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1.
Cell ; 171(3): 655-667.e17, 2017 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-29053971

RESUMO

The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic ß cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP206-214). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut. There, these effectors suppress colitis by targeting microbial antigen-loaded, antigen-presenting cells in an integrin ß7-, perforin-, and major histocompatibility complex class I-dependent manner. Like their murine counterparts, human peripheral blood T cells also recognize Bacteroides integrase. These data suggest that gut microbial antigen-specific cytotoxic T cells may have therapeutic value in inflammatory bowel disease and unearth molecular mimicry as a novel mechanism by which the gut microbiota can regulate normal immune homeostasis. PAPERCLIP.


Assuntos
Autoantígenos/imunologia , Bacteroides/imunologia , Colite/imunologia , Microbioma Gastrointestinal , Glucose-6-Fosfatase/imunologia , Adulto , Animais , Bacteroides/classificação , Bacteroides/enzimologia , Colite/microbiologia , Feminino , Glucose-6-Fosfatase/genética , Humanos , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Mimetismo Molecular , Linfócitos T/imunologia
2.
Semin Immunol ; 56: 101535, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34969600

RESUMO

Autoimmune diseases, caused by cellularly and molecularly complex immune responses against self-antigens, are largely treated with broad-acting, non-disease-specific anti-inflammatory drugs. These compounds can attenuate autoimmune inflammation, but tend to impair normal immunity against infection and cancer, cannot restore normal immune homeostasis and are not curative. Nanoparticle (NP)- and microparticle (MP)-based delivery of immunotherapeutic agents affords a unique opportunity to not only increase the specificity and potency of broad-acting immunomodulators, but also to elicit the formation of organ-specific immunoregulatory cell networks capable of inducing bystander immunoregulation. Here, we review the various NP/MP-based strategies that have so far been tested in models of experimental and/or spontaneous autoimmunity, with a focus on mechanisms of action.


Assuntos
Doenças Autoimunes , Autoimunidade , Autoantígenos , Doenças Autoimunes/tratamento farmacológico , Humanos , Fatores Imunológicos/uso terapêutico , Imunomodulação , Nanomedicina
3.
BMC Med ; 22(1): 103, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38454385

RESUMO

BACKGROUND: The emergence of new SARS-CoV-2 variants and the waning of immunity raise concerns about vaccine effectiveness and protection against COVID-19. While antibody response has been shown to correlate with the risk of infection with the original variant and earlier variants of concern, the effectiveness of antibody-mediated protection against Omicron and the factors associated with protection remain uncertain. METHODS: We evaluated antibody responses to SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from Wuhan and variants of concern by Luminex and their role in preventing breakthrough infections 1 year after a third dose of mRNA vaccination, in a cohort of health care workers followed since the pandemic onset in Spain (N = 393). Data were analyzed in relation to COVID-19 history, demographic factors, comorbidities, vaccine doses, brand, and adverse events. RESULTS: Higher levels of anti-S IgG and IgA to Wuhan, Delta, and Omicron were associated with protection against vaccine breakthroughs (IgG against Omicron S antigen HR, 0.06, 95%CI, 0.26-0.01). Previous SARS-CoV-2 infection was positively associated with antibody levels and protection against breakthroughs, and a longer time since last infection was associated with lower protection. In addition, priming with BNT162b2 followed by mRNA-1273 booster was associated with higher antibody responses than homologous mRNA-1273 vaccination. CONCLUSIONS: Data show that IgG and IgA induced by vaccines against the original strain or by hybrid immunization are valid correlates of protection against Omicron BA.1 despite immune escape and support the benefits of heterologous vaccination regimens to enhance antibodies and the prioritization of booster vaccination in individuals without recent infections.


Assuntos
COVID-19 , Humanos , COVID-19/prevenção & controle , Vacina de mRNA-1273 contra 2019-nCoV , SARS-CoV-2 , Vacina BNT162 , Infecções Irruptivas , Vacinação , Imunoglobulina A , Imunoglobulina G , Anticorpos Antivirais
4.
J Med Virol ; 96(6): e29713, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38874194

RESUMO

Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence is used to estimate the proportion of individuals within a population previously infected, to track viral transmission, and to monitor naturally and vaccine-induced immune protection. However, in sub-Saharan African settings, antibodies induced by higher exposure to pathogens may increase unspecific seroreactivity to SARS-CoV-2 antigens, resulting in false positive responses. To investigate the level and type of unspecific seroreactivitiy to SARS-CoV-2 in Africa, we measured immunoglobulin G (IgG), IgA, and IgM to a broad panel of antigens from different pathogens by Luminex in 602 plasma samples from African and European subjects differing in coronavirus disease 2019, malaria, and other exposures. Seroreactivity to SARS-CoV-2 antigens was higher in prepandemic African than in European samples and positively correlated with antibodies against human coronaviruses, helminths, protozoa, and especially Plasmodium falciparum. African subjects presented higher levels of autoantibodies, a surrogate of polyreactivity, which correlated with P. falciparum and SARS-CoV-2 antibodies. Finally, we found an improved sensitivity in the IgG assay in African samples when using urea as a chaotropic agent. In conclusion, our data suggest that polyreactive antibodies induced mostly by malaria are important mediators of the unspecific anti-SARS-CoV-2 responses, and that the use of dissociating agents in immunoassays could be useful for more accurate estimates of SARS-CoV-2 seroprevalence in African settings.


Assuntos
Anticorpos Antivirais , COVID-19 , Imunoglobulina G , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/epidemiologia , Anticorpos Antivirais/sangue , Estudos Soroepidemiológicos , SARS-CoV-2/imunologia , Imunoglobulina G/sangue , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Malária/epidemiologia , Malária/imunologia , Malária/sangue , Imunoglobulina M/sangue , Adulto Jovem , Idoso , Adolescente , Europa (Continente)/epidemiologia , Imunoglobulina A/sangue , Doenças Endêmicas , África/epidemiologia , África Subsaariana/epidemiologia
5.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34782469

RESUMO

Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Fosfatases de Especificidade Dupla/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Animais , Doenças Autoimunes/genética , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Ilhotas Pancreáticas/metabolismo , Complexo Principal de Histocompatibilidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fosfatases da Proteína Quinase Ativada por Mitógeno , Mutação
6.
Diabetologia ; 66(11): 1971-1982, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37488322

RESUMO

Type 1 diabetes results from the poorly understood process of islet autoimmunity, which ultimately leads to the loss of functional pancreatic beta cells. Mounting evidence supports the notion that the activation and evolution of islet autoimmunity in genetically susceptible people is contingent upon early life exposures affecting the islets, especially beta cells. Here, we review some of the recent advances and studies that highlight the roles of these changes as well as antigen presentation and stress response pathways in beta cells in the onset and propagation of the autoimmune process in type 1 diabetes. Future progress in this area holds promise for advancing islet- and beta cell-directed therapies that could be implemented in the early stages of the disease and could be combined with immunotherapies.


Assuntos
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Humanos , Diabetes Mellitus Tipo 1/metabolismo , Células Secretoras de Insulina/metabolismo , Autoimunidade/fisiologia , Ilhotas Pancreáticas/metabolismo , Predisposição Genética para Doença
7.
Proc Natl Acad Sci U S A ; 117(49): 31219-31230, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33229527

RESUMO

Type 1 diabetes (T1D) results from the autoimmune destruction of ß cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of ß cells. It is known that ß cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of ß cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments ß cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing ß cells, Sox9+ ductal progenitors, Nestin+ mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) ß cells and neogenesis contribute to the regeneration, with the latter predominantly coming from transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of ß cells and transdifferentiation of α cells can provide sufficient new functional ß cells to reach euglycemia in firmly established T1D.


Assuntos
Diabetes Mellitus Tipo 1/genética , Células Secretoras de Insulina/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Regeneração/genética , Animais , Autoimunidade/genética , Glicemia/efeitos dos fármacos , Transdiferenciação Celular/genética , Quimerismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Fator de Crescimento Epidérmico/farmacologia , Feminino , Gastrinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucagon/biossíntese , Células Secretoras de Glucagon/metabolismo , Insulina/genética , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Células-Tronco Mesenquimais/imunologia , Camundongos , Camundongos Endogâmicos NOD/genética , Células Precursoras de Linfócitos B/efeitos dos fármacos
8.
BMC Med ; 20(1): 347, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36109713

RESUMO

BACKGROUND: Heterogeneity of the population in relation to infection, COVID-19 vaccination, and host characteristics is likely reflected in the underlying SARS-CoV-2 antibody responses. METHODS: We measured IgM, IgA, and IgG levels against SARS-CoV-2 spike and nucleocapsid antigens in 1076 adults of a cohort study in Catalonia between June and November 2020 and a second time between May and July 2021. Questionnaire data and electronic health records on vaccination and COVID-19 testing were available in both periods. Data on several lifestyle, health-related, and sociodemographic characteristics were also available. RESULTS: Antibody seroreversion occurred in 35.8% of the 64 participants non-vaccinated and infected almost a year ago and was related to asymptomatic infection, age above 60 years, and smoking. Moreover, the analysis on kinetics revealed that among all responses, IgG RBD, IgA RBD, and IgG S2 decreased less within 1 year after infection. Among vaccinated, 2.1% did not present antibodies at the time of testing and approximately 1% had breakthrough infections post-vaccination. In the post-vaccination era, IgM responses and those against nucleoprotein were much less prevalent. In previously infected individuals, vaccination boosted the immune response and there was a slight but statistically significant increase in responses after a 2nd compared to the 1st dose. Infected vaccinated participants had superior antibody levels across time compared to naïve-vaccinated people. mRNA vaccines and, particularly the Spikevax, induced higher antibodies after 1st and 2nd doses compared to Vaxzevria or Janssen COVID-19 vaccines. In multivariable regression analyses, antibody responses after vaccination were predicted by the type of vaccine, infection age, sex, smoking, and mental and cardiovascular diseases. CONCLUSIONS: Our data support that infected people would benefit from vaccination. Results also indicate that hybrid immunity results in superior antibody responses and infection-naïve people would need a booster dose earlier than previously infected people. Mental diseases are associated with less efficient responses to vaccination.


Assuntos
COVID-19 , Vacinas Virais , Formação de Anticorpos , COVID-19/prevenção & controle , Teste para COVID-19 , Vacinas contra COVID-19 , Estudos de Coortes , Humanos , Imunoglobulina A , Imunoglobulina G , Imunoglobulina M , Pessoa de Meia-Idade , Nucleoproteínas , SARS-CoV-2 , Espanha/epidemiologia , Vacinação , Vacinas Virais/farmacologia
9.
Nature ; 530(7591): 434-40, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26886799

RESUMO

Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Antígenos CD11/imunologia , Diferenciação Celular , Citocinas/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Nanomedicina , Nanopartículas/química , Nanopartículas/uso terapêutico , Especificidade de Órgãos , Prevalência , Solubilidade , Linfócitos T Reguladores/citologia
10.
BMC Med ; 19(1): 155, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183003

RESUMO

We assessed the duration and baseline determinants of antibody responses to SARS-CoV-2 spike antigens and the occurrence of reinfections in a prospective cohort of 173 Spanish primary health care worker patients followed initially for 9 months and subsequently up to 12.5 months after COVID-19 symptoms onset. Seropositivity to SARS-CoV-2 spike and receptor-binding domain antigens up to 149-270 days was 92.49% (90.17% IgG, 76.3% IgA, 60.69% IgM). In a subset of 64 health care workers who had not yet been vaccinated by April 2021, seropositivity was 96.88% (95.31% IgG, 82.81% IgA) up to 322-379 days post symptoms onset. Four suspected reinfections were detected by passive case detection, two among seronegative individuals (5 and 7 months after the first episode), and one low antibody responder. Antibody levels significantly correlated with fever, hospitalization, anosmia/hypogeusia, allergies, smoking, and occupation. Stable sustainment of IgG responses raises hope for long-lasting COVID-19 vaccine immunity.


Assuntos
COVID-19/epidemiologia , Pessoal de Saúde/estatística & dados numéricos , Adulto , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Reinfecção/sangue , Reinfecção/epidemiologia , Reinfecção/virologia , SARS-CoV-2/isolamento & purificação , Estudos Soroepidemiológicos , Espanha/epidemiologia
11.
J Clin Microbiol ; 59(2)2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33127841

RESUMO

Reliable serological tests are required to determine the prevalence of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to characterize immunity to the disease in order to address key knowledge gaps in the coronavirus disease 2019 (COVID-19) pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and enzyme-linked immunosorbent assays (ELISAs) with their higher precision, dynamic range, throughput, miniaturization, cost-efficiency, and multiplexing capacity. We developed three qSAT assays for IgM, IgA, and IgG against a panel of eight SARS-CoV-2 antigens, including spike protein (S), nucleocapsid protein (N), and membrane protein (M) constructs. The assays were optimized to minimize the processing time and maximize the signal-to-noise ratio. We evaluated their performances using 128 prepandemic plasma samples (negative controls) and 104 plasma samples from individuals with SARS-CoV-2 diagnosis (positive controls), of whom 5 were asymptomatic, 51 had mild symptoms, and 48 were hospitalized. Preexisting IgG antibodies recognizing N, M, and S proteins were detected in negative controls, which is suggestive of cross-reactivity to common-cold coronaviruses. The best-performing antibody/antigen signatures had specificities of 100% and sensitivities of 95.78% at ≥14 days and 95.65% at ≥21 days since the onset of symptoms, with areas under the curve (AUCs) of 0.977 and 0.999, respectively. Combining multiple markers as assessed by qSAT assays has the highest efficiency, breadth, and versatility to accurately detect low-level antibody responses for obtaining reliable data on the prevalence of exposure to novel pathogens in a population. Our assays will allow gaining insights into antibody correlates of immunity and their kinetics, required for vaccine development to combat the COVID-19 pandemic.


Assuntos
Antígenos Virais/imunologia , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , Isotipos de Imunoglobulinas/sangue , SARS-CoV-2/imunologia , Adulto , Anticorpos Antivirais/sangue , COVID-19/sangue , Reações Cruzadas , Feminino , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas Estruturais Virais/imunologia
12.
Immunology ; 161(3): 209-229, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32687611

RESUMO

Nanoparticles (NPs) displaying autoimmune disease-relevant peptide-major histocompatibility complex class II molecules (pMHCII-NPs) trigger cognate T-regulatory type 1 (Tr1)-cell formation and expansion, capable of reversing organ-specific autoimmune responses. These pMHCII-NPs that display epitopes from mitochondrial protein can blunt the progression of both autoimmune hepatitis (AIH) and experimental autoimmune encephalomyelitis (EAE) in mice carrying either disease. However, with co-morbid mice having both diseases, these pMHCII-NPs selectively treat AIH. In contrast, pMHCII-NPs displaying central nervous system (CNS)-specific epitopes can efficiently treat CNS autoimmunity, both in the absence and presence of AIH, without having any effects on the progression of the latter. Here, we develop a compartmentalized population model of T-cells in co-morbid mice to identify the mechanisms by which Tr1 cells mediate organ-specific immunoregulation. We perform time-series simulations and bifurcation analyses to study how varying physiological parameters, including local cognate antigenic load and rates of Tr1-cell recruitment and retention, affect T-cell allocation and Tr1-mediated immunoregulation. Various regimes of behaviour, including 'competitive autoimmunity' where pMHCII-NP-treatment fails against both diseases, are identified and compared with experimental observations. Our results reveal that a transient delay in Tr1-cell recruitment to the CNS, resulting from inflammation-dependent Tr1-cell allocation, accounts for the liver-centric effects of AIH-specific pMHCII-NPs in co-morbid mice as compared with mice exclusively having EAE. They also suggest that cognate autoantigen expression and local Tr1-cell retention are key determinants of effective regulatory-cell function. These results thus provide new insights into the rules that govern Tr1-cell recruitment and their autoregulatory function.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Hepatite Autoimune/imunologia , Modelos Imunológicos , Modelos Teóricos , Esclerose Múltipla/imunologia , Nanomedicina/métodos , Linfócitos T Reguladores/imunologia , Animais , Apresentação de Antígeno , Autoantígenos/imunologia , Compartimento Celular , Encefalomielite Autoimune Experimental/complicações , Hepatite Autoimune/complicações , Humanos , Imunomodulação , Ativação Linfocitária , Camundongos
13.
Eur J Immunol ; 48(5): 751-756, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29427438

RESUMO

Autoimmune diseases are caused by antigenically complex immune responses of the adaptive and innate immune system against specific cells, tissues or organs. Antigen-specific approaches for induction of immune tolerance in autoimmunity, based on the use of antigenic peptides or proteins, have failed to deliver the desired therapeutic results in clinical trials. These approaches, which are largely relying on triggering clonal anergy and/or deletion of defined autoreactive specificities, do not address the overwhelming antigenic, molecular, and cellular complexity of most autoimmune diseases, which involve various immune cells and ever-growing repertoires of antigenic epitopes on numerous self-antigens. Advances in the field of regulatory T-cell (Treg) biology have suggested that Treg cells might be able to afford dominant tolerance provided they are properly activated and expanded in vivo. More recently, nanotechnology has introduced novel technical advances capable of modulating immune responses. Here, we review nanoparticle-based approaches designed to induce immune tolerance, ranging from approaches that primarily trigger clonal T-cell anergy or deletion to approaches that trigger Treg cell formation and expansion from autoreactive T-cell effectors. We will also highlight the therapeutic potential and positive outcomes in numerous experimental models of autoimmunity.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Tolerância Imunológica/imunologia , Nanopartículas/uso terapêutico , Linfócitos T Reguladores/imunologia , Autoantígenos/imunologia , Humanos , Ativação Linfocitária/imunologia
14.
Immunity ; 32(4): 437-45, 2010 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-20412754

RESUMO

Autoimmune diseases with high population prevalence such as type 1 diabetes (T1D) develop as a result of ill-defined interactions between putative environmental triggers and a constellation of genetic elements scattered throughout the genome. In T1D, these interactions somehow trigger a loss of tolerance to pancreatic beta cells, manifested in the form of a chronic autoimmune response that mobilizes virtually every cell type of the immune system and progressively erodes the host's beta cell mass. The five accompanying review articles focus on key areas of T1D research, ranging from genetics and pathogenesis to prediction and therapy. Here, I attempt to integrate and bring into focus the most salient points of these reviews in the context of other findings, with an emphasis on identifying knowledge gaps and research opportunities.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Animais , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Humanos , Insulina/imunologia , Ativação Linfocitária , Linfócitos T/imunologia
15.
Immunity ; 32(4): 568-80, 2010 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-20381385

RESUMO

Blunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8(+) T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals. pMHC-NP therapy was inconsequential in mice engineered to bear an immune system unresponsive to the corresponding epitope, owing to absence of epitope-experienced autoregulatory T cells. pMHC-NP-expanded autoregulatory T cells suppressed local presentation of autoantigens in an interferon-gamma-, indoleamine 2,3-dioxygenase-, and perforin-dependent manner. Nanoparticles coated with human diabetes-relevant pHLA complexes restored normoglycemia in a humanized model of diabetes. These observations expose a paradigm in the pathogenesis of autoimmunity amenable for therapeutic intervention.


Assuntos
Autoimunidade , Memória Imunológica , Linfócitos T Reguladores/imunologia , Sequência de Aminoácidos , Animais , Apresentação de Antígeno , Sequência de Bases , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Diabetes Mellitus Tipo 1/imunologia , Feminino , Glucose-6-Fosfatase/química , Glucose-6-Fosfatase/imunologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interferon gama/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Endogâmicos NOD , Dados de Sequência Molecular , Perforina/imunologia , Proteínas/química , Proteínas/imunologia
16.
Immunity ; 31(4): 643-53, 2009 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-19818656

RESUMO

Type 1 diabetes is a T cell-mediated autoimmune disease, characterized by lymphocytic infiltration of the pancreatic islets. It is currently thought that islet antigen specificity is not a requirement for islet entry and that diabetogenic T cells can recruit a heterogeneous bystander T cell population. We tested this assumption directly by generating T cell receptor (TCR) retrogenic mice expressing two different T cell populations. By combining diabetogenic and nondiabetogenic or nonautoantigen-specific T cells, we demonstrate that bystander T cells cannot accumulate in the pancreatic islets. Autoantigen-specific T cells that accumulate in islets, but do not cause diabetes, were also unaffected by the presence of diabetogenic T cells. Additionally, 67% of TCRs cloned from nonobese diabetic (NOD) islet-infiltrating CD4(+) T cells were able to mediate cell-autonomous islet infiltration and/or diabetes when expressed in retrogenic mice. Therefore, islet entry and accumulation appears to be a cell-autonomous and tightly regulated event and is governed by islet antigen specificity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Autoantígenos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Diabetes Mellitus Tipo 1/metabolismo , Técnicas de Transferência de Genes , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Subpopulações de Linfócitos T/metabolismo
17.
J Immunol ; 193(7): 3296-307, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25165150

RESUMO

We investigated whether a prevalent epitope of the ß-cell-specific autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP206-214) reaches regional Ag-presentation pathways via unprocessed polypeptide chains, as free IGRP206-214 peptide or via preformed IGRP206-214/K(d) complexes. This was accomplished by expressing bacterial artificial chromosome transgenes encoding wild-type (stable) or ubiquitinated (unstable) forms of IGRP in IGRP-deficient NOD mice carrying MHC class I-deficient ß-cells, dendritic cells, or B cells. We investigated the ability of the pancreatic lymph nodes of these mice to prime naive IGRP206-214-reactive CD8(+) T cells in vivo, either in response to spontaneous Ag shedding, or to synchronized forms of ß-cell necrosis or apoptosis. When IGRP was made unstable by targeting it for proteasomal degradation within ß-cells, the cross-priming, autoimmune-initiating potential of this autoantigen (designated autoantigenicity) was impaired. Yet at the same time, the direct presentation, CTL-targeting potential of IGRP (designated pathogenicity) was enhanced. The appearance of IGRP206-214 in regional Ag-presentation pathways was dissociated from transfer of IGRP206-214 or IGRP206-214/K(d) from ß cells to dendritic cells. These results indicate that autoantigenicity and pathogenicity are separable and inversely related properties and suggest that pathogenic autoantigens, capable of efficiently priming CTLs while marking target cells for CTL-induced killing, may have a critical balance of these two properties.


Assuntos
Apresentação de Antígeno , Autoantígenos/imunologia , Apresentação Cruzada , Células Dendríticas/imunologia , Glucose-6-Fosfatase/imunologia , Células Secretoras de Insulina/imunologia , Animais , Apoptose/imunologia , Autoantígenos/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Glucose-6-Fosfatase/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Necrose
18.
Proc Natl Acad Sci U S A ; 110(9): 3471-6, 2013 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-23401506

RESUMO

Polymorphisms in MHC class II molecules, in particular around ß-chain position-57 (ß57), afford susceptibility/resistance to multiple autoimmune diseases, including type 1 diabetes, through obscure mechanisms. Here, we show that the antidiabetogenic MHC class II molecule I-A(b) affords diabetes resistance by promoting the differentiation of MHC-promiscuous autoreactive CD4(+) T cells into disease-suppressing natural regulatory T cells, in a ß56-67-regulated manner. We compared the tolerogenic and antidiabetogenic properties of CD11c promoter-driven transgenes encoding I-A(b) or a form of I-A(b) carrying residues 56-67 of I-Aß(g7) (I-A(b-g7)) in wild-type nonobese diabetic (NOD) mice, as well as NOD mice coexpressing a diabetogenic and I-A(g7)-restricted, but MHC-promiscuous T-cell receptor (4.1). Both I-A transgenes protected NOD and 4.1-NOD mice from diabetes. However, whereas I-A(b) induced 4.1-CD4(+) thymocyte deletion and 4.1-CD4(+)Foxp3(+) regulatory T-cell development, I-A(b-g7) promoted 4.1-CD4(+)Foxp3(+) Treg development without inducing clonal deletion. Furthermore, non-T-cell receptor transgenic NOD.CD11cP-I-A(b) and NOD.CD11cP-IA(b-g7) mice both exported regulatory T cells with superior antidiabetogenic properties than wild-type NOD mice. We propose that I-A(b), and possibly other protective MHC class II molecules, afford disease resistance by engaging a naturally occurring constellation of MHC-promiscuous autoreactive T-cell clonotypes, promoting their deviation into autoregulatory T cells.


Assuntos
Diferenciação Celular/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Fatores de Transcrição Forkhead/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Animais , Antígeno CD11c/genética , Anergia Clonal/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/prevenção & controle , Regulação para Baixo , Tolerância Imunológica/imunologia , Queratina-14/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Timócitos/imunologia , Transgenes/genética
19.
Nat Genet ; 39(3): 329-37, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17277778

RESUMO

Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation. Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2. Reduced IL-2 production achieved by either genetic mechanism correlates with reduced function of CD4(+) CD25(+) regulatory T cells, which are critical for maintaining immune homeostasis.


Assuntos
Autoimunidade/genética , Diabetes Mellitus Tipo 1/imunologia , Interleucina-2/genética , Linfócitos T Reguladores/imunologia , Alelos , Animais , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Homeostase/imunologia , Interleucina-2/biossíntese , Interleucina-2/imunologia , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos NOD , Linfócitos T Reguladores/metabolismo , Transcrição Gênica
20.
Clin Immunol ; 160(1): 3-13, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25704658

RESUMO

The goal of immunotherapy against autoimmunity is to block pathogenic inflammation without impairing immunity against infections and tumours. Regulatory T-cells (Tregs) play a central role in maintaining immune homeostasis, and autoimmune inflammation is frequently associated with decreased numbers and/or function of these T-cells. Therapies harnessing Tregs to treat autoimmune inflammation remain under-developed with caveats ranging from the lack of antigenic and disease specificity to the potential phenotypic and functional instability of in vitro-expanded Treg cells in vivo. Here, we review nanotechnology-based approaches designed to promote immune tolerance through various mechanisms, ranging from systemic or local suppression of antigen-presenting cells and deletion of antigen-specific T-cells, to the systemic expansion of antigen- and disease-specific Treg cells in vivo.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Doenças Autoimunes/terapia , Tolerância Imunológica/imunologia , Nanopartículas/uso terapêutico , Linfócitos T Reguladores/imunologia , Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/imunologia , Portadores de Fármacos/uso terapêutico , Humanos , Imunoterapia/métodos , Inflamação/imunologia , Ativação Linfocitária/imunologia , Depleção Linfocítica/métodos
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