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1.
Nat Med ; 27(1): 28-33, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33442016

RESUMO

COVID-19, caused by SARS-CoV-2 infection, is mild to moderate in the majority of previously healthy individuals, but can cause life-threatening disease or persistent debilitating symptoms in some cases. The most important determinant of disease severity is age, with individuals over 65 years having the greatest risk of requiring intensive care, and men are more susceptible than women. In contrast to other respiratory viral infections, young children seem to be less severely affected. It is now clear that mild to severe acute infection is not the only outcome of COVID-19, and long-lasting symptoms are also possible. In contrast to severe acute COVID-19, such 'long COVID' is seemingly more likely in women than in men. Also, postinfectious hyperinflammatory disease has been described as an additional outcome after SARS-CoV-2 infection. Here I discuss our current understanding of the immunological determinants of COVID-19 disease presentation and severity and relate this to known immune-system differences between young and old people and between men and women, and other factors associated with different disease presentations and severity.


Assuntos
/imunologia , /fisiologia , Imunidade Adaptativa , Adulto , Fatores Etários , Idoso , /epidemiologia , Criança , Feminino , Humanos , Imunidade Inata , Síndromes de Imunodeficiência/induzido quimicamente , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/virologia , Masculino , Índice de Gravidade de Doença , Fatores Sexuais , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Internalização do Vírus
2.
Medicine (Baltimore) ; 99(36): e21738, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899003

RESUMO

INTRODUCTION: Anti-interferon-gamma (anti-IFN-γ) autoantibody increases susceptibility to lower-virulence pathogens and causes immunodeficiency syndrome in HIV-negative patients. PATIENT CONCERNS: A 69-year-old Chinese man presented with a 2-month history of pruritic skin lesions on his forearms, trunk, and legs. He was diagnosed with 5 opportunistic infections without conventional immunosuppression-associated factors in past. The most conspicuous characteristics were recurrent pulmonary infection, persistent immunoglobulin E elevation and eosinophilia during the whole disease course. DIAGNOSIS: Enzyme-linked immunosorbent assay showed anti-IFN-γ autoantibody positive. The final diagnosis for the patient was adult-onset immunodeficiency due to anti-IFN-γ autoantibody, non-tuberculous mycobacterial (NTM) infection and reactive dermatosis. INTERVENTIONS: The patient underwent long-term anti-NTM and corticosteroid maintenance treatment. OUTCOMES: The patient was followed for 2 years during which opportunistic infection no longer happened, the immunoglobulin E level and eosinophil count reduced, the autoantibody levels remained largely steady and lung lesions absorbed. CONCLUSION: Clinicians should be vigilant for NTM infection in patients with anti-IFN-γ autoantibodies, even when culture results are negative. Long-term anti-non-tuberculous mycobacteria and glucocorticoid regimens were effective.


Assuntos
Autoanticorpos/imunologia , Síndromes de Imunodeficiência/complicações , Interferon gama/imunologia , Infecções por Mycobacterium não Tuberculosas/complicações , Idoso , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Masculino , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções Oportunistas/complicações , Dermatopatias/complicações , Dermatopatias/imunologia
3.
Science ; 369(6500): 202-207, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32647003

RESUMO

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.


Assuntos
Actinas/metabolismo , Citocinas/biossíntese , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas de Membrana/fisiologia , Fator 1 de Ribosilação do ADP/metabolismo , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Humanos , Síndromes de Imunodeficiência/imunologia , Transtornos Linfoproliferativos/imunologia , Proteínas de Membrana/genética , Linhagem , Fosforilação , Família de Proteínas da Síndrome de Wiskott-Aldrich/química , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo
5.
Ann Hematol ; 99(6): 1231-1239, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32382770

RESUMO

Parainfluenza virus (PIV) infection is a significant cause of morbidity and mortality, especially in hematologic malignancy patients including hematopoietic stem cell transplantation (HCT) recipients. However, limited information is available for risk stratification in PIV-infected patients with hematologic malignancy with or without HCT. Patients with hematologic malignancy diagnosed with PIV from January 2009 to December 2018 were retrospectively included in a tertiary care hospital in Seoul, South Korea. Upper respiratory tract infection (URTI) was defined as the detection of PIV in a nasopharyngeal sample with URTI symptoms without new pulmonary infiltrates. Lower respiratory tract infection (LRTI) was defined as detection of PIV in either upper or lower respiratory tract samples with new pulmonary infiltrates, with or without hypoxia. PIV-associated mortality was defined as death with respiratory failure and persistent LRTI within 90 days after diagnosis. The study included 143 adult patients. Of these, 55 (38%) progressed to or initially presented with LRTI. Among these, 22 (40%) died from PIV-associated mortality. An immunodeficiency risk score was developed from associated risk factors using a multivariable Cox regression model. Patients were stratified into low (0-2), moderate (3-5), and high risk (6-8) groups with PIV-associated mortalities of 0%, 9%, and 67%, respectively (p < 0.005, Harrell's C-index = 0.84). PIV infection can result in substantial mortality in patients with hematologic malignancy if it progresses to LRTI. The immunodeficiency risk score presented here may be useful for distinguishing moderate and high risk groups that might benefit from antiviral therapy.


Assuntos
Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidade , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/mortalidade , Infecções por Paramyxoviridae/diagnóstico , Infecções por Paramyxoviridae/mortalidade , Adulto , Estudos de Coortes , Feminino , Neoplasias Hematológicas/imunologia , Humanos , Síndromes de Imunodeficiência/imunologia , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Infecções por Paramyxoviridae/imunologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco
6.
BMC Infect Dis ; 20(1): 258, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32234012

RESUMO

BACKGROUND: Mycobacterial species other than Mycobacterium tuberculosis and Mycobacterium leprae are generally free-living organisms and Mycobacterium simiae is one of the slowest growing Non-tuberculous mycobacteria. This is the first case report of Mycobacterium simiae infection in Sri Lanka and only very few cases with extrapulmonary manifestation reported in the literature. CASE PRESENTATION: A 24-year-old, previously healthy Sri Lankan male presented with generalized lymphadenopathy with discharging sinuses, evening pyrexia, weight loss, poor appetite and splenomegaly. Lymph node biopsies showed sheets of macrophages packed with organisms in the absence of granulomata. Ziehl Neelsen, Wade Fite and Giemsa stains revealed numerous red coloured acid-fast bacilli within foamy histiocytes. Slit skin smear for leprosy was negative and tuberculosis, fungal and bacterial cultures of the lymph node and bone marrow did not reveal any growth. Later he developed watery diarrhea and colonoscopy revealed multiple small polyps and ulcers throughout the colon extending up to the ileum, Which was confirmed to be due to cytomegalovirus confirmed by PCR and successfully treated with ganciclovir. Positron emission tomography scan guided biopsies of the gut and lymph nodes confirmed presence of mycobacterial spindle cell pseudo-tumours and PCR assays revealed positive HSP65. The culture grew Mycobacterium Simiae. Flow cytometry analysis on patient's blood showed extremely low T and B cell counts and immunofixation revealed low immunoglobulin levels. His condition was later diagnosed as adult onset immunodeficiency due to anti- interferon - gamma autoantibodies. He was initially commenced on empirical anti-TB treatment with atypical mycobacterial coverage. He is currently on a combination of daily clarithromycin, ciprofloxacin, linezolid with monthly 2 g/kg/intravenous immunoglobulin to which, he had a remarkable clinical response with complete resolution of lymphadenopathy and healing of sinuses. CONCLUSIONS: This infection is considered to be restricted to certain geographic areas such as mainly Iran, Cuba, Israel and Arizona and this is the first case report from Sri lanka. Even though the infection is mostly seen in the elderly patients, our patient was only 24 years old. In the literature pulmonary involvement was common presentation, but in this case the patient had generalized lymphadenopathy and colonic involvement without pulmonary involvement.


Assuntos
Síndromes de Imunodeficiência/imunologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium/patogenicidade , Autoanticorpos/sangue , Ciprofloxacino/uso terapêutico , Claritromicina/uso terapêutico , Humanos , Biópsia Guiada por Imagem , Interferon gama/sangue , Linfonodos/microbiologia , Linfadenopatia/etiologia , Masculino , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/patologia , Tomografia por Emissão de Pósitrons , Sri Lanka , Adulto Jovem
7.
Mol Immunol ; 121: 28-37, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151906

RESUMO

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.


Assuntos
Autoimunidade/genética , Contratura/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Síndromes de Imunodeficiência/genética , Proteínas de Transporte de Nucleosídeos/genética , Adolescente , Contratura/tratamento farmacológico , Contratura/imunologia , Contratura/patologia , Glucocorticoides/uso terapêutico , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Histiocitose/tratamento farmacológico , Histiocitose/imunologia , Histiocitose/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Inflamassomos/imunologia , Lisossomos/imunologia , Lisossomos/patologia , Masculino , Mitocôndrias/imunologia , Mitocôndrias/patologia , Resultado do Tratamento
8.
Hum Genet ; 139(6-7): 885-901, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32152698

RESUMO

Epstein-Barr virus (EBV) is a ubiquitous human pathogen, infecting > 90% of the adult population. In the vast majority of healthy individuals, infection with EBV runs a relatively benign course. However, EBV is by no means a benign pathogen. Indeed, apart from being associated with at least seven different types of malignancies, EBV infection can cause severe and often fatal diseases-hemophagocytic lymphohistiocytosis, lymphoproliferative disease, B-cell lymphoma-in rare individuals with specific monogenic inborn errors of immunity. The discovery and detailed investigation of inborn errors of immunity characterized by heightened susceptibility to, or increased frequency of, EBV-induced disease have elegantly revealed cell types and signaling pathways that play critical and non-redundant roles in host-defense against EBV. These analyses have revealed not only mechanisms underlying EBV-induced disease in rare genetic conditions, but also identified molecules and pathways that could be targeted to treat severe EBV infection and pathological consequences in immunodeficient hosts, or even potentially enhance the efficacy of an EBV-specific vaccine.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Predisposição Genética para Doença , Herpesvirus Humano 4/imunologia , Interações Hospedeiro-Patógeno/genética , Síndromes de Imunodeficiência/complicações , Transtornos Linfoproliferativos/etiologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/virologia , Transtornos Linfoproliferativos/patologia , Transdução de Sinais
9.
Curr Opin Rheumatol ; 32(2): 168-174, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31977526

RESUMO

PURPOSE OF REVIEW: Advances in genomics and animal models of human disease have enabled the discovery of mechanisms important for host immunity and self-tolerance. Here, we summarize conceptual and clinical discoveries identified from 2018 to 2019 in the field of primary immunodeficiencies and autoimmunity. RECENT FINDINGS: Three new primary immunodeficiencies with autoimmunity were identified and the clinical phenotypes of NFKB1 haploinsufficiency and RASGRP1 deficiency were expanded. A diversity of novel mechanisms leading to autoimmunity associated with primary immunodeficiencies (PIDs) was reported, including pathways important for the metabolism and function of regulatory T cells and germinal B cells, the contribution of neutrophil extracellular traps to plasmacytoid dendritic cell activation and the influence of commensal bacteria on the generation of autoantibodies. With regard to therapeutic developments in the field, we highlight the use of janus kinase inhibitors for immune dysregulation associated with gain-of-function variants in STAT1 and STAT3, as well as the risks of persistent hypogammaglobulinemia associated with rituximab treatment. SUMMARY: Mechanistic studies of PIDs with autoimmunity elucidate key principles governing the balance between immune surveillance and self-tolerance.


Assuntos
Autoimunidade/imunologia , Síndromes de Imunodeficiência/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoanticorpos/imunologia , Humanos , Tolerância Imunológica
10.
Int J Hematol ; 111(6): 897-902, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31993940

RESUMO

Regulatory T-cells (Tregs) are major mediators of mammalian self-tolerance via cytotoxic T-lymphocyte antigen 4 (CTLA4) signaling pathways. An immune dysregulation syndrome associated with heterozygous germline mutations in CTLA4 was recently reported. Clinical features include recurrent infections, systemic lymphadenopathy, various autoimmune conditions, hypogammaglobulinemia, and autosomal dominant inheritance, characteristic of primary immunodeficient disease (PID). PID symptoms are variable and few patients with sporadic de novo CTLA4 germline mutations have been described. Here, we report the case of a 26-year-old man with an immune dysregulation syndrome and a de novo CTLA4 germline mutation. The patient exhibited several clinical features associated with PID. Next-generation sequencing revealed a CTLA4 germline mutation, c.436G>A; p.G146R, in exon 2 of CTLA4. Sanger sequencing confirmed the patient was the only member of his family with this germline mutation. The patient was diagnosed with an immune dysregulation syndrome associated with de novo germline CTLA4 mutation, complicated by steroid-refractory rheumatoid arthritis. Treatment with abatacept, a CTLA4-immunoglobulin fusion molecule, was initiated, resulting in dramatic resolution of the patient's clinical symptoms. As PID with CTLA4 germline mutation is rare and patients may be under-diagnosed, physicians should be aware of the features of PID.


Assuntos
Abatacepte/uso terapêutico , Antígeno CTLA-4/genética , Mutação em Linhagem Germinativa , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/genética , Adulto , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/etiologia , Autoimunidade , Heterozigoto , Humanos , Tolerância Imunológica , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Masculino , Linfócitos T Reguladores/imunologia , Resultado do Tratamento
11.
Am J Dermatopathol ; 42(1): e11-e15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31313695

RESUMO

The development of T-cell lymphomas, granulomatous reactions, and autoimmunity has been observed in immunodeficiency due to milder forms of recombination activating gene (RAG) deficiency. A few cases of cutaneous clonal papulonodular CD8 lymphocytic infiltrates and cutaneous CD8 granulomatous T-cell lymphoma have been described in association with common variable immunodeficiency, and with X-linked agammaglobulinemia. We describe a 15-year-old girl with several autoimmune disorders and recurrent infections that presented with several nodules on her cheek. Histopathological studies demonstrate histological, immunohistochemical, and molecular findings compatible with a primary cutaneous clonal CD8 T-cell lymphoproliferative disorder. Vacuolar interface changes were also seen in the involved skin, reminiscent of cutaneous lupus erythematosus. Molecular genetic analysis revealed a germline novel homozygous missense mutation in RAG1 (T1003>C). The parents were heterozygous carriers. The facial cutaneous lesions recurred despite local radiation therapy. Because of recurrent life-threatening systemic infections, allogeneic bone marrow transplantation was performed. The pathogenesis of this primary cutaneous clonal CD8 T-cell lymphoproliferative disorder may have been related to a chronic stimulation of autoreactive T cells in the involved skin paired with reduced RAG1 activity.


Assuntos
Linfócitos T CD8-Positivos/patologia , Proteínas de Homeodomínio/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Adolescente , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia
13.
Biochem Pharmacol ; 174: 113671, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31634456

RESUMO

The immune system is quite remarkable having both the ability to tolerate innocuous and self-antigens while possessing a robust capacity to recognize and eradicate infectious pathogens and foreign entities. The genetics that encode this delicate balancing act include multiple genes and specialized cell types. Over the past several years, whole exome and whole genome sequencing has uncovered the genetics driving many human immune-mediated diseases including monogenic disorders and hematological malignancies. With the advent of genome editing technologies, the ability to correct genetic immune defects in autologous cells holds great promise for a number of conditions. Since assessment of novel therapeutic strategies have been difficult in mice, in recent years, immunodeficient mice capable of engrafting human cells and tissue have been developed and utilized for a variety of research applications. In this review, we discuss immune-humanized mice as a research tool to study human immunobiology and genetic immune disorders in vivo and the promise of future applications.


Assuntos
Modelos Animais de Doenças , Edição de Genes , Neoplasias Hematológicas/genética , Síndromes de Imunodeficiência/genética , Animais , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Imunoterapia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
15.
Transplantation ; 104(4): 715-723, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31764762

RESUMO

BACKGROUND: Humanized immune system immunodeficient mice have been extremely useful for the in vivo analyses of immune responses in a variety of models, including organ transplantation and graft versus host disease (GVHD) but they have limitations. Rat models are interesting complementary alternatives presenting advantages over mice, such as their size and their active complement compartment. Immunodeficient rats have been generated but human immune responses have not yet been described. METHODS: We generated immunodeficient Rat Rag-/- Gamma chain-/- human signal regulatory protein alpha-positive (RRGS) rats combining Rag1 and Il2rg deficiency with the expression of human signal regulatory protein alpha, a negative regulator of macrophage phagocytosis allowing repression of rat macrophages by human CD47-positive cells. We then immune humanized RRGS animals with human peripheral blood mononuclear cells (hPBMCs) to set up a human acute GVHD model. Treatment of GVHD was done with a new porcine antihuman lymphocyte serum active through complement-dependent cytotoxicity. We also established a tumor xenograft rejection model in these hPBMCs immune system RRGS animals by subcutaneous implantation of a human tumor cell line. RESULTS: RRGS animals receiving hPBMCs showed robust and reproducible reconstitution, mainly by T and B cells. A dose-dependent acute GVHD process was observed with progressive weight loss, tissue damage, and death censoring. Antihuman lymphocyte serum (L1S1) antibody completely prevented acute GVHD. In the human tumor xenograft model, detectable tumors were rejected upon hPBMCs injection. CONCLUSIONS: hPBMC can be implanted in RRGS animals and elicit acute GVHD or rejection of human tumor cells and these are useful models to test new immunotherapies.


Assuntos
Antígenos de Diferenciação/imunologia , Proteínas de Homeodomínio/imunologia , Hospedeiro Imunocomprometido , Cadeias gama de Imunoglobulina/imunologia , Síndromes de Imunodeficiência/imunologia , Leucócitos Mononucleares/transplante , Receptores Imunológicos/imunologia , Animais , Antígenos de Diferenciação/genética , Soro Antilinfocitário/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Cadeias gama de Imunoglobulina/genética , Síndromes de Imunodeficiência/genética , Leucócitos Mononucleares/imunologia , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores Imunológicos/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Leukoc Biol ; 107(6): 907-915, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31749173

RESUMO

The TNFR superfamily of receptors, the major focus of the recent TNFR Superfamily Conference held in June 2019, employ the TNFR-associated factor (TRAF) family of adaptor proteins in key aspects of their signaling pathways. Although many early studies investigated TRAF functions via exogenous overexpression in nonhematopoietic cell lines, it has subsequently become clear that whereas TRAFs share some overlap in function, each also plays unique biologic roles, that can be highly context dependent. This brief review summarizes the current state of knowledge of functions of each of the TRAF molecules that mediate important functions in T lymphocytes: TRAFs 1, 2, 3, 5, and 6. Due to our current appreciation of the contextual nature of TRAF function, our focus is upon findings made specifically in T lymphocytes. Key T cell functions for each TRAF are detailed, as well as future knowledge gaps of interest and importance.


Assuntos
Síndromes de Imunodeficiência/genética , Receptores do Fator de Necrose Tumoral/genética , Transdução de Sinais/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Memória Imunológica , Camundongos , Camundongos Knockout , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/deficiência , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/imunologia
17.
Clin Immunol ; 210: 108307, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760095

RESUMO

An increasing healthcare challenge in the management of haematological malignancy (HM) is secondary immunodeficiency. From January 2019, the EMA included the evaluation of specific antibody (Ab) responses to better select patients for immunoglobulin replacement therapy (IgRT). We evaluated Ab responses to pneumococcal and Salmonella typhi pure polysaccharide immunization in a cohort of 42 HM patients and 24 healthy-controls. Pre-post specific Ab concentrations were measured by ELISA at 4 weeks. Globally, significantly lower Typhim Vi (TV) seroprevalence (9%) compared to 23-valent pneumococcal polysaccharide vaccine (PPV) (76%) (p <0.001) was observed. TV non responders (88%) were higher than PPV non responders (62%) (p <0.0001) and correlated better to infectious history. By ROC analysis, pre-post 5-fold TV increase was the best cut-off to discriminate HM with recurrent infections and controls (sensitivity 91%, specificity 100%). Despite the small sample cohort, our results suggest that specific anti-S typhi Ab response is a useful complementary assay in the diagnosis and management decision of SID to HM.


Assuntos
Neoplasias Hematológicas/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Polissacarídeos Bacterianos/imunologia , Salmonella typhi/fisiologia , Febre Tifoide/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Formação de Anticorpos , Estudos de Coortes , Feminino , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/imunologia , Humanos , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Estudos Soroepidemiológicos , Espanha/epidemiologia
18.
Clin Immunol ; 211: 108326, 2020 02.
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.


Assuntos
Autoimunidade/imunologia , Síndromes de Imunodeficiência/imunologia , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Síndromes de Imunodeficiência/genética , Infecções/genética , Infecções/imunologia , Masculino
19.
Reumatol. clín. (Barc.) ; 16: 0-0, 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-193477

RESUMO

ANTECEDENTES: No es claro si los pacientes con algún grado de inmunosupresión tienen peores desenlaces en la infección por SARS-CoV-2, en comparación con la población sana. OBJETIVO: Realizar una revisión narrativa de la información disponible sobre infección por SARS-CoV-2 en pacientes inmunosuprimidos, especialmente pacientes con cáncer, trasplantados, con patologías neurológicas, inmunodeficiencias primarias y secundarias. RESULTADOS: Los pacientes con cáncer y tratamiento reciente del mismo (quimioterapia o cirugía) e infección por SARS-CoV-2 tienen mayor riesgo de peores desenlaces. En los pacientes trasplantados (renal, cardiaco y hepático), con patologías neurológicas (esclerosis múltiple [EM], neuromielitis óptica [NMODS], miastenia grave [MG]), inmunodeficiencias primarias e infección por virus de inmunodeficiencia humana (VIH) en asociación con uso de inmunosupresores, los estudios no han mostrado tendencia a peores desenlaces. CONCLUSIÓN: Dada la poca evidencia con que contamos hasta el momento no es claro el comportamiento de la infección por SARS-CoV-2 en pacientes con inmunosupresión, pero los estudios actuales no han mostrado peores desenlaces en este tipo de pacientes, a excepción de los pacientes con cáncer


BACKGROUND: It is not clear whether patients with some degree of immunosuppression have worse outcomes in SARS-CoV-2 infection, compared to healthy people. OBJECTIVE: To carry out a narrative review of the information available on infection by SARS-CoV-2 in immunosuppressed patients, especially patients with cancer, transplanted, neurological diseases, primary and secondary immunodeficiencies. RESULTS: Patients with cancer and recent cancer treatment (chemotherapy or surgery) and SARS-CoV-2 infection have a higher risk of worse outcomes. In transplant patients (renal, cardiac and hepatic), with neurological pathologies (multiple sclerosis [MS], neuromyelitis optica [NMODS], myasthenia gravis [MG]), primary immunodeficiencies and infection with human immunodeficiency virus (HIV) in association with immunosuppressants, studies have shown no tendency for worse outcomes. CONCLUSION: Given the little evidence we have so far, the behaviour of SARS-CoV-2 infection in immunosuppressed patients is unclear, but current studies have not shown worse outcomes, except for patients with cancer


Assuntos
Humanos , Infecções por Coronavirus/complicações , Vírus da SARS/patogenicidade , Imunossupressão/estatística & dados numéricos , Hospedeiro Imunocomprometido/imunologia , Fatores de Risco , Neoplasias/imunologia , Imunologia de Transplantes/imunologia , Síndromes de Imunodeficiência/imunologia , Doenças do Sistema Nervoso/imunologia , Pandemias
20.
Front Immunol ; 10: 2680, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849931

RESUMO

B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Appropriate signaling via this pre-BCR complex is followed by rearrangement of the Ig light chain genes, resulting in the formation, and selection of functional BCR molecules. Consecutive production, expression, and functional selection of the pre-BCR and BCR complexes guide the BCP differentiation process that coincides with corresponding immunophenotypic changes. We studied BCP differentiation in human BM samples from healthy controls and patients with a known genetic defect in V(D)J recombination or pre-BCR signaling to unravel normal immunophenotypic changes and to determine the effect of differentiation blocks caused by the specific genetic defects. Accordingly, we designed a 10-color antibody panel to study human BCP development in BM by flow cytometry, which allows identification of classical preB-I, preB-II, and mature B-cells as defined via BCR-related markers with further characterization by additional markers. We observed heterogeneous phenotypes associated with more than one B-cell maturation pathway, particularly for the preB-I and preB-II stages in which V(D)J recombination takes place, with asynchronous marker expression patterns. Next Generation Sequencing of complete IGH gene rearrangements in sorted BCP subsets unraveled their rearrangement status, indicating that BCP differentiation does not follow a single linear pathway. In conclusion, B-cell development in human BM is not a linear process, but a rather complex network of parallel pathways dictated by V(D)J-recombination-driven checkpoints and pre-BCR/BCR mediated-signaling occurring during B-cell production and selection. It can also be described as asynchronous, because precursor B-cells do not differentiate as full population between the different stages, but rather transit as a continuum, which seems influenced (in part) by V-D-J recombination-driven checkpoints.


Assuntos
Diferenciação Celular/genética , Diferenciação Celular/imunologia , Síndromes de Imunodeficiência/imunologia , Células Precursoras de Linfócitos B/imunologia , Criança , Feminino , Citometria de Fluxo/métodos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Síndromes de Imunodeficiência/genética , Masculino , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Recombinação V(D)J/genética , Recombinação V(D)J/imunologia
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