophils in the peripheral blood, or basopenia, has been noted, reflecting the activity of chronic spontaneous urticaria (CSU). Infiltration of basophils into the skin has also been reported, but the mechanism of basopenia in CSU has not been clarified. The phenomenon of basopenia during the active phase of urticaria was confirmed, and basophil numbers increased following symptom improvement in 15 out of 17 patients treated with omalizumab and in 13 of 15 patients treated with antihistamines. Our examination by immunostaining also revealed basophil infiltration of the CSU lesions, as in previous reports, but since most of our patients were already taking oral steroids, it was not considered appropriate to examine the relationship between basophil numbers in tissue and peripheral blood. Then, we used mouse model of contact hypersensitivity with a single application of oxazolone, which is known to stimulate basophil infiltration, and investigated basophil counts in the skin, peripheral blood, and bone marrow. In this model, a decrease in peripheral blood basophil numbers was observed one day after challenge, but not after 2 days, reflecting supplementation from the bone marrow. Indeed, when cultured basophils expressing GFP were transplanted into the peripheral blood, GFP-positive basophil numbers in the peripheral blood remained low even after 2 days of challenge. Despite differences among species and models, these results suggest that one reason for the decrease of basophils in the peripheral blood in CSU may involve migration of circulating basophils into the skin.

Urticaria is a symptom of acute skin allergies that is not clearly understood, but mast cell histamine is hypothesized to cause swelling and itching. Omalizumab, an anti-human IgE antibody that traps IgE and prevents its binding to high-affinity IgE receptors, is effective in treating urticaria. We recently experienced a case of urticaria refractory to antihistamine therapy in which the peripheral-blood basophil count responded to omalizumab therapy and its withdrawal. Furthermore, the peripheral-blood basophils showed an unexpected increase in the expression of a cell surface activation marker. This phenomenon has been reported by other analyses of basophil and mast cell dynamics during omalizumab treatment. Here, we analyze these observations and formulate a hypothesis for the role of basophils in urticaria. Specifically, that activated basophils migrate to the local skin area, lowering peripheral-blood counts, omalizumab therapy alters basophilic activity and causes their stay in the peripheral blood. We hope that our analysis will focus urticaria research on basophils and reveal new aspects of its pathogenesis.

AimsHereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies.MethodsTen Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours.ResultsAll patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence.ConclusionsHLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.

Dermatomyositis (DM) is a systemic disease characterized by chronic inflammation in the skin and muscle. A variety of myositis‐specific autoantibodies (MSAs) are detected in patients with DM. These antibodies are associated with unique clinical subsets in DM. Panniculitis is a rare cutaneous manifestation of DM that most commonly presents as tender, erythematous subcutaneous nodules on the thighs, arms, and buttocks. We herein describe the clinical features of two DM‐associated panniculitis patients with anti‐TIF1 antibodies. Both are female patients and showed characteristic cutaneous features, including heliotrope rashes and Gottron's signs with muscle involvement. While one patient had a posterior mediastinum tumor, another had no cancer. Furthermore, to elucidate the clinical significance of anti‐TIF1 antibodies in DM patients with panniculitis, we analyzed all cases with detailed information on the clinical features, including MSAs. A PubMed search of keywords “panniculitis” and “DM” was conducted. We found 23 cases with the detection of MSAs. A review of these cases and our two cases revealed a predominance of female gender (80%) with a median age of 48 years. Anti‐MDA5 antibodies were detected in 11 patients (11/23, 48%), and anti‐TIF1 antibodies were observed in four patients, including the current cases (4/23, 17%). Anti‐Mi‐2 antibodies were observed in four patients (4/23, 17%). Each patient had anti‐NXP‐2 antibodies or anti‐SAE antibodies (2/23; 9%). Although the pathogenesis of panniculitis in DM remains unknown, differences in pathogenesis of DM‐associated panniculitis according to MSAs may exist. Accumulation of additional cases is required to clarify the relationship between panniculitis and MSAs. Panniculitis is a rare cutaneous manifestation of DM. We herein describe the clinical features of two DM‐associated panniculitis patients with anti‐TIF1 antibodies. Although the pathogenesis of panniculitis in DM remains unknown, differences in pathogenesis of DM‐associated panniculitis according to MSAs may exist.

Hereditary angioedema (HAE) is an autosomal dominant disease with recurrent attacks of cutaneous and submucosal swelling caused by mutations in the SERPING1 gene. Here, we report a Japanese case of HAE with a novel mutation in the SERPING1 gene. Accumulation of gene mutations will facilitate the elucidation of HAE pathogenesis and the development of the effective treatments.

Background Blau syndrome (BS) is a rare autoinflammatory disorder with NOD2 gain-of-function mutation and characterized by autoactivation of the NFκB pathway. Classically considered a disease of high penetrance, reports on NOD2 mutations underlining BS with incomplete penetrance is limited. Case presentation The proband is a 9-year-old girl presented with brownish annular infiltrative plaques and symmetric boggy polyarthritis over bilateral wrists and ankles. Her skin biopsy revealed noncaseating granulomas inflammation with multinucleated giant cells. A novel C483W NOD2 mutation was identify in the proband and her asymptomatic father. Functional examinations including autoactivation of the NFκB pathway demonstrated by in vitro HEK293T NOD2 overexpression test as well as intracellular staining of phosphorylated-NFκB in patient’s CD11b + cells were consistent with BS. Conclusions We reported a novel C483W NOD2 mutation underlining BS with incomplete penetrance. Moreover, a phosphorylated-NFκB intracellular staining assay of CD11b + was proposed to assist functional evaluation of NFκB autoactivation in patient with BS.