Publications by authors named "Emmanuel Contassot"

The MHC class I-related molecule MR1 is ubiquitously expressed, is highly conserved among mammals, and presents bacterial and endogenous antigens in tumor cells. These features indicate that tumor-specific T cells restricted to MR1 may represent ideal candidates for novel cancer-directed T-cell immunotherapy. The very low expression of the MR1 protein at the cell surface is a potential challenge limiting the possible use of MR1-directed immunotherapies.

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Article Synopsis
  • Pityriasis rubra pilaris (PRP) is a rare skin condition with unclear causes, but recent research identified IL-1β as a crucial factor in its development.
  • Treatment with IL-1 antagonists like anakinra and canakinumab led to significant improvements in patients, including reduced skin lesions within a few weeks.
  • The findings suggest that PRP could be redefined as an autoinflammatory keratinization disorder, highlighting the need for further clinical trials to test the effectiveness of targeting IL-1β in treatment.
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The translatability of research is highly dependent on models that recapitulate human tissues and organs. Here, we describe a procedure for the generation of human epidermis organotypic cultures (HEOCs) from primary keratinocytes isolated from foreskin and adult skin as well as from an immortalized keratinocyte cell line (KerTr). We tested several media conditions to develop a defined HEOC growing and expansion media.

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  • Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe skin reactions with unclear treatment effects on systemic inflammation and no agreed-upon therapies.
  • In a study of 16 patients, treatments included high-dose intravenous immunoglobulins (IVIG), cyclosporine A (CSA), and best supportive care only (BSCO), with serum samples taken before and after treatment.
  • Results showed distinct immune response dynamics among different treatments, with IVIG leading to early significant changes, but no overall differences in clinical outcomes among treatment groups.
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  • Apremilast (Otezla) is a PDE4 inhibitor used for treating psoriasis, psoriatic arthritis, and oral ulcers in Behçet's disease, but its effects on inflammasome activation are still not well understood.
  • In a mouse model for psoriasis, treatment with apremilast led to significant improvement in skin lesions over two weeks, with reductions in inflammation, epidermal thickness, and proinflammatory cytokines.
  • Even though apremilast did not directly inhibit inflammasome activation in human cells, it indirectly reduced inflammation by lowering the levels of inflammasome components, highlighting its effectiveness in treating psoriasis symptoms.
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Verma et al. (2021) demonstrate that TNF antagonists unexpectedly downregulate systemic IL-1β by inhibiting noncanonical inflammasome activation in patients with psoriasis. Given the known involvement of IL-1β in the pathogenesis of psoriasis skin manifestations and associated comorbidities, the findings of Verma et al.

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Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity.

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In Sézary syndrome (SS) impaired T-cell function and cytokine profile lead to immune evasion. Immune checkpoints non-redundantly regulate immune responses and targeting them is promising. We evaluated the expression of BTLA, CTLA-4, FCRL3, LAG-3, and TIGIT in tumor and non-tumor SS T-cells.

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Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remain incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis.

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Acne vulgaris is treated with antibiotics and retinoids, but side effects are numerous. Novel safe and efficient therapies are still needed. Wang et al.

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By forming a protective barrier, epidermal keratinocytes represent the first line of defense against environmental insults. UVB radiation of the sun is a major challenge for the skin and can induce inflammation, aging, and eventually skin cancer. UVB induces an immune response in human keratinocytes resulting in activation and secretion of the proinflammatory cytokines proIL-1β and -18.

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Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin.

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Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT safety and efficacy is the use of new or improved adjuvants. This study investigates immune responses produced by microcrystalline tyrosine (MCT)-based vaccines as compared with conventional aluminum hydroxide (alum).

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Vaccines typically come with adjuvants that trigger the innate immune system in order to prepare best possible inflammatory conditions as to allow the adaptive immune system to become activated, generally for the induction of antibodies. The oldest approved and most abundant immunological adjuvants are salts of aluminium, which are also frequently used in animal models of immunisation and allergy desensitization. In rodents, the intraperitoneal administration of aluminium adjuvants is commonly performed and considered safe.

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Agak et al. demonstrate that different strains of Propionibacterium acnes, a bacterium colonizing pilosebaceous units in healthy skin and acne, have the ability to induce T helper type 17 cells secreting either IFN-γ or IL-10 and exhibiting either pathogenic or protective properties, respectively. This work contributes to growing evidence indicating that the phenotype of T helper type 17 cells is largely dependent on their microbiological environment.

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Inflammasomes are multimeric protein complexes that assemble upon sensing of a variety of stress factors. Their formation results in caspase-1-mediated activation and secretion of the pro-inflammatory cytokines pro-interleukin(IL)-1β and -18, which induce an inflammatory response. Inflammation is supported by a lytic form of cell death, termed pyroptosis.

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Inflammasomes are key intracellular signaling platforms involved in innate immune responses to micro-organisms and danger signals. Extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 mitogen-activated protein kinase family members are activated by numerous environmental stresses. Recently, it has been reported that Jun N-terminal kinase is involved in inflammasome activation in myeloid immune cells.

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In 2002, intracellular protein complexes known as the inflammasomes were discovered and were shown to have a crucial role in the sensing of intracellular pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Activation of the inflammasomes results in the processing and subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18. Several autoinflammatory disorders such as cryopyrin-associated periodic syndromes and Familial Mediterranean Fever have been associated with mutations of genes encoding inflammasome components.

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Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood.

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Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861.

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Purpose: Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated.

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Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by pruritic erythroderma, peripheral lymphadenopathy and the presence of malignant T cells in the blood. Unequivocal detection of malignant cells in patients with Sézary syndrome is of important diagnostic, prognostic and therapeutic value. However, no single Sézary syndrome specific cell surface marker has been identified.

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