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1.
Ann Rheum Dis ; 79(2): 225-231, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31707357

RESUMO

OBJECTIVE: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS. METHODS: We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis. RESULTS: ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes. CONCLUSIONS: These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.

2.
Paediatr Drugs ; 22(1): 29-44, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31732958

RESUMO

Macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis, is a frequently fatal complication of a variety of pediatric inflammatory disorders. MAS has been most commonly associated with systemic juvenile idiopathic arthritis (sJIA), as approximately 10% of children with sJIA develop fulminant MAS, with another 30-40% exhibiting a more subclinical form of the disease. Children with other rheumatologic conditions such as systemic lupus erythematosus and Kawasaki disease are also at risk for MAS. Moreover, MAS also complicates various genetic autoinflammatory disorders such as gain of function mutations in the cytosolic inflammasome NLRC4, pediatric hematologic malignancies (e.g., T-cell lymphoma), and primary immunodeficiencies characterized by immune dysregulation. Disease-specific and broadly inclusive diagnostic criteria have been developed to facilitate the diagnosis of MAS. Recently, simple screening tools such as the serum ferritin to erythrocyte sedimentation rate ratio have been proposed. Early diagnosis and rapid initiation of immunosuppression are essential for the effective management of MAS. With a better understanding of the pathophysiology of MAS and the advent of novel therapeutics, a broad immunosuppressive approach to treatment is giving way to targeted anti-cytokine therapies. These treatments include agents that block interleukin-1 (IL-1), IL-6, IL-18, interferon-γ, as well as inhibitors of downstream targets of cytokine signaling (e.g., Janus kinases). Increased early recognition of MAS among pediatric inflammatory disorders combined with the use of effective and less toxic cytokine-targeted therapies should lower the mortality of this frequently fatal disorder.

3.
Clin Immunol ; 211: 108326, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31838215

RESUMO

Inflammatory conditions are increasingly described in patients with primary immunodeficiencies; however, little is known about the prevalence of immune defects in patients who present first with autoimmunity. We describe the immunologic features of children with early-onset/polyautoimmunity followed in the Multiple Autoimmunity and Immunodeficiency (MAID) Clinic, where patients are co-managed by rheumatologists and immunologists. The most common autoimmune manifestations were cytopenias, lymphoproliferation, and colitis. Recurrent infections were noted in 65% of patients. Abnormalities in lymphocyte subsets and immunoglobulins were common. A pathogenic variant was identified in 19% of patients, and 2 novel inherited disorders were discovered. Additionally, 42% of patients had treatment changes implemented in the MAID clinic. By evaluating this unique cohort of patients, we report on the immunologic underpinning of early-onset/polyautoimmunity. The high rate of genetic diagnoses and treatment interventions in this population highlights the value of collaboration between rheumatologists and immunologists in the care of these complex patients.

4.
Ann Rheum Dis ; 78(12): 1722-1731, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31562126

RESUMO

OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. CONCLUSIONS: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

5.
Proc Natl Acad Sci U S A ; 116(41): 20635-20643, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31548399

RESUMO

SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17-expressing T cells. Here, we show that serpinB1 (Sb1) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, Sb1 -/- mice are resistant to EAE with a paucity of T helper (TH) cells that produce two or more of the cytokines, IFNγ, GM-CSF, and IL-17. These multiple cytokine-producing CD4 cells proliferate extremely rapidly; highly express the cytolytic granule proteins perforin-A, granzyme C (GzmC), and GzmA and surface receptors IL-23R, IL-7Rα, and IL-1R1; and can be identified by the surface marker CXCR6. In Sb1 -/- mice, CXCR6+ TH cells are generated but fail to expand due to enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death. Finally, anti-CXCR6 antibody treatment, like Sb1 deletion, dramatically reverts EAE, strongly indicating that the CXCR6+ T cells are the drivers of encephalitis.

6.
Neurol Neuroimmunol Neuroinflamm ; 6(3): e560, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31044148

RESUMO

Objective: To highlight a novel, treatable syndrome, we report 4 patients with CNS-isolated inflammation associated with familial hemophagocytic lymphohistiocytosis (FHL) gene mutations (CNS-FHL). Methods: Retrospective chart review. Results: Patients with CNS-FHL are characterized by chronic inflammation restricted to the CNS that is not attributable to any previously described neuroinflammatory etiology and have germline mutations in known FHL-associated genes with no signs of systemic inflammation. Hematopoietic stem cell transplantation (HCT) can be well tolerated and effective in achieving or maintaining disease remission in patients with CNS-FHL. Conclusions: Early and accurate diagnosis followed by treatment with HCT can reduce morbidity and mortality in CNS-FHL, a novel, treatable syndrome. Classification of evidence: This study provides Class IV evidence that HCT is well tolerated and effective in treating CNS-FHL.

7.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

9.
Pediatr Rheumatol Online J ; 17(1): 7, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764840

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) were historically thought to be distinct entities, often managed in isolation. In fact, these conditions are closely related. A collaborative approach, which incorporates expertise from subspecialties that previously treated HLH/MAS independently, is needed. We leveraged quality improvement (QI) techniques in the form of an Evidence-Based Guideline (EBG) to build consensus across disciplines on the diagnosis and treatment of HLH/MAS. METHODS: A multidisciplinary work group was convened that met monthly to develop the HLH/MAS EBG. Literature review and expert opinion were used to develop a management strategy for HLH/MAS. The EBG was implemented, and quality metrics were selected to monitor outcomes. RESULTS: An HLH/MAS clinical team was formed with representatives from subspecialties involved in the care of patients with HLH/MAS. Broad entry criteria for the HLH/MAS EBG were established and included fever and ferritin ≥500 ng/mL. The rheumatology team was identified as the "gate-keeper," charged with overseeing the diagnostic evaluation recommended in the EBG. First-line medications were recommended based on the acuity of illness and risk of concurrent infection. Quality metrics to be tracked prospectively based on time to initiation of treatment and clinical response were selected. CONCLUSION: HLH/MAS are increasingly considered to be a spectrum of related conditions, and joint management across subspecialties could improve patient outcomes. Our experience in creating a multidisciplinary approach to HLH/MAS management can serve as a model for care at other institutions.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Ativação Macrofágica/diagnóstico , Algoritmos , Consenso , Citocinas/sangue , Diagnóstico Diferencial , Medicina Baseada em Evidências/métodos , Humanos , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/terapia , Guias de Prática Clínica como Assunto , Melhoria de Qualidade
11.
Arthritis Care Res (Hoboken) ; 71(4): 482-491, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29806733

RESUMO

OBJECTIVE: Systemic immunosuppressive treatment of pediatric chronic anterior uveitis (CAU), both juvenile idiopathic arthritis-associated and idiopathic anterior uveitis, varies, making it difficult to identify best treatments. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for CAU for the purpose of reducing practice variability and allowing future comparison of treatments using comparative effectiveness analysis techniques. METHODS: A core group of pediatric rheumatologists, ophthalmologists with uveitis expertise, and a lay advisor comprised the CARRA uveitis workgroup that performed a literature review on pharmacologic treatments, held teleconferences, and developed a case-based survey administered to the CARRA membership to delineate treatment practices. We held 3 face-to-face consensus meetings using nominal group technique to develop CTPs. RESULTS: The survey identified areas of treatment practice variability. We developed 2 CTPs for the treatment of CAU, case definitions, and monitoring parameters. The first CTP is directed at children who are naive to steroid-sparing medication, and the second at children initiating biologic therapy, with options for methotrexate, adalimumab, and infliximab. We defined a core data set and outcome measures, with data collection at 3 and 6 months after therapy initiation. The CARRA membership voted to accept the CTPs with a >95% approval (n = 233). CONCLUSION: Using consensus methodology, 2 standardized CTPs were developed for systemic immunosuppressive treatment of CAU. These CTPs are not meant as treatment guidelines, but are designed for further pragmatic research within the CARRA research network. Use of these CTPs in a prospective comparison effectiveness study should improve outcomes by identifying best practice options.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/complicações , Metotrexato/uso terapêutico , Uveíte Anterior/tratamento farmacológico , Criança , Protocolos Clínicos , Técnica Delfos , Humanos , Uveíte Anterior/etiologia
12.
J Neuropathol Exp Neurol ; 77(12): 1079-1084, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295794

RESUMO

Familial hemophagocytic lymphohistiocytosis (HLH) is an immune hyperactivation syndrome caused by mutations in genes associated with cytotoxic T-cell and NK-cell function. While neurological manifestations frequently accompany systemic inflammation at initial presentation, isolated central nervous system (CNS) involvement is rare, and the histological correlates are not well described. We present 3 patients (ages 5, 6, and 7 years) with CNS-isolated familial HLH, who presented with a variety of neurological symptoms and underwent brain biopsies for multifocal enhancing supratentorial and infratentorial lesions. Biopsy slides from all 3 patients revealed similar findings: perivascular lymphocytes, predominantly CD3+ T-cells (CD4>CD8) with occasional intramural infiltration of small vessels; scattered histiocytes without hemophagocytosis; parenchymal and leptomeningeal inflammation varying from mild and focal to severe and sheet-like with associated destructive lesions. There was no evidence of demyelination, neoplasia, or infection. Genetic testing identified compound heterozygous mutations in PRF1 (Patients 1 and 2) and UNC13D (Patient 3), with no evidence of systemic disease except decreased NK-cell function. All 3 patients were treated with hematopoietic stem cell transplantation with marked improvement of symptoms. These findings combined with the poor outcomes associated with delayed diagnosis and lack of aggressive treatment highlight the need to consider HLH in the differential diagnosis of inflammatory brain lesions.


Assuntos
Encéfalo/patologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/patologia , Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos
13.
Blood ; 131(21): 2335-2344, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29653965

RESUMO

Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, CD3D, CD3E, and CD3Z gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in CD3G associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor ß (TRB) repertoire in regulatory T cells (Tregs), conventional CD4+ (Tconv), and CD8+ T cells from 6 patients with CD3G mutations and healthy controls. Treg function was assessed by studying its ability to suppress proliferation of Tconv cells. Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.


Assuntos
Complexo CD3/genética , Imunomodulação , Mutação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Biomarcadores , Complexo CD3/metabolismo , Expressão Gênica , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Complexos Multiproteicos/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo
15.
Nature ; 542(7639): 110-114, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28150777

RESUMO

CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5-CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5- 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Artrite Reumatoide/sangue , Linfócitos B/patologia , Diferenciação Celular , Movimento Celular , Quimiocina CXCL13/metabolismo , Perfilação da Expressão Gênica , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucinas/metabolismo , Fatores Ativadores de Macrófagos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR5/deficiência , Receptores CXCR5/metabolismo , Receptores de Quimiocinas/metabolismo , Proteínas Repressoras/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Líquido Sinovial/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
16.
J Oral Maxillofac Surg ; 75(6): 1191-1200, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28003132

RESUMO

PURPOSE: Most patients with juvenile idiopathic arthritis (JIA) have temporomandibular joint (TMJ) involvement, but little is known about the natural history of TMJ disease as these children enter adulthood. The purpose of this study was to evaluate adults with a history of JIA to document the frequency and severity of TMJ abnormalities and morbidity. The authors hypothesized that most would have persistent TMJ disease as adults. MATERIALS AND METHODS: This cross-sectional study included adults (>19 years of age) with JIA who were managed at Boston Children's Hospital (BCH) as children and at Brigham and Women's Hospital (BWH) as adults. History of a TMJ problem was not considered for enrollment. Patients completed a questionnaire and underwent physical examination and maxillofacial cone-beam computed tomography (CBCT). Additional data were obtained from medical records. Associations between TMJ abnormalities at CBCT and arthritis history, TMJ pain and function, facial asymmetry, malocclusion, and cephalometric analysis were examined. RESULTS: Of 129 eligible patients contacted, 21 (42 TMJs) were enrolled. Mean age was 26.0 ± 6.1 years and mean duration of care for JIA at the BCH and BWH was 13.7 ± 6.5 years. TMJ pain was present in 62% of patients (n = 13); 43% (n = 9) had a TMJ functional limitation and 76% (n = 16) had lower facial asymmetry. Abnormalities were found in the TMJs on 55% of CBCT scans, with 79% showing bilateral deformities. There was at least 1 cephalometric measurement of mandibular size or position that was more than 1 standard deviation beyond normal in 81% of patients (n = 17). Only 4 patients (19%) had previously been evaluated for a TMJ problem. CONCLUSION: TMJ abnormalities and related morbidity are common in adult patients with a history of JIA. Therefore, an early screening protocol for TMJ involvement in children with a new diagnosis of JIA would be beneficial and long-term follow-up into adulthood should be routine.


Assuntos
Artrite Juvenil/complicações , Transtornos da Articulação Temporomandibular/etiologia , Adulto , Cefalometria , Tomografia Computadorizada de Feixe Cônico , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Inquéritos e Questionários , Transtornos da Articulação Temporomandibular/diagnóstico por imagem
17.
J Clin Immunol ; 36(4): 341-53, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27063650

RESUMO

PURPOSE: DNA Ligase 4 (LIG4) is a key factor in the non-homologous end-joining (NHEJ) DNA double-strand break repair pathway needed for V(D)J recombination and the generation of the T cell receptor and immunoglobulin molecules. Defects in LIG4 result in a variable syndrome of growth retardation, pancytopenia, combined immunodeficiency, cellular radiosensitivity, and developmental delay. METHODS: We diagnosed a patient with LIG4 syndrome by radiosensitivity testing on peripheral blood cells, and established that two of her four healthy siblings carried the same compound heterozygous LIG4 mutations. An extensive analysis of the immune phenotype, cellular radiosensitivity, telomere length, and T and B cell antigen receptor repertoire was performed in all siblings. RESULTS: In the three genotypically affected individuals, variable severities of radiosensitivity, alterations of T and B cell counts with an increased percentage of memory cells, and hypogammaglobulinemia, were noticed. Analysis of T and B cell antigen receptor repertoires demonstrated increased usage of alternative microhomology-mediated end-joining (MHMEJ) repair, leading to diminished N nucleotide addition and shorter CDR3 length. However, overall repertoire diversity was preserved. CONCLUSIONS: We demonstrate that LIG4 syndrome presents with high clinical variability even within the same family, and that distinctive immunologic abnormalities may be observed also in yet asymptomatic individuals.


Assuntos
DNA Ligase Dependente de ATP/genética , Síndromes de Imunodeficiência , Adolescente , Adulto , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Linhagem Celular , Células Cultivadas , Criança , Feminino , Fibroblastos/efeitos da radiação , Granulócitos/efeitos da radiação , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Leucócitos Mononucleares/citologia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Mutação , Radiação Ionizante , Adulto Jovem
18.
Pediatr Rheumatol Online J ; 14(1): 9, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26879972

RESUMO

BACKGROUND: There is not yet a commonly accepted, standardized approach in the treatment of juvenile idiopathic uveitis when initial steroid therapy is insufficient. We sought to assess current practice patterns within a large cohort of children with juvenile uveitis. METHODS: This is a cross-sectional cohort study of patients with uveitis enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRAnet) registry. Clinical information including, demographic information, presenting features, disease complications, and medications were collected. Chi-square and Fisher's exact tests were used to assess for associations between medications and clinical characteristics. RESULTS: Ninety-two children with idiopathic and 656 with juvenile idiopathic arthritis (JIA)-associated uveitis were identified. Indication (arthritis or uveitis) for medication use was not available for JIA patients; therefore, detailed analysis was limited to children with idiopathic uveitis. In this group, 94 % had received systemic steroids. Methotrexate (MTX) was used in 76 % of patients, with oral and subcutaneous forms given at similar rates. In multivariable analysis, non-Caucasians were more likely to be treated initially with subcutaneous MTX (P = 0.003). Of the 53 % of patients treated with a biologic DMARD, all received a tumor necrosis factor (TNF) inhibitor. TNF inhibitor use was associated with a higher frequency of cataracts (52 % vs 21 %; P = 0.001) and antinuclear antibody positivity (49 % vs 29 %; P = 0.04), although overall complication rates were not higher in these patients. CONCLUSION: Among idiopathic uveitis patients enrolled in the CARRAnet registry, MTX was the most commonly used DMARD, with subcutaneous and oral forms equally favored. Patients who received a TNF inhibitor were more likely to be ANA positive and have cataracts.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/complicações , Pesquisa Biomédica , Sistema de Registros , Reumatologia/métodos , Uveíte/tratamento farmacológico , Adalimumab/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Estudos Transversais , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Infliximab/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Estudos Retrospectivos , Uveíte/etiologia
19.
Arthritis Rheumatol ; 68(7): 1758-68, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26815131

RESUMO

OBJECTIVE: Treg cell-mediated suppression of Teff cells is impaired in juvenile idiopathic arthritis (JIA); however, the basis for this dysfunction is incompletely understood. Animal models of autoimmunity and immunodeficiency demonstrate that a diverse Treg cell repertoire is essential to maintain Treg cell function. The present study was undertaken to investigate the Treg and Teff cell repertoires in JIA. METHODS: Treg cells (CD4+CD25+CD127(low) ) and Teff cells (CD4+CD25-) were isolated from peripheral blood and synovial fluid obtained from JIA patients, healthy controls, and children with Lyme arthritis. Treg cell function was measured in suppressive assays. The T cell receptor ß chain (TRB) was amplified by multiplex polymerase chain reaction and next-generation sequencing was performed, with amplicons sequenced using an Illumina HiSeq platform. Data were analyzed using ImmunoSEQ, International ImMunoGeneTics system, and the Immunoglobulin Analysis Tools. RESULTS: Compared to findings in controls, the JIA peripheral blood Treg cell repertoire was restricted, and clonotypic expansions were found in both blood and synovial fluid Treg cells. Skewed usage and pairing of TRB variable and joining genes, including overuse of gene segments that have been associated with other autoimmune conditions, was observed. JIA patients shared a substantial portion of synovial fluid Treg cell clonotypes that were private to JIA and not identified in Lyme arthritis. CONCLUSION: We identified restriction and clonotypic expansions in the JIA Treg cell repertoire with sharing of Treg cell clonotypes across patients. These findings suggest that abnormalities in the Treg cell repertoire, possibly engendered by shared antigenic triggers, may contribute to disease pathogenesis in JIA.


Assuntos
Artrite Juvenil/imunologia , Linfócitos T Reguladores/fisiologia , Adolescente , Artrite Juvenil/sangue , Células Cultivadas , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Líquido Sinovial/citologia , Subpopulações de Linfócitos T/fisiologia
20.
Sci Immunol ; 1(6)2016 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-28783691

RESUMO

Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency.

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