RÉSUMÉ
Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.
Sujet(s)
Auto-immunité , Animaux , Humains , Souris , Auto-immunité/génétique , Protéines de transport membranaire/génétique , Protéines de transport membranaire/métabolisme , Analyse de mutations d'ADN , Récepteurs de type Toll/métabolisme , Récepteurs de type Toll/génétique , Mutation , Femelle , Mâle , Souris de lignée C57BL , Cellules HEK293 , Récepteur de type Toll-7/génétique , Récepteur de type Toll-7/métabolisme , Maladies auto-immunes/génétique , Maladies auto-immunes/immunologieRÉSUMÉ
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet ß-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.
Sujet(s)
Maladies auto-immunes , Diabète de type 1 , Femelle , Animaux , Souris , Hélicase IFIH1 inductrice de l'interféron/génétique , DEAD-box RNA helicases/métabolisme , Lymphocytes T CD8+/métabolisme , Prédisposition génétique à une maladie , Souris de lignée NOD , Maladies auto-immunes/génétique , Interférons/génétiqueRÉSUMÉ
Inborn errors of immunity (IEIs) are monogenic disorders that predispose patients to immune dysregulation, autoimmunity, and infection. Autoimmune cytopenias, such as immune thrombocytopenia (ITP) and Evans syndrome (a combination of ITP and autoimmune hemolytic anemia), are increasingly recognized phenotypes of IEI. Although recent findings suggest that IEIs may commonly underlie pediatric ITP and Evans syndrome, its prevalence in adult patients with these disorders remains undefined. This study sought to estimate the prevalence of underlying IEIs among adults with persistent or chronic ITP or Evans syndrome using a next-generation sequencing panel encompassing >370 genes implicated in IEIs. Forty-four subjects were enrolled from an outpatient adult hematology clinic at a tertiary referral center in the United States, with a median age of 49 years (range, 20-83). Fourteen subjects (31.8%) had secondary ITP, including 8 (18.2%) with Evans syndrome. No cases of IEI were identified despite a high representation of subjects with a personal history of autoimmunity (45.5%) and early onset of disease (median age at diagnosis of 40 years [range, 2-77]), including 20.5% who were initially diagnosed as children. Eight subjects (18.2%) were found to be carriers of pathogenic IEI variants, which, in their heterozygous state, are not disease-causing. One case of TUBB1-related congenital thrombocytopenia was identified. Although systematic screening for IEI has been proposed for pediatric patients with Evans syndrome, findings from this real-world study suggest that inclusion of genetic testing for IEI in the routine work-up of adults with ITP and Evans syndrome has a low diagnostic yield.
Sujet(s)
Anémie hémolytique auto-immune , Purpura thrombopénique idiopathique , Thrombopénie , Humains , Adulte , Enfant , Jeune adulte , Adulte d'âge moyen , Sujet âgé , Sujet âgé de 80 ans ou plus , Enfant d'âge préscolaire , Adolescent , Anémie hémolytique auto-immune/épidémiologie , Anémie hémolytique auto-immune/génétique , Anémie hémolytique auto-immune/complications , Purpura thrombopénique idiopathique/épidémiologie , Purpura thrombopénique idiopathique/génétique , Purpura thrombopénique idiopathique/complications , Auto-immunité , Prévalence , Thrombopénie/épidémiologie , Thrombopénie/génétique , Thrombopénie/complicationsRÉSUMÉ
Heterozygous signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections and predisposition to humoral autoimmunity. To gain insights into immune characteristics of STAT1-driven inflammation, we performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome and age-matched controls. Affected individuals exhibited dysregulated CD4+ T cell and B cell activation, including expansion of TH1-skewed CXCR3+ populations that correlated with serum autoantibody titers. To dissect underlying immune mechanisms, we generated Stat1 GOF transgenic mice (Stat1GOF mice) and confirmed the development of spontaneous humoral autoimmunity that recapitulated the human phenotype. Despite clinical resemblance to human regulatory T cell (Treg) deficiency, Stat1GOF mice and humans with STAT1 GOF syndrome exhibited normal Treg development and function. In contrast, STAT1 GOF autoimmunity was characterized by adaptive immune activation driven by dysregulated STAT1-dependent signals downstream of the type 1 and type 2 interferon (IFN) receptors. However, in contrast to the prevailing type 1 IFN-centric model for STAT1 GOF autoimmunity, Stat1GOF mice lacking the type 1 IFN receptor were only partially protected from STAT1-driven systemic inflammation, whereas loss of type 2 IFN (IFN-γ) signals abrogated autoimmunity. Last, germline STAT1 GOF alleles are thought to enhance transcriptional activity by increasing total STAT1 protein, but the underlying biochemical mechanisms have not been defined. We showed that IFN-γ receptor deletion normalized total STAT1 expression across immune lineages, highlighting IFN-γ as the critical driver of feedforward STAT1 elevation in STAT1 GOF syndrome.
Sujet(s)
Auto-immunité , Mutation gain de fonction , Humains , Enfant , Souris , Animaux , Auto-immunité/génétique , Interféron gamma/métabolisme , Syndrome , Inflammation , Facteur de transcription STAT-1/génétique , Facteur de transcription STAT-1/métabolismeRÉSUMÉ
NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models of ELF4 deficiency (Elf4-/-) and using a knockdown human NK cell line, we determined that ELF4 is necessary for normal NK cell development, terminal maturation, and function. Through characterization of the NK cells of the proband, expression of the proband's variant in Elf4-/- mouse hematopoietic precursor cells, and a human in vitro NK cell maturation model, we established this ELF4 variant as a potentially novel cause of NKD.
Sujet(s)
Facteurs de transcription , Animaux , Humains , Souris , Protéines de liaison à l'ADN/génétique , Cellules tueuses naturelles , Facteurs de transcription/génétiqueRÉSUMÉ
Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.
Sujet(s)
COVID-19 , Interféron de type I , Antiviraux/métabolisme , Enfant , Humains , Modes de transmission héréditaire , Interféron de type I/génétique , Interféron de type I/métabolisme , Récepteur à l'interféron alpha-bêtaRÉSUMÉ
BACKGROUND: Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes. OBJECTIVE: We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management. METHODS: Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis. RESULTS: Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation. CONCLUSIONS: Many childhood disorders now bundled as "IPEX-like" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis.
Sujet(s)
Diabète de type 1/congénital , Diarrhée/génétique , Maladies génétiques liées au chromosome X/génétique , Maladies du système immunitaire/congénital , Adolescent , Enfant , Enfant d'âge préscolaire , Diabète de type 1/diagnostic , Diabète de type 1/génétique , Diabète de type 1/thérapie , Diarrhée/diagnostic , Diarrhée/thérapie , Femelle , Expression des gènes , Maladies génétiques liées au chromosome X/diagnostic , Maladies génétiques liées au chromosome X/thérapie , Transplantation de cellules souches hématopoïétiques , Humains , Maladies du système immunitaire/diagnostic , Maladies du système immunitaire/génétique , Maladies du système immunitaire/thérapie , Nourrisson , Nouveau-né , Mâle , MutationRÉSUMÉ
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-ALL often associated with genetic variants that alter cytokine receptor signaling, including mutations in the interleukin-7 receptor (IL7R). To investigate whether IL7R variants are leukemia-initiating, we built mouse models expressing activated Il7r (aIL7R). B-cell intrinsic aIL7R mice developed spontaneous B-ALL, demonstrating sufficiency of Il7r activating mutations in leukemogenesis. Concomitant introduction of a knock-out allele in the associated adapter protein Lnk (encoded by Sh2b3) or a dominant-negative variant of the transcription factor Ikaros (Ikzf1) increased disease penetrance. The resulting murine leukemias displayed monoclonality and recurrent somatic Kras mutations and efficiently engrafted into immunocompetent mice. Phosphoproteomic analyses of aIL7R leukemic cells revealed constitutive Stat5 signaling and B cell receptor (BCR)-like signaling despite the absence of surface pre-BCR. Finally, in vitro treatment of aIL7R leukemic B-cells with Jak, mTOR, or Syk inhibitors blocked growth, confirming that each pathway is active in this mouse model of IL7R-driven B-ALL.
Sujet(s)
Régulation de l'expression des gènes dans la leucémie , Leucémie-lymphome lymphoblastique à précurseurs B/anatomopathologie , Récepteurs à l'interleukine-7/métabolisme , Animaux , Apoptose , Prolifération cellulaire , Humains , Souris , Souris de lignée NOD , Souris SCID , Leucémie-lymphome lymphoblastique à précurseurs B/étiologie , Leucémie-lymphome lymphoblastique à précurseurs B/métabolisme , Récepteurs à l'interleukine-7/génétique , Cellules cancéreuses en culture , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
The single-nucleotide polymorphism (SNP) rs3184504 is broadly associated with increased risk for multiple autoimmune and cardiovascular diseases. Although the allele is uniquely enriched in European descent, the mechanism for the widespread selective sweep is not clear. In this study, we find the rs3184504*T allele had a strong association with reduced mortality in a human sepsis cohort. The rs3184504*T allele associates with a loss-of-function amino acid change (p.R262W) in the adaptor protein SH2B3, a likely causal variant. To better understand the role of SH2B3 in sepsis, we used mouse modeling and challenged SH2B3-deficient mice with a polymicrobial cecal-ligation puncture (CLP) procedure. We found SH2B3 deficiency improved survival and morbidity with less organ damage and earlier bacterial clearance compared with control mice. The peritoneal infiltrating cells exhibited augmented phagocytosis in Sh2b3 -/- mice with enriched recruitment of Ly6Chi inflammatory monocytes despite equivalent or reduced chemokine expression. Rapid cycling of monocytes and progenitors occurred uniquely in the Sh2b3 -/- mice following CLP, suggesting augmented myelopoiesis. To model the hypomorphic autoimmune risk allele, we created a novel knockin mouse harboring a similar point mutation in the murine pleckstrin homology domain of SH2B3. At baseline, phenotypic changes suggested a hypomorphic allele. In the CLP model, homozygous knockin mice displayed improved mortality and morbidity compared with wild-type or heterozygous mice. Collectively, these data suggest that hypomorphic SH2B3 improves the sepsis response and that balancing selection likely contributed to the relative frequency of the autoimmune risk variant.
Sujet(s)
Protéines adaptatrices de la transduction du signal/immunologie , Sepsie/immunologie , Protéines adaptatrices de la transduction du signal/génétique , Adulte , Animaux , Modèles animaux de maladie humaine , Humains , Souris , Souris congéniques , Souris de lignée C57BL , Souris knockout , Souris transgéniques , Polymorphisme de nucléotide simple/génétique , Sepsie/génétiqueRÉSUMÉ
Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.
Sujet(s)
2',5'-Oligoadenylate synthetase/métabolisme , COVID-19/virologie , SARS-CoV-2/métabolisme , Animaux , COVID-19/immunologie , Systèmes CRISPR-Cas , Lignée cellulaire , Édition de gène , Humains , Polymorphisme de nucléotide simple , SARS-CoV-2/isolement et purificationRÉSUMÉ
SAMD9L is an interferon-induced tumor suppressor implicated in a spectrum of multisystem disorders, including risk for myeloid malignancies and immune deficiency. We identified a heterozygous de novo frameshift variant in SAMD9L in an infant with B cell aplasia and clinical autoinflammatory features who died from respiratory failure with chronic rhinovirus infection. Autopsy demonstrated absent bone marrow and peripheral B cells as well as selective loss of Langerhans and Purkinje cells. The frameshift variant led to expression of a truncated protein with interferon treatment. This protein exhibited a gain-of-function phenotype, resulting in interference in global protein synthesis via inhibition of translational elongation. Using a mutational scan, we identified a region within SAMD9L where stop-gain variants trigger a similar translational arrest. SAMD9L variants that globally suppress translation had no effect or increased mRNA transcription. The complex-reported phenotype likely reflects lineage-dominant sensitivities to this translation block. Taken together, our findings indicate that interferon-triggered SAMD9L gain-of-function variants globally suppress translation.
Sujet(s)
Mutation avec décalage du cadre de lecture , Régulation de l'expression des gènes/génétique , Mutation germinale , Biosynthèse des protéines/génétique , Protéines suppresseurs de tumeurs/génétique , Cellules A549 , Lymphocytes B/métabolisme , Lymphocytes B/anatomopathologie , Issue fatale , Femelle , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Cellules HEK293 , Hétérozygote , Humains , Nouveau-né , Interférons/pharmacologie , Syndromes myélodysplasiques/génétique , Syndromes myélodysplasiques/métabolisme , Protéines suppresseurs de tumeurs/métabolisme , Séquençage du génome entierRÉSUMÉ
Glycosylation is a critical post/peri-translational modification required for the appropriate development and function of the immune system. As an example, abnormalities in glycosylation can cause antibody deficiency and reduced lymphocyte signaling, although the phenotype can be complex given the diverse roles of glycosylation. Human MGAT2 encodes N-acetylglucosaminyltransferase II, which is a critical enzyme in the processing of oligomannose to complex N-glycans. Complex N-glycans are essential for immune system functionality, but only one individual with MGAT2-CDG has been described to have an abnormal immunologic evaluation. MGAT2-CDG (CDG-IIa) is a congenital disorder of glycosylation (CDG) associated with profound global developmental disability, hypotonia, early onset epilepsy, and other multisystem manifestations. Here, we report a 4-year old female with MGAT2-CDG due to a novel homozygous pathogenic variant in MGAT2, a 4-base pair deletion, c.1006_1009delGACA. In addition to clinical features previously described in MGAT2-CDG, she experienced episodic asystole, persistent hypogammaglobulinemia, and defective ex vivo mitogen and antigen proliferative responses, but intact specific vaccine antibody titers. Her infection history has been mild despite the testing abnormalities. We compare this patient to the 15 previously reported patients in the literature, thus expanding both the genotypic and phenotypic spectrum for MGAT2-CDG.
Sujet(s)
Troubles du rythme cardiaque/génétique , Troubles congénitaux de la glycosylation/génétique , Maladies du système immunitaire/génétique , N-acetylglucosaminyltransferase/génétique , Troubles du rythme cardiaque/complications , Troubles du rythme cardiaque/immunologie , Troubles du rythme cardiaque/anatomopathologie , Enfant d'âge préscolaire , Troubles congénitaux de la glycosylation/complications , Troubles congénitaux de la glycosylation/immunologie , Troubles congénitaux de la glycosylation/anatomopathologie , Femelle , Glycosylation , Homozygote , Humains , Maladies du système immunitaire/complications , Maladies du système immunitaire/immunologie , Maladies du système immunitaire/anatomopathologie , Mutation/génétique , N-acetylglucosaminyltransferase/immunologie , PhénotypeRÉSUMÉ
Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a "cloning-free" saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.
Sujet(s)
Protéines adaptatrices de signalisation CARD/génétique , Variation génétique , Guanylate cyclase/génétique , Déficits immunitaires/génétique , Adénine/analogues et dérivés , Adénine/pharmacologie , Protéine-10 du lymphome LLC à cellules B/génétique , Lymphocytes B/cytologie , Lignée cellulaire , Diploïdie , Exons , Gènes dominants , Humains , Cellules Jurkat , Lymphomes/génétique , Sous-unité p50 de NF-kappa B/génétique , Pipéridines/pharmacologie , Polymorphisme de nucléotide simple , Maladies d'immunodéficience primaire/génétique , Sensibilité et spécificitéRÉSUMÉ
BACKGROUND: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited. CASE PRESENTATION: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. CONCLUSIONS: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.
Sujet(s)
Anémie hémolytique congénitale , Anémie hémolytique , Troubles de la croissance , Heme oxygenase-1/déficit , Hépatomégalie/imagerie diagnostique , Troubles du métabolisme du fer , Insuffisance respiratoire , Rate , Anémie hémolytique/diagnostic , Anémie hémolytique/génétique , Anémie hémolytique congénitale/sang , Anémie hémolytique congénitale/diagnostic , Anémie hémolytique congénitale/physiopathologie , Anémie hémolytique congénitale/thérapie , Bilirubine/sang , Myélogramme/méthodes , Enfant , Aggravation clinique , Soins de réanimation/méthodes , Diagnostic , Issue fatale , Troubles de la croissance/diagnostic , Troubles de la croissance/génétique , Heme oxygenase-1/génétique , Humains , Troubles du métabolisme du fer/diagnostic , Troubles du métabolisme du fer/génétique , Pneumopathies interstitielles/imagerie diagnostique , Pneumopathies interstitielles/étiologie , Pneumopathies interstitielles/anatomopathologie , Pneumopathies interstitielles/physiopathologie , Activation des macrophages , Mâle , Néphrite/diagnostic , Néphrite/étiologie , Insuffisance respiratoire/diagnostic , Insuffisance respiratoire/étiologie , Rate/imagerie diagnostique , Rate/anatomopathologieRÉSUMÉ
BACKGROUND: Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on inherited complement defects, patients with transiently low complement may be at similar risk for serious bacterial infection, but the degree of risk related to C3 level and temporal association is unknown. METHODS: We performed a retrospective study including pediatric patients with undetectable total complement activity or absent individual complement components measured at our institution from 2002 to 2018. We assessed annual rate of serious bacterial infection (SBI) defined as requiring hospitalization and/or parenteral antibiotics by manual chart review. Among included SLE patients, we assessed the 30-day probability of SBI for given C3 measurements using a logistic regression model to determine risk. Primary complement deficiency was analyzed for SBI rate as comparison. Covariates included age, level of immune suppression and history of lupus nephritis. RESULTS: Acquired complement deficiency secondary to SLE-related disease [n = 44] was the most common underlying diagnosis associated with depressed complement levels and were compared to a cohort of primary complement deficient patients [n = 18]. SBI per 100 person-years and cohort demographics were described in parallel. Our logistic regression analysis of pediatric patients with SLE showed low C3 level was temporally associated with having an SBI event. Given equivalent immunosuppression, patients with an SBI had lower C3 levels at the beginning of the observation period relative to patients without SBI. CONCLUSION: Pediatric patients with the diagnosis of SLE can develop very low C3 levels that associate with risk of serious bacterial infection comparable to that of patients with primary complement deficiency. Patients prone to severe complement consumption may particularly be at risk.
Sujet(s)
Infections bactériennes/épidémiologie , Complément C3/déficit , Déficits héréditaires en complément/épidémiologie , Lupus érythémateux disséminé/épidémiologie , Administration par voie intraveineuse , Adolescent , Antibactériens/usage thérapeutique , Infections bactériennes/traitement médicamenteux , Infections bactériennes/immunologie , Enfant , Enfant d'âge préscolaire , Études de cohortes , Complément C3/immunologie , Femelle , Déficits héréditaires en complément/immunologie , Hospitalisation/statistiques et données numériques , Humains , Sujet immunodéprimé , Immunosuppresseurs/usage thérapeutique , Lupus érythémateux disséminé/traitement médicamenteux , Lupus érythémateux disséminé/immunologie , Glomérulonéphrite lupique/épidémiologie , Glomérulonéphrite lupique/immunologie , Mâle , Études rétrospectives , Indice de gravité de la maladieRÉSUMÉ
Behçet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namely HLA-B*51, ERAP1, IL-10, IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNFα, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD-like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-κB activation (eg TNFAIP3, NFKB1, OTULIN, RELA, IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-κB pathway suggesting new elements in the elusive BD etiopathogenesis.
Sujet(s)
Maladie de Behçet/immunologie , Chromosomes humains de la paire 8/immunologie , Facteur de transcription NF-kappa B/immunologie , Trisomie/immunologie , Maladie de Behçet/génétique , Maladie de Behçet/anatomopathologie , Chromosomes humains de la paire 8/génétique , Prédisposition génétique à une maladie/génétique , Humains , Interleukine-10/génétique , Interleukine-10/immunologie , Muqueuse de la bouche/immunologie , Muqueuse de la bouche/métabolisme , Muqueuse de la bouche/anatomopathologie , Facteur de transcription NF-kappa B/génétique , Facteur de transcription NF-kappa B/métabolisme , Phénotype , Ulcère cutané/génétique , Ulcère cutané/immunologie , Ulcère cutané/anatomopathologie , Trisomie/génétiqueRÉSUMÉ
Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.