Human neutrophils drive skin autoinflammation by releasing interleukin (IL)-26.

Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils. This occurs via activation of IL-26R in keratinocytes and via the formation of complexes between IL-26 and microbiota DNA, which trigger TLR9 activation of neutrophils. Thus our findings identify neutrophils as an important source of IL-26 and point to IL-26 as the key link between neutrophils and a self-sustaining autoinflammation loop in pustular psoriasis.

Intradermal skin test with mRNA vaccines as a surrogate marker of T cell immunity in immunocompromised patients.

OBJECTIVES: Intradermal skin test (IDT) with mRNA vaccines may represent a simple, reliable, and affordable tool to measure T cell response in immunocompromised patients who failed to mount serological responses following vaccination with mRNA covid-19 vaccines. METHODS: We compared anti-SARS-CoV-2 antibodies and cellular responses in vaccinated immunocompromised patients (n = 58), healthy seronegative naive controls (NC, n = 8), and healthy seropositive vaccinated controls (VC, n = 32) by Luminex, spike-induced IFN-γ Elispot and an IDT. A skin biopsy 24 h after IDT and single-cell RNAseq was performed in three vaccinated volunteers. RESULTS: Twenty-five percent of seronegative NC had a positive Elispot (2/8) and IDT (1/4), compared to 95% (20/21) and 93% (28/30) in seropositive VC, respectively. Single-cell RNAseq data in the skin of VC showed a predominant mixed population of effector helper and cytotoxic T cells. The TCR repertoire revealed 18/1064 clonotypes with known specificities against SARS-CoV-2, among which six were spike-specific. Seronegative immunocompromised patients with positive Elispot and IDT were in 83% (5/6) treated with B cell-depleting reagents, while those with negative IDT were all transplant recipients. CONCLUSIONS: Our results indicate that delayed local reaction to IDT reflects vaccine-induced T-cell immunity opening new perspectives to monitor seronegative patients and elderly populations with waning immunity.

[Anti-IL17 induced eczema and the yin-yang of Th2 and Th17]. / Eczéma induit par les anti-IL-17 et le yin-yang Th2/Th17.

Biologics targeting specific cytokines and pathways have revolutionized the management of patients with chronic inflammatory diseases. However, these treatments have their limitations and, surprisingly, can induce novel inflammatory diseases. Here, we present a case of a psoriasis patient developing anti-IL17 induced eczema, an intriguing side effect of IL-17 blockade. The coexistence of psoriasis and eczema in a single patient is uncommon given their distinct and opposing immune mechanisms. Psoriasis is mainly driven by Th17 cells, whereas atopic dermatitis is Th2-dominated. In this article, we propose the yin yang of Th2 and Th17 with IL-4 and IL17 as principal antipodal vectors that control each other. Thus, blocking one of these cytokines can tip the balance between Th2 and Th17 and lead to the induction of the opposing inflammatory pathway via lifting the controlling mediator.

Les biologiques ciblant des cytokines spécifiques ont révolutionné la prise en charge des maladies inflammatoires chroniques. Cependant, ces thérapies possèdent leurs propres limites et peuvent ­ de manière surprenante ­ induire de nouvelles pathologies inflammatoires. Nous présentons le cas d'un patient psoriasique avec un eczéma induit par anti-IL-17. La coexistence du psoriasis et de l'eczéma atopique chez un même patient est rare, du fait de leurs mécanismes inflammatoires distincts. Le psoriasis est médié par la voie Th17, tandis que l'eczéma atopique est dominé par la voie Th2. Nous proposons un modèle yin-yang entre la voie Th17 et Th2, avec respectivement l'IL-17 et l'IL-4 comme vecteurs opposés. Le blocage de l'une de ces deux cytokines peut perturber cet équilibre dynamique et induire l'expression de la voie inflammatoire opposée par levée du médiateur de contrôle.