RESUMEN
ALPS and IPEX are two well-characterized inborn errors of immunity with immune dysregulation, considered as two master models of monogenic auto-immune diseases. Thus, with autoimmunity as their primary clinical manifestation, these two entities may show clinical overlap. Traditionally, immunological biomarkers are used to establish an accurate differential diagnosis. Herein, we describe a patient who presented with clinical features and biomarkers fulfilling the diagnostic criteria of ALPS. Severe apoptotic defect was also shown in the patient's cell lines and PHA-activated peripheral blood lymphocytes. Sanger sequencing of the FAS gene did not reveal any causal mutation. NGS screening revealed a novel deleterious variant located in the N terminal repressor domain of FOXP3 but no mutations in the FAS pathway-related genes. TEMRA cells (terminally differentiated effector memory cells re-expressing CD45RA) and PD1 expression were increased arguing in favor of T-cell exhaustion, which could be induced by unrestrained activation of T effector cells because of Treg deficiency. Moreover, defective FOXP3 observed in the patient could intrinsically induce increased proliferation and resistance to apoptosis in T effector cells. This observation expands the spectrum of FOXP3 deficiency and underscores the role of NGS in detecting mutations that induce overlapping phenotypes among inborn errors of immunity with immune dysregulation. In addition, these findings suggest a potential link between FOXP3 and FAS pathways.
Asunto(s)
Síndrome Linfoproliferativo Autoinmune/genética , Factores de Transcripción Forkhead/genética , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/inmunología , Niño , Humanos , Masculino , MutaciónRESUMEN
Hereditary C1q deficiency (C1qD) is the most penetrant genetic factor predisposing to the development of lupus pathology with more than 93% of C1q deficient patients developing this autoimmune pathology throughout their life. It is a rare autosomal recessive deficiency, with only 67 cases reported so far including one Tunisian girl who died at the age of three from complications resulting from severe systemic lupus erythematosus. Although C1qD was confirmed in the serum of this patient using C1q ELISA and classical pathway specific functional assays, no DNA sample had been obtained from this patient. Here we report the analysis of sera and DNA of members of this patient's closer family. Our analysis identified a homozygous mutation within the gene encoding the C-chain of C1q leading to a deficiency of C1q in an older sister of our original patient. This mutation, termed g.5580G4C, represents a single basepair substitution in exon 1 of the C1q C chain gene which changes the codon of Gly61 to Arg 61. Amongst the other 14 mutations leading to C1qD, g.5580G4C represents the first reported transversion leading to human C1qD.
Asunto(s)
Complemento C1q/genética , Lupus Eritematoso Cutáneo/genética , Lupus Eritematoso Sistémico/genética , Mutación/genética , Adolescente , Preescolar , Complemento C1q/metabolismo , Análisis Mutacional de ADN , Progresión de la Enfermedad , Familia , Resultado Fatal , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Hemólisis/genética , Humanos , Lupus Eritematoso Cutáneo/inmunología , Lupus Eritematoso Sistémico/inmunología , Linaje , Polimorfismo Genético , Hermanos , TúnezAsunto(s)
Factor Activador de Células B/sangre , Enfermedades Endémicas , Pénfigo/sangre , Pénfigo/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/metabolismo , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pénfigo/diagnóstico , Estudios Retrospectivos , Túnez/epidemiología , Adulto JovenRESUMEN
The aim of this study was to evaluate the prevalence of anticardiolipin antibodies (aCL) and anti-beta(2)-glycoprotein I antibodies (abeta2GPI) in patients with celiac disease and to analyze the clinical features of antiphospholipid syndrome in these patients. We conducted a prospective case-control study based on the evaluation of IgG, IgM and IgA aCL, and IgG and IgA abeta2GPI in celiac disease patients and in controls. All patients were asked about any occurrence of thrombotic manifestations. In addition, women were asked about pregnancy morbidity. Fifty celiac disease patients and 50 healthy controls were studied. IgM aCL were not detected in study group or in controls. IgG aCL were found in two patients and in one control. IgA aCL were significantly more frequent in celiac disease patients compared with controls (13/50 (26%) vs. 2/50 (4%), p=0.004, OR [95% CI]=9.09 [1.81-50]). There was no statistically significant difference for the prevalence of IgG and IgA abeta2GPI between patients and controls. Clinical features of antiphospholipid syndrome were noted in two patients with negative antibodies. Prevalence of IgM and IgG aCL and of abeta2GPI were not increased in celiac disease. IgA aCL were more frequently detected in celiac disease. However, no clinical features of antiphospholipid syndrome were noted.