RESUMO
This study reports a patient with severe skin disease in the context of profound immunodeficiency explained by two concomitant genetic diseases caused by two novel homozygous loss-of-function mutations in PLEC1 and CARMIL2. The work provides additional information on the clinical and immunological manifestations of CARMIL2 deficiency and highlights the particular diagnostic and therapeutic challenge represented by the concomitant presence of two rare monogenic disorders.
Assuntos
Epidermólise Bolhosa/genética , Síndromes de Imunodeficiência/genética , Proteínas dos Microfilamentos/genética , Plectina/genética , Pré-Escolar , Epidermólise Bolhosa/complicações , Humanos , Síndromes de Imunodeficiência/complicações , Masculino , MutaçãoAssuntos
Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/genética , Mutação , Fator de Transcrição STAT1/genética , Fatores de Transcrição/genética , Alelos , Candidíase Mucocutânea Crônica/imunologia , Candidíase Mucocutânea Crônica/terapia , Criança , Genótipo , Humanos , Imunofenotipagem , Contagem de Linfócitos , Masculino , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Proteína AIRERESUMO
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Assuntos
Síndromes de Imunodeficiência , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Diagnóstico Tardio , Feminino , Terapia Genética , Alemanha/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Adulto JovemRESUMO
Anti-cytokine autoantibodies (ACAAs) have been described in a growing number of primary immunodeficiencies with autoimmune features, including autoimmune polyendocrine syndrome type I (APS-1), a prototypical disease of defective T cell-mediated central tolerance. Whether defects in peripheral tolerance lead to similar ACAAs is unknown. Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) is caused by mutations in FOXP3, a master regulator of T regulatory cells (Treg), and consequently results in defective T cell-mediated peripheral tolerance. Unique autoantibodies have previously been described in IPEX. To test the hypothesis that ACAAs are present in IPEX, we designed and fabricated antigen microarrays. We discovered elevated levels of IgG ACAAs against interferon-α (IFN-α) in a cohort of IPEX patients. Serum from IPEX patients blocked IFN-α signaling in vitro and blocking activity was tightly correlated with ACAA titer. To show that blocking activity was mediated by IgG and not other serum factors, we purified IgG and showed that blocking activity was contained entirely in the immunoglobulin fraction. We also screened for ACAAs against IFN-α in a second geographically distinct cohort. In these samples, ACAAs against IFN-α were elevated in a post hoc analysis. In summary, we report the discovery of ACAAs against IFN-α in IPEX, an experiment of nature demonstrating the important role of peripheral T cell tolerance.