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1.
J Allergy Clin Immunol ; 143(5): 1661-1673, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31060714

RESUMO

Caspase recruitment domain (CARD) protein-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] complexes are critical signaling adaptors that facilitate immune and inflammatory responses downstream of both cell surface and intracellular receptors. Germline mutations that alter the function of members of this complex (termed CBM-opathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis. With an increasing number of patients being described in recent years, the clinical spectrum of diseases associated with CBM-opathies is rapidly expanding and becoming unexpectedly heterogeneous. Here we review major discoveries that have shaped our understanding of CBM complex biology, and we provide an overview of the clinical presentation, diagnostic approach, and treatment options for those carrying germline mutations affecting CARD9, CARD11, CARD14, BCL10, and MALT1.

2.
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
4.
Mol Genet Metab Rep ; 16: 23-29, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29922587

RESUMO

Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5  years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.

7.
Nat Genet ; 49(8): 1162-1163, 2017 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-28747751

RESUMO

Severe allergic disease is common, and few monogenic causes of atopy have been described. A new study that convincingly links severe atopic dermatitis to heterozygous CARD11 mutations with dominant-interfering activity serves as a timely reminder that clinicians should consider the possibility of an underlying monogenic immune disorder when caring for patients suffering from severe allergic disease.


Assuntos
Dermatite Atópica/imunologia , Hipersensibilidade , Humanos
9.
Clin Immunol ; 181: 75-82, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28625885

RESUMO

Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency that exemplifies the broad clinical features of primary immunodeficiencies (PIDs), extending beyond recurrent infections to include atopy, autoimmunity and cancer. It is caused by loss of function mutations in DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton. Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3. DOCK8 deficiency impairs immune cell migration, function and survival, and it impacts both innate and adaptive immune responses. Clinically, DOCK8 deficiency is characterized by allergic inflammation as well as susceptibility towards infections, autoimmunity and malignancy. This review details the pathophysiology, clinical features and management of DOCK8 deficiency. It also surveys the recently discovered combined immunodeficiency due to DOCK2 deficiency, highlighting in the process the emerging spectrum of PIDs resulting from DOCK protein family abnormalities.


Assuntos
Doenças Autoimunes/imunologia , Fatores de Troca do Nucleotídeo Guanina/imunologia , Hipersensibilidade/imunologia , Síndromes de Imunodeficiência/imunologia , Neoplasias/imunologia , Citoesqueleto de Actina/metabolismo , Transporte Ativo do Núcleo Celular , Imunidade Adaptativa/imunologia , Movimento Celular/imunologia , Sobrevivência Celular , Eczema/imunologia , Infecções por Vírus Epstein-Barr , Fatores de Troca do Nucleotídeo Guanina/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunidade Inata/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Inflamação/imunologia , Neoplasias/virologia , Infecções por Papillomavirus , Recidiva , Doenças Respiratórias/imunologia , Fator de Transcrição STAT3/metabolismo , Dermatopatias Virais/imunologia
11.
J Allergy Clin Immunol ; 138(3): 852-859.e3, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27130861

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Reports of outcomes are still limited. OBJECTIVE: We sought to analyze the results of HSCT in patients with DOCK8 deficiency and report whether approaches resulting in mixed chimerism result in clinically relevant immune reconstitution. METHODS: We performed a retrospective chart review of 11 patients with DOCK8 deficiency and measured DOCK8 expression and cytokine production. RESULTS: Of 11 patients, 7 received HSCT from related and 4 from unrelated donors; 9 patients received busulfan-based conditioning regimens. Survival was excellent (10 [91%] of 11 patients alive), including a patient who had undergone liver transplantation. Patients showed significant improvements in the frequency and severity of infections. Although eczema resolved in all, food allergies and high IgE levels persisted in some patients. Lymphopenia, eosinophilia, low numbers of naive CD8(+) T cells and switched memory B cells, and TH1/TH2 cytokine imbalance improved in most patients. Although the 8 matched related or unrelated donor recipients had full donor chimerism, all 3 recipients of mismatched unrelated donor HSCT had high levels of donor T-cell chimerism and low B-cell and myeloid cell chimerism (0% to 46%). Almost all switched memory B cells were of donor origin. All patients, including those with mixed chimerism, mounted robust antibody responses to vaccination. CONCLUSION: Allogeneic HSCT ameliorated the infectious and atopic symptoms of patients with DOCK8 deficiency. In patients with mixed chimerism, selective advantage for donor-derived T cells and switched memory B cells promoted restoration of cellular and humoral immunity and protection against opportunistic infection.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/imunologia , Linfócitos B/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Linfócitos T/imunologia , Resultado do Tratamento
12.
Blood ; 122(15): 2600-8, 2013 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-23974196

RESUMO

Individuals with X-linked lymphoproliferative disease lack invariant natural killer T (iNKT) cells and are exquisitely susceptible to Epstein-Barr virus (EBV) infection. To determine whether iNKT cells recognize or regulate EBV, resting B cells were infected with EBV in the presence or absence of iNKT cells. The depletion of iNKT cells increased both viral titers and the frequency of EBV-infected B cells. However, EBV-infected B cells rapidly lost expression of the iNKT cell receptor ligand CD1d, abrogating iNKT cell recognition. To determine whether induced CD1d expression could restore iNKT recognition in EBV-infected cells, lymphoblastoid cell lines (LCL) were treated with AM580, a synthetic retinoic acid receptor-α agonist that upregulates CD1d expression via the nuclear protein, lymphoid enhancer-binding factor 1 (LEF-1). AM580 significantly reduced LEF-1 association at the CD1d promoter region, induced CD1d expression on LCL, and restored iNKT recognition of LCL. CD1d-expressing LCL elicited interferon γ secretion and cytotoxicity by iNKT cells even in the absence of exogenous antigen, suggesting an endogenous iNKT antigen is expressed during EBV infection. These data indicate that iNKT cells may be important for early, innate control of B cell infection by EBV and that downregulation of CD1d may allow EBV to circumvent iNKT cell-mediated immune recognition.


Assuntos
Linfócitos B/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Transtornos Linfoproliferativos/imunologia , Células T Matadoras Naturais/imunologia , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Linfócitos B/virologia , Comunicação Celular/imunologia , Transformação Celular Neoplásica/imunologia , Infecções por Vírus Epstein-Barr/complicações , Humanos , Imunidade Inata/imunologia , Fator 1 de Ligação ao Facilitador Linfoide/imunologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Transtornos Linfoproliferativos/virologia , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/virologia , Tonsila Palatina/imunologia , Tonsila Palatina/virologia
13.
J Biol Chem ; 284(36): 24341-53, 2009 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-19553685

RESUMO

Target of rapamycin (TOR) is a highly conserved serine/threonine kinase that controls cell growth, primarily via regulation of protein synthesis. In Saccharomyces cerevisiae, TOR can also suppress the transcription of stress response genes by a mechanism involving Tap42, a serine/threonine phosphatase subunit, and the transcription factor Msn2. A physical association between mammalian TOR (mTOR) and the transcription factor signal transducer and activator of transcription-1 (STAT1) was recently identified in human cells, suggesting a similar role for mTOR in the transcription of interferon-gamma-stimulated genes. In the current study, we identified a macromolecular protein complex composed of mTOR, STAT1, the Tap42 homologue alpha4, and the protein phosphatase 2A catalytic subunit (PP2Ac). Inactivation of mTOR enhanced its association with STAT1 and increased STAT1 nuclear content in PP2Ac-dependent fashion. Depletion of alpha4, PP2A, or mTOR enhanced the induction of early (i.e. IRF-1) and late (i.e. caspase-1, hiNOS, and Fas) STAT1-dependent genes. The regulation of IRF-1 or caspase-1 by mTOR was independent of other known mTOR effectors p70 S6 kinase and Akt. These results describe a new role for mTOR and alpha4/PP2A in the control of STAT1 nuclear content, and the expression of interferon-gamma-sensitive genes involved in immunity and apoptosis.


Assuntos
Núcleo Celular/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Quinases/metabolismo , Proteína Fosfatase 2/metabolismo , Fator de Transcrição STAT1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/genética , Apoptose/imunologia , Linhagem Celular , Núcleo Celular/genética , Núcleo Celular/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Chaperonas Moleculares , Complexos Multiproteicos/genética , Complexos Multiproteicos/imunologia , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/imunologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Serina-Treonina Quinases TOR
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