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1.
Sci Immunol ; 5(44)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111619

RESUMO

We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.


Assuntos
Fatores de Transcrição Box Pareados/imunologia , Timo/imunologia , Síndrome Brânquio-Otorrenal/genética , Síndrome Brânquio-Otorrenal/imunologia , Síndrome Brânquio-Otorrenal/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Humanos , Lactente , Masculino , Fatores de Transcrição Box Pareados/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Timo/patologia
2.
Clin Immunol ; 213: 108366, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32092471

RESUMO

The nuclease Artemis is a enzyme for V(D)J recombination allowing for the creation of T and B lymphocytes as well as for the repair of radiation-induced DNA double strand breaks encoded by the DCLRE1C gene. Artemis-null mutations are a known cause of severe combined immunodeficiencies (SCIDs) with radiosensitivity. Hypomorphic mutations in Artemis have been reported to cause a "leaky SCID"" phenotype, typically with hypogammaglobulinemia. We present four patients, all harboring the same unique hypomorphic mutation in the DCLRE1C gene, an 8-base pair insertion (c.1299_1306dup, p.Cys436*) presenting with a relatively mild phenotype including pulmonary infectious EBV-related lymphoproliferative diseases, an autoimmune phenomenon. Non-typical findings of IgG hypergammaglobulinemia accompanied by IgA and IgE deficiency were recorded in all patients. The typical viral, fungal, and opportunistic infections were absent, and patients reached a relatively old age.


Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Hipergamaglobulinemia/genética , Imunoglobulina G , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Adolescente , Doenças Autoimunes/genética , Feminino , Humanos , Deficiência de IgA/genética , Imunoglobulina E/deficiência , Transtornos Linfoproliferativos/genética , Masculino , Mutação , Fenótipo , Imunodeficiência Combinada Severa/complicações
3.
Clin Exp Immunol ; 200(2): 176-184, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31989577

RESUMO

The absence of adenosine deaminase (ADA) causes severe combined immune deficiency (SCID), which has been treated with PEGylated bovine-extracted ADA (ADAGEN). ADAGEN was recently replaced by a PEGylated recombinant bovine ADA, expressed in Escherichia coli (elapegademase, ELA-ADA). Limited information on ELA-ADA is available.  ADA enzymatic activity of ELA-ADA and ADAGEN was assessed in vitro at diverse dilutions. ADA activity and immune reconstitution in an ADA-SCID patient treated with ELA-ADA were compared with age-matched patients previously treated with ADAGEN. ADA activity and thymus reconstitution were evaluated in ADA-deficient mice following ELA-ADA or ADAGEN administered from 7 days postpartum. In vitro, ADA activity of ELA-ADA and ADAGEN were similar at all dilutions. In an ADA-SCID patient, ELA-ADA treatment led to a marked increase in trough plasma ADA activity, which was 20% higher than in a patient previously treated with ADAGEN. A marked increase in T cell numbers and generation of naive T cells was evident following 3 months of ELA-ADA treatment, while T cell numbers increased following 4 months in 3 patients previously treated with ADAGEN. T cell proliferations stimulation normalized and thymus shadow became evident following ELA-ADA treatment. ADA activity was significantly increased in the blood of ADA-deficient mice following ELA-ADA compared to ADAGEN, while both treatments improved the mice weights, the weight, number of cells in their thymus and thymocyte subpopulations. ELA-ADA has similar in- vitro and possibly better in-vivo activity than ADAGEN. Future studies will determine whether ELA-ADA results in improved long-term immune reconstitution.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia , Imunodeficiência Combinada Severa , Linfócitos T , Timo , Adenosina Desaminase/sangue , Adenosina Desaminase/efeitos dos fármacos , Adenosina Desaminase/imunologia , Adenosina Desaminase/farmacologia , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Animais , Humanos , Camundongos , Camundongos Knockout , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
4.
Blood ; 135(9): 610-619, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31942628

RESUMO

Traditionally, primary immune deficiencies have been defined based on increased susceptibility to recurrent and/or severe infections. However, immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially true in patients affected by combined immune deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish, T-cell function. Hypomorphic mutations in the recombination activating genes RAG1 and RAG2 represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID. The study of patients with RAG deficiency and with other forms of CID has revealed distinct abnormalities in central and peripheral T- and B-cell tolerance as the key mechanisms involved in immune dysregulation. Understanding the pathophysiology of autoimmunity and hyperinflammation in these disorders may also permit more targeted therapeutic interventions.


Assuntos
Imunodeficiência Combinada Severa/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/imunologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Proteínas Nucleares/deficiência , Proteínas Nucleares/imunologia , Imunodeficiência Combinada Severa/genética
5.
Iran J Immunol ; 16(4): 334-338, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31885011

RESUMO

Severe Combined Immunodeficiency (SCID), characterized by a profound decrease in both the number and function of T cells, is related to more than 20 different mutations. Recombination-activating gene (RAG) 1 and 2 seem to be two of the most common forms presenting with various manifestations, including typical SCID, Omenn syndrome (OS), atypical SCID (AS), or delayed onset combined immunodeficiency with granulomas. One interesting manifestation in RAG mutation is the change in the immunophenotype over time, even after hematopoietic stem cell transplantation (HSCT). As bone marrow transplantation (BMT) is the only curative treatment of SCID, it is necessary to differentiate between SCID and OS due to the different conditioning regimens (CR). We present a novel case of atypical SCID (SCID manifestations with more than 300 CD3+T cells) caused by RAG 2 gene mutation whose immunophenotype changed to atypical Omenn syndrome (all Omenn syndrome manifestations except rash, eosinophilia, and elevated IgE) over time. Differentiation of leaky SCID, SCID and Omenn syndrome in RAG mutation genes and overlap manifestations is important in treatment plan and prognosis.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Aloenxertos , Complexo CD3/genética , Complexo CD3/imunologia , Proteínas de Ligação a DNA/imunologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Proteínas Nucleares/imunologia , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Linfócitos T/imunologia , Linfócitos T/patologia
6.
BMB Rep ; 52(11): 625-634, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31722780

RESUMO

Severe combined immunodeficiency (SCID) is a group of inherited disorders characterized by compromised T lymphocyte differentiation related to abnormal development of other lymphocytes [i.e., B and/or natural killer (NK) cells], leading to death early in life unless treated immediately with hematopoietic stem cell transplant. Functional NK cells may impact engraftment success of life-saving procedures such as bone marrow transplantation in human SCID patients. Therefore, in animal models, a T cell-/B cell-/NK cell+ environment provides a valuable tool for understanding the function of the innate immune system and for developing targeted NK therapies against human immune diseases. In this review, we focus on underlying mechanisms of human SCID, recent progress in the development of SCID animal models, and utilization of SCID pig model in biomedical sciences. Numerous physiologies in pig are comparable to those in human such as immune system, X-linked heritability, typical T-B+NK- cellular phenotype, and anatomy. Due to analogous features of pig to those of human, studies have found that immunodeficient pig is the most appropriate model for human SCID. [BMB Reports 2019; 52(11): 625-634].


Assuntos
Modelos Animais de Doenças , Imunodeficiência Combinada Severa/imunologia , Suínos/imunologia , Animais , Humanos , Medicina Regenerativa , Transplante Heterólogo/métodos
8.
Mol Biol Rep ; 46(6): 6571-6575, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31520268

RESUMO

The recombination activating genes, including RAG1 and RAG2, are essential for V(D)J somatic recombination in lymphocytes. Leaky severe combined immunodeficiency disorder (SCID) is characterized by normal or intermediate T cells and normal to absent B cells associated with partial T cell and B cell dysfunction. We present a newly found RAG1 deficiency in a 21-year-old boy with leaky SCID. Immunoglobulin levels, flow cytometry, and whole exome sequencing (WES) were evaluated. Flow cytometric analysis revealed a decreased number of CD3+, CD4+, and CD8+ T cells, and B cells whereas NK cell counts were normal. Immunoglobulin levels were also decreased. The WES revealed a newly found homozygous mutation of RAG1 gene (NM_000448: exon 2: c.C2275T). Atypical features, including leukopenia, candidiasis, and low lymphocyte counts in patients with late-onset combined immunodeficiency disorders (CID) such as leaky SCID due to RAG1 deficiency may result in misdiagnosis and inadequate therapy instead of adopting the curative hematopoietic stem cell transplantation in these patients.


Assuntos
Proteínas de Homeodomínio/genética , Mutação , Imunodeficiência Combinada Severa/genética , Linfócitos B/metabolismo , Homozigoto , Humanos , Mutação com Perda de Função , Contagem de Linfócitos , Masculino , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem
9.
J Dermatol ; 46(11): 1019-1023, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31456262

RESUMO

Prominent dermal infiltration by Langerhans cells (LC) is a rare finding in patients with Omenn syndrome (OS). Here, we report the case study of a 7-month-old boy with OS and with prominent dermal infiltration by LC, which is a rare histological manifestation of the skin. Striking erythroderma appeared in the patient 2 weeks after birth. We also noted alopecia, lymphadenopathy, hepatosplenomegaly, eosinophilia and an elevated serum immunoglobulin E level with hypogammaglobulinemia. Peripheral blood flow cytometry showed the Tlow NK+ B+ immunophenotype and genetic analysis, a novel mutation in the IL2RG gene (c.337_339delTCT, p.Ser113del). The final diagnosis was that of OS. He responded well to an allograft umbilical cord blood transplantation that was performed when the patient was 8 months of age. We speculate that the LC accumulated in the dermis will eventually migrate to the regional lymph node, then stimulate autoreactive T cells by overpresenting antigens, thus causing OS-specific skin symptoms.


Assuntos
Derme/patologia , Subunidade gama Comum de Receptores de Interleucina/genética , Células de Langerhans/patologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Biópsia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Derme/imunologia , Humanos , Lactente , Masculino , Mutação , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/cirurgia
10.
Pediatr Clin North Am ; 66(5): 913-923, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31466681

RESUMO

The T-cell receptor excision circle (TREC) assay is an effective screening tool for severe combined immunodeficiency (SCID). The TREC assay was designed to detect typical SCID and leaky SCID, but any condition causing low naïve T-cell counts will also be detected. Newborn screening for SCID using the TREC assay has proven itself to be highly sensitive and cost-efficient. This review covers the history of SCID newborn screening, elaborates on the SCID subtypes and TREC assay limitations, and discusses diagnostic and management considerations for infants with a positive screen.


Assuntos
Triagem Neonatal , Imunodeficiência Combinada Severa/diagnóstico , Humanos , Recém-Nascido , Imunodeficiência Combinada Severa/imunologia
11.
Immunol Res ; 67(2-3): 166-175, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31222511

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is the effective mean of immune restoration in severe combined immunodefiency (SCID). Usually, HSCT without cytoreductive conditioning is attempted. Nevertheless, conditioning procedures are still preferred in a subset of patients. Herein, we describe the immunological outcome in a cohort of conditioned and unconditioned patients, from diagnosis, through transplantation, to follow-up. This retrospective study was conducted on 17 patients with SCID (10 conditioned, 7 unconditioned) who later underwent HSCT. Immune reconstitution was assessed in the post-transplant year by quantification of T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs), among additional laboratory and clinical evaluations. Unconditioned patients were diagnosed and transplanted earlier. TREC and KREC quantification showed a gradual increase in both groups, with higher levels in the conditioned group. Engraftment percentages differed drastically between groups, favoring the conditioned group. Unconditioned patients were significantly more dependent on intravenous immunoglobulins (IVIGs). One patient from each group succumbed to disease complications. Conditioning demonstrated superior laboratorial outcomes. Patients with unique characteristics (i.e., consanguinity, Bacillus Calmette-Guérin vaccination, impaired access to IVIG) may require personalized considerations. The effort to implement secondary prevention of SCID with newborn screening should continue.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Condicionamento Pré-Transplante , Suscetibilidade a Doenças , Seguimentos , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunidade Celular , Imunidade Humoral , Imunoglobulinas Intravenosas , Imunodeficiência Combinada Severa/diagnóstico , Transplante Homólogo , Resultado do Tratamento
12.
Pediatr Transplant ; 23(5): e13464, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31081274

RESUMO

IRIS is a phenomenon describing localized inflammatory reactions at BCG vaccination site and development of lymphadenopathy as immune system recovers. It is a rare entity in children following haploidentical HSCT. We represent the successful treatment of a case with fluctuating lymphadenopathy due to BCG vaccine during immune reconstitution period following ex vivo T-cell-depleted haploidentical HSCT.


Assuntos
Vacina BCG/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Síndrome Inflamatória da Reconstituição Imune/tratamento farmacológico , Síndrome Inflamatória da Reconstituição Imune/etiologia , Imunodeficiência Combinada Severa/terapia , Antituberculosos/uso terapêutico , Feminino , Humanos , Lactente , Depleção Linfocítica , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Tuberculose dos Linfonodos/tratamento farmacológico , Tuberculose dos Linfonodos/imunologia , Turquia
13.
Wound Repair Regen ; 27(4): 426-430, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30843296

RESUMO

Transplantation of human xenografts onto immunocompromised mice is a powerful research tool for studying wound healing. However, differences in healing between humans and mice and their small size limit this model. We determined whether human cadaver skin xenografts transplanted onto pigs with severe combined immune deficiency (SCID) would survive and not be rejected. Meshed (1:1.5), cryopreserved human cadaver skin was transplanted onto 10 partial thickness dermatome wounds in each of two normal domestic pigs and two SCID pigs. Autografts (n = 2/animal) from the four animals were used as controls. In normal pigs, all autografts were engrafted and healed with a minimal, if any, inflammation and scarring. All human xenografts were rejected by the normal pigs within 5-11 days and associated with an intense T-cell inflammatory response. In contrast, both autografts and xenografts were engrafted and survived the 28-day study in the SCID pigs with a minimal inflammation and no gross scarring.


Assuntos
Cadáver , Sobrevivência de Enxerto/fisiologia , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/fisiopatologia , Transplante de Pele , Transplante Heterólogo , Animais , Modelos Animais de Doenças , Sobrevivência de Enxerto/imunologia , Humanos , Imuno-Histoquímica , Estudo de Prova de Conceito , Imunodeficiência Combinada Severa/cirurgia , Suínos , Cicatrização/imunologia , Cicatrização/fisiologia
14.
Indian J Pediatr ; 86(7): 584-589, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30879237

RESUMO

OBJECTIVES: Severe combined immunodeficiency (SCID) represents one of the most severe forms of Primary immunodeficiency (PID) disorders, characterized by T cell lymphopenia (TCL) and lack of cellular and humoral immune responses. However, not all patients with low T cell lymphocyte counts may have an abnormal T cell immunity and the observed TCL may be a temporary suppression resulting from transient lymphopenia secondary to severe infections. In such cases, it is necessary to estimate the severity of the observed TCL by assessing thymic capabilities. METHODS: In this study, patients clinically suspected of SCID were evaluated for lymphocyte subsets analysis, naïve T cells and T cell receptor excision circles (TREC). RESULTS: Patients with transient lymphopenia had detectable TREC levels and normal naïve T cells subsets. Normalization of absolute lymphocyte counts, and T cells was seen in the patients after a short duration. CONCLUSIONS: The authors highlight the importance of detailed immunological investigations in an infant with severe infections and lymphopenia before labeling the infant as SCID.


Assuntos
Linfopenia/complicações , Linfopenia/imunologia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/imunologia , Feminino , Humanos , Imunidade Humoral , Lactente , Contagem de Linfócitos , Masculino
15.
Front Immunol ; 10: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30778343

RESUMO

Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/µL <2,500) was noted in 63% of the patients. Based on immunophenotypic pattern, majority of the cases were T-B- SCID (39%) followed by T-B+ SCID (28%). MHC class II deficiency accounted for 10.5% of our patient group. A total of 49 patients were molecularly characterized in this study and 32 novel variants were identified in our cohort. The spectrum of genetic defects in our cohort revealed a wide genetic heterogeneity with the major genetic cause being RAG1/2 gene defect (n = 12) followed by IL2RG (n = 9) and JAK3 defects (n = 9). Rare forms of SCID like Purine nucleoside phosphorylase (PNP) deficiency, reticular dysgenesis, DNA-Protein Kinase (DNA-PKcs) deficiency, six cases of MHC class II deficiency and two ZAP70 deficiency were also identified in our cohort. Fourteen percent of the defects still remained uncharacterized despite the application of next generation sequencing. With the exception of MHC class II deficiency and ZAP70 deficiency, all SCID patients had extremely low T cell receptor excision (TRECs) (<18 copies/µL).


Assuntos
Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Idade de Início , Biomarcadores , Relação CD4-CD8 , Pré-Escolar , Terapia Combinada , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Variação Genética , Humanos , Índia , Lactente , Recém-Nascido , Contagem de Linfócitos , Masculino , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/virologia , Avaliação de Sintomas
16.
Clin Immunol ; 201: 30-34, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30776520

RESUMO

Severe combined immunodeficiencies (SCID) comprise a group of genetic diseases characterized by abrogated development of T lymphocytes. In some case reports of atypical SCID patients elevated proportions of γδ T lymphocytes have been reported. However, it is unknown whether these γδ T cells modulate or reflect the patient's clinical phenotype. We investigated the frequency of elevated γδ T cell proportions and associations with clinical disease manifestations in a cohort of 76 atypical SCID patients. Increased proportions of γδ T lymphocytes were present in approximately 60% of these patients. Furthermore, we identified positive correlations between elevated proportions of γδ T cells and the occurrence of CMV infections and autoimmune cytopenias. We discuss that CMV infections might trigger an expansion of γδ T lymphocytes, which could drive the development of autoimmune cytopenias. We advocate that atypical SCID patients should be screened for elevated proportions of γδ T lymphocytes, CMV infection and autoimmune cytopenias.


Assuntos
Infecções por Citomegalovirus/imunologia , Doenças Hematológicas/imunologia , Linfócitos Intraepiteliais/imunologia , Imunodeficiência Combinada Severa/imunologia , Humanos , Contagem de Linfócitos
17.
Nat Immunol ; 20(2): 152-162, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643259

RESUMO

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.


Assuntos
Interferon Tipo I/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Animais , Pré-Escolar , Chlorocebus aethiops , DNA Viral/imunologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Fibroblastos , Técnicas de Inativação de Genes , Células HEK293 , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Humanos , Imunidade Inata , Células Jurkat , Macrófagos , Masculino , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Células NIH 3T3 , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Cultura Primária de Células , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/imunologia , Células Vero
18.
Clin Immunol ; 200: 16-18, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30630113

RESUMO

Severe combined immunodeficiency (SCID) can be caused by deleterious mutations in DCLRE1C, leading to deficient non-homologous end joining by compromising the function of the Artemis protein. This impairs the process of V(D)J recombination of the T- and B-cell receptors and typically results in radiosensitive T-, B-, NK+ SCID presenting during the first months of life. We present a case of a 3-year-old girl with two novel compound heterozygous variants in DCLRE1C (c.58G>C and c.374A>C) that were associated with marked reduced numbers of peripheral T- and B-cells and undetectable total serum IgG. Despite the severe laboratory phenotype, the patient had a normal development, albeit failure to thrive (-2.5 to -3 SD), during her first years of life including day-care attendance at preschool for 1.5 years. After being diagnosed with pneumonia the clinical picture of SCID was recognized and the girl successfully underwent hematopoietic stem-cell transplantation.


Assuntos
Agamaglobulinemia/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Imunodeficiência Combinada Severa/genética , Agamaglobulinemia/complicações , Agamaglobulinemia/imunologia , Pré-Escolar , Feminino , Heterozigoto , Humanos , Mutação , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/etiologia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/imunologia
19.
Proc Natl Acad Sci U S A ; 116(3): 970-975, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30591564

RESUMO

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.


Assuntos
Diferenciação Celular , Imunidade nas Mucosas/genética , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Proteína Serina-Treonina Quinases de Interação com Receptores , Imunodeficiência Combinada Severa , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Células HCT116 , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mutação , NF-kappa B/genética , NF-kappa B/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
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