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1.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

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

3.
Front Immunol ; 9: 2984, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619340

RESUMO

B cell activation via the B cell receptor (BCR) signalosome involves participation of signaling molecules such as BTK and BLNK. Genetic defects in these molecules are known to impair B cell differentiation and subsequently lead to agammaglobulinemia. Here we identified novel mutations in BTK and BLNK in two unrelated patients that perturb the intrinsic B-cell receptor signaling pathway and lead to selective IgM deficiency, whereas production of other immunoglobulin isotypes and IgG antibody response remain intact. Currently it is unknown how BCR signaling strength affects mature B cell development in humans. Both patients show reduced levels of BCR signalosome phosphorylation as well as impaired BCR-dependent Ca2+ influx, which was accompanied by a marked decrease in IgD+IgM+CD27+ MZ-like B-cells. We further describe reduced expression of essential B cell differentiation factors such as BAFF-R and T-Bet in the patients' B-cells, which might contribute to the observed deficiency of MZ-like B cells. MZ-like B cells are known to produce natural IgM antibodies that play an essential role in immune homeostasis. By using surface plasmon resonance (SPR) technology and a synthetic blood group A trisaccharide as antigen we were able to show that both patients lack the presence of anti-blood group A IgM considered to be prototypical natural antibodies whereas IgG levels were normal. Antibody binding dynamics and binding affinity of anti-blood group A IgG were comparable between patients and healthy controls. These results indicate that human IgM deficiency can be associated with signaling defects in the BCR signalosome, defective production of natural IgM antibodies in the blood group A/B/0 system and abnormalities in B cell development.

4.
Eur J Immunol ; 47(11): 1959-1969, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28718914

RESUMO

Recent studies identified an emerging role of group 2 and 3 innate lymphoid cells (ILCs) as key players in the generation of T-dependent and T-independent antibody production. In this retrospective case-control study, CD117+ ILCs (including the majority of ILC2 and ILC3) were reduced in patients with common variable immunodeficiency (CVID). The reduction in CD117+ ILCs was distinctive to CVID and could not be observed in patients with X-linked agammaglobulinemia. Patients with a more pronounced reduction in CD117+ ILC numbers showed significantly lower numbers of peripheral MZ-like B cells and an increased prevalence of chronic, non-infectious enteropathy. Subsequent phenotyping of ILC subsets in CVID revealed that the reduction in CD117+ ILC numbers is due to a reduction in ILC2 numbers. In vitro expansion of CVID ILC2 in response to IL-2, IL-7, IL-25 and IL-33 was impaired. Furthermore, upregulation of MHCII and IL-2RA in response to IL-2, IL-7, IL-25 and IL-33 was impaired in CVID ILC2. Thus, our results indicate a dysregulation of ILC subsets with a reduction in ILC2 numbers in CVID, however, further studies are needed to explore whether ILC abnormalities are a primary finding or secondary to disease complications encountered in CVID.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Subpopulações de Linfócitos/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-kit/imunologia , Estudos Retrospectivos
5.
Clin Immunol ; 183: 41-45, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28705765

RESUMO

Over the past decades, a pleiotropic spectrum of B-cell intrinsic defects leading to early onset agammaglobulinemia and absent B cells has been described. Herein we report terminal 14q32.33 deletion as a novel cause of agammaglobulinemia. We describe a 20-year old man with a 1MB terminal 14q32.33 deletion resulting in a loss of the entire Immunoglobulin heavy chain gene region of chromosome 14. The patient presented with absent serum immunoglobulin levels and absent circulating B cells since age 2. The clinical picture was dominated by severe episodes of recurrent upper respiratory tract infections. In the literature, the most prevalent features of terminal 14q32.33 deletions include mental disability, facial malformation, hypotonia, seizures, and visual problems with retinal abnormalities. Neither increased susceptibility to infections nor agammaglobulinemia have been described as a manifestation of terminal 14q32.33 deletion. Thus, our findings expand the known clinical spectrum of terminal 14q32.33 deletion to include susceptibility to infections.


Assuntos
Agamaglobulinemia/genética , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Agamaglobulinemia/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Adulto Jovem
6.
BMC Microbiol ; 16: 13, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26830934

RESUMO

BACKGROUND: Nosocomial infections caused by the bacterial pathogen Staphylococcus aureus can lead to serious complications due to the varying presence of secreted toxins. Comparative studies of genomic information and production rates are needed to assess the pathogenic potential of isolated strains. Genotypic and phenotypic profiling of clinical and colonising isolates of S. aureus was used to characterise the release of exotoxins. Blood isolates were compared with colonisation strains to determine similarities and differences of single strains and clusters. RESULTS: Fifty-one fresh isolates obtained from colonised individuals (n = 29) and S. aureus bacteremia (SAB) patients (n = 22) were investigated. The prevalence of genes encoding for three cytolysins (alpha/beta/gamma toxin) and twenty-four superantigens (SEA-SElX) was determined. Isolates exhibited eighteen distinct combinations of superantigens. Sequence analysis identified mutated open reading frames in hla in 13.7% of all strains, in selw (92.2%) and in selx (15.7%). All corrupted genes were associated with specific clonal complexes. Functional assessment of alpha toxin activity by a rabbit erythrocyte lysis assay revealed that supernatants lacking alpha toxin still displayed hemolysis. This was due to the presence of gamma toxin, as proven by inhibition experiments using antisera raised against the respective recombinant proteins. Alpha toxin, SEC, and TSST1 production was quantified by enzyme-linked immunosorbent assays on supernatants of all hla, sec, and tst positive isolates. Blood isolates and colonising strains showed comparable amounts of secreted proteins within a wide range. Agr types I to IV were identified, but did not allow a prediction of high or low production rates. In contrast, alpha toxin production rates between distinct clonal complexes clearly differed. Spa typing was performed and revealed thirty-two unique spa gene patterns and eight small clusters comprising nineteen isolates. Recognised spa-typing clusters displayed highly similar production rates. CONCLUSION: Production rates of the three most prevalent exotoxins varied within both groups of blood isolates and colonising strains. By comparing genotypes and secretion, we found that identical complex gene patterns did not allow predictions of toxin production and function. However, identification of spa typing clusters was suitable to predict similar quantities of released exotoxins.


Assuntos
Proteínas de Bactérias/genética , Toxinas Bacterianas/metabolismo , Hemolíticos/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Animais , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/toxicidade , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Genótipo , Hemolíticos/toxicidade , Humanos , Fenótipo , Coelhos , Staphylococcus aureus/classificação , Staphylococcus aureus/isolamento & purificação , Staphylococcus aureus/metabolismo
7.
Eur J Cancer ; 51(13): 1803-11, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26164066

RESUMO

BACKGROUND: Brain metastases (BM) are a life-threatening complication. We aimed to analyse gene mutations in lung adenocarcinoma BM. METHODS: We performed next generation sequencing (NGS) of a pre-defined set of 48 cancer-related genes in a cohort of 76 neurosurgical lung adenocarcinoma BM specimens using a cancer specific gene panel on the MiSeq platform (Illumina, San Diego, CA). NGS results were statistically correlated to patient characteristics. Data on ALK, ROS1, MET and FGFR1 gene status assessed by FISH were available from previous studies in the majority of patients. RESULTS: Twenty-nine (60.4%) of the 48 investigated cancer-related genes were mutated in at least one BM sample and 64 (84.2%) of the 76 BM samples carried at least one mutated gene. The number of mutated genes per sample ranged from 0 to 9 (median 2). The most commonly mutated genes were TP53, KRAS and CDKN2A, which were affected in 35/76 (46.1%), 29/76 (38.2%) and 17/76 (22.4%) samples, respectively. Other potentially druggable alterations included EGFR mutations (3/76, 3.9% of samples), PIK3CA mutation (2/76, 2.6%), BRAF mutation (1/76, 1.3%) and SMO mutation (1/76, 1.3%). Presence of KRAS mutations was associated with positive smoking history (p=0.015, Chi square test) and presence of EGFR mutation correlated with unfavourable overall survival time from BM diagnosis (p=0.019, log rank test). CONCLUSIONS: Deleterious gene mutations, some of them with potential therapeutic implications, are found in a high fraction of lung adenocarcinoma BM.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/secundário , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Análise Mutacional de DNA/métodos , Exoma , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares/patologia , Mutação , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Idoso , Neoplasias Encefálicas/cirurgia , Biologia Computacional , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos
8.
PLoS One ; 10(7): e0133220, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26186701

RESUMO

Loss of function mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause a T-B-NK+ type of severe combined immunodeficiency. In addition identification of hypomorphic mutations in RAG1 and RAG2 has led to an expansion of the spectrum of disease to include Omenn syndrome, early onset autoimmunity, granuloma, chronic cytomegalovirus- or EBV-infection with expansion of gamma/delta T-cells, idiophatic CD4 lymphopenia and a phenotype resembling common variable immunodeficiency. Herein we describe a novel presentation of leaky RAG1 and RAG2 deficiency in two unrelated adult patients with impaired antibody production against bacterial polysaccharide antigens. Clinical manifestation included recurrent pneumonia, sinusitis, otitis media and in one patient recurrent cutaneous vasculitis. Both patients harbored a combination of a null mutation on one allele with a novel hypomorphic RAG1/2 mutation on the other allele. One of these novel mutations affected the start codon of RAG1 and resulted in an aberrant gene and protein expression. The second novel RAG2 mutation leads to a truncated RAG2 protein, lacking the C-terminus with intact core RAG2 and reduced VDJ recombination capacity as previously described in a mouse model. Both patients presented with severely decreased numbers of naïve CD4+ T cells and defective T independent IgG responses to bacterial polysaccharide antigens, while T cell-dependent IgG antibody formation e.g. after tetanus or TBEV vaccination was intact. In conclusion, hypomorphic mutations in genes responsible for SCID should be considered in adults with predominantly antibody deficiency.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Síndromes de Imunodeficiência/genética , Mutação , Proteínas Nucleares/genética , Adulto , Linfócitos T CD4-Positivos/imunologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Síndromes de Imunodeficiência/diagnóstico , Lipopolissacarídeos/imunologia , Proteínas Nucleares/metabolismo
9.
J Clin Immunol ; 34(8): 941-53, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25205547

RESUMO

PURPOSE: Idiopathic CD4 lymphopenia constitutes a heterogeneous group of immunodeficiencies with characteristically low CD4+ T-cell counts with largely unknown genetic etiology. We here sought to determine the underlying molecular cause in an index family with two patients suffering from combined immunodeficiency that evolved into predominant CD4+ lymphopenia. The more severely affected index patient also presented with selective antibody deficiency against bacterial polysaccharide antigens. METHODS: For the genetic analysis, we used combined homozygosity mapping and exome sequencing. Functional assays included immunoblot analysis, flow cytometry and TCR Vß spectratyping. RESULTS: A novel homozygous missense mutation was revealed in the kinase domain of JAK3 (c.T3196C, p.Cys1066Arg). Further analysis showed revertant chimerism in CD8+ T-cells in both patients. The additional presence of revertant CD4+ T-cells was associated with a milder clinical and immunological phenotype in the second patient, although the role somatic chimerism plays in amelioration of disease phenotype is uncertain, as presence of revertant cells had no effect on residual CD4 cell JAK3 signaling function. Residual activity of JAK3-dependent STAT3 and STAT5 signaling was also found in immortalized B-cell lines indicating a hypomorphic nature of the described mutation which likely contributes to the milder clinical phenotype. CONCLUSIONS: We here present the first case of revertant mosaicism in JAK3 deficiency, manifesting as combined immunodeficiency evolving into predominant CD4+ lymphopenia. Revertant chimerism or hypomorphic mutations in genes typically associated with more severe T-cell deficiency should be considered when assessing patients with milder forms of combined immunodeficiencies.


Assuntos
Linfócitos T CD4-Positivos , Janus Quinase 3/genética , Linfopenia , Imunodeficiência Combinada Severa , Adolescente , Adulto , Sequência de Aminoácidos , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Criança , Pré-Escolar , Quimerismo , Feminino , Humanos , Imunoglobulinas/sangue , Lactente , Janus Quinase 3/metabolismo , Linfopenia/genética , Masculino , Dados de Sequência Molecular , Mutação , Fator de Transcrição STAT5/metabolismo , Alinhamento de Sequência , Transdução de Sinais/genética
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