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1.
Arthritis Res Ther ; 23(1): 245, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34537057

RESUMO

BACKGROUND: Certain risk alleles associated with autoantibody-positive rheumatoid arthritis (RA) have been linked to poorer prognoses. In patients with autoantibody-positive RA, abatacept shows differential efficacy to tumor necrosis factor inhibitors. Our aim was to investigate the relationship between clinical response to abatacept and to adalimumab and presence of risk alleles encoding human leukocyte antigen (HLA)-DRB1 shared epitope (SE) in RA. METHODS: In this head-to-head study, biologic-naïve adults with early (≤ 12 months), moderate-to-severe RA and inadequate response to methotrexate (MTX-IR), autoantibody-positive for both anti-cyclic citrullinated peptide 2 and rheumatoid factor, were randomized 1:1 to receive subcutaneous abatacept 125 mg weekly or subcutaneous adalimumab 40 mg every 2 weeks for 24 weeks with stable, weekly oral MTX. An open-label period to 48 weeks followed, during which adalimumab-treated patients were switched to abatacept. Patients were genotyped for HLA-DRB1 alleles and classified as SE-positive (≥ 1 SE allele) or SE-negative (no SE alleles). Efficacy was assessed at weeks 24 and 48. RESULTS: Forty patients each received abatacept (9 SE-negative, 30 SE-positive, one unknown) or adalimumab (9 SE-negative, 31 SE-positive). Mean age and disease duration were 46.0 years and 5.5 months, respectively. At week 24, a greater percentage of abatacept patients achieved 50% improvement in ACR criteria (ACR50) compared with adalimumab patients (73% vs 45%, respectively) and estimate of difference (95% confidence interval [CI]), 28 (5, 48). In SE-positive patients, ACR50 estimate of difference (95% CI) was 32 (7, 55). During the open-label period, responses were sustained in the abatacept non-switch group and showed trends toward further improvement in the adalimumab-to-abatacept switch group at week 48, in both the overall and the SE-positive subpopulation. No new safety signals were identified. CONCLUSIONS: In MTX-IR patients with early, autoantibody-positive RA, abatacept resulted in numerically higher efficacy responses versus adalimumab after 24 weeks, with more pronounced treatment differences in SE-positive patients. After 48 weeks, responses were sustained in patients who continued abatacept while those who switched to abatacept showed further clinical improvement, overall, and in SE-positive patients. This supports co-stimulation blockade as an effective treatment strategy for patients with early, autoantibody-positive RA, particularly among SE-positive patients. TRIAL REGISTRATION: NIH US National Library of Medicine, NCT02557100 . Registered on September 23, 2015.

2.
BMJ Open ; 11(9): e050883, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521672

RESUMO

OBJECTIVE: Physical activity (PA) in preclinical rheumatoid arthritis (RA) is associated with lower RA risk and disease severity. As joint signs and symptoms of inflammatory arthritis serve as a barrier to PA in RA, it is important to consider whether they affect PA in the time prior to RA. Therefore, we investigated whether joint swelling, stiffness or pain were associated with PA in first-degree relatives (FDRs) of patients with RA, a population at higher risk for future RA. DESIGN: Prospective study design. SETTING: We recruited FDRs of patients with RA from academic centres, Veterans' hospitals and rheumatology clinics or through responses to advertising from six sites across the USA. PARTICIPANTS: We evaluated associations of joint stiffness, joint swelling and joint pain with PA time in 268 FDRs with ≥2 visits over an average 1.2 years. Clinicians confirmed joint swelling. Participants self-reported joint stiffness and/or pain. PRIMARY OUTCOME MEASURES: PA during a typical 24-hour day was quantified via questionnaire, weighted to reflect metabolic expenditure, where 24 hours was the minimum PA time. Linear mixed models evaluated associations between symptoms and change in PA over time, adjusting for age, sex, race, body mass index, smoking and RA-related autoantibodies. RESULTS: Average weighted PA time was 37±7 hours. In the cross-sectional analysis, PA time was 1.3±0.9 hours higher in FDRs reporting joint pain (p=0.15); and 0.8±1.6 and 0.4±1 hours lower in FDRs with joint swelling (p=0.60) and stiffness (p=0.69), respectively. Longitudinally, adjusting for baseline PA time, baseline symptoms were not significantly associated with changes in PA time. However, on average over time, joint stiffness and pain were associated with lower PA time (pinteraction=0.0002, pinteraction=0.002), and joint swelling was associated with higher PA time (pinteraction <0.0001). CONCLUSION: Baseline symptoms did not predict future PA time, but on average over time, joint symptoms influenced PA time.

3.
Elife ; 102021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342578

RESUMO

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.


Assuntos
2',5'-Oligoadenilato Sintetase/metabolismo , COVID-19/virologia , SARS-CoV-2/metabolismo , Animais , COVID-19/imunologia , Sistemas CRISPR-Cas , Linhagem Celular , Edição de Genes , Humanos , Polimorfismo de Nucleotídeo Único , SARS-CoV-2/isolamento & purificação
4.
Science ; 373(6554): 510-516, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326232

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease in which T cells attack and destroy the insulin-producing ß cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by compromising immune homeostasis. Although the discovery and use of insulin have transformed T1D treatment, insulin therapy does not change the underlying disease or fully prevent complications. Over the past two decades, research has identified multiple immune cell types and soluble factors that destroy insulin-producing ß cells. These insights into disease pathogenesis have enabled the development of therapies to prevent and modify T1D. In this review, we highlight the key events that initiate and sustain pancreatic islet inflammation in T1D, the current state of the immunological therapies, and their advantages for the treatment of T1D.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Fatores Imunológicos/uso terapêutico , Imunoterapia , Imunidade Adaptativa , Animais , Anti-Inflamatórios/uso terapêutico , Autoanticorpos/sangue , Linfócitos B/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Humanos , Imunidade Inata , Células Secretoras de Insulina/fisiologia , Interleucina-2/uso terapêutico , Linfócitos T/imunologia
5.
Nat Genet ; 53(7): 962-971, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34127860

RESUMO

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10-8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.


Assuntos
Alelos , Mapeamento Cromossômico , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Variação Genética , Genômica , Autoimunidade/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Descoberta de Drogas , Expressão Gênica , Genômica/métodos , Humanos , Terapia de Alvo Molecular , Mapeamento de Interação de Proteínas
6.
Proc Natl Acad Sci U S A ; 118(24)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34103397

RESUMO

Systemic lupus erythematous (SLE) is a female-predominant disease characterized by autoimmune B cells and pathogenic autoantibody production. Individuals with two or more X chromosomes are at increased risk for SLE, suggesting that X-linked genes contribute to the observed sex bias of this disease. To normalize X-linked gene expression between sexes, one X in female cells is randomly selected for transcriptional silencing through X-chromosome inactivation (XCI), resulting in allele-specific enrichment of epigenetic modifications, including histone methylation and the long noncoding RNA XIST/Xist on the inactive X (Xi). As we have previously shown that epigenetic regulation of the Xi in female lymphocytes from mice is unexpectedly dynamic, we used RNA fluorescence in situ hybridization and immunofluorescence to profile epigenetic features of the Xi at the single-cell level in human B cell subsets from pediatric and adult SLE patients and healthy controls. Our data reveal that abnormal XCI maintenance in B cells is a feature of SLE. Using single-cell and bulk-cell RNA sequencing datasets, we found that X-linked immunity genes escape XCI in specific healthy human B cell subsets and that human SLE B cells exhibit aberrant expression of X-linked genes and XIST RNA interactome genes. Our data reveal that mislocalized XIST RNA, coupled with a dramatic reduction in heterochromatic modifications at the Xi in SLE, predispose for aberrant X-linked gene expression from the Xi, thus defining a genetic and epigenetic pathway that affects X-linked gene expression in human SLE B cells and likely contributes to the female bias in SLE.

7.
J Clin Invest ; 131(3)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33529167

RESUMO

BACKGROUNDDespite a rapidly growing body of literature on coronavirus disease 2019 (COVID-19), our understanding of the immune correlates of disease severity, course, and outcome remains poor.METHODSUsing mass cytometry, we assessed the immune landscape in longitudinal whole-blood specimens from 59 patients presenting with acute COVID-19 and classified based on maximal disease severity. Hospitalized patients negative for SARS-CoV-2 were used as controls.RESULTSWe found that the immune landscape in COVID-19 formed 3 dominant clusters, which correlated with disease severity. Longitudinal analysis identified a pattern of productive innate and adaptive immune responses in individuals who had a moderate disease course, whereas those with severe disease had features suggestive of a protracted and dysregulated immune response. Further, we identified coordinate immune alterations accompanying clinical improvement and decline that were also seen in patients who received IL-6 pathway blockade.CONCLUSIONThe hospitalized COVID-19 negative cohort allowed us to identify immune alterations that were shared between severe COVID-19 and other critically ill patients. Collectively, our findings indicate that selection of immune interventions should be based in part on disease presentation and early disease trajectory due to the profound differences in the immune response in those with mild to moderate disease and those with the most severe disease.FUNDINGBenaroya Family Foundation, the Leonard and Norma Klorfine Foundation, Glenn and Mary Lynn Mounger, and the National Institutes of Health.


Assuntos
Imunidade Adaptativa , COVID-19/imunologia , Imunidade Inata , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/tratamento farmacológico , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade
8.
JCI Insight ; 6(5)2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33507879

RESUMO

Tenascin-C (TNC), an extracellular matrix protein that has proinflammatory properties, is a recently described antibody target in rheumatoid arthritis (RA). In this study, we utilized a systematic discovery process and identified 5 potentially novel citrullinated TNC (cit-TNC) T cell epitopes. CD4+ T cells specific for these epitopes were elevated in the peripheral blood of subjects with RA and showed signs of activation. Cit-TNC-specific T cells were also present among synovial fluid T cells and secreted IFN-γ. Two of these cit-TNC T cell epitopes were also recognized by antibodies within the serum and synovial fluid of individuals with RA. Detectable serum levels of cit-TNC-reactive antibodies were prevalent among subjects with RA and positively associated with cyclic citrullinated peptide (CCP) reactivity and the HLA shared epitope. Furthermore, cit-TNC-reactive antibodies were correlated with rheumatoid factor and elevated in subjects with a history of smoking. This work confirms cit-TNC as an autoantigen that is targeted by autoreactive CD4+ T cells and autoantibodies in patients with RA. Furthermore, our findings raise the possibility that coinciding epitopes recognized by both CD4+ T cells and B cells have the potential to amplify autoimmunity and promote the development and progression of RA.

9.
Ann Rheum Dis ; 80(2): 154-161, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32928740

RESUMO

OBJECTIVES: Little is known about the likelihood of developing inflammatory arthritis (IA) in individuals who screen autoantibody positive (aAb+) in a non-clinical research setting. METHODS: We screened for serum cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor isotype aAbs in subjects who were at increased risk for rheumatoid arthritis (RA) because they are a first-degree relative of an individual with classified RA (n=1780). We evaluated combinations of aAbs and high titre aAbs, as defined by 2-times (2 x) the standard cut-off and an optimal cut-off, as predictors of our two outcomes, aAb+ persistence and incident IA. RESULTS: 304 subjects (17.1%) tested aAb+; of those, 131 were IA-free and had at least one follow-up visit. Sixty-four per cent of these tested aAb+ again on their next visit. Anti-CCP+ at levels ≥2 x the standard cut-off was associated with 13-fold higher likelihood of aAb +persistence. During a median of 4.4 years (IQR: 2.2-7.2), 20 subjects (15.3%) developed IA. Among subjects that screened anti-CCP+ at ≥ 2 x or ≥an optimal cut-off, 32% and 26% had developed IA within 5 years, respectively. Both anti-CCP cut-offs conferred an approximate fourfold increased risk of future IA (HR 4.09 and HR 3.95, p<0.01). CONCLUSIONS: These findings support that aAb screening in a non-clinical setting can identify RA-related aAb+ individuals, as well as levels and combinations of aAbs that are associated with higher risk for future IA. Monitoring for the development of IA in aAb+ individuals and similar aAb testing approaches in at-risk populations may identify candidates for prevention studies in RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/genética , Autoanticorpos/sangue , Programas de Rastreamento/estatística & dados numéricos , Fator Reumatoide/sangue , Adulto , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Progressão da Doença , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Prospectivos , Fatores de Risco
10.
Case Rep Rheumatol ; 2020: 5620471, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282427

RESUMO

Relapsing polychondritis (RP) is a systemic autoimmune disease characterized by relapsing and remitting inflammation of the cartilaginous structures of the ears, nose, tracheobronchial tree, and joints. Diagnosis is challenging due to the heterogeneity of clinical manifestations, the relapsing and remitting nature of the disease, the presence of coexistent diseases in at least one-third of patients, and the lack of a diagnostic blood test. Although RP-associated cardiac disease is the second most common cause of death behind tracheobronchial complications, coronary artery vasculitis is rare. This report describes a case of sudden cardiac death due to vasculitis affecting the coronary arteries in a patient with RP. The pathologic findings included obliterative coronary arteritis with plasma cells and storiform fibrosis, features suggesting that IgG4-related disease (IgG4-RD) may have contributed to the patient's cardiac disease. The literature on vasculitis and cardiac disease in RP and the possible role of IgG4-RD in this setting is also reviewed. The primary take-home message from this case report is the importance of frequent screening for cardiac disease, regardless of symptoms, in patients with RP. In addition, considering the diagnosis of IgG4-RD in some cases thought to be RP may also be warranted.

11.
Sci Transl Med ; 12(546)2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493794

RESUMO

Thymic regulatory T cells (tTregs) are potent inhibitors of autoreactive immune responses, and loss of tTreg function results in fatal autoimmune disease. Defects in tTreg number or function are also implicated in multiple autoimmune diseases, leading to growing interest in use of Treg as cell therapies to establish immune tolerance. Because tTregs are present at low numbers in circulating blood and may be challenging to purify and expand and also inherently defective in some subjects, we designed an alternative strategy to create autologous Treg-like cells from bulk CD4+ T cells. We used homology-directed repair (HDR)-based gene editing to enforce expression of FOXP3, the master transcription factor for tTreg Targeted insertion of a robust enhancer/promoter proximal to the first coding exon bypassed epigenetic silencing, permitting stable and robust expression of endogenous FOXP3. HDR-edited T cells, edTregs, manifested a transcriptional program leading to sustained expression of canonical markers and suppressive activity of tTreg Both human and murine edTregs mediated immunosuppression in vivo in models of inflammatory disease. Further, this engineering strategy permitted generation of antigen-specific edTreg with robust in vitro and in vivo functional activity. Last, edTreg could be enriched and expanded at scale using clinically relevant methods. Together, these findings suggest that edTreg production may permit broad future clinical application.


Assuntos
Fatores de Transcrição Forkhead , Edição de Genes , Animais , Fatores de Transcrição Forkhead/genética , Humanos , Tolerância Imunológica , Camundongos , Fenótipo , Linfócitos T Reguladores
12.
JCI Insight ; 5(13)2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32484790

RESUMO

Rheumatoid arthritis (RA) is characterized by synovial joint inflammation, cartilage damage, and dysregulation of the adaptive immune system. While neutrophil extracellular traps (NETs) have been proposed to play a role in the generation of modified autoantigens and in the activation of synovial fibroblasts, it remains unknown whether NETs are directly involved in cartilage damage. Here, we report a new mechanism by which NET-derived elastase disrupts cartilage matrix and induces release of membrane-bound peptidylarginine deiminase-2 by fibroblast-like synoviocytes (FLSs). Cartilage fragments are subsequently citrullinated, internalized by FLSs, and then presented to antigen-specific CD4+ T cells. Furthermore, immune complexes containing citrullinated cartilage components can activate macrophages to release proinflammatory cytokines. HLA-DRB1*04:01 transgenic mice immunized with NETs develop autoantibodies against citrullinated cartilage proteins and display enhanced cartilage damage. Inhibition of NET-derived elastase rescues NET-mediated cartilage damage. These results show that NETs and neutrophil elastase externalized in these structures play fundamental pathogenic roles in promoting cartilage damage and synovial inflammation. Strategies targeting neutrophil elastase and NETs could have a therapeutic role in RA and in other inflammatory diseases associated with inflammatory joint damage.


Assuntos
Artrite Reumatoide/imunologia , Cartilagem Articular/lesões , Armadilhas Extracelulares/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Cartilagem Articular/imunologia , Citrulina/metabolismo , Humanos , Camundongos
13.
Arthritis Rheumatol ; 72(4): 598-608, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31702112

RESUMO

OBJECTIVE: 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. We undertook this study to develop a novel multiparameter approach to phenotype synovial responses in knee OA. METHODS: Cell composition and soluble protein production were measured by flow cytometry and multiplex enzyme-linked immunosorbent assay 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 it negatively impacted CD4+ T cell and CD56+ natural killer 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 nonmesenchymal populations, including macrophages and T cells (CD45+CD11b+HLA-DR+ myeloid cells with PDPN+CD73+CD90-CD34- mesenchymal cells [r = 0.65, P < 0.0001]; and CD45+CD3+ T cells with PDPN+CD73+CD90+CD34+ mesenchymal cells [r = 0.50, P = 0.003]). Interleukin-6 (IL-6) measured by flow cytometry strongly correlated with IL-6 released by ex vivo culture of synovial tissue (r = 0.59, P = 0.0012) and was highest in mesenchymal cells coexpressing CD90 and CD34. IL-6, IL-8, complement factor D, and IL-10 release correlated positively with tissue cellularity (P = 0.0042, P = 0.018, P = 0.0012, and P = 0.038, respectively). Additionally, increased CD8+ T cell numbers correlated with retinol binding protein 4 (P = 0.033). Finally, combining flow cytometry and multiplex data identified patient clusters with different types of inflammatory responses. CONCLUSION: We used a novel approach to analyze OA synovium, identifying patient-specific inflammatory clusters. Our findings indicate that phenotyping synovial inflammation may provide new insights into OA patient heterogeneity and biomarker development.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Células Matadoras Naturais/metabolismo , Osteoartrite do Joelho/metabolismo , Membrana Sinovial/metabolismo , Idoso , Artroplastia do Joelho , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/patologia , Feminino , Citometria de Fluxo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Células Matadoras Naturais/patologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/cirurgia , Membrana Sinovial/patologia
15.
J Rheumatol ; 46(12): 1556-1559, 2019 12.
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.


Assuntos
Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/sangue , Autoanticorpos/sangue , Imunoglobulina A/sangue , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
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.


Assuntos
Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Adulto , Idoso , Autoanticorpos/imunologia , Autoimunidade , Biomarcadores , Estudos de Casos e Controles , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Receptores de Lipopolissacarídeos/sangue , Lúpus Eritematoso Sistêmico/patologia , Lisossomos/metabolismo , Masculino , Pessoa de Meia-Idade
17.
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
18.
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.


Assuntos
Doenças Autoimunes , Diabetes Mellitus Tipo 1 , Autoimunidade , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos
19.
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
20.
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
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