Measles Sclerosing Subacute PanEncephalitis (SSPE), an intriguing and ever-present disease: Data, assumptions and new perspectives.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a rare, non-treatable and fatal neurological complication of measles, still present due to the return of the epidemic linked to the loosening of vaccination policies. Its mechanism remains unexplained. OBJECTIVE: The main objective was to investigate explanatory variables relating to the risk of developing SSPE and its pathophysiology. METHODS: Literature analysis was focused on different varieties of SSPE: perinatal forms, short-incubation forms similar to acute measles inclusion body encephalitis (MIBE), rapidly evolving forms, forms occurring in the immunosuppressed, adult forms, and family forms. In addition, several studies on the parameters of innate immunity and interferon responses of patients were analyzed. RESULTS: Two main data were highlighted: a relationship between the so-called fulminant forms and the prescription of corticosteroids was established. In familial SSPE, two groups were individualized according to the duration of the latency period, prompting an analysis of patient exomes. CONCLUSION: Treatment with corticosteroids should be banned. Knowledge of the genes involved and epigenetics should be useful for understanding the pathophysiology of SSPE and other late-onset neurological infections with RNA viruses.

Delay in the Diagnosis of APECED: A Case Report and Review of Literature from Iran.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the AIRE (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.

Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation.

Interleukin (IL)-17A is a pro-inflammatory cytokine in mice and humans. It is recognized as a key factor for the protection of mice against various pathogens, but it also underlies pathogenic inflammatory responses in numerous mouse models. The inborn errors of IL-17A- and IL-17F-mediated immunity identified in humans in the last decade have revealed that IL-17A and IL-17F are key players in mucocutaneous immunity to Candida albicans, and, to a lesser extent, Staphylococcus aureus. By contrast, there is currently no genetic evidence for a causal link between excess of IL-17 and autoimmunity, autoinflammation, or allergy in humans. We discuss here the physiological and pathological roles of mouse and human IL-17A and IL-17F in host defense and excessive inflammation. We highlight recent advances in our understanding of the consequences of deficient or excessive IL-17 immunity at various mucocutaneous sites, including the oral cavity, skin, intestine, lungs, and vagina.

A novel homozygous mutation with different clinical presentations in 2 IRAK-4-deficient siblings: first case with recurrent salmonellosis and non-hodgkin lymphoma

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Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Disseminated BCG infectious disease and hyperferritinemia in a patient with a novel NEMO mutation

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Pott's disease in Moroccan children: clinical features and investigation of the interleukin-12/interferon-γ pathway.

SETTING: Tuberculosis spondylodiscitis (TS), or Pott's disease, an extra-pulmonary form of tuberculosis (TB), is rare and difficult to diagnose in children. Some cases of severe TB in children were recently explained by inborn errors of immunity affecting the interleukin-12/interferon-gamma (IL-12/IFN-γ) axis. OBJECTIVE: To analyse clinical data on Moroccan children with TS, and to perform immunological and genetic explorations of the IL-12/IFN-γ axis. DESIGN: We studied nine children with TS diagnosed between 2012 and 2014. We investigated the IL-12/IFN-γ circuit by both whole-blood assays and sequencing of the coding regions of 14 core genes of this pathway. RESULTS: A diagnosis of TS was based on a combination of clinical, biological, histological and radiological data. QuantiFERON(®)-TB Gold In-Tube results were positive in 75% of patients. Whole-blood assays showed normal IL-12 and IFN-γ production in all but one patient, who displayed impaired decreased response to IL-12. No candidate disease-causing mutations were detected in the exonic regions of the 14 genes. CONCLUSIONS: TS diagnosis in children remains challenging, and is based largely on imaging. Further investigations of TS in children are required to determine the role of genetic defects in pathways that may or may not be related to the IL-12/IFN-γ axis.

[Purulent pericarditis and colonic infiltrating to Salmonella enteritidis complicated by acute intussusception in a case of IL-12Rß1 deficiency]. / Péricardite purulente et infiltration colique à Salmonella enteritidis compliquée d'invagination intestinale aiguë dans un cas de déficit en IL-12Rß1.

IL-12 receptor ß1 deficiency (IL-12Rß1) predisposes patients to mycobacteria and Salmonella infections. We report a case of IL-12Rß1 deficiency with a fatal multi-resistant Salmonella enteritidis infection. This boy was born after from a consanguineous marriage, and diagnosed as having a IL-12Rß1 deficiency since the age of 3 months. He presented with recurrent Salmonella enteritidis essentially digestive localization, complicated by purulent pericarditis at the same germ at the age of two and a half years. At the age of 3, a colonic infiltration due to a Salmonella enteritidis resistant to antibiotics, was complicated by acute intussusception, and the child died. The IL-12Rß1 deficiency is considered as having a good prognosis, in contrast to what happened in our patient. We review therapeutic issues in these patients.

Safety of hematopoietic stem cell transplantation from hepatitis B core antibodies-positive donors with low/undetectable viremia in HBV-naïve children.

Scarce data exist on allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in hepatitis B virus (HBV)-naïve recipients from HBV-experienced donors. Long-term follow-up is herein reported for 17 allogeneic HSCT performed in 13 HBV-naïve children from HBc-antibodies-positive donors between 2006 and 2012. Four donors were HBs-antigen-positive, with detectable but low viremia in 2 cases (<2 log10IU/ml). HBV-DNA was undetectable in all transplanted cell products. Recipients' HBV prophylaxis consisted of pre-transplant vaccination, polyvalent immune globulins, specific anti-HBV immune globulins, and/or oral lamivudine in 3, 12, 8, and 8 children, respectively. No case of HBV transmission occurred based on negative close monitoring of recipients' HBV serology and plasma HBV-DNA during a median follow-up of 22 months. In case of undetectable viremia in the donor, prophylaxis with vaccination and/or immune globulins in the recipient seems to be sufficient and lamivudine prophylaxis might be unnecessary to prevent viral transmission. In case of undetectable viremia in the donor, a systematic screening of HBV DNA in the stem cell product might be unnecessary to confirm the low risk of viral transmission. Prior exposure to HBV in the donor should not be considered a contraindication to HSCT.

[Human genetics of tuberculosis]. / Génétique humaine de la tuberculose.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major public health problem worldwide, resulting in 8.7 million new cases and 1.4 million deaths each year. One third of the world's population is exposed to M. tuberculosis and, after exposure, most, but not all, individuals become infected. Among infected subjects, only a minority (∼10%) will eventually develop clinical disease, which is typically either a primary, often extra-pulmonary, TB in children, or a reactivation, pulmonary TB in adults. Considerable genetic epidemiological evidence has accumulated to support a major role for human genetic factors in the development of TB. Numerous association studies with various candidate genes have been conducted in pulmonary TB, with very few consistent results. Recent genome-wide association studies revealed only a modest role for two inter-genic polymorphisms. However, a first major locus for pulmonary TB was mapped to chromosome 8q12-q13 in a Moroccan population after a genome-wide linkage screen. Using a similar strategy, two other major loci controlling TB infection were recently identified. While the precise identification of these major genes is ongoing, the other fascinating observation of these last years was the demonstration that TB can also reflect a Mendelian predisposition. Following the findings obtained in the syndrome of Mendelian susceptibility to mycobacterial diseases, several children with complete IL-12Rß1 deficiency, were found to have severe TB as their sole phenotype. Overall, these recent findings provide the proof of concept that the human genetics of TB involves a continuous spectrum from Mendelian to complex predisposition with intermediate major gene involvement. The understanding of the molecular genetic basis of TB will have fundamental immunological and medical implications, in particular for the development of new vaccines and treatments.

[Fungal infections and congenital immune deficiencies]. / Infections fongiques et déficits immunitaires héréditaires.

Different types of hereditary immune deficiencies are at risk of severe fungal infections. Such infections can reveal the deficit. The type of micro-organisms involved, the clinical presentation, the immune reaction observed around the germ can then guide the etiological diagnosis. As often in the field of immunodeficiencies, advances in the pathophysiology provide crucial informations on the natural defense mechanisms against these organisms. Therapeutic advances have dramatically improved the prognosis of these potentially serious and disabling infections.

[Multifocal infection due to Mycobacterium intracellulare: first case of interferon gamma receptor partial dominant deficiency in tropical French territory]. / Infection multifocale à Mycobacterium intracellulare: premier cas de déficit partiel dominant du récepteur de l'interféron gamma en milieu tropical français.

Nontuberculous mycobacterial infections are rare in immunocompetent children, and usually present as adenitis. We report a case of a 6-year-old girl with a multifocal chronic osteomyelitis and pulmonary localisation due to Mycobacterium intracellulare associated with an autosomal dominant mutation of interferon gamma receptor 1 gene (INFGR1) leading to a syndrome of mendelian predisposition to mycobacteria infections by partial deficiency of intracellular signalisation of gamma interferon. This child has been cured with anti-mycobacteria drugs and gamma interferon. This report focus on the importance of looking for a susceptibility of the host to infectious diseases, which can lead to a specific treatment. As far as we know, this is the first case described in a tropical area.

[Genetic predisposition and children infectious disease]. / Prédisposition génétique et infections de l'enfant.

The classic primary immunodeficiencies confer predisposition to multiple infectious diseases. However since ten years severe pediatric infections which were idiopathic have now molecular explanation. Indeed, defects in several genes confer a predisposition to infection with specific pathogenes in otherwise healthy individuals. These children present a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one microorganisms family, in opposition of others patients with "classic" primary immunodeficiency.

[Genetic susceptibility to mycobacterial disease: Mendelian disorders of the interleukin-12 -interferon-gamma axis]. / Syndrome de susceptibilite mendélienne aux infections mycobacteriennes: défauts de l'axe Interleukine-12 - Interféron-gamma.

INTRODUCTION: Environmental non tuberculous mycobacteria and Bacillus Calmette-Guerin vaccines are weakly virulent mycobacteria. Nevertheless they may cause severe diseases in otherwise healthy children with no overt immunodeficiency. Parental consanguinity and familial forms are frequently observed among these patients, therefore this syndrome was named "Mendelian Susceptibility to Mycobacterial Disease". STATE OF THE ART: In the last nine years, fife genes have been found to be mutated in patients with this syndrome: IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1. Allelic heterogeneity accounts for ten distinct genetic disorders. Clinical phenotype differs between patients. The spectrum of disease extends from early-onset overwhelming mycobacterial infection to adult-onset localized disease and tuberculosis. Impaired IFN-gamma-mediated immunity is the common mechanism of the disease, outlining its major role in mycobacterial immunity. PERSPECTIVES AND CONCLUSIONS: Better understanding of these disorders reveals an expanding clinical phenotype which justifies studying adult patients with pulmonary non tuberculous mycobacterial infection without known risk factors, severe BCGitis and recurrent tuberculosis. Molecular diagnosis makes it possible to introduce a specific regimen based on physiopathology.

Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: a single-center comparative analysis of genoidentical, haploidentical or unrelated donors.

SUMMARY: Hematological inherited diseases can be cured by hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical sibling donor (MSD), but the outcome of unrelated donors (URD) or haploidentical donors (HMD) has been a cause of concern. In all, 94 children affected with inherited diseases underwent HSCT at a single center using MSD (group A, n=31), URD (group B, n=23) or HMD (group C, n=40). There was no difference in the rate of engraftment or in the incidence of grades III-IV acute graft-versus-host disease (GVHD) between the groups. Survival rate was 80.6% in group A, 62.5% in group B and 47.5% in group C (P=0.023). In group B, survival rate was 73.7% in the subgroup with zero or one class I mismatch, and 25% in the subgroup with two or more class I mismatches (P=0.04). In group C, survival rate was 83.3% in the 9/10-identical subgroup, 64.3% in the seven or 8/10 subgroup, and 25% in the five or 6/10 subgroup (P=0.0007). Thus, engraftment, incidence of GVHD and survival are similar in recipients of grafts from MSD, URD with 0-1 class I-mismatch, or HMD with at least 7/10 HLA matches. The low success of HSCT using more disparate donors suggests reserving them for patients with very poor prognosis.

Inherited disorders of the Interleukin-12/ Interferon-gamma axis: Mendelian predisposition to mycobacterial disease in man / Alteraciones hereditarias del eje il-12/ifn-gamma: susceptibilidad mendeliana a la enfermedad por micobacterias en el hombre

Severe disseminated infections with weakly virulent mycobacteria, Salmonella and/or Mycobacterium tuberculosis, in otherwise healthy individuals, characterise a recently defined primary immunodeficiency syndrome named mendelian susceptibility to mycobacterial disease (MSMD, MIM 209950). Molecular analysis of affected families has identified mutations in five genes in the IL- 12/IFN-γ axis, highlighting the importance of this pathway in human immunity to mycobacteria. Genetic heterogeneity accounts for the clinical spectrum of MSMD, ranging from mutations in IFNGR1 or IFNGR2 which result in complete receptor deficiency, disseminated infection in early childhood and progressively fatal disease to, at the other end of the spectrum, mutations involving IFNGR1, STAT1, IL-12 and IL-12Rβ1 in individuals who have not developed infection with either mycobacteria or salmonella. Correlation between clinical phenotype and histopathological findings has also been observed. Immune function in patients with MSMD is in general remarkably normal. Inherited defects of IL-12/IFN-γ axis should be considered in the differential diagnosis of all patients presenting with severe infection with intracellular microorganisms, particularly when the organism is considered to be non-pathogenic in the «immunocompetent» individual. Circulating IFN-γ levels, protein expression, functional studies and ultimately DNA analysis are diagnostic but in approximately half of the patients with the clinical syndrome of MSMD, mutations in IFNGR1, IFNGR2, STAT1, IL-12B, or IL-12RB1 have not been found. Children with MSMD should be treated on an individual basis, in close collaboration with a centre specialised in the care of such patients. The investigation of more patients is necessary to further understand human mycobacterial immunity (AU)

El síndrome de inmunodeficiencia primaria descrito recientemente y denominado susceptibilidad mendeliana a las enfermedades micobacterianas (MSDM, MIM 209950), se caracteriza por infecciones diseminadas causadas por micobacterias poco virulentas, Salmonella y/o Mycobacterium Tuberculosis, en individuos, por lo demás, sanos. El análisis molecular de las familias afectas ha permitido identificar mutaciones en cinco genes del eje IL-12/IFN-γ, destacando la importancia de esta vía en la inmunidad humana frente a las micobacterias. La heterogeneidad genética explica el amplio espectro clínico de la MSMD que abarca desde las mutaciones en los genes IFNGR1 o IFNGR2, con un defecto completo de receptor e infecciones diseminadas y fatales en la infancia, hasta el otro extremo, en el que se han hallado mutaciones en los genes IFNGR1, STAT1, IL-12 e IL-12Rβ1 en individuos que no han padecido infecciones por micobacterias ni salmonella. También se ha podido observar que existe una correlación entre el fenotipo clínico y los hallazgos histopatológicos. La función inmunológica en los pacientes con MSMD es en general normal. Los defectos hereditarios del eje IL-12/IFN-γ deberían considerarse en el diagnóstico diferencial de todos los pacientes con infecciones severas por microorganismos intracelulares, sobretodo cuando éstos se consideran no patógenos en el individuo inmunocompetente. Los niveles plasmáticos de IFN-γ, la expresión de la proteína, los estudios funcionales y en última instancia el análisis del DNA, son procedimientos diagnósticos, pero en la mitad de los casos con el síndrome clínico de MSMD no se han hallado mutaciones en IFNGR1, IFNGR2, STAT1, IL-12B o IL- 12RB1. Los niños con MSMD deberían ser tratados a nivel individual, en colaboración con algún centro especializado en el manejo de estos pacientes. Es necesario investigar un número mayor de pacientes para poder entender mejor la inmunidad micobacteriana humana (AU)

Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway.

Patients with genetic lesions in the Type-1 cytokine/cytokine receptor pathway exhibit a selective susceptibility to severe infections with poorly pathogenic mycobacteria and non-typhi salmonella spp. These experiments of nature demonstrate that IL-12-dependent IFNgamma production is critical for granuloma formation and therefore host immunity against such pathogens. The essential role of granuloma formation for protective immunity to these organisms is emphasized by the differing granuloma forming capabilities and resultant clinical sequelae observed in these patients which seems to reflect their ability to produce or respond to IFNgamma (Fig. 9). At one pole of this spectrum, represented by the complete IFNgammaR1/2 deficient patients, there is a complete absence of mature granuloma formation, whereas with the less severe mutations (i.e. partial IFNgammaR1/2, complete IL-12p40 and complete IL-12Rbeta1 deficiency), granuloma formation is very heterogenous with wide variations in composition being observed. This suggests that in the latter individuals, who produce partial but suboptimal IFNgamma responses, other influences, including pathogen virulence and host genotype may also affect the type and scale of the cellular response elicited.