RESUMEN
BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-ß1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc. METHODS: To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays. RESULTS: On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1. CONCLUSIONS: Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.
Asunto(s)
Anticuerpos Monoclonales , Quimiocina CX3CL1 , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped , Fibrosis Pulmonar , Esclerodermia Sistémica , Piel , Animales , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/patología , Esclerodermia Sistémica/inmunología , Ratones , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/antagonistas & inhibidores , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/prevención & control , Piel/patología , Piel/efectos de los fármacos , Piel/metabolismo , Piel/inmunología , Fibrosis , Femenino , Ratones Endogámicos C57BL , Humanos , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/inmunologíaRESUMEN
Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.
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Predisposición Genética a la Enfermedad , Esclerodermia Sistémica , Humanos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Receptores de IgG/genética , Puntuación de Riesgo Genético , Esclerodermia Sistémica/genética , Polimorfismo de Nucleótido Simple , Factores Reguladores del Interferón/genética , Sitios GenéticosRESUMEN
Dermatomyositis constitutes a heterogeneous group of autoimmune inflammatory conditions with a wide variety of clinical outcomes. The symptomatic heterogeneity carries skin, muscle, and joint manifestations; pulmonary and cardiac involvements; and concomitant malignancy. Any of these symptoms often appear at different combinations and time courses, thus posing difficulty in early diagnosis and appropriate treatment choice. Recent progress in laboratory investigations explored the identification of several myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies, allowing precise characterization for a clinical perspective of the disease. MSAs can be detectable in approximately 80% of patients with whole dermatomyositis, some of which closely reflect unique clinical features in the particular disease subset(s), including the distribution and severity of organ involvement, treatment response, and prognosis. However, only limited evidence has been available in dermatomyositis-associated panniculitis, mostly that in anti- melanoma differentiation-associated protein 5 antibody-positive disease. We present a rare case of a patients with dermatomyositis with extensive panniculitis on the trunk whose serum IgG autoantibodies reacted with both subunits of small ubiquitin-like modifier activating enzymes (SAEs), SAE1 and SAE2. The onset of panniculitis coincided with increased disease activity, including disease-related skin manifestations, fever, dysphagia, and muscle weakness in the extremities. These symptoms responded well to a high dose of systemic steroid, but even upon receiving a high-dose intravenous immunoglobulin, the panniculitic lesions and pruritic erythema flared with tapering of steroid dose, further requiring tacrolimus and mycophenolate mofetil to achieve disease remission. To our knowledge, this is the third reported case of anti-SAE autoantibody-positive dermatomyositis with panniculitis. We aim to extend the understanding of the current limitation and further perspective in the clinical management of the extremely rare skin manifestation associated with dermatomyositis.
Asunto(s)
Enfermedades Autoinmunes , Dermatomiositis , Miositis , Paniculitis , Humanos , Dermatomiositis/complicaciones , Dermatomiositis/diagnóstico , Dermatomiositis/tratamiento farmacológico , Enfermedades Autoinmunes/complicaciones , Autoanticuerpos , Paniculitis/complicaciones , Paniculitis/diagnóstico , Paniculitis/tratamiento farmacológico , Enzimas Activadoras de Ubiquitina , EsteroidesRESUMEN
BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that is characterized by fibrosis in the skin and internal organs, such as the lungs. Activated differentiation of progenitor cells, which are mainly resident fibroblasts, into myofibroblasts is considered a key mechanism underlying the overproduction of extracellular matrix and the resultant tissue fibrosis in SSc. Calpains are members of the Ca2+-dependent cysteine protease family, whose enzymatic activities participate in signal transduction and tissue remodeling, potentially contributing to fibrosis in various organs. However, the roles of calpain in the pathogenesis of SSc remain unknown. This study aimed to examine the anti-fibrotic properties of N-acetyl-Leu-Leu-norleucinal (ALLN), one of the cysteine proteinase inhibitors that primarily inhibit calpain, in vitro and in vivo, to optimally translate into the therapeutic utility in human SSc. METHODS: Normal human dermal and lung fibroblasts pretreated with ALLN were stimulated with recombinant transforming growth factor beta 1 (TGF-ß1), followed by assessment of TGF-ß1/Smad signaling and fibrogenic molecules. RESULTS: ALLN treatment significantly inhibited TGF-ß1-induced phosphorylation and nuclear transport of Smad2/3 in skin and lung fibroblasts. TGF-ß1-dependent increases in α-smooth muscle actin (αSMA), collagen type I, fibronectin 1, and some mesenchymal transcription markers were attenuated by ALLN. Moreover, our findings suggest that ALLN inhibits TGF-ß1-induced mesenchymal transition in human lung epithelial cells. Consistent with these in vitro findings, administering ALLN (3 mg/kg/day) three times a week intraperitoneally remarkably suppressed the development of skin and lung fibrosis in a SSc mouse model induced by daily subcutaneous bleomycin injection. The number of skin- and lung-infiltrating CD3+ T cells decreased in ALLN-treated mice compared with that in control-treated mice. Phosphorylation of Smad3 and/or an increase in αSMA-positive myofibroblasts was significantly inhibited by ALLN treatment on the skin and lungs. However, no adverse effects were observed. CONCLUSIONS: Our results prove that calpains can be a novel therapeutic target for skin and lung fibrosis in SSc, considering its inhibitor ALLN.
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Fibrosis Pulmonar , Esclerodermia Sistémica , Humanos , Animales , Ratones , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Factor de Crecimiento Transformador beta1 , Calpaína , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/tratamiento farmacológico , Bleomicina/toxicidadAsunto(s)
Carcinoma de Células Transicionales , Inmunoconjugados , Neoplasias de la Vejiga Urinaria , Humanos , Nectinas , Carcinoma de Células Transicionales/tratamiento farmacológico , Moléculas de Adhesión Celular , Eritema/inducido químicamente , Eritema/diagnóstico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
In older patients with facial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), surgery should be aimed to reduce treatment-related sequelae and burden with achieving local tumor care. Therefore, we adopted a two-step surgery (TSS) involving the application of a dermal regeneration template onto the skin defect after tumor resection and subsequent reconstruction by full-thickness skin grafting. We performed a detailed comparison of conventional one-step surgery (OSS) and TSS, including evaluation of local tumor curability, postoperative cosmetic and/or functional impairments, and patient burden. Forty-six patients who underwent TSS and 104 patients treated with OSS were retrospectively investigated. The cohort consisted of 77 men and 73 women (median age, 83â years). The BCC: SCC ratio was 56.7%: 43.3%. The tumor size and excision margin were significantly larger in the TSS group than in the OSS group (p = 0.03). The histopathological margin was positive after the first surgery in six cases, but was negative after additional resection in all cases, regardless of OSS or TSS. Local recurrence was not observed in this study. The frequency of postoperative sequelae (POS) in TSS was slightly lower than in OSS (17.4% vs. 27.9%, p = 0.16). A shorter average operation time per session was significantly associated with the location of the vertical defect [below adipose tissue vs. within adipose tissue, estimate: -0.28 (hour), p < 0.001] and surgical procedure [OSS vs. TSS, estimate: -0.13 (hour), p = 0.03] by multiple regression models. The ratio of general anesthesia was relatively lower in TSS than in OSS (9.8% vs. 17.3%, p = 0.12). Thus, TSS showed a good local curability and POS statistically equivalent to OSS, reducing the surgical burden, particularly shortening each operation time without any adverse events, despite the TSS group having significantly larger tumors than the OSS group. Since TSS is a simple procedure, it can be an outstanding option for facial BCC and SCC.
RESUMEN
BACKGROUND: Systemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-ß (TGF-ß)/Smad signaling plays a central role in extracellular matrix (ECM) production by α-SMA-positive myofibroblasts. Myofibroblasts may be partially derived from various precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that may disrupt the differentiation of epithelial cells into myofibroblasts. This compound was originally generated as a curcumin derivative. METHODS: In this study, we investigated the effect of LG283 on inhibiting fibrosis and its mechanism. The action of LG283 on TGF-ß-dependent fibrogenic activity and epithelial-mesenchymal transition (EMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model. RESULTS: LG283 suppressed TGF-ß-induced expression of ECM, α-SMA, and transcription factors Snail 1 and 2, and Smad3 phosphorylation in cultured human dermal fibroblasts. LG283 was also found to block EMT induction in cultured human epithelial cells. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and decrease of capillary vessels without significantly affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of α-SMA and phosphorylated Smad3, as well as those of Snail 1 and 2, in the bleomycin-injected skin. CONCLUSIONS: The LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-ß/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for the treatment of SSc. Although the involvement of EMT in the pathogenesis of SSc remains unclear, the screening of EMT regulatory compounds may be an attractive approach for SSc therapy.
Asunto(s)
Esclerodermia Sistémica , Lesiones del Sistema Vascular , Animales , Bleomicina/toxicidad , Fibrosis , Humanos , Ratones , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/patología , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Pancreatic panniculitis (PP) is a rare clinical variant of subcutaneous fat necrosis, developing in patients with a variety of pancreatic diseases such as acute or chronic pancreatitis, tumors and cysts. The tumor-associated PP represents a noteworthy skin manifestation of underlying internal malignancies, also known as dermadrome. Among causative pancreatic tumors, acinar cell carcinoma is the most frequent malignancy; however, little is known about how the origin of tumor cells and progression stage of pancreatic tumors potentially contribute to the establishment of panniculitis. Here, we present a 69-year-old Japanese male case of clinically aggressive PP on the bilateral legs, whose skin lesions developed prior to the diagnosis of occult pancreatic tumor and liver metastasis. Moreover, the immunopathology of the pancreatic lesion revealed neuroendocrine tumor (NET), a rare pathological variant. Skin lesions immediately spread to the upper limbs with extensive ulcerations and necrosis, accompanied by high levels of serum lipase and elastase, but not with other pancreatic enzymes. He died 2 months after the initial development of the skin lesion due to rapid deterioration of general condition. We reviewed 14 cases, including ours, of PP with NET in the pancreas thus far reported, to identify the clinicopathological characteristics regarding to what extent this rare complication could reflect the clinical course of pancreatic tumors and overall prognosis. Our published work review found that the disease has a significant male predominance (male : female, 13:1) and cases with occult pancreatic tumors died within 4 months after the development of their skin lesions. Our case was the poorest prognostic outcome. This report emphasizes that dermatologists should recognize PP with NET, reflecting a fatal prognosis, and to make a prompt diagnosis.