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1.
PLoS One ; 14(6): e0218258, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31194850

RESUMO

Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.

2.
J Neuroimmunol ; 326: 19-27, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30447419

RESUMO

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-ß) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-ß-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-ß ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30420245

RESUMO

OBJECTIVES: To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. METHODS: The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. RESULTS: ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3). CONCLUSIONS: The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.

4.
JCI Insight ; 3(11)2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29875313

RESUMO

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-ß is an established treatment for MS; however, up to 30% of IFN-ß-treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-ß. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-ß administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-ß administration.

5.
PLoS One ; 12(6): e0179896, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28665947

RESUMO

OBJECTIVES: In cross-sectional studies of time-to-event data collected by patient examinations at a single random point in time, a fraction of them will not experience the event regardless of the length of the follow-up time. This is the case in clinical immunology studies that include a mixed population, with both immune-reactive and immune-tolerant (or non-susceptible) patients. In these cases, classical tests of current status data may perform poorly. New methods for testing these data are needed. METHODS: In the two-sample comparison setting, we propose a score test for testing the null hypothesis that survival does not differ in either the non-susceptible fraction or the time-to-event distribution among the susceptible fraction. RESULTS: In a wide range of scenarios, simulation results show interesting improvements in power for the proposed score test compared to the logrank-type test in most of the configurations we investigated. In a cross-sectional study of drug immunogenicity among treated multiple sclerosis patients, the proposed score test reveals that gender is associated with the immunogenicity of interferon.


Assuntos
Esclerose Múltipla/imunologia , Análise de Sobrevida , Estudos Transversais , Feminino , Humanos , Masculino , Modelos Teóricos , Esclerose Múltipla/patologia
6.
PLoS One ; 12(2): e0170395, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28170401

RESUMO

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNß) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNß preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNß-1a subcutaneous (s.c.) and IFNß-1b s.c. in favor of the least immunogenic preparation IFNß-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNß-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNß-1a i.m. (1.41 and 2.27 years), IFNß-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNß-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNß ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.


Assuntos
Anticorpos/imunologia , Fatores Imunológicos/efeitos adversos , Interferon beta/efeitos adversos , Esclerose Múltipla/imunologia , Natalizumab/efeitos adversos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Interferon beta/imunologia , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Natalizumab/imunologia , Natalizumab/uso terapêutico , Estudos Retrospectivos , Fatores Sexuais , Fatores de Tempo , Adulto Jovem
7.
PLoS One ; 11(11): e0162752, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27806057

RESUMO

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFNß)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFNß-1a subcutaneous and IFNß-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNß-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFNß therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFNß in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFNß. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.


Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Anticorpos/imunologia , Interferon beta/efeitos adversos , Interferon beta/imunologia , Esclerose Múltipla/complicações , Natalizumab/efeitos adversos , Natalizumab/imunologia , Adulto , Idoso , Anticorpos/sangue , Anticorpos Anti-Idiotípicos/sangue , Estudos de Coortes , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Humanos , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/mortalidade , Natalizumab/uso terapêutico , Avaliação de Resultados da Assistência ao Paciente , Vigilância da População , Modelos de Riscos Proporcionais , Fatores de Risco
8.
J Autoimmun ; 42: 1-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23122533

RESUMO

Patients with the monogenic disease autoimmune polyendocrine syndrome type I (APSI) develop autoimmunity against multiple endocrine organs and suffer from chronic mucocutaneous candidiasis (CMC), a paradoxical complication with an unknown mechanism. We report here that saliva from APSI patients with CMC is defective in inhibiting growth of Candida albicans in vitro and show reduced levels of a salivary protein identified as cystatin SA1. In contrast, APSI patients without CMC express salivary cystatin SA1 and can inhibit C. albicans to the same extent as healthy controls. We evaluated the anti-fungal activity of cystatin SA1 and found that synthesized full length cystatin SA1 efficiently inhibits growth of C. albicans in vitro. Moreover, APSI patients exhibit salivary IgA autoantibodies recognizing myosin-9, a protein expressed in the salivary glands, thus linking autoimmunity to cystatin SA1 deficiency and CMC. This data suggests an autoimmune mechanism behind CMC in APSI and provides rationale for evaluating cystatin SA1 in antifungal therapy.


Assuntos
Candidíase Mucocutânea Crônica/imunologia , Inibidores do Crescimento/metabolismo , Poliendocrinopatias Autoimunes/imunologia , Cistatinas Salivares/metabolismo , Adulto , Autoanticorpos/metabolismo , Autoimunidade , Candidíase Mucocutânea Crônica/etiologia , Candidíase Mucocutânea Crônica/genética , Feminino , Predisposição Genética para Doença , Inibidores do Crescimento/genética , Inibidores do Crescimento/imunologia , Humanos , Imunoglobulina A/metabolismo , Masculino , Proteínas Motores Moleculares/imunologia , Cadeias Pesadas de Miosina/imunologia , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/genética , Saliva/metabolismo , Cistatinas Salivares/genética , Cistatinas Salivares/imunologia , Adulto Jovem
9.
PLoS Pathog ; 8(8): e1002841, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22916010

RESUMO

Intracellular Toll-like receptors (TLRs) expressed by dendritic cells recognize nucleic acids derived from pathogens and play an important role in the immune responses against the influenza virus (IAV), a single-stranded RNA sensed by different receptors including TLR7. However, the importance of TLR7 processing in the development of anti-viral immune responses is not known. Here we report that asparagine endopeptidase (AEP) deficient mice are unable to generate a strong anti-IAV response, as demonstrated by reduced inflammation, cross presentation of cell-associated antigens and priming of CD8(+) T cells following TLR7-dependent pulmonary infection induced by IAV. Moreover, AEP deficient lung epithelial- or myeloid-cells exhibit impaired TLR7 signaling due to defective processing of this receptor. Indeed, TLR7 requires a proteolytic cleavage by AEP to generate a C-terminal fragment competent for signaling. Thus, AEP activity is critical for TLR7 processing, opening new possibilities for the treatment of influenza and TLR7-dependent inflammatory diseases.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Endopeptidases/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Glicoproteínas de Membrana/imunologia , Infecções por Orthomyxoviridae/imunologia , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Endopeptidases/genética , Endopeptidases/metabolismo , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/metabolismo , Transdução de Sinais/genética , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo
10.
Proc Natl Acad Sci U S A ; 105(47): 18466-71, 2008 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-19011083

RESUMO

Autoimmune polyendocrine syndrome type I (APS I) results in multiple endocrine organ destruction and is caused by mutations in the autoimmune regulator gene (AIRE). APS I is characterized by circulating tissue-specific autoantibodies, and the presence of these antibodies is often predictive of organ destruction. The importance of AIRE in ensuring central tolerance by regulating the negative selection of autoreactive T cells has been shown clearly. However, in Aire(-/-) mice the phenotype (i.e., autoantibodies, liver infiltrates of B cells, splenomegaly, and marginal zone B-cell lymphoma) is predominantly B-cell mediated, suggesting an exaggerated activation of B cells. We have studied T-cell-independent B-cell responses in the absence of AIRE and found that Aire(-/-) mice have an increased response against T-cell-independent type II antigens. We linked this exaggerated response to the elevated serum levels of the B-cell-activating factor of the TNF family (BAFF) that were found both in APS I patients and in Aire(-/-) mice. Transfer of Aire(-/-) bone marrow into irradiated nude mice resulted in increased percentage of BAFF-expressing antigen-presenting cells compared with wt bone marrow, suggesting a T-cell-independent mechanism behind our findings. Furthermore, in vitro experiments showed that AIRE-deficient murine bone marrow-derived dendritic cells produced significantly more BAFF than wt cells when stimulated with IFN-gamma but not when stimulated with IL-10. Our results suggest a cell-intrinsic role for AIRE in peripheral dendritic cells by regulating IFN-gamma-receptor signaling and point toward complementary mechanisms by which AIRE is involved in maintaining tolerance.


Assuntos
Fator Ativador de Células B/fisiologia , Linfócitos B/imunologia , Linfócitos T/imunologia , Fatores de Transcrição/fisiologia , Animais , Autoantígenos/imunologia , Fator Ativador de Células B/sangue , Sequência de Bases , Proliferação de Células , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Camundongos , Camundongos Knockout , Camundongos Nus , Receptores de Interferon/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Fatores de Transcrição/genética
11.
Clin Immunol ; 121(3): 265-73, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16982213

RESUMO

Patients with Autoimmune polyendocrine syndrome type I (APS I) present with multiple endocrine failures due to organ-specific autoimmune disease, thought to be T-cell-mediated. Paradoxically, APS I patients suffer from chronic mucocutaneous candidiasis. The mutated gene has been identified as the Autoimmune regulator (AIRE). Aire is expressed in medullary epithelial cells of the thymus and in antigen presenting cells in the periphery. T cells from Aire deficient mice and men displayed an enhanced proliferative response against Candida antigen in vitro, suggesting that Aire deficient T cells are competent in recognizing Candida albicans. In contrast, monocytes from APS I patients displayed a decreased and delayed internalization of zymosan. Furthermore, Candida antigen activated monocytes from APS I patients show decreased and altered phoshotyrosine kinase activation. In conclusion, Aire deficient APCs have a defect receptor mediated internalization of Candida which affects kinase activation, likely altering the innate Candida immune response.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos de Fungos/imunologia , Candida albicans/imunologia , Proteínas Fúngicas/imunologia , Proteínas Tirosina Quinases/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo , Animais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/enzimologia , Células Apresentadoras de Antígenos/metabolismo , Extratos Celulares , Proliferação de Células , Parede Celular/imunologia , Células Cultivadas , Ativação Enzimática , Feminino , Humanos , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/metabolismo , Poliendocrinopatias Autoimunes/patologia , Transdução de Sinais , Linfócitos T/citologia , Linfócitos T/imunologia , Fatores de Transcrição/genética , Zimosan/imunologia
12.
Blood ; 108(6): 1941-8, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16709926

RESUMO

Autoimmune polyendocrine syndrome type I (APS I) is an inherited recessive disorder with a progressive immunological destruction of many tissues including the adrenal cortex, the parathyroid glands, and the gonads. APS I is caused by mutations in the AIRE gene (autoimmune regulator), expressed in cells of the thymus and spleen, suggesting a role in central and peripheral tolerance. Aire(-/-) mice replicate the autoimmune features of APS I patients with the presence of multiple autoantibodies and lymphocytic infiltrates in various tissues, but young mice appear clinically healthy. We here report the investigation of 15- to 24-month-old Aire(-/-) mice. We did not observe any endocrinological abnormalities, nor did sera from these mice recognize known APS I autoantigens. Interestingly, however, there was a high frequency of marginal zone B-cell lymphoma in Aire(-/-) mice and liver infiltrates of B cells, suggesting chronic antigen exposure and exaggerated activation. Furthermore, increased numbers of monocytes in blood were identified as well as augmented numbers of metallophilic macrophages in the spleen. We propose that Aire, in addition to its function in the thymus, also has a peripheral regulatory role by controlling the development of antigen-presenting cells (APCs) and marginal zone B-cell activation.


Assuntos
Hematopoese/genética , Linfoma de Células B/genética , Linfoma de Células B/patologia , Fatores de Transcrição/deficiência , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Feminino , Humanos , Fígado/imunologia , Fígado/patologia , Ativação Linfocitária , Linfoma de Células B/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
13.
Eur J Immunol ; 36(2): 305-17, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16421949

RESUMO

Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire(-/-) dendritic cells (DC) activate naive T cells more efficiently than do Aire(+/+) DC. Expression array analyses of Aire(-/-) DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire(-/-) DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire(-/-) DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire(-/-) DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire(-/-) mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.


Assuntos
Doenças Autoimunes/imunologia , Doenças do Sistema Endócrino/imunologia , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Fatores de Transcrição/deficiência , Animais , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Adesão Celular/genética , Adesão Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Doenças do Sistema Endócrino/genética , Doenças do Sistema Endócrino/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Humanos , Tolerância Imunológica/genética , Ativação Linfocitária/genética , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/patologia , Linfócitos T/patologia , Timo/imunologia , Timo/patologia , Fatores de Transcrição/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/imunologia
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