Familial HLH

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon condition that can be fatal due to overwhelming macrophage activation and cytokine production. It can be primary (familial/genetic) or secondary. It is associated with infections, malignancies, and rheumatologic and immunodeficiency disorders. We report a middle-aged female patient with sickle cell anemia who presented with COVID-19 infection that triggered a vaso-occlusive crisis and resulted in HLH. She had preexisting high ferritin levels and cytopenias, making the diagnosis more challenging...

BACKGROUND: Burkholderia pseudomallei ( B. pseudomallei ) is a short, straight, medium-sized Gram-negative bacterium that mostly exists alone, without a capsule or spores, has more than three flagella at one end, and actively moves. B. pseudomallei confers high morbidity and mortality, with frequent granulocytopenia in B. pseudomallei sepsis-related deaths. However, mortality may be related to hemophagocytic lymphohistiocytosis (HLH) secondary to B. pseudomallei infection. CASE SUMMARY: A 12-year-old female was referred from a local hospital to the pediatric intensive care unit with suspected septic shock and fever, cough, dyspnea, and malaise...

Hemophagocytic lymphohistiocytosis (HLH) is a disorder of impaired immune regulation resulting in hyperinflammation that is ultimately fatal if not treated. HLH is categorized into familial disease, caused by genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer cells, and secondary disease, triggered by infections, malignancies, rheumatologic disorders, or immune deficiency. Adolescent and young adults with HLH represent a unique population with specific diagnostic challenges...

Hemophagocytic lymphohistiocytosis (HLH) is a disease of abnormal activation of the immune system, either due to a familial cause or a sporadic cause, in relation to various triggering agents. Secondary HLH is a complication of various diseases, such as infections, malignancies, and autoimmune disorders. In our case series, we present three cases of secondary HLH with varied etiologies. Case 1 involved an 18-year-old male with a history of pulmonary tuberculosis, presenting with fever, hepatosplenomegaly, and elevated inflammatory markers...

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) or hemophagocytic syndrome (HPS) is a life-threatening and relatively rare condition that usually presents as a multisystem febrile illness. It is associated with excessive activation of the immune system and hypercytokinemia, leading to an unregulated aggregation of macrophages and lymphocytes. Here, we present the first likely case of HLH with metastatic pancreatic carcinoma being the underlying etiology. CASE: A 44-year-old male with past medical history significant for heart transplant for which he was on tacrolimus, End-Stage Renal Disease (ESRD) on hemodialysis, recently treated CMV viremia, and necrotizing pancreatitis presented to the emergency with complaints of chills, decreased appetite, worsening non-bloody emesis, and dull left upper quadrant abdominal pain with radiation to the back for four days...

Hemophagocytic lymphohistiocytosis is usually considered a rapidly progressive fatal illness with poor outcomes. It is of two types: primary or familial and secondary. In patients with HIV, opportunistic infections are the secondary triggers of HLH. First line of management of infection associated HLH is treatment of the underlying infection. Here, we present a case of HLH in HIV infection due to disseminated histoplasmosis managed with liposomal amphotericin B, who required immunosuppressive therapy with intravenous immunoglobulin and dexamethasone due to nonresponse to primary therapy...

Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS) are life-threatening hyperinflammatory syndromes. Familial HLH is caused by genetic impairment of granule-mediated cytotoxicity (e.g., perforin-deficiency). MAS is linked to excess activity of the inflammasome-activated cytokine IL-18. Though individually tolerated, mice with dual susceptibility (Prf1-/-Il18tg; DS) succumb to spontaneous, lethal hyperinflammation. We hypothesized that understanding how these susceptibility factors synergize would uncover key pathomechanisms in the activation, function, and persistence of hyperactivated CD8 T-cells...

OBJECTIVES: To investigate the association of brain MRI and clinical variables with death in children with central nervous system involvement of hemophagocytic lymphohistiocytosis (CNS-HLH). METHODS: Clinical and brain MRI data of children with CNS-HLH from January 2012 to March 2022 were reviewed retrospectively. Patients were divided into the deceased group and the surviving group. The intergroup differences of seven brain MRI variables, twelve clinical variables, and underlying diseases were studied...

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3 (FHL3) accounts for approximately 30% of all inborn HLH cases worldwide. It is caused by mutations in the UNC13D gene that result in impaired degranulation of cytotoxic vesicles and hence compromised T-cell- and natural killer-cell-mediated killing. Current treatment protocols, including allogeneic hematopoietic stem cell (HSC) transplantation, still show high mortality...

BACKGROUND: Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect. OBJECTIVE: We sought to identify the genetic basis of the disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia that resulted in death. METHODS: Genetic analysis was done using next-generation sequencing. Protein expression and phosphorylation were determined by immunoblotting...

The survival of hosts during infections relies on their ability to mount effective molecular and behavioral immune responses. Despite extensive research on these defense strategies in various species, including the model organism Caenorhabditis elegans , the neural mechanisms underlying their interplay remain poorly understood. Previous studies have highlighted the role of neural G protein-coupled receptors (GPCRs) in regulating both immunity and pathogen avoidance, which is particularly dependent on aerotaxis...

Cancer is a genetic and complex disorder, resulting from several events associated with onset, development, and metastasis. Tumor suppressors and oncogenes are among the main regulators of tumor progression, contributing to various cancer-related behaviors like cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis. Transcription factors (TFs) could act as tumor suppressors or oncogenes in cancer progression. E-twenty-six/E26 (ETS) family of TFs have a winged helix-turn-helix (HLH) motif, which interacted with specific DNA regions with high levels of purines and GGA core...

Hemophagocytic Lymphohistiocytosis (HLH) is a group of disorders culminating in systemic inflammation and multi-organ failure with high incidence of hepatic dysfunction. Overproduction of IFN-γ is the main immunopathological driver in this disorder. Monokine induced by IFN-γ (CXCL9) serves as a biomarker for disease activity and response to treatment in this disorder. However, very little is understood about the actual functional role of CXCL9 in pathogenesis in HLH. In the current study, we sought to determine the role of CXCL9 in pathogenesis in murine models of both Familial HLH (prf1-/- ) and Toll Like Receptor (TLR) 9 repeated stimulation induced Macrophage Activation Syndrome (MAS), a form of secondary HLH...

Hemophagocytic lymphohistiocytosis(HLH) is a rare highly-fatal disease presenting with fever, hepatosplenomegaly, and pancytopenia and has a poor prognosis. Homozygous or semi-zygous or complex heterozygous variants can cause familial HLH and heterozygous carriers are frequently seen in secondary HLH. A 42-year-old male patient was admitted to the hospital for persistent fever, fatigue, and splenomegaly. Investigations revealed hypertriglyceridemia, hyperlactatemia dehydrogenaseemia, hyperferritinemia, and elevated levels of soluble cluster of differentiation 25...

Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical condition characterized by sustained but ineffective immune system activation, leading to severe and systemic hyperinflammation. It may occur as a genetic or sporadic condition, often triggered by an infection. The multifaceted pathogenesis results in a wide range of non-specific signs and symptoms, hampering early recognition. Despite a great improvement in terms of survival in the last decades, a considerable proportion of patients with HLH still die from progressive disease...

B cell expansion with NF-κB and T cell anergy (BENTA) is a disease genetically linked with heterozygous gain-of-function (GOF) mutations in the CARD11 gene with an autosomal dominant expression. Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of disorders characterized by systemic inflammation and hypercytokinaemia. Some BENTA patients share similar clinical manifestations as HLH in various aspects, including fever and splenomegaly. In this study, we reported a 15-month-old boy diagnosed as BENTA meeting with diagnostic criteria of HLH...

INTRODUCTION: Inborn errors of immunity (IEI) are characterized by a dysfunction of the immune system leading to increased susceptibility to infections, impaired immune regulation and cancer. We present a unique consanguineous family with a history of Hodgkin lymphoma, impaired EBV control and a late onset hemophagocytic lymphohistiocytosis (HLH). METHODS AND RESULTS: Overall, family members presented with variable impairment of NK cell and cytotoxic T cell degranulation and cytotoxicity...

Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disorder characterized by the proliferation and infiltration of macrophages and hyperactivated T lymphocytes that escape from the physiological control pathways and favour the existence of an environment of excessive inflammation and tissue destruction. HLH has been classified into two types: a primary or familial autosomal recessive form, caused by mutations in genes encoding proteins involved in the granule-dependent cytotoxic pathway (familial hemophagocytic lymphohistiocytosis [FHL] types 1-5); and other secondary or acquired form, generally associated with infections, malignancy, autoimmune diseases, metabolic disorders or primary immunodeficiencies...

Deficiency of adenosine deaminase-2 (DADA2) is an autosomal recessive autoinflammatory disease with an extremely variable disease presentation. This paper provides a comprehensive overview of the Dutch DADA2 cohort. We performed a retrospective cohort study in 29 ADA2-deficient patients from 23 families with a median age at inclusion of 26 years. All patients had biallelic pathogenic variants in the ADA2 gene. The most common clinical findings included cutaneous involvement (79.3%), (hepato)splenomegaly (70...

BACKGROUND: Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) belongs to the b HLH- PAS domain transcription factor family and is one of the key clock genes that control the circadian rhythm. ARNTL2 plays an important role in human biological functions. However, its role in various tumors, especially in the tumor immune microenvironment (TIME) and immunotherapy, remains unclear. METHODS: We integrated data from cancer patients from multiple databases, including the Cancer Genome Atlas, Cancer Cell Lineage Encyclopedia, Genotype Tissue Expression, Human Protein Atlas, cBioPortal, TIMER, and ImmuCellAI, with data from a large clinical study, three immunotherapy cohorts, and in vitro experiments to investigate the involvement of ARNTL2 expression in cancer prognosis and immune response...