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1.
Arthritis Rheumatol ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31702112

RESUMO

BACKGROUND: Synovial membrane inflammation is common in osteoarthritis (OA) and increases cartilage injury. However, synovial fluid and histology studies suggest that OA inflammatory responses are not homogeneous. Greater understanding of these responses may provide new insights into OA disease mechanisms. Our objective was to develop a novel, multi-parameter approach to phenotype synovial responses in knee OA. METHODS: Cell composition and soluble protein production was measured by flow cytometry and multiplex ELISA in synovium collected from OA patients undergoing knee replacement surgery (n=35). RESULTS: Testing disaggregation conditions showed that aggressive digestion improved synovial cell yield and mesenchymal staining by flow cytometry, but negatively impacted CD4+ T cell and CD56+ natural killer (NK) cell staining. Less aggressive digestion preserved these markers and showed highly variable T cell infiltration (range 0-43%, n=32). Correlation analysis identified mesenchymal subpopulations associated with different non-mesenchymal populations, including macrophages and T cells (CD45+CD11b+HLA-DR+ myeloid cells with podoplanin (PDPN)+CD73+CD90-CD34-mesenchymal cells, r=0.65 p<0.0001; CD45+CD3+T cells withPDPN+CD73+CD90+CD34+ mesenchymal cells, r=0.50 p=0.003). IL-6 measured by flow cytometry correlated strongly with IL-6 released by ex vivo culture of synovial tissue (r=0.59 p=0.0012) and was highest in mesenchymal cells co-expressing CD90 and CD34. IL-6, IL-8, complement factor D (CFD), and IL-10 release positively correlated with tissue cellularity (p=0.0042, 0.018, 0.0012, and 0.038, respectively). Additionally, increased CD8+ T cell numbers also correlated with retinol binding protein 4 (RBP4) (p=0.033). Finally, combining flow cytometry and multiplex data identified patient clusters with different types of inflammatory responses. CONCLUSIONS: We used a novel approach to analyze OA synovium, identifying patient-specific inflammatory clusters. This study argues that phenotyping synovial inflammation may provide new insights into OA patient heterogeneity and biomarker development.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31600025

RESUMO

OBJECTIVE: The aim of this study was to determine the association of perceived stress with incident inflammatory arthritis (IA) defined as having at least 1 joint consistent with rheumatoid arthritis (RA)-like synovitis based on exam. METHODS: We conducted a prospective cohort study in the Studies of the Etiologies of Rheumatoid Arthritis (SERA). Participants without IA were recruited if they were a first degree relative of a RA proband or screened positive for anti-cyclic citrullinated peptide autoantibody (ACPA). Perceived stress was measured using the Perceived Stress Scale-14 (PSS) in which scores can range from 0 to 56 and a higher score indicates greater perceived stress. The total PSS score as well as two sub-scores indicative of perceived distress and self-efficacy were averaged across all study visits until development of IA or last follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) of IA associated with average PSS scores were obtained using Cox proportional hazards models. RESULTS: The mean total PSS score was 20.4. We found that a one-point increase in the perceived distress score was significantly associated with a 10 percent increase in the risk of IA (adjusted HR: 1.10; 95%CI: 1.02, 1.19). Total PSS and self-efficacy were not associated with IA risk (adjusted HR: 1.05 (95%CI: 0.99, 1.10) and 1.04 (95%CI: 0.91, 1.18), respectively. CONCLUSIONS: An association between perceived distress and incident IA was observed in this at-risk cohort. Replication of this finding in other preclinical and at-risk RA populations is needed.

4.
J Rheumatol ; 46(12): 1556-1559, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30988128

RESUMO

OBJECTIVE: We investigated the association of age and anticyclic citrullinated peptide antibodies (anti-CCP) in subjects without rheumatoid arthritis (RA). METHODS: Serum was tested for anti-CCP3.1 (IgG/IgA) in 678 first-degree relatives (FDR) of patients with RA and 330 patients with osteoarthritis (OA). Individual isotypes (anti-CCP-IgA and anti-CCP-IgG) were also tested in all FDR. RESULTS: In FDR, increasing age was significantly associated with positivity for anti-CCP3.1 (per year, OR 1.03) and anti-CCP-IgA (per year, OR 1.05) but not anti-CCP-IgG. In FDR and OA subjects, anti-CCP3.1 prevalence was significantly increased after age 50 years. CONCLUSION: Increasing age in individuals without RA should be considered in the interpretation of anti-CCP3.1 positivity.

5.
Front Immunol ; 10: 658, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019506

RESUMO

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by dysregulated autoantibody production and complement activation leading to multi-organ damage. The disease is associated with increased intestinal permeability. In this study, we tested the hypothesis that SLE subjects have increased systemic exposure to bacteria. Since bacteria induce the expression of antimicrobial response factors (ARFs), we measured the levels of a series of clinically relevant ARFs in the plasma of SLE subjects. We found that levels of sCD14, lysozyme, and CXCL16 were significantly elevated in SLE subjects. A strong positive correlation was also observed between sCD14 and SELENA-SLEDAI score. Interestingly, the ratio of EndoCAb IgM:total IgM was significantly decreased in SLE and this ratio was negatively correlated with sCD14 levels. Although, there were no significant differences in the levels of lipopolysaccharide binding protein (LBP) and fatty acid binding protein 2 (FABP2), we observed significant positive correlations between lysozyme levels and sCD14, LBP, and FABP2. Moreover, galectin-3 levels also positively correlate with lysozyme, sCD14, and LBP. Since our SLE cohort comprised 43.33% males, we were able to identify gender-specific changes in the levels of ARFs. Overall, these changes in the levels and relationships between ARFs link microbial exposure and SLE. Approaches to reduce microbial exposure or to improve barrier function may provide therapeutic strategies for SLE patients.

6.
EBioMedicine ; 42: 76-85, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952617

RESUMO

BACKGROUND: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. METHODS: Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb-) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. FINDINGS: Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. INTERPRETATION: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. FUND: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.


Assuntos
Artrite Reumatoide/etiologia , Autoimunidade/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/etiologia , Núcleo Familiar , Adulto , Idoso , Alelos , Artrite Reumatoide/diagnóstico , Autoanticorpos/imunologia , Meio Ambiente , Feminino , Frequência do Gene , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos/imunologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
7.
Diabetes ; 68(6): 1240-1250, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894366

RESUMO

Multiple studies of B- and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell-mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T- and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.


Assuntos
Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Adulto , Doenças Assintomáticas , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Criança , Progressão da Doença , Feminino , Humanos , Memória Imunológica/imunologia , Interleucina-2/farmacologia , Masculino , Fenótipo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Interleucina-21/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Adulto Jovem
8.
Curr Diab Rep ; 19(5): 20, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30888520

RESUMO

PURPOSE OF REVIEW: To highlight pathways important for the development of autoimmune diabetes by investigating shared mechanisms of disease in polygenic and monogenic diabetes. RECENT FINDINGS: Genome-wide association studies have identified 57 genetic risk loci for type 1 diabetes. Progress has been made in unravelling the mechanistic effects of some of these variants, providing key insights into the pathogenesis of type 1 diabetes. Seven monogenic disorders have also been described where diabetes features as part of an autoimmune syndrome. Studying these genes in relation to polygenic risk loci provides a unique opportunity to dissect pathways important for the development of immune-mediated diabetes. Monogenic autoimmune diabetes can result from the dysregulation of multiple pathways suggesting that small effects on many immune processes are required to drive the autoimmune attack on pancreatic beta cells in polygenic type 1 diabetes. A breakdown in central and peripheral immune tolerance is a common theme in the genetic mechanisms of both monogenic and polygenic disease which highlights the importance of these checkpoints in the development and treatment of islet autoimmunity.

9.
J Immunol ; 202(8): 2210-2219, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30824481

RESUMO

The aim of this study was to test whether autoantibodies against neurologic surface Ags are found in nonneurologic autoimmune diseases, indicating a broader loss of tolerance. Patient and matched healthy donor (HD) sera were derived from four large cohorts: 1) rheumatoid arthritis (RA) (n = 194, HD n = 64), 2) type 1 diabetes (T1D) (n = 200, HD n = 200), 3) systemic lupus erythematosus (SLE) (n = 200, HD n = 67; neuro-SLE n = 49, HD n = 33), and 4) a control cohort of neurologic autoimmunity (relapsing-remitting multiple sclerosis [MS] n = 110, HD n = 110; primary progressive MS n = 9; secondary progressive MS n = 10; neuromyelitis optica spectrum disorders n = 15; and other neurologic disorders n = 26). Screening of 1287 unique serum samples against four neurologic surface Ags (myelin oligodendrocyte glycoprotein, aquaporin 4, acetylcholine receptor, and muscle-specific kinase) was performed with live cell-based immunofluorescence assays using flow cytometry. Positive samples identified in the screening were further validated using autoantibody titer quantification by serial dilutions or radioimmunoassay. Autoantibodies against neurologic surface Ags were not observed in RA and T1D patients, whereas SLE patients harbored such autoantibodies in rare cases (2/200, 1%). Within the CNS autoimmunity control cohort, autoantibodies against aquaporin 4 and high-titer Abs against myelin oligodendrocyte glycoprotein were, as expected, specific for neuromyelitis optica spectrum disorders. We conclude that neurologic autoantibodies do not cross disease barriers in RA and T1D. The finding of mildly increased neurologic autoantibodies in SLE may be consistent with a broader loss of B cell tolerance in this form of systemic autoimmunity.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Proteínas do Tecido Nervoso/imunologia , Doenças Autoimunes/patologia , Linfócitos B/patologia , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade
10.
Front Immunol ; 10: 44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740104

RESUMO

TYK2 is a JAK family member that functions downstream of multiple cytokine receptors. Genome wide association studies have linked a SNP (rs34536443) within TYK2 encoding a Proline to Alanine substitution at amino acid 1104, to protection from multiple autoimmune diseases including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). The protective role of this SNP in autoimmune pathogenesis, however, remains incompletely understood. Here we found that T follicular helper (Tfh) cells, switched memory B cells, and IFNAR signaling were decreased in healthy individuals that expressed the protective variant TYK2 A1104 (TYK2 P ). To study this variant in vivo, we developed a knock-in murine model of this allele. Murine Tyk2 P expressing T cells homozygous for the protective allele, but not cells heterozygous for this change, manifest decreased IL-12 receptor signaling, important for Tfh lineage commitment. Further, homozygous Tyk2 P T cells exhibited diminished in vitro Th1 skewing. Surprisingly, despite these signaling changes, in vivo formation of Tfh and GC B cells was unaffected in two models of T cell dependent immune responses and in two alternative SLE models. TYK2 is also activated downstream of IL-23 receptor engagement. Here, we found that Tyk2 P expressing T cells had reduced IL-23 dependent signaling as well as a diminished ability to skew toward Th17 in vitro. Consistent with these findings, homozygous, but not heterozygous, Tyk2 P mice were fully protected in a murine model of MS. Homozygous Tyk2 P mice had fewer infiltrating CD4+ T cells within the CNS. Most strikingly, homozygous mice had a decreased proportion of IL-17+/IFNγ+, double positive, pathogenic CD4+ T cells in both the draining lymph nodes (LN) and CNS. Thus, in an autoimmune model, such as EAE, impacted by both altered Th1 and Th17 signaling, the Tyk2 P allele can effectively shield animals from disease. Taken together, our findings suggest that TYK2P diminishes IL-12, IL-23, and IFN I signaling and that its protective effect is most likely manifest in the setting of autoimmune triggers that concurrently dysregulate at least two of these important signaling cascades.


Assuntos
Autoimunidade/imunologia , TYK2 Quinase/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Adulto , Animais , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Técnicas de Introdução de Genes , Humanos , Interferon Tipo I/metabolismo , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-12/metabolismo , TYK2 Quinase/genética , Adulto Jovem
11.
J Immunol ; 202(5): 1373-1382, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683697

RESUMO

Abatacept is a CTLA-4-Ig fusion protein that binds to the costimulatory ligands CD80 and CD86 and blocks their interaction with the CD28 and CTLA-4 receptors expressed by T cells, therefore inhibiting T cell activation and function. Abatacept has shown clinical efficacy in treating some autoimmune diseases but has failed to show clinical benefit in other autoimmune conditions. The reasons for these disparate results are not clear and warrant further investigation of abatacept's mode of action. Longitudinal specimens from the Immune Tolerance Network's A Cooperative Clinical Study of Abatacept in Multiple Sclerosis trial were used to examine the effects of abatacept treatment on the frequency and transcriptional profile of specific T cell populations in peripheral blood. We found that the relative abundance of CD4+ T follicular helper (Tfh) cells and regulatory T cells was selectively decreased in participants following abatacept treatment. Within both cell types, abatacept reduced the proportion of activated cells expressing CD38 and ICOS and was associated with decreased expression of genes that regulate cell-cycle and chromatin dynamics during cell proliferation, thereby linking changes in costimulatory signaling to impaired activation, proliferation, and decreased abundance. All cellular and molecular changes were reversed following termination of abatacept treatment. These data expand upon the mechanism of action of abatacept reported in other autoimmune diseases and identify new transcriptional targets of CD28-mediated costimulatory signaling in human regulatory T and Tfh cells, further informing on its potential use in diseases associated with dysregulated Tfh activity.


Assuntos
Abatacepte/farmacologia , Imunossupressores/farmacologia , Esclerose Múltipla/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Método Duplo-Cego , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
12.
Arthritis Rheumatol ; 71(4): 518-528, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30390384

RESUMO

OBJECTIVE: Recognition of citrullinated antigens such as vimentin, fibrinogen, and α-enolase is associated with rheumatoid arthritis (RA). Emerging data suggest that the matrix protein aggrecan is also recognized as a citrullinated antigen. This study was undertaken to directly visualize Cit-aggrecan-specific T cells and characterize them in patients with RA. METHODS: Citrullinated aggrecan peptides with likely DRB1*04:01 binding motifs were predicted using a previously published scanning algorithm. Peptides with detectable binding were assessed for immunogenicity by HLA tetramer staining, followed by single cell cloning. Selectivity for citrullinated peptide was assessed by tetramer staining and proliferation assays. Ex vivo tetramer staining was then performed to assess frequencies of aggrecan-specific T cells in peripheral blood. Finally, disease association was assessed by comparing T cell frequencies in RA patients and controls and correlating aggrecan-specific T cells with levels of aggrecan-specific antibodies. RESULTS: We identified 6 immunogenic peptides, 2 of which were the predominant T cell targets in peripheral blood. These 2 epitopes were citrullinated at HLA binding residues and shared homologous sequences. RA patients had significantly higher frequencies of Cit-aggrecan-specific T cells than healthy subjects. Furthermore, T cell frequencies were significantly correlated with antibodies against citrullinated aggrecan. CONCLUSION: Our findings indicate that T cells that recognize citrullinated aggrecan are present in patients with RA and correlate with antibodies that target this same antigen. Consequently, aggrecan-specific T cells and antibodies are potentially relevant markers that could be used to monitor patients with RA or at-risk subjects.


Assuntos
Agrecanas/imunologia , Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Agrecanas/metabolismo , Artrite Reumatoide/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Estudos de Casos e Controles , Citrulina/metabolismo , Cadeias HLA-DRB1/imunologia , Humanos , Sistema de Registros
13.
Front Immunol ; 9: 1978, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233580

RESUMO

B cells are implicated in rheumatoid arthritis (RA) based on the presence of autoantibodies and the therapeutic response to B cell depletion. IL-21 has a significant role in B cell development and function. Here we assess B cell responses to IL-21 and the mechanisms responsible for altered IL-21R expression in RA. Flow cytometry of PBMC and cultured B cells was used to quantify protein and mRNA levels of IL-21R, IL-21 signaling through pSTAT3, specificity protein 1 (SP1) and to determine cytokine production (IL-6) and maturation status of B cells in RA and healthy control subjects. SP1 binding to the IL21R promoter region in B cells was assessed with ChIP-qPCR. We demonstrate an increase in IL-21R expression in total and memory B cells from RA subjects, which correlated with responsiveness to IL-21 stimulation. Stimulation of naïve RA B cells with IL-21 and CD40L resulted in an increase in differentiation into plasmablasts and an increase in IL-6 production in comparison to healthy controls, which was dose dependent on IL-21 stimulation. IL-21R expression on memory B cells in RA synovial fluid was comparable to peripheral blood making our study pertinent to understanding B cell responses in the joint and site of inflammation. We identified an increase in SP1 protein and mRNA in RA B cells and demonstrate an increase in binding of SP1 to the IL21R promoter region, which suggests a mechanism by which IL-21R expression is enhanced on B cells in RA. Taken together, our results indicate a mechanism by which IL-21 enhances B cell development and function in RA through an SP1 mediated increase in IL-21R expression on B cells.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Regiões Promotoras Genéticas/genética , Receptores de Interleucina-21/genética , Fator de Transcrição Sp1/metabolismo , Adulto , Animais , Células Cultivadas , Estudos de Coortes , Estudos Transversais , Humanos , Memória Imunológica , Interleucinas/metabolismo , Ativação Linfocitária , Camundongos , Pessoa de Meia-Idade , Ligação Proteica , Transdução de Sinais
14.
Curr Opin Immunol ; 55: 9-14, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30248523

RESUMO

IL-6 is implicated in the development and progression of autoimmune diseases in part by influencing CD4 T cell lineage and regulation. Elevated IL-6 levels drive inflammation in a wide range of autoimmune diseases, some of which are also characterized by enhanced T cell responses to IL-6. Notably, the impact of IL-6 on inflammation is contextual in nature and dependent on the cell type, cytokine milieu and tissue. Targeting the IL-6/IL-6R axis in humans has been shown to successfully ameliorate a subset of autoimmune conditions. In this review, we discuss recent studies investigating how IL-6 regulates the CD4 T cell response in the context of autoimmune disease and highlight how blocking different aspects of the IL-6 pathway is advantageous in the treatment of disease.


Assuntos
Autoimunidade/imunologia , Interleucina-6/imunologia , Animais , Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Inflamação/imunologia
15.
Nat Rev Rheumatol ; 14(9): 542-557, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30111803

RESUMO

Individuals at high risk of developing seropositive rheumatoid arthritis (RA) can be identified for translational research and disease prevention studies through the presence of highly informative and predictive patterns of RA-related autoantibodies, especially anti-citrullinated protein antibodies (ACPAs), in the serum. In serologically positive individuals without arthritis, designated ACPA positive at risk, the presence of mucosal inflammatory processes associated with the presence of local ACPA production has been demonstrated. In other at-risk populations, local RA-related autoantibody production is present even in the absence of serum autoantibodies. Additionally, a proportion of at-risk individuals exhibit local mucosal ACPA production in the lung, as well as radiographic small-airway disease, sputum hypercellularity and increased neutrophil extracellular trap formation. Other mucosal sites in at-risk individuals also exhibit autoantibody production, inflammation and/or evidence of dysbiosis. As the proportion of individuals who exhibit such localized inflammation-associated ACPA production is substantially higher than the likelihood of an individual developing future RA, this finding raises the hypothesis that mucosal ACPAs have biologically relevant protective roles. Identifying the mechanisms that drive both the generation and loss of externally focused mucosal ACPA production and promote systemic autoantibody expression and ultimately arthritis development should provide insights into new therapeutic approaches to prevent RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/diagnóstico , Membrana Mucosa/imunologia , Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Diagnóstico Precoce , Humanos , Especificidade de Órgãos
16.
J Autoimmun ; 92: 47-56, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29853344

RESUMO

ACPA-positive rheumatoid arthritis (RA) is associated with distinct HLA-DR alleles and immune responses to many citrullinated self-antigens. Herein we investigated the T cell epitope confined within α-enolase326-340 in the context of HLA-DRB1*04:01 and assessed the corresponding CD4+ T cells in both the circulation and in the rheumatic joint. Comparative crystallographic analyses were performed for the native and citrullinated α-enolase326-340 peptides in complex with HLA-DRB1*04:01. HLA-tetramers assembled with either the native or citrullinated peptide were used for ex vivo and in vitro assessment of α-enolase-specific T cells in peripheral blood, synovial fluid and synovial tissue by flow cytometry. The native and modified peptides take a completely conserved structural conformation within the peptide-binding cleft of HLA-DRB1*04:01. The citrulline residue-327 was located N-terminally, protruding towards TCRs. The frequencies of T cells recognizing native eno326-340 were similar in synovial fluid and peripheral blood, while in contrast, the frequency of T cells recognizing cit-eno326-340 was significantly elevated in synovial fluid compared to peripheral blood (3.6-fold, p = 0.0150). Additionally, citrulline-specific T cells with a memory phenotype were also significantly increased (1.6-fold, p = 0.0052) in synovial fluid compared to peripheral blood. The native T cell epitope confined within α-enolase326-340 does not appear to lead to complete negative selection of cognate CD4+ T cells. In RA patient samples, only T cells recognizing the citrullinated version of α-enolase326-340 were found at elevated frequencies implicating that neo-antigen formation is critical for breach of tolerance.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/metabolismo , Articulações/imunologia , Peptídeos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Adulto , Idoso , Células Cultivadas , Citrulinação , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Citometria de Fluxo , Humanos , Tolerância Imunológica , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/imunologia , Fosfopiruvato Hidratase/química , Fosfopiruvato Hidratase/imunologia , Adulto Jovem
17.
Clin Immunol ; 193: 24-32, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29842945

RESUMO

Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/imunologia , Integrinas/metabolismo , Intestinos/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Circulação Sanguínea , Citocinas/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Fator de Transcrição Ikaros/metabolismo , Tolerância Imunológica , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Integrinas/imunologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR5/metabolismo
18.
Diabetes ; 67(7): 1216-1225, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29769238

RESUMO

The early to mid-1980s were an inflection point in the history of type 1 diabetes research. Two landmark events occurred: the initiation of immune-based interventions seeking to prevent type 1 diabetes and the presentation of an innovative model describing the disorder's natural history. Both formed the basis for hundreds of subsequent studies designed to achieve a dramatic therapeutic goal-a means to prevent and/or reverse type 1 diabetes. However, the need to screen large numbers of individuals and prospectively monitor them using immunologic and metabolic tests for extended periods of time suggested such efforts would require a large collaborative network. Hence, the National Institutes of Health formed the landmark Diabetes Prevention Trial-Type 1 (DPT-1) in the mid-1990s, an effort that led to Type 1 Diabetes TrialNet. TrialNet studies have helped identify novel biomarkers; delineate type 1 diabetes progression, resulting in identification of highly predictable stages defined by the accumulation of autoantibodies (stage 1), dysglycemia (stage 2), and disease meeting clinical criteria for diagnosis (stage 3); and oversee numerous clinical trials aimed at preventing disease progression. Such efforts pave the way for stage-specific intervention trials with improved hope that a means to effectively disrupt the disorder's development will be identified.


Assuntos
Pesquisa Biomédica/organização & administração , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 1/terapia , Biomarcadores/análise , Pesquisa Biomédica/métodos , Ensaios Clínicos como Assunto/história , Ensaios Clínicos como Assunto/métodos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Descoberta de Drogas/história , Descoberta de Drogas/tendências , História do Século XX , História do Século XXI , Humanos , Planejamento de Assistência ao Paciente , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Medicina Preventiva/história , Medicina Preventiva/métodos , Medicina Preventiva/tendências , Indução de Remissão , Terapias em Estudo/métodos , Terapias em Estudo/tendências , Resultado do Tratamento
19.
Sci Immunol ; 3(21)2018 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-29602804

RESUMO

The citrullinome cargo in neutrophil extracellular traps varies according to disease condition and stimulation conditions.

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