HLH: genomics illuminates pathophysiological diversity

Tesi, Bianca; Bryceson, Yenan T.

doi:10.1182/blood-2018-05-845818

Cited by 14 publications

(5 citation statements)

References 10 publications

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“…Younger patients with HLH are more likely to have a monogenic intrinsic defect and older patients may have been triggered by various antigenic challenges such as infection, autoimmunity and hematologic malignancy leading to immune hyper inflammation. A number of genetic defects and metabolic disorders caused by different pathogenic mechanisms (impaired lymphocyte cytotoxicity, dysregulated inflammasome activity, dysregulated metabolism, impaired autophagy and control of viruses) render predisposition to HLH (38,39).…”

Section: Acute Liver Failure and Immune Dysregulationmentioning

confidence: 99%

Proceedings of ESPGHAN Monothematic Conference 2020

Zellos

Debray

Indolfi

et al. 2021

J. pediatr. gastroenterol. nutr.

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Objectives:The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to educate pediatric gastroenterologists, members of ESPGHAN and professionals from other specialties promoting an exchange of clinical expertise in the field of pediatric hepatology. Herewith we have concentrated on detailing the recent advances in acute liver failure in infants and children.Methods:The 2020 ESPGHAN monothematic three-day conference on pediatric hepatology disease, entitled “acute liver failure” (ALF), was organized in Athens, Greece. ALF is a devastating disease with high mortality and most cases remain undiagnosed. As knowledge in diagnosis and treatment of ALF in infants and children has increased in the past decades, the objective was to update physicians in the field with the latest research and developments in early recognition, curative therapies and intensive care management, imaging techniques and treatment paradigms in these age groups.Results:In the first session, the definition, epidemiology, various causes of ALF, in neonates and older children and recurrent ALF (RALF) were discussed. The second session was dedicated to new aspects of ALF management including hepatic encephalopathy (HE), coagulopathy, intensive care interventions, acute on chronic liver failure, and the role of imaging in treatment and prognosis. Oral presentations by experts in various fields are summarized highlighting key learning points.Conclusions:The current report summarizes the major learning points from this meeting. It also identifies areas where there is gap of knowledge, thereby identifying the research agenda for the near future.

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Section: Acute Liver Failure and Immune Dysregulationmentioning

confidence: 99%

Proceedings of ESPGHAN Monothematic Conference 2020

Zellos

Debray

Indolfi

et al. 2021

J. pediatr. gastroenterol. nutr.

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“…AIFEC patients have normal NK cell function between flares, and the MAS phenotype is thought to be mediated by cytokine excess, particularly IL-1β and IL-18, with IFNγ also playing a role through its induction by IL-18 [55,56,61]. Thus, mechanisms other than decreased cytolytic function can also contribute to MAS pathophysiology [62,63].…”

Section: Rheumatologicmentioning

confidence: 99%

“…Hermansky-Pudlak type 2 results from mutations in the AP3B1 gene, which is important for lysosome trafficking [77]. These genetic syndromes all result in decreased perforin-mediated cytolytic activity of lymphocytes as in FHL [63,78,79].…”

Section: Primary Immunodeficiencymentioning

confidence: 99%

Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management

2019

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Macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis, is a frequently fatal complication of a variety of pediatric inflammatory disorders. MAS has been most commonly associated with systemic juvenile idiopathic arthritis (sJIA), as approximately 10% of children with sJIA develop fulminant MAS, with another 30-40% exhibiting a more subclinical form of the disease. Children with other rheumatologic conditions such as systemic lupus erythematosus and Kawasaki disease are also at risk for MAS. Moreover, MAS also complicates various genetic autoinflammatory disorders such as gain of function mutations in the cytosolic inflammasome NLRC4, pediatric hematologic malignancies (e.g., T-cell lymphoma), and primary immunodeficiencies characterized by immune dysregulation. Disease-specific and broadly inclusive diagnostic criteria have been developed to facilitate the diagnosis of MAS. Recently, simple screening tools such as the serum ferritin to erythrocyte sedimentation rate ratio have been proposed. Early diagnosis and rapid initiation of immunosuppression are essential for the effective management of MAS. With a better understanding of the pathophysiology of MAS and the advent of novel therapeutics, a broad immunosuppressive approach to treatment is giving way to targeted anti-cytokine therapies. These treatments include agents that block interleukin-1 (IL-1), IL-6, IL-18, interferon-γ, as well as inhibitors of downstream targets of cytokine signaling (e.g., Janus kinases). Increased early recognition of MAS among pediatric inflammatory disorders combined with the use of effective and less toxic cytokine-targeted therapies should lower the mortality of this frequently fatal disorder.

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“…Clinically, HLH is characterized by a combination of mainly unspecific symptoms due to lymphoproliferation (e.g., splenomegaly), inflammation (e.g., fever), various system/organ dysfunctions (liver injury, central nervous system inflammation), and a number of nonpathognomonic biological abnormalities (including pancytopenia, coagulopathy, hyperlipidemia, hyperferritinemia, and sCD25 elevation). HLH is traditionally divided into two categories: primary (or familial), associated with genetic defects in lymphocyte cytotoxicity, and secondary, in which patients do not carry a mutation in genes known to predispose to HLH ( Janka, 2012 ; Tesi and Bryceson, 2018 ). Secondary HLH can be triggered by a viral infection or an autoimmune or malignant disease ( Al-Samkari and Berliner, 2018 ; Tangye et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

NCKAP1Ldefects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation

Castro

Rosenzwajg

Carapito

et al. 2020

Journal of Experimental Medicine

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The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage–specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients’ T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.

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HLH: genomics illuminates pathophysiological diversity

Cited by 14 publications

References 10 publications

Proceedings of ESPGHAN Monothematic Conference 2020

Proceedings of ESPGHAN Monothematic Conference 2020

Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management

NCKAP1Ldefects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation

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