A Novel Case of Homozygous Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency With Hemophagocytic Lymphohistiocytosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Gothe F
PROVIDER: S-EPMC8752251 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ObjectiveFamilial hemophagocytic lymphohistiocytosis (FHLH) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and natural killer cells incapable of cytolytic killing. In murine models of FHLH, interferon-? (IFN?) produced by CD8+ T cells has been identified as a critical mediator of disease, and an IFN?-blocking antibody (emapalumab) has recently been approved by the Food and Drug Administration. However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFN? questions the absolute necessity of IFN? in driving disease. This study was undertaken to determine the necessity of IFN? in driving HLH.MethodsIFN?-/- Prf1-/- mice were infected with lymphocytic choriomeningitis virus (LCMV), and HLH immunopathologic features, including survival, weight loss, cytopenias, cytokine profiles, and immune cell phenotypes, were assessed. Mixed bone marrow chimeras were created to determine the immune cell-intrinsic role of IFN? receptor signaling. CD8+ T cell depletion and interleukin-33 (IL-33)/ST2 blockade were performed using monoclonal antibodies.ResultsLCMV infection of IFN?-/- Prf1-/- mice resulted in severe HLH-like disease. CD8+ T cells and the IL-33/ST2 axis remained essential mediators of disease; however, IFN?-independent HLH immunopathology correlated with a 10-15-fold increase in neutrophilia (P < 0.001) and an altered cytokine milieu dominated by IL-6, IL-1?, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.05). Furthermore, IFN? regulated CD8+ T cell expression of GM-CSF and neutrophil survival.ConclusionIFN? is not necessary for the development of fulminant HLH, requiring physicians to consider case-by-case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL-33/ST2 signaling, may be more universally applicable treatment options that ameliorate both IFN?-dependent and -independent manifestations of HLH/MAS.
| S-EPMC6994338 | biostudies-literature
Project description:BACKGROUND:Hemophagocytic lymfohistiocytosis (HLH) is a rare, life-threatening hyperinflammation, characterized by immune system over-activation resulting in hemophagocytosis. HLH could appear as a primary disease caused by mutations of immune-regulatory genes, or develop as a result of viral or bacterial infections, or malignancy. Congenital factor VII (FVII) deficiency is a rare autosomal recessive disorder characterized by prolonged prothrombin time (PT) and low FVII, which may increase bleeding risk. CASE PRESENTATION:A 50-year-old woman was admitted for a fever persisted for 20 days, presenting with cytopenia, high hyperferritinemia, low activity of NK cells. Bone marrow aspiration showed hemophagocytosis. CT scanning found pulmonary infection. EBV and CMV were not detected. Genetic scanning did not find pathogenic mutation of a HLH NGS panel including 26 genes. This patient was treated as recommended by the HLH 2004 Guidelines. Coagulation tests identified FVII deficiency. Genetic analysis of F7 gene in the patient and her family members identified recurrent compound heterozygous F7 c.64?+?5G?>?A and c.1224 T?>?G (p.His408Gln) mutations in this patient and her brother who showed postoperative hemorrhage after surgical resection of renal cell carcinoma. Heterozygotes in this family were asymptomatic. CONCLUSIONS:To our knowledge, this is the first report of HLH in combination with congenital FVII deficiency in Chinese population.
| S-EPMC6134588 | biostudies-literature
Project description:The interaction of IFN-β with its receptor IFNAR1 (interferon α/β receptor subunit 1) is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. Whereas it is established that IFNAR1 is an essential component of the IFNAR signaling complex, the key residues underpinning the IFN-β-IFNAR1 interaction are unknown. Guided by the crystal structure of the IFN-β-IFNAR1 complex, we used truncation variants and site-directed mutagenesis to investigate domains and residues enabling complexation of IFN-β to IFNAR1. We have identified an interface on IFNAR1-subdomain-3 that is differentially utilized by IFN-β and IFN-α for signal transduction. We used surface plasmon resonance and cell-based assays to investigate this important IFN-β binding interface that is centered on IFNAR1 residues Tyr240 and Tyr274 binding the C and N termini of the B and C helices of IFN-β, respectively. Using IFNAR1 and IFN-β variants, we show that this interface contributes significantly to the affinity of IFN-β for IFNAR1, its ability to activate STAT1, the expression of interferon stimulated genes, and ultimately to the anti-viral and anti-proliferative properties of IFN-β. These results identify a key interface created by IFNAR1 residues Tyr240 and Tyr274 interacting with IFN-β residues Phe63, Leu64, Glu77, Thr78, Val81, and Arg82 that underlie IFN-β-IFNAR1-mediated signaling and biological processes.
| S-EPMC5418053 | biostudies-literature
Project description:Mycobacterium iranicum has recently been recognised as an opportunistic human pathogen. Although infectious conditions represent frequent triggers for hemophagocytic lymphohistiocytosis, non-tuberculous mycobacterial infections are rarely associated with this entity. To this date, M. iranicum infection has never been reported in France, has never been associated with hemophagocytic lymphohistiocytosis and has never been found to be multi-resistant on standardized antimicrobial susceptibility testing.We report a case of a French Caucasian man with secondary hemophagocytic lymphohistiocytosis in the context of M. iranicum bacteraemia and Hodgkin's disease. We review available data concerning M. iranicum antimycobacterial susceptibility testing and treatment outcomes. We also review the association between hemophagocytic lymphohistiocytosis and non-tuberculous mycobacterial infections.Interpretation of M. iranicum positive cultures remains a clinical challenge and non-tuberculous mycobacterial infections need to be considered in secondary hemophagocytic lymphohistiocytosis differential diagnosis.
| S-EPMC5549388 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by an exaggerated but dysregulated immune response resulting in hyperinflammation, with a potential for progression to multiple organ dysfunction and failure. Infectious diseases, inflammatory disorders, malignancies and immunodeficiency syndromes are known triggers of HLH in adults. The present study reported the case of a middle-aged man with HLH triggered by B-cell lymphoma who was successfully treated with dexamethasone; etoposide, prednisone, vincristine, cyclophosphamide, hydroxy-doxorubicin and rituximab chemotherapy; and multiple intrathecal methotrexate with a good outcome.
| S-EPMC9214690 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a syndrome describing patients with severe systemic hyperinflammation. Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. Patients can develop hepatitis, coagulopathy, liver failure, central nervous system involvement, multiorgan failure, and other manifestations. The syndrome has a high mortality rate. More and more, it is recognized that while HLH can be appropriately used as a broad summary diagnosis, many pediatric patients actually suffer from an expanding spectrum of genetic diseases that can be complicated by the syndrome of HLH. Classic genetic diseases in which HLH is a typical and common manifestation include pathogenic changes in familial HLH genes (PRF1, UNC13D, STXBP2, and STX11), several granule/pigment abnormality genes (RAB27A, LYST, and AP3B1), X-linked lymphoproliferative disease genes (SH2D1A and XIAP), and others such as NLRC4, CDC42, and the Epstein-Barr virus susceptibility diseases. There are many other genetic diseases in which HLH is an infrequent complication of the disorder as opposed to a prominent manifestation of the disease caused directly by the genetic defect, including other primary immune deficiencies and inborn errors of metabolism. HLH can also occur in patients with underlying rheumatologic or autoinflammatory disorders and is usually designated macrophage activation syndrome in those settings. Additionally, HLH can develop in patients during infections or malignancies without a known (or as-yet-identified) genetic predisposition. This article will attempt to summarize current concepts in the pediatric HLH field as well as offer a practical diagnostic and treatment overview.
| S-EPMC8212354 | biostudies-literature
Project description:Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4+ CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH.
| S-EPMC8057258 | biostudies-literature
Project description:Adult hemophagocytic lymphohistiocytosis is a secondary immunopathologic phenomenon, mainly secondary to malignancy, infection, or autoimmune disorders. The performance of diagnostic criteria, studied in the pediatric population, is yet to be validated in the adult population. Some of the criteria include cytopenias and organomegaly that are inherent features to malignant processes, thus making the diagnosis of hemophagocytic lymphohistiocytosis a challenge in patients with cancer.We describe the case of a 54-year-old white man with history of metastatic maxillary sinus adenoid cystic carcinoma who had severe liver injury and cytopenias with progressive clinical deterioration. We performed an evaluation, by flow cytometry, of the expression of surface markers in his natural killer cells that revealed remarkable abnormalities. His syndrome eventually fulfilled criteria for hemophagocytic lymphohistiocytosis and he received therapy with steroids with interval clinical improvement. Unfortunately, he refused further cytotoxic treatment and died 2 weeks later.The conventional criteria for the diagnosis of hemophagocytic lymphohistiocytosis are suboptimal for adult patients with cancer resulting in delays in diagnosis and timely initiation of treatment. The diagnostic criteria have to be re-evaluated in patients with cancer; novel, easily available, and accurate diagnostic methods are needed.
| S-EPMC5485603 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal disease primarily of children, characterized by a severe hyperinflammatory state. We describe a case of adult onset familial HLH with a novel exon 19, c.1607G>T (p.Arg536Leu) heterozygous mutation of the UNC13D gene in a 40-year-old woman who developed HLH during her first and second pregnancies, both episodes occurring during the first trimester. Our patient was treated successfully both times with HLH-94 protocol following spontaneous abortions and is currently in the process of getting a bone marrow transplant. We also discuss pregnancy as a potential trigger for late onset familial HLH.
| S-EPMC6134992 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition.
| S-EPMC3204727 | biostudies-literature