Lymphoproliferation, immunodeficiency and early-onset inflammatory bowel disease associated with a novel mutation in Caspase 8

Kanderová, Veronika; Grombiříková, Hana; Zentsová, Irena; Réblová, Kamila; Klocperk, Adam; Fejtková, Martina; Bloomfield, Markéta; Ravčuková, Barbora; Kalina, Tomáš; Freiberger, Tomáš; Šedivá, Anna

doi:10.3324/haematol.2018.201673

Cited by 15 publications

(11 citation statements)

References 13 publications

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“…Immunophenotyping of T and B cells was performed according to a previously published protocol 47 , and the gating strategy is shown in Supplementary Fig. 2B.…”

Section: T-and B-cell Analysismentioning

confidence: 99%

Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn’s disease

et al. 2020

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X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine-and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2.

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“…Immunophenotyping of T and B cells was performed according to a previously published protocol 47 , and the gating strategy is shown in Supplementary Fig. 2B.…”

Section: T-and B-cell Analysismentioning

confidence: 99%

Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn’s disease

et al. 2020

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“…The expression of catalytically inactive caspase-8 leads to embryonic lethality in mice that can be prevented by deletion of Ripk3 or co-ablation of Mlkl and Casp1 [ 6 , 8 ], suggesting that the enzymatic activity of caspase-8 plays a critical role in the regulation of pyroptosis when apoptosis and necroptosis are compromised. In addition to the regulation of cell death, caspase-8 contributes to the maintenance of immune homeostasis [ 11 , 25 – 27 ]. When embryonic lethality in Casp8 -deficient mice is rescued by Ripk3 or Mlkl ablation, the Casp8 −/− Ripk3 −/− and Casp8 −/− Mlkl −/− mice develop lymphadenopathy [ 11 ] that resembles the abnormality observed in Fas ligand (FasL, CD95L) [ 28 ] or FAS [ 29 , 30 ] deficient mice and human autoimmune lymphoproliferative syndrome (ALPS) [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia

Zhang

et al. 2022

Cell Death Differ

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Caspase-8 is an initiator of death receptor-induced apoptosis and an inhibitor of RIPK3-MLKL-dependent necroptosis. In addition, caspase-8 has been implicated in diseases such as lymphoproliferation, immunodeficiency, and autoimmunity in humans. Although auto-cleavage is indispensable for caspase-8 activation, its physiological functions remain poorly understood. Here, we generated a caspase-8 mutant lacking E385 in auto-cleavage site knock-in mouse (Casp8ΔE385/ΔE385). Casp8ΔE385/ΔE385 cells were expectedly resistant to Fas-induced apoptosis, however, Casp8ΔE385/ΔE385 cells could switch TNF-α-induced apoptosis to necroptosis by attenuating RIPK1 cleavage. More importantly, CASP8(ΔE385) sensitized cells to RIPK3-MLKL-dependent necroptosis through promoting complex II formation and RIPK1-RIPK3 activation. Notably, Casp8ΔE385/ΔE385Ripk3−/− mice partially rescued the perinatal death of Ripk1−/− mice by blocking apoptosis and necroptosis. In contrast to the Casp8−/−Ripk3−/− and Casp8−/−Mlkl−/− mice appearing autoimmune lymphoproliferative syndrome (ALPS), both Casp8ΔE385/ΔE385Ripk3−/− and Casp8ΔE385/ΔE385Mlkl−/− mice developed transplantable lymphopenia that could be significantly reversed by RIPK1 heterozygosity, but not by RIPK1 kinase dead mutation. Collectively, these results demonstrate previously unappreciated roles for caspase-8 auto-cleavage in regulating necroptosis and maintaining lymphocytes homeostasis.

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“…In ALPS, homozygous mutations in FAS and FASL genes are associated with impaired cytotoxicity and severely reduced activation-induced cell death (AICD) in B- and T-cells resulting in clinically severe disease and massive LP including lymphomagenesis ( 39 ). Besides ALPS, Caspase-8 mutations may also present as end-organ LP, granulomatous inflammation, mesenteric lymphadenopathy, and recurrent EBV infection ( 40 ). CD25, CD122, cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) deficiencies, and signal transducer and activator of transcription 3 ( STAT-3 ) gain-of-function mutations lead to impaired Treg function leading to impaired suppression of effector T cells causing immune dysregulation with autoimmunity and may present with LP with recurrent EBV infections ( 19 , 41 ).…”

Section: Pathophysiology and Histopathological Alterationsmentioning

confidence: 99%

Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know

et al. 2022

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Inborn errors of immunity (IEIs) are a group of heterogeneous disorders characterized by a broad clinical spectrum of recurrent infections and immune dysregulation including autoimmunity and lymphoproliferation (LP). LP in the context of IEI may be the presenting feature of underlying immune disorder or may develop during the disease course. However, the correct diagnosis of LP in IEI as benign or malignant often poses a diagnostic dilemma due to the non-specific clinical features and overlapping morphological and immunophenotypic features which make it difficult to treat. There are morphological clues to LP associated with certain IEIs. A combination of ancillary techniques including EBV-associated markers, flow cytometry, and molecular assays may prove useful in establishing a correct diagnosis in an appropriate clinical setting. The present review attempts to provide comprehensive insight into benign and malignant LP, especially the pathogenesis, histological clues, diagnostic strategies, and treatment options in patients with IEIs.

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Lymphoproliferation, immunodeficiency and early-onset inflammatory bowel disease associated with a novel mutation in Caspase 8

Cited by 15 publications

References 13 publications

Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn’s disease

Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn’s disease

Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia

Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know

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