Impact of human CD95 mutations on cell death and autoimmunity: a model

Seyrek, Kamil; Ivanisenko, Nikita V.; Wohlfromm, Fabian; Espe, Johannes; Lavrik, Inna N.

doi:10.1016/j.it.2021.11.006

Cited by 12 publications

(8 citation statements)

References 119 publications

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“…CD95 is a cell surface receptor that plays a pivotal role in regulating apoptosis or programmed cell death 18. Mutation or dysregulation of the CD95 apoptotic pathway can be involved in various diseases, including AD 18 19. We hypothesise that continuous exposure to self-antigens can keep these T cells activated, leading to increased CD95 expression as a part of the feedback mechanism to regulate excessive immune responses.…”

Section: Discussionmentioning

confidence: 99%

Deep immunophenotyping reveals that autoimmune and autoinflammatory disorders are spread along two immunological axes capturing disease inflammation levels and types

Tchitchek,

Binvignat,

Roux

et al. 2024

Ann Rheum Dis

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ObjectivesBased on genetic associations, McGonagle and McDermott suggested a classification of autoimmune and autoinflammatory diseases as a continuum ranging from purely autoimmune to purely autoinflammatory diseases and comprising diseases with both components. We used deep immunophenotyping to identify immune cell populations and molecular targets characterising this continuum.MethodsWe collected blood from 443 patients with one of 15 autoimmune or autoinflammatory diseases and 71 healthy volunteers. Deep phenotyping was performed using 13 flow cytometry panels characterising over 600 innate and adaptive cell populations. Unsupervised and supervised analyses were conducted to identify disease clusters with their common and specific cell parameters.ResultsUnsupervised clustering categorised these diseases into five clusters. Principal component analysis deconvoluted this clustering into two immunological axes. The first axis was driven by the ratio of LAG3+ to ICOS+ in regulatory T lymphocytes (Tregs), and segregated diseases based on their inflammation levels. The second axis was driven by activated Tregs and type 3 innate lymphoid cells (ILC3s), and segregated diseases based on their types of affected tissues. We identified a signature of 23 cell populations that accurately characterised the five disease clusters.ConclusionsWe have refined the monodimensional continuum of autoimmune and autoinflammatory diseases as a continuum characterised by both disease inflammation levels and targeted tissues. Such classification should be helpful for defining therapies. Our results call for further investigations into the role of the LAG3+/ICOS+ balance in Tregs and the contribution of ILC3s in autoimmune and autoinflammatory diseases.Trial registration numberNCT02466217.

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Section: Discussionmentioning

confidence: 99%

Deep immunophenotyping reveals that autoimmune and autoinflammatory disorders are spread along two immunological axes capturing disease inflammation levels and types

Tchitchek,

Binvignat,

Roux

et al. 2024

Ann Rheum Dis

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“…For instance, CD95(Fas) signaling would theoretically “mop up” autoreactive B cells and ASCs that were generated within the THY ( Figure 2E ). However, if this failsafe was lost due to gene mutation ( 108 – 110 ) or other forms of regulation ( 111 ), then pathogenic THY B cells and ASCs would be allowed to survive ( Figure 2F ) and potentially escape the THY. Interestingly, alterations in CD95(Fas) signaling have been observed in aging ( 112 , 113 ).…”

Section: Looking Towards the Future: Insights Into Autoimmunity?mentioning

confidence: 99%

Thymus antibody-secreting cells: once forgotten but not lost

Pioli

2023

Front. Immunol.

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Antibody-secreting cells are essential contributors to the humoral response. This is due to multiple factors which include: 1) the ability to secrete thousands of antibodies per second, 2) the ability to regulate the immune response and 3) the potential to be long-lived. Not surprisingly, these cells can be found in numerous sites within the body which include organs that directly interface with potential pathogens (e.g., gut) and others that provide long-term survival niches (e.g., bone marrow). Even though antibody-secreting cells were first identified in the thymus of both humans and rodents in the 1960s, if not earlier, only recently has this population begun to be extensively investigated. In this article, we provide an update regarding the current breath of knowledge pertaining to thymus antibody-secreting cells and discuss the potential roles of these cells and their impact on health.

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“…In ALPS patients lacking germline mutations in FAS, some dominant somatic mutations in the DR and notably in the Death Domain were found. These somatic mutations were identified as missense variants likely to change the normal structure and impact the oligomerization and functionality of CD95 [176]. Of note, a large study in a cohort of 100 ALPS patients with CD95 DD mutations reported that the risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected [177].…”

Section: Systemic Autoimmune Diseasesmentioning

confidence: 99%

Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases

2022

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Cell death plays a pivotal role in the maintenance of tissue homeostasis. Key players in the controlled induction of cell death are the Death Receptors (DR). CD95 is a prototypic DR activated by its cognate ligand CD95L triggering programmed cell death. As a consequence, alterations in the CD95/CD95L pathway have been involved in several disease conditions ranging from autoimmune diseases to inflammation and cancer. CD95L-induced cell death has multiple roles in the immune response since it constitutes one of the mechanisms by which cytotoxic lymphocytes kill their targets, but it is also involved in the process of turning off the immune response. Furthermore, beyond the canonical pro-death signals, CD95L, which can be membrane-bound or soluble, also induces non-apoptotic signaling that contributes to its tumor-promoting and pro-inflammatory roles. The intent of this review is to describe the role of CD95/CD95L in the pathophysiology of cancers, autoimmune diseases and chronic inflammation and to discuss recently patented and emerging therapeutic strategies that exploit/block the CD95/CD95L system in these diseases.

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Impact of human CD95 mutations on cell death and autoimmunity: a model

Cited by 12 publications

References 119 publications

Deep immunophenotyping reveals that autoimmune and autoinflammatory disorders are spread along two immunological axes capturing disease inflammation levels and types

Deep immunophenotyping reveals that autoimmune and autoinflammatory disorders are spread along two immunological axes capturing disease inflammation levels and types

Thymus antibody-secreting cells: once forgotten but not lost

Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases

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