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.
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The NLRC4 Inflammasome Duncan, Joseph A.; Canna, Scott W.
Immunological reviews,
January 2018, Letnik:
281, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Summary
15 years ago, the fundamental biology of an inflammatory signaling complex eventually dubbed “the inflammasome” began to unravel in chronologic parallel with the discovery that many ...inflammatory diseases were associated with its hyperactivity. Though the genetic origins of Familial Mediterranean Fever (FMF, caused my mutations in MEFV) were discovered first, it would take nearly two decades before the mechanistic connections to a PYRIN inflammasome were made. In the interim, the intensive study of the NLRP3 inflammasome, and the diseases associated with its hyperactivation, have largely dictated the paradigm of inflammasome composition and function. Despite impressive gains, focusing on NLRP3 left gaps in our understanding of inflammasome biology. Foremost among these gaps were how inflammasomes become activated and the connections between inflammasome structure and function. Fortunately, work in another inflammasome inducer, NLRC4, grew to fill those gaps. The current understanding of the NLRC4 inflammasome is perhaps the most comprehensive illustration of the inflammasome paradigm: trigger (e.g. cytosolic flagellin), sensor (NAIP), nucleator (NLRC4), adaptor (ASC), and effector (CASP1). Detailed work has also identified observations that challenge this paradigm. Simultaneously, the features unique to each inflammasome offer a lesson in contrast, providing perspectives on inflammasome activation, regulation, and function. In this review, we endeavor to highlight recent breakthroughs related to NLRC4 inflammasome structure and activation, important in vivo work in infection and systemic inflammation, and the characterization of a spectrum of human NLRC4‐associated autoinflammatory diseases.
Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine ...responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.
Poor outcomes in COVID‐19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent ...immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID‐19.
Abstract
Hyperferritinemia and pronounced hemophagocytosis help distinguish a subset of patients with a particularly inflammatory and deadly systemic inflammatory response syndrome. Two clinically ...similar disorders typify these hyperferritinemic syndromes: hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). HLH is canonically associated with a complete disturbance of perforin/granzyme-mediated cytotoxicity, whereas MAS occurs in the context of the related rheumatic diseases systemic juvenile idiopathic arthritis and adult-onset Still’s disease, with associated IL-1 family cytokine activation. In practice, however, there are accumulating lines of evidence for innate immune dysregulation in HLH as well as partial impairments of cytotoxicity in MAS, and these mechanisms likely represent only a fraction of the host and environmental factors driving hyperferritinemic inflammation. Herein, we present new findings that highlight the pathogenic differences between HLH and MAS, two conditions that present with life-threatening hyperinflammation, hyperferritinemia and hemophagocytosis.
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes ...familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.
•IL-18 distinguishes susceptibility to MAS amongst hyperferritinemic and autoinflammatory diseases.•Excess IL-18 in NLRC4 gain-of-function mice derives from intestinal epithelia, and free IL-18 promotes experimental MAS.
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Clinical application of several rapidly evolving technologies-next-generation DNA sequencing, biomarker discovery, and targeted cytokine blockade-has been particularly beneficial to understanding an ...expanding spectrum of genetically defined autoinflammatory diseases.1 Our understanding of the pathways that cause hemophagocytic disorders, such as macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH), is evolving similarly. MAS and HLH are life-threatening sepsis-like conditions notable for hyperferritinemia, acute cytopenias, and hepatitis. If not promptly recognized and treated, they can progress to consumptive coagulopathy, hemophagocytosis, multiorgan failure, and high mortality. HLH is classically associated with genetic defects in cytotoxicity, whereas MAS is observed as a complication of rheumatic diseases.1
Since the first textbook devoted to cytokine storm syndromes (CSSs) was published in 2019, the world has changed dramatically and the term’s visibility has broadened. Herein, we define CSSs broadly ...to include life/organ-threatening systemic inflammation and immunopathology regardless of the context in which it occurs, recognizing that the indistinct borders of such a definition limit its utility. Nevertheless, we are focused on the pathomechanisms leading to CSSs, including impairment of granule-mediated cytotoxicity, specific viral infections, excess IL-18, and chimeric antigen receptor T-cell therapy. These mechanisms are often reflected in distinct clinical features, functional tests, and/or biomarker assessments. Moreover, these mechanisms often indicate specific, definitive treatments. This mechanism-focused organization is vital to both advancing the field and understanding the complexities in individual patients. However, increasing evidence suggests that these mechanisms interact and overlap. Likewise, the utility of a broad term such as “cytokine storm” is that it reflects a convergence on a systemic inflammatory phenotype that, regardless of cause or context, may be amenable to “inflammo-stabilization.” CSS research must improve our appreciation of its various mechanisms and their interactions and treatments, but it must also identify the signs and interventions that may broadly prevent CSS-induced immunopathology.
Hemophagocytic lymphohistiocytosis (HLH) comprises an emerging spectrum of inherited and noninherited disorders of the immune system characterized by the excessive production of cytokines, including ...interferon-γ and interleukins 2, 6, and 10 (IL-2, IL-6, and IL-10). The Janus kinases (JAKs) transduce signals initiated following engagement of specific receptors that bind a broad array of cytokines, including those overproduced in HLH. Based on the central role for cytokines in the pathogenesis of HLH, we sought to examine whether the inhibition of JAK function might lessen inflammation in murine models of the disease. Toward this end, we examined the effects of JAK inhibition using a model of primary (inherited) HLH in which perforin-deficient (Prf1−∕−) mice are infected with lymphocytic choriomeningitis virus (LCMV) and secondary (noninherited) HLH in which C57BL/6 mice receive repeated injections of CpG DNA. In both models, treatment with the JAK1/2 inhibitor ruxolitinib significantly lessened the clinical and laboratory manifestations of HLH, including weight loss, organomegaly, anemia, thrombocytopenia, hypercytokinemia, and tissue inflammation. Importantly, ruxolitinib treatment also significantly improved the survival of LCMV-infected Prf1−∕− mice. Mechanistic studies revealed that in vivo exposure to ruxolitinib inhibited signal transducer and activation of transcription 1–dependent gene expression, limited CD8+ T-cell expansion, and greatly reduced proinflammatory cytokine production, without effecting degranulation and cytotoxic function. Collectively, these findings highlight the JAKs as novel, druggable targets for mitigating the cytokine-driven hyperinflammation that occurs in HLH. These observations also support the incorporation of JAK inhibitors such as ruxolitinib into future clinical trials for patients with these life-threatening disorders.
•Ruxolitinib treatment lessens immunopathology and prolongs survival in murine models of hemophagocytic lymphohistiocytosis.•In vivo exposure to ruxolitinib limits CD8+ T-cell expansion and proinflammatory cytokine production.
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