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1.
J Exp Med ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727781

RESUMO

Chronic inflammatory diseases like psoriasis, Crohn's disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), and others are increasingly recognized as disease entities, where dysregulated cytokines contribute substantially to tissue-specific inflammation. A dysregulation in the IL-23/IL-17 axis can lead to inflammation of barrier tissues, whereas its role in internal organ inflammation remains less clear. Here we discuss the most recent developments in targeting IL-17 for the treatment of chronic inflammation in preclinical models and in patients afflicted with chronic inflammatory diseases.

2.
Proc Natl Acad Sci U S A ; 116(41): 20700-20706, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31527267

RESUMO

Microbial invasion into the intestinal mucosa after allogeneic hematopoietic cell transplantation (allo-HCT) triggers neutrophil activation and requires antibiotic interventions to prevent sepsis. However, antibiotics lead to a loss of microbiota diversity, which is connected to a higher incidence of acute graft-versus-host disease (aGVHD). Antimicrobial therapies that eliminate invading bacteria and reduce neutrophil-mediated damage without reducing the diversity of the microbiota are therefore highly desirable. A potential solution would be the use of antimicrobial antibodies that target invading pathogens, ultimately leading to their elimination by innate immune cells. In a mouse model of aGVHD, we investigated the potency of active and passive immunization against the conserved microbial surface polysaccharide poly-N-acetylglucosamine (PNAG) that is expressed on numerous pathogens. Treatment with monoclonal or polyclonal antibodies to PNAG (anti-PNAG) or vaccination against PNAG reduced aGVHD-related mortality. Anti-PNAG treatment did not change the intestinal microbial diversity as determined by 16S ribosomal DNA sequencing. Anti-PNAG treatment reduced myeloperoxidase activation and proliferation of neutrophil granulocytes (neutrophils) in the ileum of mice developing GVHD. In vitro, anti-PNAG treatment showed high antimicrobial activity. The functional role of neutrophils was confirmed by using neutrophil-deficient LysM cre Mcl1 fl/fl mice that had no survival advantage under anti-PNAG treatment. In summary, the control of invading bacteria by anti-PNAG treatment could be a novel approach to reduce the uncontrolled neutrophil activation that promotes early GVHD and opens a new avenue to interfere with aGVHD without affecting commensal intestinal microbial diversity.

3.
Front Immunol ; 10: 951, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114586

RESUMO

The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic Fas mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.

4.
Front Immunol ; 10: 297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941118

RESUMO

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

5.
Eur J Immunol ; 49(2): 212-220, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30653669

RESUMO

High-dimensional single-cell (HDcyto) technologies, such as mass cytometry (CyTOF) and flow cytometry, are the key techniques that hold a great promise for deciphering complex biological processes. During the last decade, we witnessed an exponential increase of novel HDcyto technologies that are able to deliver an in-depth profiling in different settings, such as various autoimmune diseases and cancer. The concurrent advance of custom data-mining algorithms has provided a rich substrate for the development of novel tools in translational medicine research. HDcyto technologies have been successfully used to investigate cellular cues driving pathophysiological conditions, and to identify disease-specific signatures that may serve as diagnostic biomarkers or therapeutic targets. These technologies now also offer the possibility to describe a complete cellular environment, providing unanticipated insights into human biology. In this review, we present an update on the current cutting-edge HDcyto technologies and their applications, which are going to be fundamental in providing further insights into human immunology and pathophysiology of various diseases. Importantly, we further provide an overview of the main algorithms currently available for data mining, together with the conceptual workflow for high-dimensional cytometric data handling and analysis. Overall, this review aims to be a handy overview for immunologists on how to design, develop and read HDcyto data.

6.
Front Immunol ; 9: 1730, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30083170

RESUMO

DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, with low switched-memory B cells and a wide spectrum of antibody deficiencies or dysgammaglobulinemia, presumably due to impaired germinal center responses. We set out to evaluate circulating follicular helper T cells (cTFHs) in DiGeorge syndrome, as markers of T-B interaction in the germinal centers in a cohort of 17 patients with partial DiGeorge and 21 healthy controls of similar age. cTFHs were characterized as CXCR5+CD45RA- CD4+ T cells using flow cytometry. We verify previous findings that the population of memory CD4+ T cells is relatively increased in diGeorge patients, corresponding to low naïve T cells and impaired T cell production in the thymus. The population of CXCR5+ memory CD4+ T cells (cTFHs) was significantly expanded in patients with DiGeorge syndrome, but only healthy controls and not DiGeorge syndrome patients showed gradual increase of CXCR5 expression on cTFHs with age. We did not observe correlation between cTFHs and serum IgG levels or population of switched memory B cells. There was no difference in cTFH numbers between DiGeorge patients with/without thrombocytopenia and with/without allergy. Interestingly, we show strong decline of PD1 expression on cTFHs in the first 5 years of life in DiGeorge patients and healthy controls, and gradual increase of PD1 and ICOS expression on CD4- T cells in healthy controls later in life. Thus, here, we show that patients with DiGeorge syndrome have elevated numbers of cTFHs, which, however, do not correlate with autoimmunity, allergy, or production of immunoglobulins. This relative expansion of cTFH cells may be a result of impaired T cell development in patients with thymic dysplasia.

7.
J Clin Immunol ; 38(4): 527-536, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29948574

RESUMO

PURPOSE: All reported patients with hypomorphic X-linked severe combined immunodeficiency (X-SCID) due to c.664C>T (p.R222C) mutations in the gene (IL2RG) encoding the common γ chain (γc) have presented with opportunistic infections within the first year of life, despite the presence of nearly normal NK and T cell numbers. Reporting five children of one extended family with hemizygous mutations in IL2RG, we explore potential diagnostic clues and extend our comprehension of the functional impact of this mutation. METHODS: Whole exome sequencing (WES); detailed immune phenotyping; cytokine-induced STAT phosphorylation; B, T, and NK cell activation; and quantification of sjTRECs in five Arab children with c.664C>T (p.R222C) IL2RG mutation. RESULTS: The mean age at clinical presentation with respiratory tract infection or diarrhea was 6.8 (range: 2-12) months. None of the children presented with opportunistic infections. Diagnostic clues were early onset in the first year of life, and a suggestive family history associated with reduced naïve CD4 T cells and absent switched memory B cells. Number and phenotype of NK cells and innate-like lymphocytes were normal. The diagnosis was made by WES and corroborated by absent STAT phosphorylation and reduced functional response after IL-2 and IL-21 stimulation. Four patients underwent successful hematopoietic stem cell transplantation. CONCLUSIONS: As early diagnosis and treatment are important, a high index of suspicion in the diagnosis of c.664C>T (p.R222C) X-SCID is needed. This requires prompt genetic testing by next generation sequencing in order to avoid unnecessary delays in the definite diagnosis since immunological work up may not be discriminating. Assays directly testing cytokine signaling or cytokine-dependent functions are helpful in confirming the functional impact of the identified hypomorphic variants.

8.
J Allergy Clin Immunol ; 141(2): 730-740, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28554560

RESUMO

BACKGROUND: A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. OBJECTIVES: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. METHODS: We quantified TH1/TH2/TH17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. RESULTS: Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3+CCR6- TH1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)+ B cells in lymph nodes, and an accumulation of T-bet+CD21low B cells in peripheral blood of affected patients. CONCLUSION: Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21low B cells might serve as a marker of this IFN-γ-associated dysregulation.

9.
J Clin Immunol ; 37(8): 759-769, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28936778

RESUMO

PURPOSE: Over a third of patients with common variable immunodeficiency (CVID) suffer from secondary complications like inflammatory organ disease, autoimmune manifestations, or lymphoproliferation contributing to increased morbidity and mortality in affected patients. Innate lymphoid cells (ILCs) have emerging roles in setting the milieu for physiological, but also pathological, immune responses and inflammation. We therefore sought to correlate the recently identified disturbed homeostasis of ILCs with alterations of the adaptive immune system in complex CVID patients (CVIDc). METHODS: We quantified peripheral blood ILC and T helper cell subsets of 58 CVID patients by flow cytometry and compared the results to the clinical and immunological phenotype. RESULTS: Total ILCs were significantly reduced in peripheral blood of CVIDc patients compared to healthy individuals, but not to CVID patients who suffered only from infections (CVIDio). This reduction was mainly due to a decrease in ILC2s, while ILC3s were relatively increased in CVIDc compared to CVIDio patients. This alteration in ILC phenotype was more prominent in patients with an expansion of CD21low B cells, but we could not detect an association of the altered ILC phenotype with a TH1-shift among circulating CD4 T cells, which was also prominent in CVIDc patients. CONCLUSION: We confirm a relative shift in ILCs of CVIDc patients towards ILC3s which was associated with the expansion of CD21low B cells, but not overtly with the relative expansion of TH1-like T cells. Given the relative abundance of TH1-like T cells compared to ILCs, these probably represent a more prominent source of the observed IFNγ-signature in CVIDc patients.


Assuntos
Doenças Autoimunes/imunologia , Imunodeficiência de Variável Comum/imunologia , Imunidade Inata , Linfócitos/imunologia , Transtornos Linfoproliferativos/imunologia , Imunidade Adaptativa , Adulto , Idoso , Doenças Autoimunes/etiologia , Circulação Sanguínea , Imunodeficiência de Variável Comum/complicações , Citocinas/metabolismo , Feminino , Homeostase , Humanos , Tolerância Imunológica , Inflamação , Transtornos Linfoproliferativos/etiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Células Th2/imunologia , Adulto Jovem
11.
Respir Med ; 126: 39-45, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28427548

RESUMO

BACKGROUND: In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown. OBJECTIVE: To investigate the cause and mechanism predisposing a patient to severe bronchiectasis. METHODS: A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping. RESULTS: The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD- GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon γ (IFN-γ). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen. CONCLUSIONS: Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD- GOF mutations in STAT1 to suppurative sinopulmonary disease.


Assuntos
Bronquiectasia/genética , Mutação , Fator de Transcrição STAT1/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Linfócitos B/citologia , Linfócitos B/imunologia , Bronquiectasia/diagnóstico por imagem , Bronquiectasia/epidemiologia , Bronquiectasia/imunologia , Candidíase Mucocutânea Crônica/diagnóstico por imagem , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/microbiologia , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Feminino , Humanos , Interferon gama/imunologia , Síndrome de Kartagener/diagnóstico , Masculino , Óxido Nítrico , Fosforilação , Prevalência , Fator de Transcrição STAT1/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologia
12.
Clin Immunol ; 180: 80-83, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28323147

RESUMO

This study investigated whether circulating α4ß7+ expressing T cells could serve as a potential marker for gastrointestinal (GI) disease activity in patients with CVID. The analysis of α4ß7+ T cells in the peripheral blood of 36 patients and 22 healthy donors (HD) revealed increased percentages of α4ß7+ conventional memory CD4 T cells and Tregs, but not among CD8 T-cell populations in patients with CVID compared to HD. No differences between patients with and without chronic or acute GI symptoms were observed. EUROClass smB- and 21lo patients, had higher percentages of α4ß7+ memory CD4 T cells compared to HD and smB+ or 21norm patients, respectively. In summary, the detection of α4ß7+ T cells in the peripheral blood did not correlate with active or chronic gastrointestinal disease. The increase of these cells in smB- and 21lo patients adds another piece to the immune dysregulation observed in these patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunodeficiência de Variável Comum/imunologia , Gastroenteropatias/imunologia , Integrinas/imunologia , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Feminino , Gastroenteropatias/diagnóstico , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade
13.
J Exp Med ; 213(7): 1185-99, 2016 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-27242165

RESUMO

The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca(2+) mobilization, residual T cells were able to induce Ca(2+) influx and nuclear factor (NF) κB signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Doenças Autoimunes , Sinalização do Cálcio , Homozigoto , Proteínas de Membrana , Mutação , Imunodeficiência Combinada Severa , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Sinalização do Cálcio/genética , Sinalização do Cálcio/imunologia , Éxons/imunologia , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia
14.
J Clin Immunol ; 36(4): 406-12, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26980224

RESUMO

PURPOSE: The aim of this study was to identify characteristics of hypogammaglobulinemia secondary to glucocorticoid therapy and their value in the differential diagnosis to primary forms of antibody deficiency. METHODS: We investigated prevalence and character of hypogammaglobulinemia in a cohort of 36 patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) on glucocorticoid therapy in comparison to a gender- and age-matched cohort of hospital controls. We therefore determined serum immunoglobulin levels as well as B- and T cell-subsets in the peripheral blood of all participants. In addition, prior serum immunoglobulin levels and clinical data of the GCA and PMR patients were extracted from the electronic patient data-base. RESULTS: 21/36 GCA/PMR patients on glucocorticoid treatment developed antibody deficiency. In 19 patients this included IgG and in 13 patients IgG was the only affected isotype. The reduction of IgG was persistent in nearly 50 % of these patients during the observed period. GCA/PMR patients had reduced circulating naive and transitional B cells (p = 0.0043 and p = 0.0002 respectively) while IgM, IgG and IgA memory B cells were preserved. Amongst T-cell subsets, we found a reduction of CD4 memory T cells (p < 0.0001), CD4 regulatory T cells (p = 0.0002) and few CD8 memory T-cell subtypes. CONCLUSION: Persistent humoral immunodeficiency occurs in about a quarter of GCA/PMR patients under glucocorticoid therapy. Because most patients have isolated IgG deficiency, preserved IgA production and class-switched memory B cells, by these markers this form of secondary hypogammaglobulinemia can be clearly distinguished from common variable immunodeficiency (CVID).


Assuntos
Agamaglobulinemia/induzido quimicamente , Arterite de Células Gigantes/imunologia , Glucocorticoides/efeitos adversos , Polimialgia Reumática/imunologia , Prednisona/efeitos adversos , Agamaglobulinemia/sangue , Agamaglobulinemia/epidemiologia , Agamaglobulinemia/imunologia , Idoso , Idoso de 80 Anos ou mais , Subpopulações de Linfócitos B/imunologia , Feminino , Arterite de Células Gigantes/sangue , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/epidemiologia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas/sangue , Masculino , Pessoa de Meia-Idade , Polimialgia Reumática/sangue , Polimialgia Reumática/tratamento farmacológico , Polimialgia Reumática/epidemiologia , Prednisona/uso terapêutico , Prevalência , Subpopulações de Linfócitos T/imunologia
16.
J Clin Immunol ; 35(4): 356-60, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25893637

RESUMO

B-cell linker (BLNK) protein is a non-redundant adaptor molecule in the signaling pathway activated by (pre) B-cell antigen receptor signals. We present two siblings with a homozygous deleterious frameshift mutation in BLNK, resulting in a block of B cell development in the bone marrow at the preB1 to preB2 stage, absence of circulating B cells and agammaglobulinemia. This is the first description of an enteroviral infection associated arthritis and dermatitis in a patient with BLNK deficiency.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Agamaglobulinemia/congênito , Agamaglobulinemia/complicações , Infecções por Enterovirus/etiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/tratamento farmacológico , Artrite/diagnóstico , Artrite/etiologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Criança , Consanguinidade , Análise Mutacional de DNA , Dermatite/diagnóstico , Dermatite/etiologia , Infecções por Enterovirus/diagnóstico , Homozigoto , Humanos , Imunofenotipagem , Masculino , Mutação , Fenótipo , Irmãos
17.
J Allergy Clin Immunol ; 136(2): 392-401, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25702838

RESUMO

BACKGROUND: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described ß2-microglobulin (ß2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed. OBJECTIVE: We sought to describe the molecular and immunologic features of ß2m deficiency in 2 Turkish siblings with new diagnoses. METHODS: Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry. RESULTS: Here we provide the first extensive clinical and immunologic description of ß2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of ß2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except ß2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill." CONCLUSION: The clinical presentation of patients with ß2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of ß2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency.


Assuntos
Bronquiectasia/imunologia , Síndromes de Imunodeficiência/imunologia , Infecções Respiratórias/imunologia , Úlcera Cutânea/imunologia , Microglobulina beta-2/imunologia , Imunidade Adaptativa , Adolescente , Adulto , Antígenos CD1/genética , Antígenos CD1/imunologia , Bronquiectasia/complicações , Bronquiectasia/genética , Bronquiectasia/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Consanguinidade , Feminino , Deleção de Genes , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata , Imunoglobulina G/sangue , Imunoglobulina G/genética , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Linhagem , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores Fc/deficiência , Receptores Fc/genética , Receptores Fc/imunologia , Recidiva , Infecções Respiratórias/complicações , Infecções Respiratórias/genética , Infecções Respiratórias/patologia , Irmãos , Úlcera Cutânea/complicações , Úlcera Cutânea/genética , Úlcera Cutânea/patologia , Microglobulina beta-2/deficiência , Microglobulina beta-2/genética
19.
Nat Med ; 20(12): 1410-1416, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25329329

RESUMO

The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.


Assuntos
Agamaglobulinemia/genética , Doenças Autoimunes/genética , Antígeno CTLA-4/genética , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Agamaglobulinemia/imunologia , Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/imunologia , Animais , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Antígeno B7-1/metabolismo , Antígeno CTLA-4/imunologia , Criança , Códon sem Sentido , Endocitose/genética , Endocitose/imunologia , Éxons , Feminino , Granuloma/genética , Granuloma/imunologia , Heterozigoto , Humanos , Doenças do Sistema Imunitário/genética , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Recidiva , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Síndrome , Adulto Jovem
20.
PLoS One ; 9(6): e100328, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24945754

RESUMO

Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.


Assuntos
Diferenciação Celular , Plasmócitos/citologia , Plasmócitos/metabolismo , Fatores de Transcrição SOXD/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXD/genética
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