Assuntos
Suscetibilidade a Doenças , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/etiologia , Mycobacterium xenopi , Adulto , Predisposição Genética para Doença , Humanos , Mycobacterium xenopi/imunologiaAssuntos
Autoimunidade/genética , Predisposição Genética para Doença , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Febre Tifoide/diagnóstico , Febre Tifoide/etiologia , Alelos , Biomarcadores , Biópsia , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Imunofenotipagem , Lactente , Masculino , Fenótipo , RecidivaRESUMO
OBJECTIVE: Interleukin 12 receptor beta 1 (IL-12Rß1) deficiency is a primary immunodeficiency that exposes affected individuals to an augmented risk of intracellular pathogen-mediated infections. The paradoxical presence of autoimmune manifestations in immune-deficient patients has been recognized, but the basis of this phenomenon is unclear, with the role of frequent infections being a possible trigger to break tolerance. Our study aimed to analyze extensively a profile of autoantibodies in a clinically well-defined case series of patients with IL-12Rß1 deficiency. METHODS: Eight patients with IL-12Rß1 deficiency referred to Children's Medical Center in Tunis, Tunisia, during 1995-2012 were enrolled in the study. Sixteen age- and gender-matched blood donors served as controls. Serum, liver-related autoantibodies immunoglobulin (Ig)G, IgM, IgA were tested by ELISA and by standard indirect immunofluorescence on Hep-2 cells. RESULTS: We found a significant prevalence of liver autoantibodies in the study group. Regarding primary biliary cholangitis (PBC), two of eight patients were positive for MIT3 autoantibodies, both confirmed by immunofluorescence, and one patient was positive for PBC-specific antinuclear antibodies, sp100. Moreover, two patients had significantly increased gamma-glutamyltransferase levels and one had IgM levels twice the upper limit of normal. Intriguingly two patients were positive for anti-actin antibodies; a typical feature of autoimmune hepatitis type 1, along with a significant increase in IgG levels. CONCLUSIONS: This is the first report of a serological analysis in patients with an IL-12Rß1 deficiency. Despite the difficulty in interpreting the role of the IL-12, the evidence of liver-specific autoantibodies confirms the importance its signal in liver autoimmunity.
Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/sangue , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Hepatopatias/sangue , Adulto , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Feminino , Humanos , Lactente , Subunidade beta 1 de Receptor de Interleucina-12/imunologia , Fígado/imunologia , Hepatopatias/imunologia , MasculinoRESUMO
PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rß1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rß1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rß1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rß1-deficient patients with a complete loss of IL-12Rß1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n = 1) or in trans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rß1 deficiency.
Assuntos
Elementos Alu , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Alelos , Sequência de Bases , Mapeamento Cromossômico , Feminino , Expressão Gênica , Humanos , Interferon gama , Masculino , Mutação , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Infecções por Mycobacterium/metabolismo , Linhagem , FenótipoRESUMO
Host adaptation is a key factor contributing to the emergence of new bacterial, viral and parasitic pathogens. Many pathogens are considered promiscuous because they cause disease across a range of host species, while others are host-adapted, infecting particular hosts1. Host adaptation can potentially progress to host restriction where the pathogen is strictly limited to a single host species and is frequently associated with more severe symptoms. Host-adapted and host-restricted bacterial clades evolve from within a broader host-promiscuous species and sometimes target different niches within their specialist hosts, such as adapting from a mucosal to a systemic lifestyle. Genome degradation, marked by gene inactivation and deletion, is a key feature of host adaptation, although the triggers initiating genome degradation are not well understood. Here, we show that a chronic systemic non-typhoidal Salmonella infection in an immunocompromised human patient resulted in genome degradation targeting genes that are expendable for a systemic lifestyle. We present a genome-based investigation of a recurrent blood-borne Salmonella enterica serotype Enteritidis (S. Enteritidis) infection covering 15 years in an interleukin (IL)-12 ß-1 receptor-deficient individual that developed into an asymptomatic chronic infection. The infecting S. Enteritidis harbored a mutation in the mismatch repair gene mutS that accelerated the genomic mutation rate. Phylogenetic analysis and phenotyping of multiple patient isolates provides evidence for a remarkable level of within-host evolution that parallels genome changes present in successful host-restricted bacterial pathogens but never before observed on this timescale. Our analysis identifies common pathways of host adaptation and demonstrates the role that immunocompromised individuals can play in this process.
Assuntos
Adaptação Fisiológica/genética , Genoma Bacteriano , Interações Hospedeiro-Patógeno , Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/complicações , Infecções por Salmonella/microbiologia , Salmonella enteritidis/genética , Adulto , Bacteriemia/microbiologia , Doença Crônica , Evolução Molecular , Especificidade de Hospedeiro , Humanos , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Subunidade beta 1 de Receptor de Interleucina-12/genética , Mutação , Taxa de Mutação , Infecções por Salmonella/complicações , Salmonella enteritidis/classificação , Salmonella enteritidis/isolamento & purificação , Salmonella enteritidis/patogenicidade , VirulênciaRESUMO
Primary immunodeficiences are often accompanied by autoimmune phenomena. IL-12 receptor deficiency is a well characterized primary immunodeficiency that leads to propensity to intracellular infections mainly with mycobacteria and Salmonella. We report on two patients with IL-12 receptor ß1 deficiency that presented with autoimmune manifestations and photosensitivity dermatitis and describe possible pathogenetic mechanisms leading to development of clinically significant autoimmune phenomena.
Assuntos
Doenças Autoimunes/genética , Autoimunidade/genética , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Transtornos de Fotossensibilidade/genética , Doenças Autoimunes/diagnóstico , Biópsia , Criança , Humanos , Pulmão/patologia , Masculino , Transtornos de Fotossensibilidade/diagnóstico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Interleukin 12Rß1 (IL-12Rß1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rß1 deficiency. RESULTS: Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. CONCLUSIONS: Patients who are deficient in IL-12Rß1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.
Assuntos
Candidíase/imunologia , Candidíase/patologia , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , RecidivaRESUMO
A patient presented with late onset disseminated nontuberculous mycobacterium (NTM) infection due to a novel interleukin-12/interleukin-23 receptor ß1 (IL-12/IL-23Rß1) mutation, r.1561C>G, leading to the amino acid substitution R521G. This is the second patient reported with a partial IL-12/IL-23Rß1 defect.
Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/imunologia , Micobactérias não Tuberculosas/imunologia , Receptores de Interleucina/deficiência , Adulto , Sequência de Bases , Citocinas/biossíntese , Citocinas/imunologia , Genótipo , Humanos , Imunofenotipagem , Subunidade beta 1 de Receptor de Interleucina-12/genética , Subunidade beta 1 de Receptor de Interleucina-12/metabolismo , Masculino , Mutação , Fosforilação , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Fator de Transcrição STAT4/metabolismoRESUMO
Interleukin-12 receptor ß1 (IL-12Rß1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rß1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.
Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Subunidade beta 1 de Receptor de Interleucina-12/genética , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/genética , Mycobacterium bovis/isolamento & purificação , Mycobacterium tuberculosis/isolamento & purificação , Micobactérias não Tuberculosas/isolamento & purificação , Análise de SobrevidaRESUMO
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder with predisposition to severe, sometimes lethal, disease caused by otherwise poorly virulent, non-tuberculous environmental mycobacteria and poorly virulent salmonellae. In patients with MSMD, mutations have been identified in five genes that encode for the proteins IL-12/IL-23p40, IL-12/ IL-23Rbeta1, IFN-R1, IFN-gammaR2 and STAT1. These proteins play important roles in the type-1 cytokine pathway, which is crucial for human host defence against intracellular pathogens such as mycobacteria and salmonellae. We report a girl with mild Mycobacterium bovis Bacille Calmette-Guérin (BCG) disease and Salmonella enteritidis cervical lymphadenitis. Despite treatment, she has remained a fecal carrier of S. enteritidis for the past 14 years. She was found to have complete IL-12/IL-23Rbeta1 deficiency. A homozygous r.518G>C IL12RB1 mutation was identified, leading to a non-functional R173P substitution in the IL-12/IL-23Rbeta1 protein. This mutation abrogated IL-12/IL-23Rbeta1 cell-surface expression and resulted in complete lack of T cell responsiveness to both IL-12 and IL-23.
Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Linfadenite/microbiologia , Mycobacterium bovis/isolamento & purificação , Receptores de Interleucina/deficiência , Infecções por Salmonella/microbiologia , Salmonella enteritidis/isolamento & purificação , Tuberculose/microbiologia , Adulto , Feminino , Humanos , Subunidade beta 1 de Receptor de Interleucina-12/genética , Mutação Puntual , Receptores de Interleucina/genética , Infecções por Salmonella/imunologia , Tuberculose/imunologiaAssuntos
Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Tuberculose Miliar/genética , Tuberculose Miliar/imunologia , Tuberculose Resistente a Múltiplos Medicamentos/genética , Antibacterianos/uso terapêutico , Antituberculosos/uso terapêutico , Povo Asiático/genética , Vacina BCG/efeitos adversos , Pré-Escolar , Consanguinidade , Predisposição Genética para Doença , Humanos , Masculino , Tuberculose Miliar/etiologia , Tuberculose Miliar/terapia , Tuberculose Resistente a Múltiplos Medicamentos/etiologia , Tuberculose Resistente a Múltiplos Medicamentos/imunologia , Tuberculose Resistente a Múltiplos Medicamentos/terapiaAssuntos
Subunidade beta 1 de Receptor de Interleucina-12 , Infecção por Mycobacterium avium-intracellulare , Infecções Pneumocócicas/microbiologia , Sepse , Códon sem Sentido , Consanguinidade , Feminino , Humanos , Lactente , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Subunidade beta 1 de Receptor de Interleucina-12/genética , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/genética , Infecção por Mycobacterium avium-intracellulare/imunologia , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecções Pneumocócicas/genética , Infecções Pneumocócicas/imunologia , Sepse/genética , Sepse/imunologia , Sepse/microbiologia , Streptococcus pneumoniae , Estados UnidosRESUMO
To investigate whether protective immune responses can be induced in the absence of normal interleukin-12/23/gamma interferon (IL-12/23/IFN-gamma) axis signaling, we vaccinated with the seasonal influenza virus subunit vaccine two patients with complete IL-12/23 receptor beta1 (IL-12/23R beta 1) deficiencies, two patients with partial IFN-gamma receptor I (pIFN-gamma RI) deficiencies, and five healthy controls. Blood samples were analyzed before, 7 days after, and 28 days after vaccination. In most cases, antibody titers reached protective levels. Moreover, although T-cell responses in patients were lower than those observed in controls, significant influenza virus-specific T-cell proliferation, IFN-gamma production, and numbers of IFN-gamma-producing cells were found in all patients 7 days after the vaccination. Interestingly, influenza virus-specific IFN-gamma responses were IL-12/23 independent, in striking contrast to mycobacterium-induced IFN-gamma production. In conclusion, influenza virus vaccination induces IL-12/23-independent IFN-gamma production by T cells and can result in sufficient humoral protection in both IL-12/23R beta 1- and pIFN-gamma RI-deficient individuals.