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Plasmacytoid DCs (pDC) produce large amounts of type I IFN (IFN-I), cytokines convincingly linked to systemic lupus erythematosus (SLE) pathogenesis. BIIB059 is a humanized mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. A first-in-human study was conducted to assess safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects of single BIIB059 doses in healthy volunteers (HV) and patients with SLE with active cutaneous disease as well as proof of biological activity and preliminary clinical response in the SLE cohort. A randomized, double-blind, placebo-controlled clinical trial was conducted in HV (n = 54) and patients with SLE (n = 12). All subjects were monitored for adverse events. Serum BIIB059 concentrations, BDCA2 levels on pDCs, and IFN-responsive biomarkers in whole blood and skin biopsies were measured. Skin disease activity was determined using the Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A). Single doses of BIIB059 were associated with favorable safety and PK profiles. BIIB059 administration led to BDCA2 internalization on pDCs, which correlated with circulating BIIB059 levels. BIIB059 administration in patients with SLE decreased expression of IFN response genes in blood, normalized MxA expression, reduced immune infiltrates in skin lesions, and decreased CLASI-A score. Single doses of BIIB059 were associated with favorable safety and PK/PD profiles and robust target engagement and biological activity, supporting further development of BIIB059 in SLE. The data suggest that targeting pDCs may be beneficial for patients with SLE, especially those with cutaneous manifestations. ClinicalTrials.gov NCT02106897. Biogen Inc.

Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex. We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years of age] and adolescents [12 to <18 years of age, weighing ≥40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed. In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation. In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor–MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.

Amphibian skin is a mucosal surface in direct and continuous contact with a microbially diverse and laden aquatic and/or terrestrial environment. As such, frog skin is an important innate immune organ and first line of defence against pathogens in the environment. Critical to the innate immune functions of frog skin are the maintenance of physical, chemical, cellular, and microbiological barriers and the complex network of interactions that occur across all the barriers. Despite the global decline in amphibian populations, largely as a result of emerging infectious diseases, we understand little regarding the cellular and molecular mechanisms that underlie the innate immune function of amphibian skin and defence against pathogens. In this review, we discuss the structure, cell composition and cellular junctions that contribute to the skin physical barrier, the antimicrobial peptide arsenal that, in part, comprises the chemical barrier, the pattern recognition receptors involved in recognizing pathogens and initiating innate immune responses in the skin, and the contribution of commensal microbes on the skin to pathogen defence. We briefly discuss the influence of environmental abiotic factors (natural and anthropogenic) and pathogens on the immunocompetency of frog skin defences. Although some aspects of frog innate immunity, such as antimicrobial peptides are well-studied; other components and how they contribute to the skin innate immune barrier, are lacking. Elucidating the complex network of interactions occurring at the interface of the frog's external and internal environments will yield insight into the crucial role amphibian skin plays in host defence and the environmental factors leading to compromised barrier integrity, disease, and host mortality.

A proof-of-concept phase I clinical trial demonstrates that targeting interleukin (IL)-23 with an antibody that binds to the p19 subunit leads to clinical improvement of disease in patients with moderate to severe psoriasis. Antibody treatment of psoriasis Sauzanne Khalilieh and colleagues report a proof-of-concept phase I clinical trial which demonstrates that targeting the pro-inflammatory cytokine interleukin-23 (IL-23) with tildrakizumab, an antibody that binds to the p19 subunit of IL-23, leads to symptomatic improvement of disease in patients with moderate to severe psoriasis. The antibody is well tolerated, suggesting that selective targeting of IL-23 merits further study. Psoriasis is a chronic inflammatory skin disorder that affects approximately 2–3% of the population worldwide and has severe effects on patients’ physical and psychological well-being 1 , 2 , 3 . The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg −1 groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg −1 group and 13 out of 14 subjects in the 10 mg kg −1 group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

ObjectivesSkin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment—the faSScinate study—in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor.MethodsWe analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains.ResultsThe hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFβ-regulated genes and molecular pathways.ConclusionsWe demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases.Trial registration number NCT01532869; Post-results.

PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti–PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole-genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti–PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti–PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti–PD-L1 monotherapy in bladder cancer.

Homologous vaccination has proven to be an effective tool to control and eradicate lumpy skin disease. However, their use has been met with some trepidation for diverse reasons, in some regions, and has resulted in the use of heterologous vaccines (sheeppox or goatpox-based). However, conflicting data (field and experimental) raises questions about their effectiveness. As comparative data under standardized conditions are lacking, this study aimed to evaluate four sheeppox-based and one goatpox-based vaccine using a standard vaccination/challenge protocol previously used to evaluate homologous LSDV vaccines. Although some minor differences were observed between the different sheeppox-based vaccines, none of them were able to completely protect the animals against a virulent LSDV challenge, as witnessed by the development of nodules, viremia and the detection of viral genomes in the different organs and tissues. In contrast, the goatpox-based vaccine provided complete protection (no nodules nor viremia) and induced an immunological profile (seroconversion and IFNγ response) similar to the homologous vaccines. Based upon the obtained data it can be concluded that none of the tested sheeppox-based vaccines are suitable for vaccination to prevent LSDV infection, at the dose used, while the goatpox-based vaccine, Caprivac, is. It should, however, be emphasized that this cannot be extrapolated to other goatpox-based vaccines without extensive validation.

The skin is an important organ that acts as a physical barrier to the outer environment. It is rich in immune cells such as keratinocytes, Langerhans cells, mast cells, and T cells, which provide the first line of defense mechanisms against numerous pathogens by activating both the innate and adaptive response. Cutaneous immunological processes may be stimulated or suppressed by numerous plant extracts via their immunomodulatory properties. Several plants are rich in bioactive molecules; many of these exert antimicrobial, antiviral, and antifungal effects. The present study describes the impact of plant extracts on the modulation of skin immunity, and their antimicrobial effects against selected skin invaders. Plant products remain valuable counterparts to modern pharmaceuticals and may be used to alleviate numerous skin disorders, including infected wounds, herpes, and tineas.

Whether graft rejection occurs by direct or indirect presentation of antigen is still controversial. However, using a mouse ear skin allograft model and a two-photon intravital imaging approach, Susanna Celli and her colleagues have been able to dissect some of the dynamic processes involved in graft rejection, including early- and late-stage events at the transplant site, as well as intermediate events in the draining lymph node. Transplant rejection involves a coordinated attack of the innate and the adaptive immune systems of the host. To investigate this dynamic process and the contributions of both donor and host cells, we developed an ear skin graft model suitable for intravital imaging. We found that donor dermal dendritic cells (DCs) migrated rapidly from the graft and were replaced by host CD11b + mononuclear cells. The infiltrating host cells captured donor antigen, reached the draining lymph node and cross-primed graft-reactive CD8 + T cells. Furthermore, we defined the mechanisms by which host T cells target graft cells. We found that primed T cells entered the graft from the surrounding tissue and localized selectively at the dermis-epidermis junction. Later, CD8 + T cells disseminated throughout the graft and many became arrested. These results provide insights into the antigen presentation pathway and the stepwise progression of CD8 + T cell activity, thereby offering a framework for evaluating how immunotherapy might abrogate the key steps in allograft rejection.