RESUMO
The risk to develop ACPA positive rheumatoid arthritis (RA), the most destructive type of autoimmune arthritis, is carried by HLA-DRB1 alleles containing a 5 amino acid motif: the shared epitope (SE). RA is preceded by the emergence of disease specific anti citrullinated protein antibodies (ACPA). SE positive HLA-DRB1 alleles are associated with ACPA and ACPA positive RA, not with ACPA negative RA, suggesting that ACPA contribute to the pathogenesis of RA. Understanding how HLA-DRB1 genotypes influence ACPA could lead to a curative or preventive treatment of RA. The "Shared epitope binds citrullinated peptides " hypothesis suggests that RA associated HLA-DR alleles present citrullinated peptides to T cells that help ACPA producing B cells. The "Hapten carrier model" suggests that PAD4 is the target of the T cells which help ACPA specific B cells through a hapten carrier mechanism in which PAD4 is the carrier and citrullinated peptides are the haptens. Direct binding assay of citrullinated peptides to purified HLA-DR molecules does not support the "shared epitope binds citrullinated peptides" hypothesis. The Odds Ratios to develop ACPA positive RA associated with each of 12 common HLA-DRB1 genotypes match the probability that the two HLA-DR molecules they encode can bind at least one peptide from PAD4, not from citrullinated fibrinogen. Thus, PAD4 tolerization might stop the carrier effect and switch off production of ACPA.
Assuntos
Artrite Reumatoide , Autoanticorpos , Citrulinação , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/biossíntese , Epitopos , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Haptenos/genética , Haptenos/imunologia , Humanos , Peptídeos/genética , Peptídeos/imunologia , Peptídeos Cíclicos/genética , Peptídeos Cíclicos/imunologiaRESUMO
Viruses are a possible cause for Sjögren's syndrome (SS) as an environmental factor related to SS onset, which exhibits exocrine gland dysfunction and the emergence of autoantibodies. Although retroviruses may exhibit lymphocytic infiltration into exocrine glands, human T-cell leukemia virus type 1 (HTLV-1) has been postulated to be a causative agent for SS. Transgenic mice with HTLV-1 genes showed sialadenitis resembling SS, but their phenotypic symptoms differed based on the adopted region of HTLV-1 genes. The dominance of tax gene differed in labial salivary glands (LSGs) of SS patients with HTLV 1-associated myelopathy (HAM) and adult T-cell leukemia. Although HTLV-1 was transmitted to salivary gland epithelial cells (SGECs) by a biofilm-like structure, no viral synapse formation was observed. After infection to SGECs derived from SS patients, adhesion molecules and migration factors were time-dependently released from infected SGECs. The frequency of the appearance of autoantibodies including anti-Ro/SS-A, La/SS-B antibodies in SS patients complicated with HAM is unknown; the observation of less frequent ectopic germinal center formation in HTLV-1-seropositive SS patients was a breakthrough. In addition, HTLV-1 infected cells inhibited B-lymphocyte activating factor or C-X-C motif chemokine 13 through direct contact with established follicular dendritic cell-like cells. These findings show that HTLV-1 is directly involved in the pathogenesis of SS.
Assuntos
Infecções por HTLV-I , Síndrome de Sjogren/virologia , Animais , Autoanticorpos/biossíntese , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Genes Virais , Infecções por HTLV-I/complicações , Infecções por HTLV-I/epidemiologia , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Linfócitos/virologia , Camundongos , Camundongos Transgênicos , Paraparesia Espástica Tropical/complicações , Paraparesia Espástica Tropical/epidemiologia , Paraparesia Espástica Tropical/imunologia , Paraparesia Espástica Tropical/virologia , Fenótipo , Ratos , Proteínas dos Retroviridae/genética , Proteínas dos Retroviridae/metabolismo , Glândulas Salivares/citologia , Glândulas Salivares/metabolismo , Glândulas Salivares/virologia , Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/imunologiaRESUMO
SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.
Assuntos
Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/imunologia , COVID-19/prevenção & controle , Proteínas do Capsídeo/efeitos adversos , ChAdOx1 nCoV-19/efeitos adversos , Contaminação de Medicamentos , Vetores Genéticos/efeitos adversos , Células HEK293/imunologia , Imunoglobulina G/imunologia , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/etiologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/efeitos adversos , Adenoviridae/imunologia , Animais , Complexo Antígeno-Anticorpo/ultraestrutura , Autoanticorpos/biossíntese , Síndrome de Vazamento Capilar/etiologia , Proteínas do Capsídeo/imunologia , Linhagem Celular Transformada , ChAdOx1 nCoV-19/química , ChAdOx1 nCoV-19/imunologia , ChAdOx1 nCoV-19/toxicidade , Difusão Dinâmica da Luz , Epitopos/química , Epitopos/imunologia , Armadilhas Extracelulares/imunologia , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Vetores Genéticos/imunologia , Células HEK293/química , Humanos , Imageamento Tridimensional , Imunoglobulina G/biossíntese , Inflamação , Camundongos , Microscopia/métodos , Ativação Plaquetária , Proteômica , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/imunologia , Trombose dos Seios Intracranianos/diagnóstico por imagem , Trombose dos Seios Intracranianos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Cultura de VírusAssuntos
Adenoviridae , Apresentação de Antígeno , Autoanticorpos/biossíntese , Autoantígenos/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Vetores Genéticos/efeitos adversos , Antígenos HLA-D/imunologia , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Trombótica/etiologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Vacinas contra COVID-19/efeitos adversos , Micropartículas Derivadas de Células/imunologia , ChAdOx1 nCoV-19 , Humanos , Imunoglobulina G/imunologia , Ativação Plaquetária , Fator Plaquetário 4/química , Ligação Proteica , Multimerização Proteica/imunologia , Púrpura Trombocitopênica Trombótica/imunologia , Subpopulações de Linfócitos T/imunologia , Timo/imunologiaRESUMO
It has been more than a year since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged. Many studies have provided insights into the various aspects of the immune response in coronavirus disease 2019 (COVID-19). Especially for antibody treatment and vaccine development, humoral immunity to SARS-CoV-2 has been studied extensively, though there is still much that is unknown and controversial. Here, we introduce key discoveries on the humoral immune responses in COVID-19, including the immune dynamics of antibody responses and correlations with disease severity, neutralizing antibodies and their cross-reactivity, how long the antibody and memory B-cell responses last, aberrant autoreactive antibodies generated in COVID-19 patients, and the efficacy of currently available therapeutic antibodies and vaccines against circulating SARS-CoV-2 variants, and highlight gaps in the current knowledge.
Assuntos
Anticorpos Neutralizantes/biossíntese , Linfócitos B/imunologia , COVID-19/imunologia , Switching de Imunoglobulina , Imunoglobulina G/biossíntese , SARS-CoV-2/patogenicidade , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/biossíntese , Anticorpos Facilitadores , Autoanticorpos/biossíntese , Linfócitos B/virologia , COVID-19/mortalidade , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina A/biossíntese , Imunoglobulina M/biossíntese , Memória Imunológica , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Análise de Sobrevida , Tratamento Farmacológico da COVID-19RESUMO
Today the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global health problem. After more than a year with the pandemic, although our knowledge has progressed on COVID-19, there are still many unknowns in virological, pathophysiological and immunological aspects. It is obvious that the most efficient solution to end this pandemic are safe and efficient vaccines. This manuscript summarizes the pathophysiological and thrombotic features of COVID-19 and the safety and efficacy of currently approved COVID-19 vaccines with an aim to clarify the recent concerns of thromboembolic events after COVID-19 vaccination. The influx of newer information is rapid, requiring periodic updates and objective assessment of the data on the pathogenesis of COVID-19 variants and the safety and efficacy of currently available vaccines.
Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , SARS-CoV-2 , Trombose/etiologia , Ad26COVS1 , Autoanticorpos/biossíntese , Vacina BNT162 , COVID-19/epidemiologia , COVID-19/fisiopatologia , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , ChAdOx1 nCoV-19 , Ensaios Clínicos como Assunto , Coagulação Intravascular Disseminada/epidemiologia , Coagulação Intravascular Disseminada/etiologia , Aprovação de Drogas , Feminino , Vetores Genéticos , Glicosaminoglicanos/imunologia , Humanos , Masculino , Modelos Cardiovasculares , Pandemias/prevenção & controle , Fator Plaquetário 4/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Segurança , Trombose dos Seios Intracranianos/epidemiologia , Trombose dos Seios Intracranianos/etiologia , Trombose/epidemiologia , Trombose/fisiopatologia , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas de mRNARESUMO
Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.
Assuntos
Interferon Tipo I/fisiologia , Rim/patologia , Nefrite Lúpica/etiologia , Complexo Antígeno-Anticorpo/metabolismo , Autoanticorpos/biossíntese , Fibrose , Humanos , Rim/irrigação sanguínea , Rim/imunologia , Glomérulos Renais/patologiaRESUMO
Vaccination is crucial in combatting the severe acute respiratory syndrome coronavirus 2 pandemic. The rare complication of thrombocytopenia and thrombotic complications at unusual sites after ChAdOx1 nCov-19 vaccination is caused by platelet-activating antibodies directed against platelet factor 4 (PF4). We present a widely applicable whole-blood standard flow cytometric assay to identify the pathogenic antibodies associated with vaccine-induced immune-mediated thrombotic thrombocytopenia (VITT) after ChAdOx1 nCov-19 vaccination. This assay will enable rapid diagnosis by many laboratories. This trial was registered at www.clinicaltrials.gov as #NCT04370119.
Assuntos
Autoanticorpos/sangue , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Citometria de Fluxo/métodos , Imunoglobulina G/sangue , Ativação Plaquetária/imunologia , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/diagnóstico , Receptores de IgG/imunologia , SARS-CoV-2 , Vacinação/efeitos adversos , Especificidade de Anticorpos , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Vacinas contra COVID-19/imunologia , ChAdOx1 nCoV-19 , Heparina/efeitos adversos , Heparina/imunologia , Humanos , Técnicas Imunoenzimáticas , Imunogenicidade da Vacina , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Selectina-P/análise , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/imunologiaRESUMO
Non-infectious uveitis is an inflammatory disorder of the eye that accounts for severe visual loss without evident infectious agents. While T cells are supposed to dominate the induction of inflammation in non-infectious uveitis, the role of B cells in the pathogenesis of this disease is obscure. Therefore, this review aimed to discuss diverse B-cell participation in different non-infectious uveitides and their roles in the pathogenesis of this disease as well as the mechanism of action of rituximab. Increasing evidence from experimental models and human non-infectious uveitis has suggested the participation of B cells in non-infectious uveitis. The participation levels vary in different uveitides. Furthermore, B cells play multiple roles in the pathogenic mechanisms. B cells produce autoantibodies, regulate T cell responses via antibody-independent functions, and constitute ectopic lymphoid structures. Regulatory B cells perform pivotal anti-inflammatory functions in non-infectious uveitis. Rituximab may work by depleting pro-inflammatory B cells and restoring the quantity and function of regulatory B cells in this disease. Identifying the levels of B-cell participation and the associated roles is beneficial for optimizing therapy. Diversified experimental model choices and emerging tools and/or methods are conducive for future studies on this topic.
Assuntos
Linfócitos B/fisiologia , Uveíte/imunologia , Animais , Autoanticorpos/biossíntese , Doenças Autoimunes/etiologia , Citocinas/biossíntese , Modelos Animais de Doenças , Humanos , Rituximab/uso terapêutico , Uveíte/etiologiaRESUMO
Carbohydrate-binding antibodies play diverse and critical roles in human health. Endogenous carbohydrate-binding antibodies that recognize bacterial, fungal, and other microbial carbohydrates prevent systemic infections and help maintain microbiome homeostasis. Anti-glycan antibodies can have both beneficial and detrimental effects. For example, alloantibodies to ABO blood group carbohydrates can help reduce the spread of some infectious diseases, but they also impose limitations for blood transfusions. Antibodies that recognize self-glycans can contribute to autoimmune diseases, such as Guillain-Barre syndrome. In addition to endogenous antibodies that arise through natural processes, a variety of vaccines induce anti-glycan antibodies as a primary mechanism of protection. Some examples of approved carbohydrate-based vaccines that have had a major impact on human health are against pneumococcus, Haemophilus influeanza type b, and Neisseria meningitidis. Monoclonal antibodies specifically targeting pathogen associated or tumor associated carbohydrate antigens (TACAs) are used clinically for both diagnostic and therapeutic purposes. This review aims to highlight some of the well-studied and critically important applications of anti-carbohydrate antibodies.
Assuntos
Síndrome de Guillain-Barré/imunologia , Infecções por Haemophilus/imunologia , Meningite Meningocócica/imunologia , Pneumonia Pneumocócica/imunologia , Polissacarídeos/imunologia , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/uso terapêutico , Autoanticorpos/biossíntese , Autoanticorpos/sangue , Vacinas Bacterianas/biossíntese , Vacinas Bacterianas/uso terapêutico , Sequência de Carboidratos , Síndrome de Guillain-Barré/patologia , Infecções por Haemophilus/microbiologia , Infecções por Haemophilus/prevenção & controle , Vacinas Anti-Haemophilus/biossíntese , Vacinas Anti-Haemophilus/uso terapêutico , Haemophilus influenzae/imunologia , Humanos , Meningite Meningocócica/microbiologia , Meningite Meningocócica/prevenção & controle , Neisseria meningitidis/imunologia , Vacinas Pneumocócicas/biossíntese , Vacinas Pneumocócicas/uso terapêutico , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/prevenção & controle , Polissacarídeos/antagonistas & inibidores , Polissacarídeos/química , Streptococcus pneumoniae/imunologiaRESUMO
Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.
Assuntos
Apresentação de Antígeno , Autoimunidade , Coagulação Sanguínea/imunologia , Receptor de Proteína C Endotelial/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lisofosfolipídeos/imunologia , Monoglicerídeos/imunologia , Animais , Anticorpos Antifosfolipídeos/biossíntese , Autoanticorpos/biossíntese , Modelos Animais de Doenças , Perda do Embrião/imunologia , Endossomos/imunologia , Receptor de Proteína C Endotelial/genética , Humanos , Imunidade Inata , Lúpus Eritematoso Sistêmico/sangue , Camundongos , Camundongos Mutantes , Esfingomielina Fosfodiesterase/metabolismo , Trombose/imunologia , Receptor 7 Toll-Like/imunologiaRESUMO
Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPß1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (ß = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
Assuntos
Autoanticorpos/genética , Doenças Autoimunes/genética , Predisposição Genética para Doença , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Cadeias HLA-DRB1/genética , Proteinose Alveolar Pulmonar/genética , Adulto , Idoso , Alelos , Povo Asiático , Autoanticorpos/biossíntese , Doenças Autoimunes/etnologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Estudos de Casos e Controles , Cromossomos Humanos Par 6 , Feminino , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Cadeias HLA-DRB1/imunologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Isoformas de Proteínas/genética , Proteinose Alveolar Pulmonar/etnologia , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/patologia , Surfactantes Pulmonares/imunologia , Surfactantes Pulmonares/metabolismo , RiscoRESUMO
The SARS-CoV-2 pandemic has focused attention on prevention, restriction and treatment methods that are acceptable worldwide. This means that they should be simple and inexpensive. This review examines the possible role of glycosaminoglycan (GAG) antithrombotics in the treatment of COVID-19. The pathophysiology of this disease reveals a complex interplay between the hemostatic and immune systems that can be readily disrupted by SARS-CoV-2. Some of the GAG antithrombotics also possess immune-modulatory actions and since they are relatively inexpensive they could play an important role in the management of COVID-19 and its complications.
Assuntos
Tratamento Farmacológico da COVID-19 , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Autoanticorpos/biossíntese , COVID-19/complicações , COVID-19/fisiopatologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Endotélio Vascular/virologia , Feminino , Glicosaminoglicanos/uso terapêutico , Hemorragia/etiologia , Transtornos Hemostáticos/tratamento farmacológico , Transtornos Hemostáticos/etiologia , Transtornos Hemostáticos/fisiopatologia , Humanos , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/fisiopatologia , Masculino , Pandemias , Fatores de Risco , SARS-CoV-2/patogenicidade , Trombina/biossíntese , Trombose/etiologiaRESUMO
Factor V inhibitors are a rare cause of life-threatening bleeding. We present a case of an acquired factor V inhibitor likely caused by coronavirus disease 2019 infection. Bleeding was manifested by severe anemia requiring frequent red-cell transfusion, left psoas muscle hematoma, and left retroperitoneal cavity hematoma. Factor V activity was less than 1% and the factor V inhibitor titer was 31.6 Bethesda units. Severe acute respiratory syndrome coronavirus 2 RNA testing of the nasopharynx was positive 2 weeks before presentation and continued to be positive for 30 days. The patient failed treatment with intravenous immunoglobulin and dexamethasone. Three cycles of plasmapheresis with fresh frozen plasma replacement resulted in correction of the bleeding and laboratory coagulopathy. This is the first reported case of a factor V inhibitor in a coronavirus disease 2019 patient and suggests that plasmapheresis may be a successful treatment strategy.
Assuntos
Autoanticorpos/biossíntese , COVID-19/sangue , Fator V/imunologia , Transtornos Hemorrágicos/etiologia , SARS-CoV-2 , Idoso de 80 Anos ou mais , Anemia/etiologia , Anemia/terapia , Anticorpos Antivirais/sangue , Especificidade de Anticorpos , Autoanticorpos/imunologia , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/imunologia , Terapia Combinada , Comorbidade , Diagnóstico Tardio , Dexametasona/uso terapêutico , Transfusão de Eritrócitos , Fator V/antagonistas & inibidores , Feminino , Hematoma/etiologia , Transtornos Hemorrágicos/tratamento farmacológico , Transtornos Hemorrágicos/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Inibidor de Coagulação do Lúpus/sangue , Octreotida/uso terapêutico , Plasma , Plasmaferese , SARS-CoV-2/imunologia , Vitamina K/uso terapêuticoRESUMO
OBJECTIVE: To assess the role of STAT4 activation in driving pathogenic follicular helper T (Tfh) cell secretion of the cytokines interleukin-21 (IL-21) and interferon-γ (IFNγ) in murine and human lupus. METHODS: The effect of STAT4-dependent Tfh cell signaling on cytokine production and autoreactive B cell maturation was assessed temporally during the course of lupus in a murine model, with further assessment of Tfh cell gene transcription performed using RNA-Seq technology. STAT4-dependent signaling and cytokine production were also determined in circulating Tfh-like cells in patients with systemic lupus erythematosus (SLE), as compared to cells from healthy control subjects, and correlations with disease activity were assessed in the Tfh-like cells from SLE patients. RESULTS: IL-21- and IFNγ-coproducing Tfh cells expanded prior to the detection of potentially pathogenic IgG2c autoantibodies in lupus-prone mice. Tfh cells transcriptionally evolved during the course of disease with acquisition of a STAT4-dependent gene signature. Maintenance of Tfh cell cytokine synthesis was dependent upon STAT4 signaling, driven by type I IFNs. Circulating Tfh-like cells from patients with SLE also secreted IL-21 and IFNγ, with STAT4 phosphorylation enhanced by IFNß, in association with the extent of clinical disease activity. CONCLUSION: We identified a role for type I IFN signaling in driving STAT4 activation and production of IL-21 and IFNγ by Tfh cells in murine and human lupus. Enhanced STAT4 activation in Tfh cells may underlie pathogenic B cell responses in both murine and human lupus. These data indicate that STAT4 guides pathogenic cytokine and immunoglobulin production in SLE, demonstrating a potential therapeutic target to modulate autoimmunity.
Assuntos
Autoanticorpos/imunologia , Citocinas/imunologia , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fator de Transcrição STAT4/imunologia , Células T Auxiliares Foliculares/imunologia , Adulto , Animais , Formação de Anticorpos/imunologia , Autoanticorpos/biossíntese , Linfócitos B/imunologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulinas , Interferon gama/imunologia , Interleucinas/imunologia , Masculino , Camundongos Endogâmicos MRL lpr , Pessoa de Meia-Idade , RNA-SeqRESUMO
Systemic lupus erythematosus (SLE) is a multifactorial and heterogeneous autoimmune disease involving multiple organ systems and tissues. Lupus nephritis occurs in approximately 60% of patients with SLE and is the leading cause of morbidity. Diffuse alveolar hemorrhage (DAH) is a rare but very serious complication of SLE with a greater than 50% associated mortality. The etiology of SLE is unclear but has proposed genetic, hormonal, and environmental aspects. Pristane is a saturated terpenoid alkane and has become the most popular laboratory model for inducing lupus in mice. The pristane model of SLE has the capacity to reproduce many components of the human presentation of the disease. Previous studies have demonstrated that virus-derived immune-modulating proteins have the potential to control inflammatory and autoimmune disorders. Serp-1, a 55 kDa secreted and highly glycosylated immune modulator derived from myxoma virus (MYXV), has potent immunomodulatory activity in models of vasculitis, viral sepsis, collagen-induced arthritis, and transplant rejection. This chapter describes the mouse preclinical pristane lupus model as a method to examine virus-derived protein efficacy for treating autoimmune diseases and specifically lupus nephritis and DAH.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Hemorragia/prevenção & controle , Fatores Imunológicos/farmacologia , Nefrite Lúpica/tratamento farmacológico , Myxoma virus/química , Proteinúria/tratamento farmacológico , Proteínas Virais/farmacologia , Animais , Autoanticorpos/biossíntese , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Hemorragia/imunologia , Hemorragia/patologia , Humanos , Fatores Imunológicos/imunologia , Injeções Intraperitoneais , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteinúria/induzido quimicamente , Proteinúria/imunologia , Proteinúria/patologia , Terpenos/administração & dosagem , Resultado do Tratamento , Proteínas Virais/imunologiaRESUMO
BACKGROUND: To make an accurate estimate of the response to thrombopoietin (TPO) receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. METHODS: A prospective study was conducted at 2 hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analyzed changes in platelet counts from baseline to the maximum platelet count on days 9-14. The definition of clinical response was a platelet count of ≥5 × 104/µL with an increased platelet count of ≥2 × 104/µL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. RESULTS: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/µL (95% CI 2.8-4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064-0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (regression coefficient [B] = 0.089; CI 0.021-0.157, p = 0.013). CONCLUSION: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease.
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Autoanticorpos/biossíntese , Linfócitos B/imunologia , Cinamatos/uso terapêutico , Hepatopatias/complicações , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Tiazóis/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/imunologia , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Plaquetas/patologia , Cinamatos/administração & dosagem , Feminino , Humanos , Hepatopatias/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Tamanho do Órgão , Contagem de Plaquetas , Estudos Prospectivos , Baço/patologia , Tiazóis/administração & dosagem , Trombocitopenia/sangue , Trombocitopenia/complicaçõesRESUMO
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease including the cardiovascular system. Atherosclerosis is the most common cardiovascular complication of SLE and a significant risk factor for morbidity and mortality. Vascular damage/protection mechanism in SLE patients is out of balance, caused by the cascade reaction among oxidative stress, proinflammatory cytokines, Neutrophil Extracellular Traps, activation of B cells and autoantibodies and abnormal T cells. As a precursor cell repairing vascular endothelium, endothelial progenitor cells (EPCs) belong to the protective mechanism and show the reduced number and impaired function in SLE. However, the pathological mechanism of EPCs dysfunction in SLE remains ill-defined. This paper reviews the latest SLE epidemiology and pathogenesis, discusses the changes in the number and function of EPCs in SLE, expounds the role of EPCs in SLE atherosclerosis, and provides new guidance and theoretical basis for exploring novel targets for SLE treatment.
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Aterosclerose/etiologia , Aterosclerose/imunologia , Células Progenitoras Endoteliais/imunologia , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Aterosclerose/fisiopatologia , Autoanticorpos/biossíntese , Linfócitos B/imunologia , Citocinas/imunologia , Células Progenitoras Endoteliais/classificação , Células Progenitoras Endoteliais/fisiologia , Armadilhas Extracelulares/imunologia , Humanos , Lúpus Eritematoso Sistêmico/fisiopatologia , Modelos Imunológicos , Estresse Oxidativo , Transdução de Sinais/imunologia , Linfócitos T/imunologiaRESUMO
We studied the effect of single and repeated intranasal administration of antibodies to glutamate in experimental parkinsonian syndrome induced by injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6J mice. Intranasal administration of anti-glutamate antibodies to mice in parallel with administration of MPTP over 10 days alleviated parkinsonian symptoms (oligokinesia and rigidity). In the serum of mice injected with antibodies to glutamate and/or MPTP, the titers of autoantibodies to glutamate and dopamine were higher than in control animals receiving saline. Single intranasal administration of anti-glutamate antibodies to mice with established parkinsonian syndrome did not affect the severity of parkinsonian symptoms.
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Anticorpos/farmacologia , Antiparkinsonianos/farmacologia , Dopamina/imunologia , Ácido Glutâmico/imunologia , Hipocinesia/tratamento farmacológico , Transtornos Parkinsonianos/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Administração Intranasal , Animais , Anticorpos/química , Anticorpos/isolamento & purificação , Antiparkinsonianos/química , Antiparkinsonianos/isolamento & purificação , Autoanticorpos/biossíntese , Dopamina/química , Ácido Glutâmico/química , Cavalos , Hipocinesia/induzido quimicamente , Hipocinesia/imunologia , Hipocinesia/fisiopatologia , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/imunologia , Transtornos Parkinsonianos/fisiopatologia , Coelhos , gama-Globulinas/química , gama-Globulinas/imunologiaRESUMO
Atherosclerosis is responsible for a large percentage of all-cause mortality worldwide, but it is only now beginning to be understood as a complex disease process involving metabolic insult, chronic inflammation, and multiple immune mechanisms. Abs targeting apolipoprotein A-I (ApoA-I) have been found in patients with cardiovascular disease, autoimmune conditions, as well as those with no documented history of either. However, relatively little is known about how these Abs are generated and their relationship to diet and sex. In the current study, we modeled this aspect of autoimmunity using anti-ApoA-I immunization of male and female C57BL/6 mice. Unexpectedly, we found that autoantibodies directed against a single, previously unknown, epitope within the ApoA-I protein developed irrespective of immunization status or dyslipidemia in mice. When total IgG subclasses were analyzed over the course of time, we observed that rather than driving an increase in inflammatory IgG subclasses, consumption of Western diet suppressed age-dependent increases in IgG2b and IgG2c in male mice only. The lack of change observed in female mice suggested that diet and sex might play a combined role in Th1/Th2 balance and, ultimately, in immunity to pathogen challenge. This report demonstrates the need for inclusion of both sexes in studies pertaining to diet and aging and suggests that further study of immunogenic epitopes present in ApoA-I is warranted.