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Introduction: Although the treatment for pemphigus vulgaris (PV) has been revolutionized by the use of rituximab combined with corticosteroids, new effective therapies with a better safety profile are needed. Observation: A 67-year-old woman was diagnosed with severe mucosal PV, which was initially misdiagnosed as atypical Behçet's disease. Following an unsuccessful colchicine treatment, significant improvement was observed upon the introduction of apremilast: reduced pain, fewer lesions, and a stabilized weight. The discontinuation of apremilast led to a rapid relapse. Retrospective analysis through anti-Dsg3 ELISA indicated a gradual decrease in antibody levels during the apremilast treatment. Discussion: Apremilast, a phosphodiesterase 4 inhibitor approved for psoriasis and Behçet's disease's related oral ulcers treatment, demonstrated its efficacy in this PV case. This is the second case report highlighting the effectiveness of apremilast for PV treatment. Apremilast's ability to upregulate cyclic adenosine monophosphate (cAMP) levels appears to contribute to the stabilization of keratinocyte adhesion. Conclusion: Apremilast may be a promising therapeutic option for the treatment of pemphigus, with an innovative mechanism of action, no induced immunosuppression, and good tolerance. It could be a good alternative to steroids, in the treatment regimen of steroids combined with rituximab.
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Pênfigo , Talidomida , Humanos , Pênfigo/tratamento farmacológico , Pênfigo/diagnóstico , Feminino , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Idoso , Resultado do Tratamento , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêuticoRESUMO
Although tocilizumab treatment in severe and critical coronavirus disease 2019 (COVID-19) patients has proven its efficacy at the clinical level, there is little evidence supporting the effect of short-term use of interleukin-6 receptor blocking therapy on the B cell sub-populations and the cross-neutralization of SARS-CoV-2 variants in convalescent COVID-19 patients. We performed immunological profiling of 69 tocilizumab-treated and non-treated convalescent COVID-19 patients in total. We observed that SARS-CoV-2-specific IgG1 titers depended on disease severity but not on tocilizumab treatment. The plasma of both treated and non-treated patients infected with the ancestral variant exhibit strong neutralizing activity against the ancestral virus and the Alpha, Beta, and Delta variants of SARS-CoV-2, whereas the Gamma and Omicron viruses were less sensitive to seroneutralization. Overall, we observed that, despite the clinical benefits of short-term tocilizumab therapy in modifying the cytokine storm associated with COVID-19 infections, there were no modifications in the robustness of B cell and IgG responses to Spike antigens.
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Objective: The frequency of vasculitis may be increased in patients with Familial Mediterranean Fever (FMF), according to several studies. Our aim was to assess the characteristics of French adult patients with both diseases. Methods: Patients with vasculitis were selected from patients followed for FMF in the French JIR-cohort. Results: Twenty-two patients were included [polyarteritis nodosa (PAN) n = 10, IgA vasculitis n = 8, unclassified vasculitis n = 2, granulomatosis with polyangiitis n = 1, and microscopic polyangiitis n = 1]. Pathogenic mutations in exon 10 were found in all 21 patients (96%) for which MEFV testing results were available, and 18 (82%) had two pathogenic mutations. Histology showed vasculitis in 59% of patients. Most patients with FMF-associated PAN were HBV-negative and had an inactive FMF before PAN onset, and 40% had a peri-renal or central nervous system bleeding. Most patients with FMF-associated IgA vasculitis had an active FMF before vasculitis onset, and 25% had digestive bleeding. Both patients with unclassified vasculitis had ischemic and/or hemorrhagic complications. Conclusion: This study confirms the predominance of PAN and IgA vasculitis in patients with FMF and the high frequency of bleeding in FMF-associated PAN. FMF should be considered in case of persistent symptoms and/or inflammatory syndrome despite vasculitis treatment in Mediterranean patients.
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Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected millions, with more than 275,000 fatal cases as of May 8, 2020. Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. In view of uncertainty associated with immunosuppressive treatments, such as corticosteroids and their possible secondary effects, including risks of secondary infections, we suggest immunotherapies as an adjunct therapy in severe COVID-19 cases. Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation, and passive viral neutralization not only reduce inflammation, inflammation-associated lung damage, or viral load but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation, both of which are limited resources.
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COVID-19/terapia , Imunoterapia , Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , COVID-19/imunologia , Terapia Combinada , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Citocinas/imunologia , Humanos , Imunização Passiva , Imunoglobulinas Intravenosas/uso terapêutico , Inflamação , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/terapia , SARS-CoV-2 , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplanteAssuntos
Antineoplásicos/efeitos adversos , Bortezomib/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Polirradiculoneuropatia/patologia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Polirradiculoneuropatia/induzido quimicamente , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Autophagy plays an important role in the regulation of autoimmune and autoinflammatory responses of the immune cells. Defective autophagy process is associated with various autoimmune and inflammatory diseases. Moreover, in many of these diseases, the therapeutic use of normal immunoglobulin G or intravenous immunoglobulin (IVIG), a pooled normal IgG preparation, is well documented. Therefore, we explored if IVIG immunotherapy exerts therapeutic benefits via induction of autophagy in the immune cells. Here we show that IVIG induces autophagy in peripheral blood mononuclear cells (PBMCs). Further dissection of this process revealed that IVIG-induced autophagy is restricted to inflammatory cells like monocytes, dendritic cells, and M1 macrophages but not in cells associated with Th2 immune response like M2 macrophages. IVIG induces autophagy by activating AMP-dependent protein kinase, beclin-1, class III phosphoinositide 3-kinase and p38 mitogen-activated protein kinase and by inhibiting mammalian target of rapamycin. Mechanistically, IVIG-induced autophagy is F(ab')2-dependent but sialylation independent, and requires endocytosis of IgG by innate cells. Inhibition of autophagy compromised the ability of IVIG to suppress the inflammatory cytokines in innate immune cells. Moreover, IVIG therapy in inflammatory myopathies such as dermatomyositis, antisynthetase syndrome and immune-mediated necrotizing myopathy induced autophagy in PBMCs and reduced inflammatory cytokines in the circulation, thus validating the translational importance of these results. Our data provide insight on how circulating normal immunoglobulins maintain immune homeostasis and explain in part the mechanism by which IVIG therapy benefits patients with autoimmune and inflammatory diseases.
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Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Imunoglobulinas Intravenosas/farmacologia , Leucócitos Mononucleares/metabolismo , Adenilato Quinase/metabolismo , Proteína Beclina-1/metabolismo , Linhagem Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/ultraestrutura , Endocitose/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Fragmentos Fab das Imunoglobulinas/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Organelas/efeitos dos fármacos , Organelas/metabolismo , Organelas/ultraestrutura , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Doadores de Tecidos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoAssuntos
Doenças Autoimunes , Doenças Hematológicas , Leucemia Linfocítica Crônica de Células B , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Quinazolinonas/administração & dosagem , Adenina/análogos & derivados , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/mortalidade , Intervalo Livre de Doença , Feminino , Doenças Hematológicas/tratamento farmacológico , Doenças Hematológicas/mortalidade , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Piperidinas , Taxa de SobrevidaRESUMO
BACKGROUND: Therapeutic normal IgG or intravenous immunoglobulin (IVIG) exerts anti-inflammatory effects through several mutually nonexclusive mechanisms. Recent data in mouse models of autoimmune disease suggest that IVIG induces IL-4 in basophils by enhancing IL-33 in SIGN-related 1-positive innate cells. However, translational insight on these data is lacking. OBJECTIVE: We sought to investigate the effect of IVIG on human basophil functions. METHODS: Isolated circulating basophils from healthy donors were cultured in the presence of IL-3, IL-33, GM-CSF, thymic stromal lymphopoietin, or IL-25. The effect of IVIG and F(ab')2 and Fc IVIG fragments was examined based on expression of various surface molecules, phosphorylation of spleen tyrosine kinase, induction of cytokines, and histamine release. Basophil phenotypes were also analyzed from IVIG-treated patients with myopathy. Approaches, such as depletion of anti-IgE reactivity from IVIG, blocking antibodies, or inhibitors, were used to investigate the mechanisms. RESULTS: We report that IVIG directly induces activation of IL-3-primed human basophils, but IL-33 and other cytokines were dispensable for this effect. Activation of basophils by IVIG led to enhanced expression of CD69 and secretion of IL-4, IL-6, and IL-8. IVIG-treated patients with myopathy displayed enhanced expression of CD69 on basophils. The spleen tyrosine kinase pathway is implicated in these functions of IVIG and were mediated by F(ab')2 fragments. Mechanistically, IVIG induced IL-4 in human basophils by interacting with basophil surface-bound IgE but independent of FcγRII, type II Fc receptors, C-type lectin receptors, and sialic acid-binding immunoglobulin-like lectins. CONCLUSION: These results uncovered a pathway of promoting the TH2 response by IVIG through direct interaction of IgG with human basophils.
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Anti-Inflamatórios/farmacologia , Basófilos/imunologia , Fragmentos Fc das Imunoglobulinas/farmacologia , Imunoglobulinas Intravenosas/farmacologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Basófilos/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Liberação de Histamina , Humanos , Imunoglobulina E/metabolismo , Interleucina-3/metabolismo , Lectinas Tipo C/metabolismo , Camundongos , Quinase Syk/metabolismo , Regulação para CimaAssuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença de Hodgkin/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/etiologia , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , HumanosRESUMO
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency, the presence of anti-ADAMTS13 autoantibodies and an open ADAMTS13 conformation with a cryptic epitope in the spacer domain exposed. A detailed knowledge of anti-ADAMTS13 autoantibodies will help identifying pathogenic antibodies and elucidating the cause of ADAMTS13 deficiency. We aimed at cloning anti-ADAMTS13 autoantibodies from iTTP patients to study their epitopes and inhibitory characteristics. We sorted anti-ADAMTS13 autoantibody expressing B cells from peripheral blood mononuclear cells of 13 iTTP patients to isolate anti-ADAMTS13 autoantibody sequences. Ninety-six B cell clones producing anti-ADAMTS13 autoantibodies were identified from which 30 immunoglobulin M (IgM) and 5 IgG sequences were obtained. For this study, we only cloned, expressed and purified the five IgG antibodies. In vitro characterization revealed that three of the five cloned IgG antibodies, TTP73-1, ELH2-1 and TR8C11, indeed recognize ADAMTS13. Epitope mapping showed that antibodies TTP73-1 and TR8C11 bind to the cysteine-spacer domains, while the antibody ELH2-1 recognizes the T2-T3 domains in ADAMTS13. None of the antibodies inhibited ADAMTS13 activity. Given the recent findings regarding the open ADAMTS13 conformation during acute iTTP, we studied if the cloned antibodies could recognize cryptic epitopes in ADAMTS13. Interestingly, all three antibodies recognize cryptic epitopes. In conclusion, we cloned three anti-ADAMTS13 autoantibodies from iTTP patients that recognize cryptic epitopes. Hence, these data nicely fit our recent finding that the conformation of ADAMTS13 is open during acute iTTP.
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Proteína ADAMTS13/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Linfócitos B/imunologia , Epitopos de Linfócito B/imunologia , Imunoglobulina G/sangue , Púrpura Trombocitopênica Trombótica/imunologia , Proteína ADAMTS13/genética , Autoantígenos/genética , Células Cultivadas , Células Clonais , Clonagem Molecular , Mapeamento de Epitopos , Epitopos de Linfócito B/genética , Humanos , Leucócitos Mononucleares/imunologia , Conformação Proteica , RNA Mensageiro/genéticaRESUMO
OBJECTIVES: To describe clinicopathologic features of muscular sarcoidosis and the associated sarcoidosis phenotype through a nationwide multicenter study. METHODS: Patients were included if they had histologically proven sarcoidosis and symptomatic muscular involvement confirmed by biological, imaging, or histologic examinations. RESULTS: Forty-eight patients (20 males) were studied, with a median age at muscular symptoms onset of 45 years (range 18-71). Four patterns were identified: a nodular pattern (27%); smoldering phenotype (29%); acute, subacute, or progressive myopathic type (35%); and combined myopathic and neurogenic pattern (10%). In all patterns, sarcoidosis was multivisceral with a median of 3 extramuscular organs involved (mostly lungs, lymph nodes, eyes, and skin) and a prolonged course with long-term use of corticosteroids and immunosuppressive drugs. Muscular patterns differed according to clinical presentation (myalgia, nodules, or weakness), electromyographic findings, muscular MRI, and response to sarcoidosis treatment. The myopathic and neuromuscular patterns were more severe. CONCLUSION: This nationwide study of muscular sarcoidosis allowed the identification of 4 patterns of granulomatous myositis, which differed by phenotypes and the clinical course.
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Development of neutralizing antibodies against therapeutic Factor VIII (FVIII) is the most serious complication of the treatment of hemophilia A. There is growing evidence to show the multifactorial origin of the anti-FVIII immune response, combining both genetic and environmental factors. While a role for the complement system on innate as well as adaptive immunity has been documented, the implication of complement activation on the onset of the anti-FVIII immune response is unknown. Here, using in vitro assays for FVIII endocytosis by human monocyte-derived dendritic cells and presentation to T cells, as well as in vivo complement depletion in FVIII-deficient mice, we show a novel role for complement C3 in enhancing the immune response against therapeutic FVIII. In vitro, complement C3 and its cleavage product C3b enhanced FVIII endocytosis by dendritic cells and presentation to a FVIII-specific CD4+ T-cell hybridoma. The C1 domain of FVIII had previously been shown to play an important role in FVIII endocytosis, and alanine substitutions of the K2092, F2093 and R2090 C1 residues drastically reduce FVIII uptake in vitro Interestingly, complement activation rescued the endocytosis of the FVIII C1 domain triple mutant. In a mouse model of severe hemophilia A, transient complement C3 depletion by humanized cobra venom factor, which does not generate anaphylatoxin C5a, significantly reduced the primary anti-FVIII immune response, but did not affect anti-FVIII recall immune responses. Taken together, our results suggest an important adjuvant role for the complement cascade in the initiation of the immune response to therapeutic FVIII.
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Anticorpos Neutralizantes/imunologia , Complemento C3/farmacologia , Fator VIII/imunologia , Animais , Apresentação de Antígeno/imunologia , Ativação do Complemento , Células Dendríticas/fisiologia , Endocitose/efeitos dos fármacos , Humanos , Imunidade/efeitos dos fármacos , CamundongosRESUMO
IMMUNOTHERAPY OF HODGKIN LYMPHOMA: Classical Hodgkin lymphoma (HL) is a rare hematological cancer, affecting preferentially young adults. Using a risk-adapted approach, HL has become highly curable (>80%) with front-line chemotherapy in addition with radiotherapy, despite long term significant toxicity. Some patients are primary refractory or relapse after first-line chemotherapy, requiring high dose chemotherapy with serious side effects. Studies of the microenvironment from HL tissue reveal ineffective inflammatory and immune cell infiltrate surrounding Reed-Sternberg cells, involving the Programmed cell Death 1 (PD-1)/PD-ligand-1 checkpoint pathways. Recently, immune checkpoint inhibitors demonstrated high efficacy for relapsed and refractory patients, with a favorable safety profile but indeterminate long term outcome. Guidelines for nivolumab or pembrolizumab treatment in HL remain to be established.
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Antígeno B7-H1/antagonistas & inibidores , Doença de Hodgkin/terapia , Imunoterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Brentuximab Vedotin , Ensaios Clínicos como Assunto , Doença de Hodgkin/patologia , Humanos , Imunoconjugados/uso terapêutico , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Recidiva , Células de Reed-Sternberg , Microambiente TumoralRESUMO
Acquired thrombotic thrombocytopenic purpura is a rare and severe disease characterized by auto-antibodies directed against "A Disintegrin And Metalloproteinase with Thrombospondin type 1 repeats, 13th member" (ADAMTS13), a plasma protein involved in hemostasis. Involvement of CD4+ T cells in the pathogenesis of the disease is suggested by the IgG isotype of the antibodies. However, the nature of the CD4+ T-cell epitopes remains poorly characterized. Here, we determined the HLA-DR-restricted CD4+ T-cell epitopes of ADAMTS13. Candidate T-cell epitopes were predicted in silico and binding affinities were confirmed in competitive enzyme-linked immunosorbent assays. ADAMTS13-reactive CD4+ T-cell hybridomas were generated following immunization of HLA-DR1 transgenic mice (Sure-L1 strain) and used to screen the candidate epitopes. We identified the ADAMTS131239-1253 peptide as the single immunodominant HLA-DR1-restricted CD4+ T-cell epitope. This peptide is located in the CUB2 domain of ADAMTS13. It was processed by dendritic cells, stimulated CD4+ T cells from Sure-L1 mice and was recognized by CD4+ T cells from an HLA-DR1-positive patient with acute thrombotic thrombocytopenic purpura. Interestingly, the ADAMTS131239-1253 peptide demonstrated promiscuity towards HLA-DR11 and HLA-DR15. Our work paves the way towards the characterization of the ADAMTS13-specific CD4+ T-cell response in patients with thrombotic thrombocytopenic purpura using ADAMTS131239-1253-loaded HLA-DR tetramers.
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Proteína ADAMTS13/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Antígeno HLA-DR1/imunologia , Epitopos Imunodominantes/imunologia , Fragmentos de Peptídeos/imunologia , Proteína ADAMTS13/química , Alelos , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Epitopos de Linfócito T/química , Antígeno HLA-DR1/química , Antígeno HLA-DR1/metabolismo , Humanos , Imunização , Epitopos Imunodominantes/química , Imunoglobulina G/imunologia , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/imunologia , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/imunologia , Púrpura Trombocitopênica Trombótica/metabolismoRESUMO
Renal transplant is the treatment of choice for patients with terminal end-stage renal disease. We have previously identified low levels of catalytic IgG as a potential prognosis marker for chronic allograft rejection. The origin and physiopathological relevance of catalytic Abs is not well understood, owing to the fact that catalytic Abs have been studied in relatively small cohorts of patients with rare diseases and/or without systematic follow-up. In the current study, we have followed the evolution of the levels of catalytic IgG in a large cohort of renal transplant patients over a 2-y period. Our results demonstrate that, prior to transplant, patients with renal failure present with heterogeneous levels of IgG hydrolyzing the generic proline-phenylalanine-arginine-methylcoumarinamide (PFR-MCA) substrate. PFR-MCA hydrolysis was greater for patients' IgG than for a therapeutic preparation of pooled IgG from healthy donors. Renal transplant was marked by a drastic decrease in levels of catalytic IgG over 3 mo followed by a steady increase during the next 21 mo. Patients who displayed high levels of catalytic IgG pretransplant recovered high levels of catalytic Abs 2 y posttransplant. Interestingly, IgG-mediated hydrolysis of a model protein substrate, procoagulant factor VIII, did not correlate with that of PFR-MCA prior transplantation, whereas it did 12 mo posttransplant. Taken together, our results suggest that the level of circulating catalytic IgG under pathological conditions is an intrinsic property of each individual's immune system and that recovery of pretransplant levels of catalytic IgG is accompanied by changes in the repertoire of target Ags.
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Biomarcadores/metabolismo , Rejeição de Enxerto/imunologia , Sistema Imunitário , Imunoglobulina G/metabolismo , Transplante de Rim , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Catalíticos , Autoanticorpos/metabolismo , Coagulação Sanguínea , Doença Crônica , Fator VIII/metabolismo , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Transplantados , Adulto JovemRESUMO
Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.
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Autoanticorpos/sangue , Doenças Autoimunes/sangue , Dermatomiosite/sangue , Hidroximetilglutaril-CoA Redutases/imunologia , Doenças Musculares/sangue , Miosite/imunologia , Neoplasias/sangue , Adulto , Idoso , Doenças Autoimunes/epidemiologia , Comorbidade , Dermatomiosite/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/epidemiologia , Neoplasias/epidemiologiaAssuntos
Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Doenças Neuromusculares/tratamento farmacológico , Penfigoide Mucomembranoso Benigno/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Humanos , Síndrome de Linfonodos Mucocutâneos/imunologia , Doenças Neuromusculares/imunologia , Penfigoide Mucomembranoso Benigno/imunologia , Púrpura Trombocitopênica Idiopática/imunologiaRESUMO
Intravenous immunoglobulin (IVIg) is used in the therapy of various autoimmune and inflammatory diseases. Recent studies in experimental models propose that anti-inflammatory effects of IVIg are mainly mediated by α2,6-sialylated Fc fragments. These reports further suggest that α2,6-sialylated Fc fragments interact with DC-SIGN(+) cells to release IL-33 that subsequently expands IL-4-producing basophils. However, translational insights on these observations are lacking. Here we show that IVIg therapy in rheumatic patients leads to significant raise in plasma IL-33. However, IL-33 was not contributed by human DC-SIGN(+) dendritic cells and splenocytes. As IL-33 has been shown to expand basophils, we analyzed the proportion of circulating basophils in these patients following IVIg therapy. In contrast to mice data, IVIg therapy led to basophil expansion only in two patients who also showed increased plasma levels of IL-33. Importantly, the fold-changes in IL-33 and basophils were not correlated and we could hardly detect IL-4 in the plasma following IVIg therapy. Thus, our results indicate that IVIg-induced IL-33 is insufficient to mediate basophil expansion in autoimmune patients. Hence, IL-33 and basophil-mediated anti-inflammatory mechanism proposed for IVIg might not be pertinent in humans.