RESUMO
The clinical course and serological profile of the late-age onset systemic sclerosis (LAO SSc) and the early-age onset SSc (EAO SSc) was compared. The study enrolled 157 patients that fulfilled the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) classification criteria for systemic sclerosis (SSc). Among them, 69 had diffuse cutaneous SSc (dcSSc) and 88 limited cutaneous SSc (lcSSc). Within this population, 39 patients developed the disease over the age of 60 years old (LAO SSc) and 118 prior to that age (EAO SSc). The subtype of SSc, the incidence of internal organ involvement, the prevalence of malignancy, mortality, and serological profile were compared between both groups. The LAO SSc was observed in 39 of total 157 patients with SSc and exhibited a notably higher prevalence of pulmonary arterial hypertension (p = 0.014), heart involvement (p = 0.0014), and renal involvement (p = 0.0002). The occurrence of arthralgias was less common in the LAO SSc group (p = 0.02) than in the EAO SSc group. Furthermore, in the LAO SSc group, the prevalence of anti -RNA polymerase III antibodies (p = 0.008) and antiPM/Scl antibodies (p = 0.048) were significantly lower than in the EAO SSc group. On the other hand, higher anti-Th/To antibody levels (p = 0.014) were recorded in the LAO SSc group. Approximately 25% of SSc patients experienced a delayed onset of the disease after the age of 60 years old. Some clinical and serological features of late-onset SSc were markedly different from that in early-onset disease. Particularly noteworthy is the fact that involvement of internal organs such as heart and kidneys, as well as pulmonary arterial hypertension were much more often observed among patients with LAO SSc which in our suggestion may be referred to age-related co-morbidities. Key Points ⢠Significant differences in clinical and serological profile of the disease were found between late-age onset (LAO) and early-age onset (EAO) SSc. ⢠Incidence of dcSSc as well as prevalence of anti-RNA polymerase III and anti-PM/Scl antibodies were found to be lower in patients over 60 years old compared to those before 60, but regardless of the age of the disease onset. ⢠Internal organ morbidity, notably pulmonary arterial hypertension, renal impairment and heart disease were significantly more common in elder SSc patients as well as in those with late disease onset. ⢠These findings may suggest an impact of age-related co-morbidities on the course of late-age onset SSc.
Assuntos
Idade de Início , Escleroderma Sistêmico , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Adulto , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/complicações , Idoso , RNA Polimerase III/imunologia , Autoanticorpos/sangue , PrevalênciaRESUMO
RIG-I-like receptors (RLRs) are involved in the discrimination of self versus non-self via the recognition of double-stranded RNA (dsRNA). Emerging evidence suggests that immunostimulatory dsRNAs are ubiquitously expressed but are disrupted or sequestered by cellular RNA binding proteins (RBPs). TDP-43 is an RBP associated with multiple neurological disorders and is essential for cell viability. Here, we demonstrate that TDP-43 regulates the accumulation of immunostimulatory dsRNA. The immunostimulatory RNA is identified as RNA polymerase III transcripts, including 7SL and Alu retrotransposons, and we demonstrate that the RNA-binding activity of TDP-43 is required to prevent immune stimulation. The dsRNAs activate a RIG-I-dependent interferon (IFN) response, which promotes necroptosis. Genetic inactivation of the RLR-pathway rescues the interferon-mediated cell death associated with loss of TDP-43. Collectively, our study describes a role for TDP-43 in preventing the accumulation of endogenous immunostimulatory dsRNAs and uncovers an intricate relationship between the control of cellular gene expression and IFN-mediated cell death.
Assuntos
Proteína DEAD-box 58/genética , Proteínas de Ligação a DNA/genética , Herpesvirus Humano 8/genética , Necroptose/genética , RNA de Cadeia Dupla/genética , Receptores Imunológicos/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Elementos Alu , Linhagem Celular Tumoral , Sobrevivência Celular , Citocinas/genética , Citocinas/imunologia , Proteína DEAD-box 58/antagonistas & inibidores , Proteína DEAD-box 58/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/imunologia , Células Epiteliais/imunologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Células HEK293 , Herpesvirus Humano 8/crescimento & desenvolvimento , Herpesvirus Humano 8/imunologia , Humanos , Imunização , Interferons/genética , Interferons/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Necroptose/imunologia , Neurônios/imunologia , Neurônios/virologia , RNA Polimerase III/genética , RNA Polimerase III/imunologia , RNA de Cadeia Dupla/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , RNA Citoplasmático Pequeno/genética , RNA Citoplasmático Pequeno/imunologia , RNA Viral/genética , RNA Viral/imunologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Partícula de Reconhecimento de Sinal/genética , Partícula de Reconhecimento de Sinal/imunologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Ubiquitinas/genética , Ubiquitinas/imunologiaRESUMO
OBJECTIVES: The aims of this study were to investigate the relationship between the type of autoantibody and gene expression profile in skin lesions from patients with SSc, and to identify specific dysregulated pathways in SSc patients compared with healthy controls. METHODS: Sixty-one patients with SSc from the Genetics vs Environment in Scleroderma Outcome Study cohort and 36 healthy controls were included in this study. Differentially expressed genes were extracted and functional enrichment and pathway analysis were conducted. RESULTS: Compared with healthy controls, lists containing 2, 71, 10, 144 and 78 differentially expressed genes were created for patients without specific autoantibody, ACA, anti-U1 RNP antibody (RNP), anti-RNA polymerase III antibody (RNAP) and anti-topoisomerase I antibody (ATA), respectively. While part of the enriched pathways overlapped, distinct pathways were identified except in those patients lacking specific autoantibody. The distinct enriched pathways included 'keratinocyte differentiation' for ACA, 'nuclear factor κB signalling' and 'cellular response to TGF-ß stimulus' for RNAP, 'interferon α/ß signalling' for RNP, and 'cellular response to stress' for ATA. Cell type signature score analysis revealed that macrophages/monocytes, endothelial cells and fibroblasts were associated with ACA, RNAP, ATA and the severity of the SSc skin lesions. CONCLUSION: Pathogenic pathways were identified according to the type of autoantibody by leveraging gene expression data of patients and controls from a multicentre cohort. The current study may promote the search for new therapeutic targets for SSc.
Assuntos
Autoanticorpos/sangue , Escleroderma Sistêmico , Biópsia/métodos , Correlação de Dados , DNA Topoisomerases Tipo I/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , RNA Polimerase III/imunologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Índice de Gravidade de Doença , Pele/patologiaRESUMO
OBJECTIVES: SSc is an autoimmune disease characterized by fibrosis, microangiopathy and immune dysfunctions including dysregulation of proinflammatory cytokines. Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations in haematopoietic stem cells leading to detectable clones in the blood. Recent data have shown a higher risk of cardiovascular disease in patients with CHIP resulting from increased production of proinflammatory cytokines and accelerated atherosclerosis. Eventual links between CHIP and autoimmune diseases are undetermined. The aim of our study was to evaluate the prevalence of CHIP in SSc patients and its association with clinical phenotype. METHODS: Forty-one genes frequently mutated in myeloid malignancies were sequenced in peripheral blood mononuclear cells from 90 SSc patients and 44 healthy donors. RESULTS: A total of 15 somatic variants were detected in 13/90 SSc patients (14%) and four somatic variants in 4/44 (9%) healthy donors (HD) (P = 0.58). The prevalence of CHIP was significantly higher in younger SSc patients than in HD: 25% (6/24) vs 4% (1/26) (P = 0.045) under 50 years and 17% (7/42) vs 3% (1/38) (P = 0.065) under 60 years. The prevalence of CHIP in patients over 70 years was similar in SSc patients and healthy donors. The most common mutations occurred in DNMT3A (seven variants). No major clinical differences were observed between SSc patients with or without CHIP. CONCLUSION: Whether CHIP increases the risk to develop SSc or is a consequence of a SSc-derived modified bone marrow micro-environment remains to be explored.
Assuntos
Hematopoiese Clonal , Escleroderma Sistêmico/sangue , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Autoanticorpos/imunologia , Estudos de Casos e Controles , Hematopoiese Clonal/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Proteínas de Ligação a DNA/genética , Dioxigenases , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas/genética , RNA Polimerase III/imunologia , Proteínas Repressoras/genética , Escleroderma Sistêmico/imunologia , Adulto JovemRESUMO
You are consulted to evaluate a 56-year-old woman with known Raynaud's phenomenon, finger swelling of several; months' duration, and new hypertension with a blood pressure of 160/100 mm/Hg. She also reports progressive shortness of breath. Physical examination reveals telangiectasias, sclerodactyly, and proximal skin sclerosis (thick shiny skin on the chest and upper arms), and bibasilar crackles are found on chest examination. Laboratory tests reveal evidence of microangiopathic hemolytic anemia, thrombocytopenia, and elevation of the serum creatinine level (previously normal), and chest computed tomography shows evidence of ground-glass opacification in both lower lung fields.
Assuntos
Anti-Hipertensivos/uso terapêutico , Antirreumáticos/uso terapêutico , Hipertensão/terapia , Doenças Pulmonares Intersticiais/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Insuficiência Renal/terapia , Esclerodermia Difusa/terapia , Esclerodermia Limitada/terapia , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Complemento C3/imunologia , Complemento C4/imunologia , Inativadores do Complemento/uso terapêutico , Ciclofosfamida/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Humanos , Hipertensão/diagnóstico , Hipertensão/etiologia , Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Troca Plasmática , RNA Polimerase III/imunologia , Doença de Raynaud , Insuficiência Renal/etiologia , Insuficiência Renal/imunologia , Insuficiência Renal/patologia , Esclerodermia Difusa/complicações , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/imunologia , Esclerodermia Limitada/complicações , Esclerodermia Limitada/diagnóstico , Esclerodermia Limitada/imunologia , Transplante de Células-Tronco , Tomografia Computadorizada por Raios X , Transplante Autólogo , Vasodilatadores/uso terapêuticoRESUMO
In systemic sclerosis, the presence of an anti-RNA polymerase III antibody (ARNpol3) is associated with an increased risk of cancer. The characteristic picture of this serotype includes severe diffuse cutaneous involvement, a high risk of renal scleroderma crisis and a 10 year survival of only around 30%. Pulmonary involvement is less common. We report the case of a woman initially treated for drug-induced acute interstitial lung disease revealing chronic interstitial pneumonia with autoimmune features. The disease evolved in three stages with the occurrence of a rapidly progressive diffuse skin sclerosis with anti-ARNPol3 antibodies in the context of ovarian cancer remission.
Assuntos
Cistadenocarcinoma Seroso/complicações , Flecainida/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Neoplasias Ovarianas/complicações , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Idoso , Autoanticorpos/sangue , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/terapia , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , RNA Polimerase III/imunologia , Indução de Remissão , Escleroderma Sistêmico/sangueRESUMO
OBJECTIVE: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti-RNA polymerase III antibody (ARA) autoantibodies. We investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with SRC. METHODS: ARA-positive patients (n = 99) with at least 5 years' follow-up (49% with a history of SRC) were selected from a well characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort. RESULTS: Analysis of 641,489 SNP suggested association of POU2F1 (rs2093658; P = 1.98 × 10-5), CTNND2 (rs1859082; P = 5.58 × 10-5), HECW2 (rs16849716; P = 1.2 × 10-4), and GPATCH2L (rs935332; P = 4.92 × 10-5) with SRC. Further, the validation cohort showed an association between rs935332 within the GPATCH2L region, with SRC (P = 0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L (P = 0.026) and glomerular expression of CTNND2 (P = 0.026) in SRC samples (n = 8) compared with normal human kidney controls (n = 8), despite absence of any genetic replication for the associated SNP. CONCLUSION: Increased expression of 2 candidate proteins, GPATCH2L and CTNND2, in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L, this may reflect genetic susceptibility in ARA-positive patients with SSc based upon 2 independent cohorts.
Assuntos
Injúria Renal Aguda , Esclerodermia Localizada , Escleroderma Sistêmico , Autoanticorpos , Humanos , RNA Polimerase III/imunologia , Esclerodermia Localizada/imunologia , Escleroderma Sistêmico/imunologia , Ubiquitina-Proteína LigasesRESUMO
Systemic sclerosis (SSc) is a rare autoimmune disease with high mortality, characterized by chronic inflammation and fibrosis, which are processes associated with higher serum tumor necrosis factor-α (sTNF-α) levels. TNFA -308G>A and -238G>A polymorphisms have been associated with higher sTNF-α levels. In this study, we genotyped the TNFA -308G>A and -238G>A polymorphisms in 53 SSc patients and 115 unrelated control subjects (CS) from southern Mexico. The TNFA mRNA expression and sTNF-α levels were also quantified by qPCR and enzyme-linked immunosorbent assays, respectively. TNFA -308GA genotype was associated with disease susceptibility according to a codominant genetic model (OR = 3.2, 95% CI 1.05-9.75, p = 0.03), and with higher anti-fibrillarin antibodies (p = 0.01), and higher skin thickening (p = 0.006). TNFA -238GA was not associated with SSc risk. TNFA mRNA expression and sTNF-α levels were similar between SSc patients and CS and were not statistically associated with the TNFA polymorphisms; however, a correlation (rho = 0.362, p = 0.009) between sTNF-α levels with anti-RNA polymerase III antibodies was observed in the SSc patients. In conclusion, the -308G>A polymorphism is a genetic marker of SSc susceptibility in population from southern Mexico, and it is associated with skin thickening and anti-fibrillarin antibodies. In addition, sTNF-α levels correlate positively with the anti-RNA pol III antibodies levels.
Assuntos
Autoanticorpos/metabolismo , Escleroderma Sistêmico/genética , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Adulto , Estudos de Casos e Controles , Proteínas Cromossômicas não Histona/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , México , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , RNA Polimerase III/imunologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologiaRESUMO
OBJECTIVE: While compelling data suggest a cancer-induced autoimmunity model in scleroderma patients with anti-RNA polymerase III large subunit (anti-RPC155) antibodies, ~85% of these patients do not manifest cancer. This study was undertaken to determine whether additional autoantigens are targeted in anti-RPC155-positive scleroderma patients without detectable cancer. METHODS: The study included 168 scleroderma patients with anti-RPC155 antibodies (80 with a history of cancer and 88 with no cancer diagnosis after >5 years of follow-up). Thirty-five sera (17 from patients with cancer and 18 from patients without cancer) were randomly selected for autoantibody discovery using immunoprecipitation (IP). An ~194-kd band was enriched in the subgroup without cancer; this was identified as RNA polymerase I large subunit (RPA194). RESULTS: RPA194 generated by in vitro transcription/translation was used for IPs performed on the entire cohort to test whether anti-RPA194 was enriched among anti-RPC155-positive patients without cancer. Anti-RPA194 antibodies were significantly more common in the group without cancer (16 [18.2%] of 88) than in the group with cancer (3 [3.8%] of 80) (P = 0.003). Patients with both anti-RPA194 and anti-RPC155 were significantly less likely to have severe gastrointestinal disease than patients with anti-RPC155 only (26.3% versus 51.0%; P = 0.043). CONCLUSION: Anti-RPA194 antibodies are enriched in anti-RPC155-positive scleroderma patients without cancer. Since somatic mutations in the gene encoding RPC155 in cancer in scleroderma patients appears to play a role in immune response initiation against RPC155 in those patients, these data raise the possibility that the development of immune responses to both RPC155 and RPA194 may influence clinical cancer emergence. Further study is required to define whether different autoantibody combinations have utility as tools for cancer risk stratification in scleroderma.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Neoplasias/imunologia , RNA Polimerase III/imunologia , RNA Polimerase I/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Autoantígenos/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Escleroderma Sistêmico/sangueRESUMO
Systemic sclerosis (SSc) is a systemic disease characterized by vasculopathy, progressive fibrosis and autoimmune activation. Tryptophan (Trp) metabolism has been linked to altered immune cell function and to malignancy. We have investigated the role of Trp metabolic pathway in SSc measuring serum Trp, Kynurenine (Kyn) and Trp/Kyn ratio in a cohort of 97 SSc patients and 10 healthy controls. Association with disease characteristics was evaluated. We found that Trp levels in SSc patients were significantly lower compared to HCs. We also found that patients with diffuse cutaneous (dcSSc) had lower levels of Trp compared to limited cutaneous (lcSSc). These results were paralleled by higher levels of Kyn found in SSc patients compared to HCs and significantly lower levels in dcSSc compared to lcSSc. The autoantibody profile was also found to be significantly associated with Kyn and Trp levels as anti-RNA-polymerase III (ARA) positive patients were shown to have lower Trp levels and higher Kyn levels compared with anti-centromere and anti-topoisomerase I positive patients. Moreover, the highest Trp/Kyn was found in ARA+ patients with dcSSc, suggesting that an activation of the Kyn pathway, is more specifically associated with this subset of SSc patients. Stability over time makes these markers of Trp metabolism feasible for SSc stratification.
Assuntos
Autoanticorpos/sangue , Cinurenina/sangue , RNA Polimerase III/imunologia , Esclerodermia Difusa/metabolismo , Escleroderma Sistêmico/metabolismo , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerodermia Difusa/imunologia , Escleroderma Sistêmico/imunologia , Triptofano/metabolismoRESUMO
OBJECTIVES: To evaluate the clinical features and survival of patients with positive anti-RNA polymerase III (anti-RNAP III) in a Spanish single centre. METHODS: We analysed 221 patients with SSc according to LeRoy and Medsger criteria. Twenty-six patients with positivity for anti-RNAP III antibodies were compared with 195 negative patients. Epidemiological, clinical, immunological features and survival were analysed. RESULTS: In patients with anti-RNAP III positivity diffuse cutaneous SSc (dcSSc) subset was the most prevalent (20, 76.9% vs. 35, 17.9%, p < 0.001), with shorter diagnosis delay (4.11 ± 7.34 years vs. 6.77 ± 9.22 years, p = 0.005). Patients with anti-RNAP III antibodies had higher frequency of arterial hypertension (13, 50% vs. 55, 28.2%, p = 0.024), scleroderma renal crisis (SRC) (3, 11.5% vs. 3, 1.5%, p = 0.023), arthritis (9, 34.6% vs. 35, 17.9%, p = 0.046), tendon friction rubs (4, 15.4% vs. 1, 0.5%, p = 0.001) and contractures (5, 19.2% vs. 10, 5.1%, p = 0.02). There were no differences found in the presence of cancer or in global survival. In the multivariate survival analysis, severe interstitial lung disease (ILD) (HR: 8.61, 95%CI 3.40 - 21.81), pulmonary arterial hypertension (PAH) (HR: 4.05, 95%CI 1.42 - 11.61) and SRC (HR: 17.27, 95%CI 3.36 - 88.97) were the only factors associated with poor prognosis. CONCLUSIONS: In this cohort anti-RNAP III antibodies are related with dcSSc subset, shorter diagnostic delay and higher prevalence of musculoskeletal involvement, arterial hypertension and SRC. ILD, PAH and SRC were independent prognostic factors.
Assuntos
Autoanticorpos/imunologia , Doenças Pulmonares Intersticiais , RNA Polimerase III/imunologia , Escleroderma Sistêmico , Adulto , Autoanticorpos/sangue , Diagnóstico Tardio , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , EspanhaRESUMO
In most individuals, varicella zoster virus (VZV) causes varicella upon primary infection and zoster during reactivation. However, in a subset of individuals, VZV may cause severe disease, including encephalitis. Host genetics is believed to be the main determinant of exacerbated disease manifestations. Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity. Here we describe the roles of POL III in housekeeping and immune surveillance during VZV infection. We present the latest knowledge on the role of POL III in VZV infection and discuss outstanding questions related to the role of POL III in VZV immunity, and how this insight can be translated into clinical medicine.
Assuntos
Varicela/genética , Encefalite por Varicela Zoster/genética , Herpes Zoster/genética , Interações Hospedeiro-Patógeno , RNA Polimerase III/genética , Ativação Viral , Adulto , Varicela/imunologia , Varicela/patologia , Varicela/virologia , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/imunologia , DNA Viral/genética , DNA Viral/imunologia , Encefalite por Varicela Zoster/imunologia , Encefalite por Varicela Zoster/patologia , Encefalite por Varicela Zoster/virologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Herpes Zoster/imunologia , Herpes Zoster/patologia , Herpes Zoster/virologia , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/imunologia , Humanos , Imunidade Inata , Vigilância Imunológica , Interferons/genética , Interferons/imunologia , Subunidades Proteicas/genética , Subunidades Proteicas/imunologia , RNA Polimerase III/imunologia , Receptores ImunológicosAssuntos
Anticorpos Antinucleares/sangue , Linfoma de Zona Marginal Tipo Células B/diagnóstico , RNA Polimerase III/imunologia , Escleroderma Sistêmico/diagnóstico , Idoso de 80 Anos ou mais , Anticorpos Antinucleares/imunologia , Epiderme/patologia , Humanos , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologiaRESUMO
Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, characterized by multisystem involvement, vasculopathy, and fibrosis. An increased risk of malignancy is observed in SSc (including breast and lung cancers), and in a subgroup of patients with specific autoantibodies (i.e., anti-RNA polymerase III and related autoantibodies), SSc could be a paraneoplastic syndrome and might be directly related to an immune response against cancer. Herein, we reviewed the literature, focusing on the most recent articles, and shed light onto the potential relationship between cancer and scleroderma regarding temporal and immunological dimensions.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Neoplasias/imunologia , Síndromes Paraneoplásicas/imunologia , Escleroderma Sistêmico/imunologia , Doenças Autoimunes/complicações , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Fibrose , Humanos , Neoplasias/complicações , Neoplasias/genética , Síndromes Paraneoplásicas/complicações , Síndromes Paraneoplásicas/genética , RNA Polimerase III/imunologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Pele/imunologia , Pele/patologiaRESUMO
BACKGROUND: The incidence of cancer is increased in patients with systemic sclerosis (SSc). Further, recent studies have also shown that the presence of anti-RNA polymerase III antibodies is associated with a higher incidence of cancer in this population. PATIENTS AND METHODS: Herein we present the cases of two men aged 56 and 23 years presenting SSc without anti-Scl70 or anti-centromere antibodies but with anti-RNA polymerase III antibodies. Clinical symptoms led us to prescribe more laboratory exams and both patients were diagnosed with cancer of the nasopharyngeal area. DISCUSSION: Anti-RNA polymerase III antibodies are useful for SSc diagnosis in patients without anti-centromere or anti-Scl70 antibodies. Their presence must lead physicians to screen for associated cancer, even in the absence of clinical signs.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Carcinoma/etiologia , Neoplasias Nasofaríngeas/etiologia , RNA Polimerase III/imunologia , Escleroderma Sistêmico/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/radioterapia , Carcinoma/secundário , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Cisplatino/administração & dosagem , Terapia Combinada , Docetaxel , Fluoruracila/administração & dosagem , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/radioterapia , Radioterapia Adjuvante , Doença de Raynaud/etiologia , Indução de Remissão , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/imunologia , Taxoides/administração & dosagem , Tonsilectomia , Adulto JovemRESUMO
A 69-year-old Japanese man was presented with hypertensive crisis. Renal histology revealed malignant nephrosclerosis, including an onion skin pattern with fibrinoid necrosis of the small arteries from arterioles up to interlobular arteries. Immunological investigation clarified positive anti-RNA polymerase (RNAP) III antibody, and limited cutaneous systemic sclerosis (Lc SSc) was diagnosed by skin biopsy as the underlying disease causing scleroderma renal crisis (SRC). Angiotensin covering enzyme (ACE) inhibitor therapy and calcium antagonist were effective for his renal condition. Although an association between SRC and anti-RNAP III antibody has already been reported in patients with diffuse cutaneous SSc (Dc SSc), this case indicates that SRC with hypetensive emergency with malignant nephrosclerosis can also be diagnosed on patients with Lc SSc patients by the examination of anti-RNAP III antibody.
Assuntos
Nefroesclerose/etiologia , Nefrose/etiologia , RNA Polimerase III/imunologia , Escleroderma Sistêmico/complicações , Idoso , Anticorpos/imunologia , Humanos , Masculino , Nefroesclerose/imunologia , Nefrose/imunologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Pele/patologiaRESUMO
OBJECTIVE: To analyze the characteristics of anti-RNA polymerase III antibodies (anti-RNAP3)- positive patients with systemic sclerosis (SSc) in the European League Against Rheumatism Scleroderma Trials and Research group (EUSTAR) registry with a focus on the risk of cancer and the characteristics of malignancies, and the aim to provide guidelines about potential cancer screening in these patients. METHODS: (1) Analysis of the EUSTAR database: 4986 patients with information on their anti-RNAP3 status were included. (2) Case-control study: additional retrospective data, including malignancy history, were queried in 13 participating EUSTAR centers; 158 anti-RNAP3+ cases were compared with 199 local anti-RNAP3- controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset. (3) A Delphi exercise was performed by 82 experts to reach consensus for cancer screening in anti-RNAP3+ patients. RESULTS: In the EUSTAR registry, anti-RNAP3 were associated in multivariable analysis with renal crisis and diffuse cutaneous involvement. In the case-control study, anti-RNAP3 were associated with gastric antral vascular ectasia, rapid progression of skin involvement, and malignancies concomitant to SSc onset (OR 7.38, 95% CI 1.61-33.8). When compared with other anti-RNAP3+ patients, those with concomitant malignancies had older age (p < 0.001) and more frequent diffuse cutaneous involvement (p = 0.008). The Delphi exercise highlighted the need for malignancy screening at the time of diagnosis for anti-RNAP3+ patients and tight followup in the following years. CONCLUSION: Anti-RNAP3+ patients with SSc have a high risk of concomitant malignancy. These results have implications for clinical practice and suggest regular screening for cancer in anti-RNAP3+ patients.
Assuntos
Autoanticorpos/sangue , Neoplasias/complicações , RNA Polimerase III/imunologia , Escleroderma Sistêmico/complicações , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/imunologia , Estudos Retrospectivos , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologiaRESUMO
Scleroderma is a chronic autoimmune rheumatic disease associated with widespread tissue fibrosis and vasculopathy. Approximately two-thirds of all patients with scleroderma present with three dominant autoantibody subsets. Here, we used a pair of complementary high-throughput methods for antibody epitope discovery to examine patients with scleroderma with or without known autoantibody specificities. We identified a specificity for the minor spliceosome complex containing RNA Binding Region (RNP1, RNA recognition motif) Containing 3 (RNPC3) that is found in patients with scleroderma without known specificities and is absent in unrelated autoimmune diseases. We found strong evidence for both intra- and intermolecular epitope spreading in patients with RNA polymerase III (POLR3) and the minor spliceosome specificities. Our results demonstrate the utility of these technologies in rapidly identifying antibodies that can serve as biomarkers of disease subsets in the evolving precision medicine era.
Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Escleroderma Sistêmico/imunologia , Neoplasias Cutâneas/imunologia , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Autoantígenos/química , Autoantígenos/genética , Técnicas de Visualização da Superfície Celular , Comorbidade , Epitopos/genética , Humanos , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Fases de Leitura Aberta , RNA Polimerase III/química , RNA Polimerase III/genética , RNA Polimerase III/imunologia , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Ribonucleoproteínas Nucleares Pequenas/química , Ribonucleoproteínas Nucleares Pequenas/genética , Ribonucleoproteínas Nucleares Pequenas/imunologia , Escleroderma Sistêmico/sangue , Análise de Sequência de DNA , Neoplasias Cutâneas/sangue , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
OBJECTIVES: We sought to identify the clinical factors associated with calcinosis in an international multicenter collaborative effort with the Scleroderma Clinical Trials Consortium (SCTC). METHODS: This is a retrospective cohort study of 5218 patients with systemic sclerosis (SSc). Logistic regression was used to obtain odds ratios (OR) relating calcinosis to various clinical features in multivariate analyses. RESULTS: A total of 1290 patients (24.7%) had calcinosis. In univariate analyses, patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from the first non-Raynaud phenomenon symptom. Patients with calcinosis were more likely to have digital ulcers, telangiectasias, acro-osteolysis, cardiac disease, pulmonary hypertension, gastrointestinal involvement, arthritis, and osteoporosis, but less likely to have muscle disease. Anti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while anticentromere (ACA), anti-PM/Scl, and anticardiolipin antibodies were more frequent. In multivariate analysis, the strongest associations with calcinosis were digital ulcers (OR = 3.9; 95% CI: 2.7-5.5; p < 0.0001) and osteoporosis (OR = 4.2; 95% CI: 2.3-7.9; p < 0.0001). CONCLUSION: One quarter of patients with SSc have calcinosis at some time during their illness. Our data confirm a strong association of calcinosis with digital ulcers, and support a novel association with osteoporosis.