Hemophagocytic Lymphohistiocytosis as a Complication in Patients with MSMD

Muriel-Vizcaino, Rodolfo; Yamazaki‐Nakashimada, Marco Antonio; López‐Herrera, Gabriela; Santos‐Argumedo, Leopoldo; Ramírez-Alejo, Noé

doi:10.1007/s10875-016-0292-3

Cited by 18 publications

(16 citation statements)

References 5 publications

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“…Since the discovery of its first genetic etiology in 1996, MSMD has been reported and a causal genetic lesion described in 501 individuals from 356 kindreds originating from 57 countries on five continents (Figure a). Over this period, the genetic dissection of MSMD in these patients has revealed this condition to be caused by inborn errors of interferon (IFN)‐γ immunity . These findings confirm that IFN‐γ, first described in 1965 as an antiviral IFN, is actually the macrophage‐activating factor, as shown in 1983 .…”

Section: Introductionsupporting

confidence: 61%

“…Clinical manifestations are, therefore, highly variable. Macrophage activation syndrome or vasculitis may occur in rare cases, probably as a consequence of uncontrolled infection. Since the discovery of its first genetic etiology in 1996, MSMD has been reported and a causal genetic lesion described in 501 individuals from 356 kindreds originating from 57 countries on five continents (Figure a).…”

Section: Introductionmentioning

confidence: 99%

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Mendelian susceptibility to mycobacterial disease: 2014–2018 update

et al. 2018

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Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-c immunity. Since 1996, disease-causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase-like 2 A deficiency, (2) TYK2-deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN-cR2 deficiency, and (4) two forms of syndromic MSMD: RORc/RORcT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.

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Section: Introductionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

et al. 2018

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“…Hemophagocytic lymphohistiocytosis has been increasingly reported as an infectious (viral or bacterial) complication in PID defects, including chronic granulomatous disease (X-linked and autosomal recessive), severe-combined immunodeficiency, Wiskott–Aldrich syndrome, DiGeorge anomaly, X-linked agammaglobulinemia, Hyper-IgD syndrome, ectodermal dysplasia with immunodeficiency, autoimmune lymphoproliferative syndrome (FAS-ALPS), cyclic neutropenia, tumor necrosis factor-1 receptor associated periodic syndrome (TRAPS), familial Mediterranean fever, NLRC4; and thus far five patients with defects in the IFN-γ circuit (9, 10). In addition, several monogenic PID diseases have been linked to HLH (11), including the four known genes causing familial HLH ( PRF1, UNC13D, STX11, STXBP2 ), and other defects considered as predisposing to HLH: the partial albinism syndromes with an “accelerated phase”: Griscelli syndrome type 2 ( RAB27A ), Chediak Higashi syndrome ( LYST ), the Hermansky Pudlak syndrome type 2 ( AP3B1 ); and the X-linked lymphoproliferative diseases (both SAP and XIAP deficiencies, caused by SH2D1A and BIRC4 mutations, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…It is generally considered a T-cell disorder of impaired activation (11), to depend on activated NK cells (9), and to be driven by elevated IFN-γ, TNFα, and IL-6 (4). However, IFN-γ receptors are located on macrophages (and elsewhere).…”

Section: Discussionmentioning

confidence: 99%

Multifocal Recurrent Osteomyelitis and Hemophagocytic Lymphohistiocytosis in a Boy with Partial Dominant IFN-γR1 Deficiency: Case Report and Review of the Literature

et al. 2017

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Mutations in the genes coding for cytokines, receptors, second messengers, and transcription factors of interferon gamma (IFN-γ) immunity cause Mendelian susceptibility to mycobacterial disease (MSMD). We report the case of a 7-year-old male patient with partial dominant (PD) IFN-γ receptor 1 deficiency who had suffered from multifocal osteomyelitis attributable to bacille Calmette–Guérin vaccination since the age of 18 months. He developed hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory complication, and died with multiorgan dysfunction, despite having been diagnosed and treated relatively early. Patients with PD IFN-γR1 deficiency usually have good prognosis and might respond to human recombinant subcutaneous IFN-γ. Several monogenic congenital defects have been linked to HLH, a catastrophic “cytokine storm” that is usually ascribed to lymphocyte dysfunction and thought to be triggered by interferon gamma. This is the sixth patient with both MSMD and HLH of whom we are aware. The fact that patients with macrophages that cannot respond to IFN-γ still develop HLH, bring these assumptions into question.

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“…9,11,13,14 However, the role of IFN-g has been recently challenged, with the findings of HLH in patients with genetic defects in the IFN-g pathway. [15][16][17] Specifically, 3 patients have been reported to have HLH disease and an IFN-gR defect, although among these, only 1 patient received a definitive diagnosis of a complete absence of IFN-g signaling through IFN-gR2, whereas the other 2 patients had either a partial or implied defect of IFN-g receptor 1 (IFN-gR1). 15,16 Supporting the IFN-g independence of disease, development of systemic juvenile idiopathic arthritis-like inflammation has been described in Ifng knockout mice.…”

Section: Abbreviations Usedmentioning

confidence: 99%

IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis

Humblet-Baron

Franckaert

Dooley

et al. 2019

Journal of Allergy and Clinical Immunology

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Background: Inflammatory activation of CD8 1 T cells can, when left unchecked, drive severe immunopathology. Hyperstimulation of CD8 1 T cells through a broad set of triggering signals can precipitate hemophagocytic lymphohistiocytosis (HLH), a life-threatening systemic inflammatory disorder. Objective: The mechanism linking CD8 1 T-cell hyperactivation to pathology is controversial, with excessive production of IFNg and, more recently, excessive consumption of IL-2, which are proposed as competing hypotheses. We formally tested the proximal mechanistic events of each pathway in a mouse model of HLH. Methods: In addition to reporting a complete autosomal recessive IFN-g receptor 1-deficient patient with multiple aspects of HLH pathology, we used the mouse model of perforin (Prf1) KO mice infected with lymphocytic choriomeningitis virus to genetically eliminate either IFN-g production or CD25 expression and assess the immunologic, hematologic, and physiologic disease measurement. Results: We found a striking dichotomy between the mechanistic basis of the hematologic and inflammatory components of CD8 1 T cell-mediated pathology. The hematologic features of HLH were completely dependent on IFN-g production, with complete correction after loss of IFN-g production without any role for CD8 1 T cell-mediated IL-2 consumption. By contrast, the mechanistic contribution of the immunologic features was reversed, with no role for IFN-g production but substantial correction after reduction of IL-2 consumption by hyperactivated CD8 1 T cells. These results were complemented by the characterization of an IFN-g receptor 1-deficient patients with HLH-like disease, in whom multiple aspects of HLH pathology were observed in the absence of IFN-g signaling. Conclusion: These results synthesize the competing mechanistic models of HLH pathology into a dichotomous pathogenesis driven through discrete pathways. A holistic model provides a new paradigm for understanding HLH and, more broadly, the consequences of CD8 1 T-cell hyperactivation, thereby paving the way for clinical intervention based on the features of HLH in individual patients.

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Hemophagocytic Lymphohistiocytosis as a Complication in Patients with MSMD

Cited by 18 publications

References 5 publications

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

Multifocal Recurrent Osteomyelitis and Hemophagocytic Lymphohistiocytosis in a Boy with Partial Dominant IFN-γR1 Deficiency: Case Report and Review of the Literature

IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis

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