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1.
Arch. Soc. Esp. Oftalmol ; 97(11): 655-658, nov. 2022. ilus
Artigo em Espanhol | IBECS | ID: ibc-ADZ-898

RESUMO

Se presenta el caso de retinopatía autoinmune en un paciente con carcinoma microcítico de pulmón, no conocido hasta el momento, que se diagnosticó tras la exploración oftalmológica. La serología fue positiva para anticuerpos onconeuronales CV2/CRMP5. La retinopatía autoinmune es una entidad rara que puede pasarse por alto, y ser infradiagnosticada. Se produce por una reacción inmunomediada contra antígenos retinianos. La importancia de su diagnóstico precoz radica en que en muchos de los pacientes la sintomatología ocular aparece antes del diagnóstico del cáncer primario, por lo que su identificación y derivación precoz para estudio de extensión puede suponer el diagnóstico de una neoplasia primaria oculta hasta el momento. (AU)


We present a case of autoimmune retinopathy in a patient with unknown small cell lung cáncer (SCLC), which was diagnosed after ophthalmological examination. Serology was positive for CV2/CRMP5 onconeuronal antibodies. Autoimmune retinopathy is a rare entity that can be missed and underdiagnosed. It is produced by an immune-mediated reaction against retinal antigens. The importance of its early diagnosis lies in the fact that in many of the patients, ocular symptoms appear before the diagnosis of the primary cancer, so its early identification and referral for an extension study may lead to the diagnosis of a hidden primary neoplasm. (AU)


Assuntos
Humanos , Masculino , Idoso , Doenças Retinianas/imunologia , Autoanticorpos/imunologia , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/imunologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Detecção Precoce de Câncer , Angiofluoresceinografia
2.
Front Immunol ; 13: 980805, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091038

RESUMO

Observations from numerous clinical, epidemiological and serological studies link periodontitis with severity and progression of rheumatoid arthritis. The strong association is observed despite totally different aetiology of these two diseases, periodontitis being driven by dysbiotic microbial flora on the tooth surface below the gum line, while rheumatoid arthritis being the autoimmune disease powered by anti-citrullinated protein antibodies (ACPAs). Here we discuss genetic and environmental risk factors underlying development of both diseases with special emphasis on bacteria implicated in pathogenicity of periodontitis. Individual periodontal pathogens and their virulence factors are argued as potentially contributing to putative causative link between periodontal infection and initiation of a chain of events leading to breakdown of immunotolerance and development of ACPAs. In this respect peptidylarginine deiminase, an enzyme unique among prokaryotes for Porphyromonas gingivalis, is elaborated as a potential mechanistic link between this major periodontal pathogen and initiation of rheumatoid arthritis development.


Assuntos
Anticorpos Anti-Proteína Citrulinada , Artrite Reumatoide , Periodontite , Desiminases de Arginina em Proteínas , Anticorpos Anti-Proteína Citrulinada/genética , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Humanos , Periodontite/complicações , Periodontite/genética , Periodontite/imunologia , Periodontite/microbiologia , Porphyromonas gingivalis/enzimologia , Porphyromonas gingivalis/genética , Desiminases de Arginina em Proteínas/genética , Desiminases de Arginina em Proteínas/imunologia
3.
Front Immunol ; 13: 945021, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36032086

RESUMO

Autoantibodies to multiple targets are found during acute COVID-19. Whether all, or some, persist after 6 months, and their correlation with sustained anti-SARS-CoV-2 immunity, is still controversial. Herein, we measured antibodies to multiple SARS-CoV-2 antigens (Wuhan-Hu-1 nucleoprotein (NP), whole spike (S), spike subunits (S1, S2 and receptor binding domain (RBD)) and Omicron spike) and 102 human proteins with known autoimmune associations, in plasma from healthcare workers 8 months post-exposure to SARS-CoV-2 (n=31 with confirmed COVID-19 disease and n=21 uninfected controls (PCR and anti-SARS-CoV-2 negative) at baseline). IgG antibody responses to SARS-CoV-2 antigens were significantly higher in the convalescent cohort than the healthy cohort, highlighting lasting antibody responses up to 8 months post-infection. These were also shown to be cross-reactive to the Omicron variant spike protein at a similar level to lasting anti-RBD antibodies (correlation r=0.89). Individuals post COVID-19 infection recognised a common set of autoantigens, specific to this group in comparison to the healthy controls. Moreover, the long-term level of anti-Spike IgG was associated with the breadth of autoreactivity post-COVID-19. There were further moderate positive correlations between anti-SARS-CoV-2 responses and 11 specific autoantigens. The most commonly recognised autoantigens were found in the COVID-19 convalescent cohort. Although there was no overall correlation in self-reported symptom severity and anti-SARS-CoV-2 antibody levels, anti-calprotectin antibodies were associated with return to healthy normal life 8 months post infection. Calprotectin was also the most common target for autoantibodies, recognized by 22.6% of the overall convalescent cohort. Future studies may address whether, counter-intuitively, such autoantibodies may play a protective role in the pathology of long-COVID-19.


Assuntos
Anticorpos Antivirais , COVID-19 , Glicoproteína da Espícula de Coronavírus , Anticorpos Antivirais/imunologia , Autoanticorpos/imunologia , Autoantígenos , COVID-19/complicações , COVID-19/imunologia , Humanos , Imunoglobulina G , Complexo Antígeno L1 Leucocitário/imunologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia
4.
Front Immunol ; 13: 932627, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967356

RESUMO

Background: Despite immune cell dysregulation being an important event preceding the onset of rheumatoid arthritis (RA), the phenotype of T and B cells in preclinical RA is less understood. The aim of this study was to characterize T and B cell populations in RA patients and their autoantibody (aAb) negative and positive first-degree relatives (FDR). Methods: Cryopreserved peripheral blood mononuclear cells (PBMCs) collected at scheduled visits from aAb-(n=25), and aAb+ FDR (n=10) and RA patients (n=13) were thawed and stained using optimized antibody cocktails as per a specific 13-color T or B cell panel. Immunophenotyping was performed using a Cytoflex LX (Beckman-Coulter) flow cytometer and FlowJo software was used for analyzing the frequency of immune cell populations. Results: Multicolor flow cytometry experiments identified an increased TIGIT expression in circulating lymphocytes of aAb+ FDR and RA patients, relative to aAb- FDR (P<0.01). These TIGIT+ T cells exhibited a memory phenotype and expressed high levels of PD-1, ICOS, HLA-DR, CXCR3 and CXCR5. Moreover, increased TIGIT+ CD4 T cell frequency correlated with the frequency of PD-1+ CD4 T cells (r = 0.4705: P = 0.0043) and circulating levels of ACPA and RF. We also identified a decreased frequency of CD27+IgD- switched memory B cells in RA patients (P < 0.01), while increased frequency of TIGIT+ CD4 T cells in FDR correlated with the frequency of PD1+PTEN+ B cells (r = 0.6838, P = 0.0004) and autoantibody positivity (P = 0.01). Conclusion: We demonstrate TIGIT as a distinct CD4 T cell marker for differentiating aAb- FDR from aAb+FDR and might play a critical role in regulating T and B cell crosstalk in preclinical RA.


Assuntos
Artrite Reumatoide , Linfócitos T CD4-Positivos , Receptores Imunológicos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Subpopulações de Linfócitos T/imunologia
5.
Nature ; 611(7934): 139-147, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36044993

RESUMO

Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2-5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6-10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14-18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.


Assuntos
Autoanticorpos , Linfócitos B , COVID-19 , Humanos , Autoanticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/fisiopatologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Imunoglobulina G/imunologia , Análise de Célula Única , Autoantígenos/imunologia , Membrana Basal/imunologia
6.
Proc Natl Acad Sci U S A ; 119(31): e2120028119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35878027

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic ß-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to the insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these 17 peptides, the hprt4-18 peptide, found in the normal human gut commensal Parabacteroides distasonis, activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with P. distasonis insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8+ T cells, while decreasing FoxP3+ regulatory T cells. Western blot analysis identified P. distasonis-reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis-treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the hprt4-18 peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9-23-mimic peptide as a molecular trigger of T1D pathogenesis.


Assuntos
Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Mimetismo Molecular , Peptídeos , Animais , Autoanticorpos/imunologia , Bacteroidetes , Linfócitos T CD8-Positivos , Criança , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Insulina/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Peptídeos/química
7.
Front Immunol ; 13: 884248, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844545

RESUMO

The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10 and ADAM17 are involved in the turnover of the desmosomal cadherin Dsg2 and ADAM10 has been shown to contribute to acantholysis in a murine pemphigus model. In the present study, we further examined the role of ADAM10 and ADAM17 both in keratinocyte adhesion and in the pathogenesis of PV. First, we found that inhibition of ADAM10 enhanced adhesion of primary human keratinocytes but not of immortalized keratinocytes. In dissociation assays, inhibition of ADAM10 shifted keratinocyte adhesion towards a hyperadhesive state. However, ADAM inhibition did neither modulate protein levels of Dsg1 and Dsg3 nor activation of EGFR at Y1068 and Y845. In primary human keratinocytes, inhibition of ADAM10, but not ADAM17, reduced loss of cell adhesion and fragmentation of Dsg1 and Dsg3 immunostaining in response to a PV1-IgG from a mucocutaneous PV patient. Similarly, inhibition of ADAM10 in dissociation assay decreased fragmentation of primary keratinocytes induced by a monoclonal antibody against Dsg3 and by PV-IgG from two other patients both suffering from mucosal PV. However, such protective effect was not observed in both cultured cells and ex vivo disease models, when another mucocutaneous PV4-IgG containing more Dsg1 autoantibodies was used. Taken together, ADAM10 modulates both hyperadhesion and PV-IgG-induced loss of cell adhesion dependent on the autoantibody profile.


Assuntos
Proteína ADAM10 , Proteína ADAM17 , Queratinócitos , Pênfigo , Proteína ADAM10/imunologia , Proteína ADAM17/imunologia , Secretases da Proteína Precursora do Amiloide , Animais , Autoanticorpos/imunologia , Adesão Celular/imunologia , Desmogleína 1/imunologia , Desmogleína 3/imunologia , Humanos , Imunoglobulina G/imunologia , Queratinócitos/imunologia , Queratinócitos/patologia , Proteínas de Membrana/metabolismo , Camundongos , Pênfigo/imunologia , Pênfigo/patologia
8.
Front Immunol ; 13: 895501, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757687

RESUMO

Introduction: Inflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ETA) autoantibodies have been implicated in the pathogenesis of PAH, and endothelin receptor antagonists are routinely used treatments for PAH. However, immunological functions of the endothelin B receptor (ETB) remain obscure. Methods: Serum levels of anti-ETB receptor autoantibodies were quantified in healthy donors and SSc patients with or without PAH. Age-dependent effects of overexpression of prepro-endothelin-1 or ETB deficiency on pulmonary inflammation and the cardiovascular system were studied in mice. Rescued ETB-deficient mice (ETB -/-) were used to prevent congenital Hirschsprung disease. The effects of pulmonary T-helper type 2 (Th2) inflammation on PAH-associated pathologies were analyzed in ETB -/- mice. Pulmonary vascular hemodynamics were investigated in isolated perfused mouse lungs. Hearts were assessed for right ventricular hypertrophy. Pulmonary inflammation and collagen deposition were assessed via lung microscopy and bronchoalveolar lavage fluid analyses. Results: Anti-ETB autoantibody levels were elevated in patients with PAH secondary to SSc. Both overexpression of prepro-endothelin-1 and rescued ETB deficiency led to pulmonary hypertension, pulmonary vascular hyperresponsiveness, and right ventricular hypertrophy with accompanying lymphocytic alveolitis. Marked perivascular lymphocytic infiltrates were exclusively found in ETB -/- mice. Following induction of pulmonary Th2 inflammation, PAH-associated pathologies and perivascular collagen deposition were aggravated in ETB -/- mice. Conclusion: This study provides evidence for an anti-inflammatory role of ETB. ETB seems to have protective effects on Th2-evoked pathologies of the cardiovascular system. Anti-ETB autoantibodies may modulate ETB-mediated immune homeostasis.


Assuntos
Hipertensão Arterial Pulmonar , Receptor de Endotelina B , Animais , Autoanticorpos/imunologia , Endotelina-1/imunologia , Hipertensão Pulmonar Primária Familiar/imunologia , Humanos , Hipertrofia Ventricular Direita/imunologia , Inflamação/imunologia , Camundongos , Hipertensão Arterial Pulmonar/imunologia , Receptor de Endotelina B/imunologia , Escleroderma Sistêmico/imunologia
9.
J Neuroimmunol ; 369: 577898, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35717737

RESUMO

OBJECTIVE: Bilateral parafalcine cortical and leptomeningeal impairment (BPCLI) is a rare finding observed in cases of myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). The failure to recognize BPCLI may lead to misdiagnosis and delayed treatment. This study aimed to delineate the clinical and imaging characteristics of patients with BPCLI. METHODS: Clinical data from a cohort of 366 patients diagnosed with NMOSD or MOGAD were retrospectively reviewed. Subsequently, the clinical features of the seven patients with BPCLI were analyzed. RESULTS: Of the 366 patients, 33 had MOGAD, whereas 264 were positive for antibodies (Abs) against aquaporin-4 (AQP4) and had NMOSD. BPCLI was detected in five patients (15.1%) with MOGAD and two patients (0.7%) with AQP4-Ab-positive NMOSD. All seven patients (four males) presented with meningoencephalitis-like symptoms at the time of BPCLI. Six patients had seizures, and three of them also presented with fever. Three patients were misdiagnosed with intracranial infection, and one was misdiagnosed with cerebral venous thrombosis. Analysis of the cerebrospinal fluid revealed elevated total protein levels in two patients and increased leukocyte counts in five. In addition to BPCLI, impairments in the hippocampus and corpus callosum were confirmed in one and four patients, respectively. Moreover, five patients exhibited meningeal enhancement, and two showed callosal enhancement. In all cases, BPCLI attacks responded well to high-dose methylprednisolone or immunoglobulin therapy. CONCLUSIONS: BPCLI can be observed in both MOGAD and AQP4 NMOSD. It appears to be characteristic of MOGAD but is relatively rare in AQP4 NMOSD. These findings should be noted to avoid misdiagnosis.


Assuntos
Aquaporina 4 , Autoanticorpos , Neuromielite Óptica , Aquaporina 4/imunologia , Autoanticorpos/imunologia , Humanos , Masculino , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/líquido cefalorraquidiano , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/tratamento farmacológico , Estudos Retrospectivos
10.
J Mol Cell Cardiol ; 170: 121-123, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35764120

RESUMO

BACKGROUND: There is growing recognition that COVID-19 does cause cardiac sequelae. The underlying mechanisms involved are still poorly understood to date. Viral infections, including COVID-19, have been hypothesized to contribute to autoimmunity, by exposing previously hidden cryptic epitopes on damaged cells to an activated immune system. Given the high incidence of cardiac involvement seen in COVID-19, our aim was to determine the frequency of anti-DSG2 antibodies in a population of post COVID-19 patients. METHODS AND RESULTS: 300 convalescent serum samples were obtained from a group of post COVID-19 infected patients from October 2020 to February 2021. 154 samples were drawn 6 months post-COVID-19 infection and 146 samples were drawn 9 months post COVID infection. 17 samples were obtained from the same patient at the 6- and 9- month mark. An electrochemiluminescent-based immunoassay utilizing the extracellular domain of DSG2 for antibody capture was used. The mean signal intensity of anti-DSG2 antibodies in the post COVID-19 samples was significantly higher than that of a healthy control population (19 ± 83.2 in the post-COVID-19 sample vs. 2.1 ± 7.2 (p < 0. 0001) in the negative control healthy population). Of note, 29.3% of the post COVID-19 infection samples demonstrated a signal higher than the 90th percentile of the control population and 8.7% were higher than the median found in ARVC patients. The signal intensity between the 6-month and 9-month samples did not differ significantly. CONCLUSIONS: We report for the first time that recovered COVID-19 patients demonstrate significantly higher and sustained levels of anti-DSG2 autoantibodies as compared to a healthy control population, comparable to that of a diagnosed ARVC group.


Assuntos
COVID-19 , Autoanticorpos/imunologia , COVID-19/sangue , COVID-19/complicações , COVID-19/imunologia , Desmogleína 2/imunologia , Humanos
11.
Arch Toxicol ; 96(10): 2785-2797, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35763063

RESUMO

Occupational exposure to trichloroethylene (TCE) causes a systemic skin disorder with hepatitis known as TCE hypersensitivity syndrome (TCE-HS). Human Leukocyte Antigen (HLA)-B*13:01 is its susceptibility factor; however, the immunological pathogenesis of TCE-HS remains unknown. We herein examined the hypothesis that autoantibodies to CYP2E1 are primarily involved in TCE-HS. A case-control study of 80 TCE-HS patients, 186 TCE-tolerant controls (TCE-TC), and 71 TCE-nonexposed controls (TCE-nonEC) was conducted to measure their serum anti-CYP2E1 antibody (IgG) levels. The effects of TCE exposure indices, such as 8-h time-weighted-average (TWA) airborne concentrations, urinary metabolite concentrations, and TCE usage duration; sex; smoking and drinking habits; and alanine aminotransferase (ALT) levels on the antibody levels were also analyzed in the two control groups. There were significant differences in anti-CYP2E1 antibody levels among the three groups: TCE-TC > TCE-HS patients > TCE-nonEC. Antibody levels were not different between HLA-B*13:01 carriers and noncarriers in TCE-HS patients and TCE-TC. The serum CYP2E1 measurement suggested increased immunocomplex levels only in patients with TCE-HS. Multiple regression analysis for the two control groups showed that the antibody levels were significantly higher by the TCE exposure. Women had higher antibody levels than men; however, smoking, drinking, and ALT levels did not affect the anti-CYP2E1 antibody levels. Anti-CYP2E1 antibodies were elevated at concentrations lower than the TWA concentration of 2.5 ppm for TCE exposure. Since HLA-B*13:01 polymorphism was not involved in the autoantibody levels, the possible mechanism underlying the pathogenesis of TCE-HS is that TCE exposure induces anti-CYP2E1 autoantibody production, and HLA-B*13:01 is involved in the development of TCE-HS.


Assuntos
Citocromo P-450 CYP2E1 , Síndrome de Hipersensibilidade a Medicamentos , Exposição Ocupacional , Tricloroetileno , Autoanticorpos/sangue , Autoanticorpos/genética , Autoanticorpos/imunologia , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Citocromo P-450 CYP2E1/sangue , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/imunologia , Síndrome de Hipersensibilidade a Medicamentos/sangue , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Síndrome de Hipersensibilidade a Medicamentos/imunologia , Feminino , Antígenos HLA-B/sangue , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Hepatite Autoimune/sangue , Hepatite Autoimune/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Masculino , Exposição Ocupacional/efeitos adversos , Polimorfismo Genético , Tricloroetileno/imunologia , Tricloroetileno/toxicidade
12.
BMJ Case Rep ; 15(5)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35606030

RESUMO

Hydroxyl-methyl-glutaryl-Co-A reductase (HMGCR) immune mediated necrotising myopathy (IMNM) is a rare autoimmune myositis that is thought to be triggered by statins and responds to immunomodulation. We report a case of a woman in her 30s with HMGCR IMNM without a history of statin exposure who had a clear flare of her myositis after beginning mushroom supplements. Mushrooms are natural HMGCR inhibitors, and this is the first case to demonstrate a flare triggered by mushrooms in a patient with known HMGCR IMNM. This case highlights the importance of reviewing diet and supplements in patients with IMNM. It also emphasises the importance of strict statin avoidance for patients with IMNM even when the myositis is under good control.


Assuntos
Agaricales , Doenças Autoimunes , Suplementos Nutricionais , Doenças Musculares , Adulto , Autoanticorpos/imunologia , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Suplementos Nutricionais/efeitos adversos , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/diagnóstico , Doenças Musculares/imunologia , Doenças Musculares/patologia , Miosite/induzido quimicamente , Miosite/diagnóstico , Miosite/imunologia , Miosite/patologia , Necrose/induzido quimicamente , Necrose/imunologia , Fitoterapia/efeitos adversos , Exacerbação dos Sintomas
13.
Int J Mol Sci ; 23(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35628640

RESUMO

Anti-citrullinated protein antibodies (ACPAs) are involved in the pathogenesis of rheumatoid arthritis. N-glycosylation pattern of ACPA-IgG and healthy IgG Fc differs. The aim of this study is to determine the relative sialylation and galactosylation level of ACPAs and control IgG to assess their capability of inducing TNFα production, and furthermore, to analyze the correlations between the composition of Fc glycans and inflammatory markers in RA. We isolated IgG from sera of healthy volunteers and RA patients, and purified ACPAs on a citrulline-peptide column. Immunocomplexes (IC) were formed by adding an F(ab)2 fragment of anti-human IgG. U937 cells were used to monitor the binding of IC to FcγR and to trigger TNFα release determined by ELISA. To analyze glycan profiles, control IgG and ACPA-IgG were digested with trypsin and the glycosylation patterns of glycopeptides were analyzed by determining site-specific N-glycosylation using nano-UHPLC-MS/MS. We found that both sialylation and galactosylation levels of ACPA-IgG negatively correlate with inflammation-related parameters such as CRP, ESR, and RF. Functional assays show that dimerized ACPA-IgG significantly enhances TNFα release in an FcγRI-dependent manner, whereas healthy IgG does not. TNFα production inversely correlates with the relative intensities of the G0 glycoform, which lacks galactose and terminal sialic acid moieties.


Assuntos
Artrite Reumatoide , Imunoglobulina G , Fator de Necrose Tumoral alfa , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Glicosilação , Humanos , Imunoglobulina G/imunologia , Receptores Fc/imunologia , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/imunologia
14.
J Biol Chem ; 298(6): 101962, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35452676

RESUMO

Atypical hemolytic uremic syndrome (aHUS) is a disease associated with dysregulation of the immune complement system, especially of the alternative pathway (AP). Complement factor H (CFH), consisting of 20 domains called complement control protein (CCP1-20), downregulates the AP as a cofactor for mediating C3 inactivation by complement factor I. However, anomalies related to CFH are known to cause excessive complement activation and cytotoxicity. In aHUS, mutations and the presence of anti-CFH autoantibodies (AAbs) have been reported as plausible causes of CFH dysfunction, and it is known that CFH-related aHUS carries a high probability of end-stage renal disease. Elucidating the detailed functions of CFH at the molecular level will help to understand aHUS pathogenesis. Herein, we used biophysical data to reveal that a heavy-chain antibody fragment, termed VHH4, recognized CFH with high affinity. Hemolytic assays also indicated that VHH4 disrupted the protective function of CFH on sheep erythrocytes. Furthermore, X-ray crystallography revealed that VHH4 recognized the Leu1181-Leu1189CCP20 loop, a known anti-CFH AAbs epitope. We next analyzed the dynamics of the C-terminal region of CFH and showed that the epitopes recognized by anti-CFH AAbs and VHH4 were the most flexible regions in CCP18-20. Finally, we conducted mutation analyses to elucidate the mechanism of VHH4 recognition of CFH and revealed that VHH4 inserts the Trp1183CCP20 residue of CFH into the pocket formed by the complementary determining region 3 loop. These results suggested that anti-CFH AAbs may adopt a similar molecular mechanism to recognize the flexible loop of Leu1181-Leu1189CCP20, leading to aHUS pathogenesis.


Assuntos
Anticorpos Monoclonais/química , Síndrome Hemolítico-Urêmica Atípica , Fator H do Complemento/química , Síndrome Hemolítico-Urêmica Atípica/metabolismo , Autoanticorpos/imunologia , Ativação do Complemento , Epitopos , Humanos , Mutação
15.
Nat Commun ; 13(1): 1220, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35264564

RESUMO

COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity.


Assuntos
Autoanticorpos/imunologia , COVID-19/imunologia , Receptores Acoplados a Proteínas G/imunologia , Sistema Renina-Angiotensina/imunologia , Autoanticorpos/sangue , Autoimunidade , Biomarcadores/sangue , COVID-19/sangue , COVID-19/classificação , Estudos Transversais , Feminino , Humanos , Aprendizado de Máquina , Masculino , Análise Multivariada , Receptor Tipo 1 de Angiotensina/imunologia , Receptores CXCR3/imunologia , SARS-CoV-2 , Índice de Gravidade de Doença
16.
Front Endocrinol (Lausanne) ; 13: 840668, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35273575

RESUMO

Background: This is the first study, that aimed: a) to compare immune response, namely the kinetics of neutralizing antibodies (Nabs), after vaccination with BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) between patients with autoimmune thyroiditis and controls, and b) to investigate changes in thyroid function in healthy subjects with no history of thyroid dysfunction before and after vaccination with BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech). Methods: The entire study consisted of two sub-studies. In the first sub-study, NAbs levels after BNT162b2 mRNA vaccination were compared between 56 patients with autoimmune thyroiditis and 56 age and gender-matched healthy controls from the day of the first dose until a period of up to three months after the second dose. In the second sub-study, thyroid hormones (T3, T4, TSH) and thyroid auto-antibodies levels (anti-TG, anti-TPO) of 72 healthy subjects with no history of thyroid disease were examined before (D1) and one month after completion of the second dose (D50). Results: Among patients with autoimmune thyroiditis, the median neutralizing inhibition on D22, immediately before second dose, was 62.5%. One month later (D50), values increased to 96.7%, while three months after the second dose NAbs titers remained almost the same (94.5%). In the healthy group, median NAbs levels at D22 were 53.6%. On D50 the median inhibition values increased to 95.1%, while after three months they were 89.2%. The statistical analysis did not show significant differences between two groups (p-values 0.164, 0.390, 0.105 for D22, D50 and three months). Regarding changes in thyroid function, the mean value for T4 before vaccination was 89.797 nmol/L and one month after the second dose was 89.11 nmol/L (p-value=0.649). On D1 the mean T3 value was 1.464 nmol/L, which dropped to 1.389 nmol/L on D50 (p-value = 0.004). For TSH, mean levels were 2.064 mIU/ml on D1 and fell to 1.840 mIU/ml one month after the second dose (p-value=0.037). Despite decrease, all thyroid hormone levels remained within the normal range. No changes were found for anti-TPO or anti-TG. Conclusions: This study provided evidence that patients with autoimmune thyroiditis present similar immunological response to COVID-19 BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) with healthy subjects, while vaccination may affect thyroid function.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Tireoidite Autoimune/imunologia , Adulto , Autoanticorpos/sangue , Autoanticorpos/imunologia , /genética , COVID-19/prevenção & controle , COVID-19/virologia , Estudos de Casos e Controles , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/genética , Glândula Tireoide/metabolismo , Hormônios Tireóideos/sangue , Hormônios Tireóideos/metabolismo , Tireoidite Autoimune/metabolismo , Vacinação
17.
Inflamm Res ; 71(5-6): 537-554, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35298669

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE), the most common form of lupus, is a multisystemic rheumatic disease with different clinical features that generally affect women of childbearing age. The common symptoms of SLE are very similar to other autoimmune and non-autoimmune disorders, thereby it is known as a thousand faces disease. In this article, we are going to discuss some of the most updated information about immune system-related factors, cells, and cytokines involved in SLE pathogenesis. METHODS: Different electronic databases, especially PubMed/MEDLINE, Scopus, and Google Scholar, were searched to review and analyze relevant literature on the role of innate and adaptive immune cells and cytokines in the pathogenesis of SLE. A search for relevant literature was accomplished using various keywords including systemic lupus erythematosus, apoptosis, autoantibodies, immunopathogenesis of SLE, adaptive and innate immune cells, inflammatory cytokines, hormones, etc. RESULTS AND CONCLUSION: The most important characteristic of SLE is the production of antibodies against different nuclear autoantigens like double-strand DNA and RNA. The depositions of the immune complexes (ICs) that are generated between autoantibodies and autoantigens, along with aberrant clearance of them, can lead to permanent inflammation and contribute to tissue or organ damage. Related mechanisms underlying the initiation and development of SLE have not been clarified yet. Although, defects in immune tolerance, enhanced antigenic load, hyperactivity of T cells, and inappropriate regulation of B cells contribute to the pathogenic autoantibodies generation. Besides, sex hormones that influence the immune system seem to act as triggers or protectors of SLE development.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Lúpus Eritematoso Sistêmico , Autoanticorpos/imunologia , Autoantígenos/imunologia , Citocinas/metabolismo , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/imunologia
18.
Ann Neurol ; 91(6): 801-813, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35253937

RESUMO

OBJECTIVE: The encephalitis associated with antibodies against contactin-associated proteinlike 2 (CASPR2) is presumably antibody-mediated, but the antibody effects and whether they cause behavioral alterations are not well known. Here, we used a mouse model of patients' immunoglobulin G (IgG) transfer and super-resolution microscopy to demonstrate the antibody pathogenicity. METHODS: IgG from patients with anti-CASPR2 encephalitis or healthy controls was infused into the cerebroventricular system of mice. The levels and colocalization of CASPR2 with transient axonal glycoprotein 1 (TAG1) were determined with stimulated emission depletion microscopy (40-70µm lateral resolution). Hippocampal clusters of Kv1.1 voltage-gated potassium channels (VGKCs) and GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) were quantified with confocal microscopy. Behavioral alterations were assessed with standard behavioral paradigms. Cultured neurons were used to determine the levels of intracellular CASPR2 and TAG1 after exposure to patients' IgG. RESULTS: Infusion of patients' IgG, but not controls' IgG, caused memory impairment along with hippocampal reduction of surface CASPR2 clusters and decreased CASPR2/TAG1 colocalization. In cultured neurons, patients' IgG led to an increase of intracellular CASPR2 without affecting TAG1, suggesting selective CASPR2 internalization. Additionally, mice infused with patients' IgG showed decreased levels of Kv1.1 and GluA1 (two CASPR2-regulated proteins). All these alterations and the memory deficit reverted to normal after removing patients' IgG. INTERPRETATION: IgG from patients with anti-CASPR2 encephalitis causes reversible memory impairment, inhibits the interaction of CASPR2/TAG1, and decreases the levels of CASPR2 and related proteins (VGKC, AMPAR). These findings fulfill the postulates of antibody-mediated disease and provide a biological basis for antibody-removing treatment approaches. ANN NEUROL 2022;91:801-813.


Assuntos
Autoanticorpos , Encefalite , Proteínas de Membrana , Proteínas do Tecido Nervoso , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Autoanticorpos/imunologia , Contactina 2/imunologia , Encefalite/imunologia , Humanos , Imunoglobulina G/metabolismo , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/metabolismo
19.
Front Immunol ; 13: 845365, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35320933

RESUMO

Objective: We aimed to investigate the mortality rate and identify the predictors of death in patients with anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis. Methods: Patients with anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis were recruited from the Neurology Department of the First Hospital of Jilin University from March 2015 to November 2021. The primary outcome variable was a binary variable of death vs. survival. The potential risk factors for mortality were evaluated. The mortality rates were determined, and the independent predictors of death were identified using multivariable logistic regression analysis. Results: A total of 100 hospitalized patients with anti-NMDAR, anti-LGI1, or anti-GABABR encephalitis were included in the final analysis. Fifteen patients (15%) died during a median follow-up period of 18 months. The mortality rates were 10% for anti-NMDAR encephalitis, 2.8% for anti-LGI1 encephalitis, and 41.7% for anti-GABABR encephalitis. The multivariable analysis results showed that older age at onset [adjusted odds ratio (OR) = 1.017, 95% confidence interval (CI) = 1.009-1.136; p = 0.023] was independently associated with an increased risk of death. Antibody type was also associated with mortality. Patients with anti-GABABR encephalitis had 13.458-fold greater odds of dying than patients with anti-LGI1 encephalitis (adjusted OR = 13.458, 95% CI = 1.270-142.631; p = 0.031). Conclusion: The general mortality rate of anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis was 15%. Age at onset and type of autoimmune encephalitis antibody were independent predictors of death in these patients.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Doença de Hashimoto , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Autoanticorpos/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Receptores de GABA-A/imunologia , Receptores de N-Metil-D-Aspartato , Fatores de Risco
20.
Front Immunol ; 13: 746068, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154091

RESUMO

Antibody-induced complement activation may cause injury of the neuromuscular junction (NMJ) and is thus considered as a primary pathogenic factor in human myasthenia gravis (MG) and animal models of experimental autoimmune myasthenia gravis (EAMG). In this study, we tested whether CRIg/FH, a targeted complement inhibitor, could attenuate NMJ injury in rat MG models. We first demonstrated that CRIg/FH could inhibit complement-dependent cytotoxicity on human rhabdomyosarcoma TE671 cells induced by MG patient-derived IgG in vitro. Furthermore, we investigated the therapeutic effect of CRIg/FH in a passive and an active EAMG rodent model. In both models, administration of CRIg/FH could significantly reduce the complement-mediated end-plate damage and suppress the development of EAMG. In the active EAMG model, we also found that CRIg/FH treatment remarkably reduced the serum concentration of autoantibodies and of the cytokines including IFN-γ, IL-2, IL-6, and IL-17, and upregulated the percentage of Treg cells in the spleen, which was further verified in vitro. Therefore, our findings indicate that CRIg/FH may hold the potential for the treatment of MG via immune modulation.


Assuntos
Inativadores do Complemento/farmacologia , Imunomodulação/efeitos dos fármacos , Miastenia Gravis Autoimune Experimental/imunologia , Miastenia Gravis Autoimune Experimental/prevenção & controle , Proteínas Recombinantes de Fusão/farmacologia , Animais , Autoanticorpos/imunologia , Autoimunidade , Diferenciação Celular , Linhagem Celular , Ativação do Complemento/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Imunoglobulina G/imunologia , Mediadores da Inflamação/metabolismo , Ativação Linfocitária , Miastenia Gravis Autoimune Experimental/diagnóstico , Ratos , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
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