JID innovations : skin science from molecules to population health最新文献

A subgroup of patients with atopic dermatitis (AD) suffers from recurrent, disseminated herpes simplex virus skin infection, termed eczema herpeticum. To determine the transcriptional mechanisms of the skin and immune system pathobiology that underlie development of AD with eczema herpeticum (ADEH), we performed RNA-sequencing analysis of nonlesional skin (epidermis, dermis) from AD patients with and without a history of ADEH (ADEH⁺, n = 15; ADEH⁻, n = 13) along with healthy controls (n = 15). We also performed RNA sequencing on participants’ plasmacytoid dendritic cells infected in vitro with herpes simplex virus 1. ADEH⁺ patients exhibited dysregulated gene expression, limited in the dermis (14 differentially expressed genes) and more widespread in the epidermis (129 differentially expressed genes). ADEH⁺-upregulated epidermal differentially expressed genes were enriched in type 2 cytokine (IL4R, CCL22, CRLF2, IL7R), interferon (CXCL10, ICAM1, IFI44, IRF7), and IL-36γ (IL36G) inflammatory gene pathways. All ADEH⁺ participants exhibited type 2 cytokine and inteferon endotypes, and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH⁻ participants. ADEH⁺ skin also had dysregulated epidermal differentiation complex gene expression of the late-cornified envelope, S100A, and small proline-rich gene families, which are involved in skin barrier function and antimicrobial activities. Plasmacytoid dendritic cell transcriptional responses to herpes simplex virus 1 infection were unaltered by ADEH status. The study concluded that the pathobiology underlying ADEH⁺ risk is associated with a unique, multifaceted epidermal inflammation that accompanies dysregulation of epidermal differentiation complex genes. These findings will help direct future studies that define how these inflammatory patterns may drive risk of eczema herpeticum in AD.

Most viral infections can be self-limited, with no requirement for medical intervention. However, the same viruses can cause severe diseases in patients with compromised immunity due to single-gene diseases, acquired immune deficiency syndrome, or hematologic malignancies or those receiving immunosuppressive drugs. Occasionally, these immunocompromised patients harbor >1 infectious agent, requiring several concomitant diagnostic tests. We have developed, to our knowledge, a previously unreported whole-transcriptome sequencing–based pipeline that allows virome profiling, quantitation, and expression pattern analysis of 926 distinct viruses by sequencing of RNA isolated from a single lesional skin biopsy. This pipeline can also explore host genetics if there is a Mendelian predisposition to infection. We applied this pipeline to 6 Iranian patients with viral-induced skin lesions associated with immune deficiency secondary to HIV, human T-lymphotropic virus 1, chronic lymphocytic leukemia, and post transplant immunosuppression. In 5 cases, definitive human papillomavirus infections were identified, some caused by multiple viral types. In addition to human papillomavirus, coinfection with other viruses (Merkle cell polyomavirus, cytomegalovirus, and human herpesvirus 4) was detected in some lesions. In 1 case, whole-transcriptome sequencing validated the clinical diagnosis of adult T-cell leukemia/lymphoma in a patient with an initial diagnosis of mycosis fungoides/Sézary syndrome. These findings attest to the power of whole-transcriptome sequencing in profiling the cutaneous virome in the context of compromised immunity.

In persons with limb loss, prosthetic devices cause skin breakdown, largely because residual limb skin (nonvolar) is not intended to bear weight such as palmoplantar (volar) skin. Before evaluation of treatment efficacy to improve skin resiliency, efforts are needed to establish normative data and assess outcome metric reliability. The purpose of this study was to use optical coherence tomography to (i) characterize volar and nonvolar skin epidermal thickness and (ii) examine the reliability of optical coherence tomography. Four orientations of optical coherence tomography images were collected on 33 volunteers (6 with limb loss) at 2 time points, and the epidermis was traced to quantify thickness by 3 evaluators. Epidermal thickness was greater (P < .01) for volar skin (palm) (265.1 ± 50.9 μm, n = 33) than for both nonvolar locations: posterior thigh (89.8 ± 18.1 μm, n = 27) or residual limb (93.4 ± 27.4 μm, n = 6). The inter-rater intraclass correlation coefficient was high for volar skin (0.887–0.956) but low for nonvolar skin (thigh: 0.292–0.391, residual limb: 0.211–0.580). Correlation improved when comparing only 2 evaluators who used the same display technique (palm: 0.827–0.940, thigh: 0.633–0.877, residual limb: 0.213–0.952). Despite poor inter-rater agreement for nonvolar skin, perhaps due to challenges in identifying the dermal–epidermal junction, this study helps to support the utility of optical coherence tomography to distinguish volar from nonvolar skin.

We have previously identified that a structural membrane protein Caveolin-1 (Cav1) is involved in the regulation of aberrant keratinocyte proliferation and differentiation. The aim of this study was to elucidate the role of Cav1, Caveolin-2 (Cav2), and Cavin-1 in the pathogenesis of psoriasis vulgaris and between psoriasis subtypes. We utilized human biopsies from validated cases of psoriasis vulgaris (n = 21) at the University of Miami Hospital and compared the expression of Cav1, Cav2, and Cavin-1 by immunohistochemistry staining with that in normal healthy age-/sex-/location-matched skin (n = 15) and chronic spongiotic dermatitis skin samples (as control inflammatory skin condition) and quantified using QuPath. Distinct subtypes of psoriasis included guttate, inverse, nail, plaque, palmoplantar, and pustular. All biopsy samples exhibited a trend toward downregulation of Cav1, with nail, plaque, and palmoplantar psoriasis exhibiting the most pronounced effects. Only nail and pustular psoriasis samples exhibited significant downregulation of Cav2 and Cavin-1, suggesting Cav1 to be the main caveolar contributor to the pathogenesis of psoriasis. Together, these data support caveolae as pathophysiological targets in nail and pustular psoriasis, whereas Cav1 seems to be a general biomarker of multiple subtypes of psoriasis.

Previous work done by our laboratory described the use of an immunocompetent spontaneous melanoma-prone mouse model, TGS (TG-3/SKH-1), to evaluate treatment outcomes using inhibitors of glutamatergic signaling and immune checkpoint for 18 weeks. We showed a significant therapeutic efficacy with a notable sex-biased response in male mice. In this follow-up 18-week study, the dose of the glutamatergic signaling inhibitor was increased (from 1.7 mg/kg to 25 mg/kg), which resulted in improved responses in female mice but not male mice. The greatest reduction in tumor progression was observed in male mice treated with single-agent troriluzole and anti–PD-1. Furthermore, a randomly selected group of mice was removed from treatment after 18 weeks and maintained for up to an additional 48 weeks demonstrating the utility of the TGS mouse model to perform a ≥1-year preclinical therapeutic study in a physiologically relevant tumor–host environment. Digital spatial imaging analyses were performed in tumors and tumor microenvironments across treatment modalities using antibody panels for immune cell types and immune cell activation. The results suggest that immune cell populations and cytotoxic activities of T cells play critical roles in treatment responses in these mice. Examination of a group of molecular protein markers based on the proposed mechanisms of action of inhibitors of glutamatergic signaling and immune checkpoint showed that alterations in expression levels of xCT, γ-H2AX, EAAT2, PD-L1, and PD-1 are likely associated with the loss of treatment responses. These results suggest the importance of tracking changes in molecular markers associated with the mechanism of action of therapeutics over the course of a longitudinal preclinical therapeutic study in spatial and temporal manners.

IL-23 is central to psoriasis pathogenesis. Biologics targeting IL-23 are important therapies against psoriasis. IL-23 inhibitors risankizumab, tildrakizumab, and guselkumab bind the IL-23 p19 subunit, whereas ustekinumab binds p40; however, the structural composition of the IL-23–binding epitopes and how these molecular properties relate to clinical efficacy are not known. Utilizing epitope data derived from hydrogen-deuterium exchange or crystallographic experiments, we mapped inhibitor epitope locations, hydrophobicity, and surface charge onto the IL-23 surface. Molecular properties of each inhibitor epitope, including solvent-accessible surface area, were correlated to binding affinity, kinetic values, and clinical efficacy scores for plaque psoriasis through linear regression analysis. Each IL-23 inhibitor binds an epitope with a unique size, composition, and location except for a 10-residue overlap region outside of the IL-23 receptor epitope. We observed strong correlations between epitope surface area and K_D and k_off but not k_on. Epitope surface area, K_D, and k_off were further associated with short-term (10–16 weeks) and long-term (44–60 weeks) clinical efficacy according to PASI-90 responses, with risankizumab demonstrating highest efficacy among IL-23 biologics. In contrast, k_on, epitope hydrophobicity, polarity, and charge content did not correlate with efficacy. These data exemplify how molecular principles of medications within a therapeutic class can explain their differential clinical responses.

Inhibition of IL-4/IL-13 signaling has dramatically improved the treatment of atopic dermatitis (AD). However, in many patients, clinical responses are slow to develop and remain modest. Indeed, some symptoms of AD are dependent on IL-31, which is only partially reduced by IL-4/IL-13 inhibition. Thus, there is an unmet need for AD treatments that concomitantly block IL-4/IL-13 and IL-31 pathways. We engineered NM26-2198, a bispecific tetravalent antibody designed to accomplish this task. In reporter cell lines, NM26-2198 concomitantly inhibited IL-4/IL-13 and IL-31 signaling with a potency comparable with that of the combination of an anti–IL-4Rα antibody (dupilumab) and an anti–IL-31 antibody (BMS-981164). In human PBMCs, NM26-2198 inhibited IL-4–induced upregulation of CD23, demonstrating functional binding to FcγRII (CD32). NM26-2198 also inhibited the secretion of the AD biomarker thymus and activation-regulated chemokine (TARC) in blood samples from healthy human donors. In male cynomolgus monkeys, NM26-2198 exhibited favorable pharmacokinetics and significantly inhibited IL-31–induced scratching at a dose of 30 mg/kg. In a repeat-dose, good laboratory practice toxicology study in cynomolgus monkeys, no adverse effects of NM26-2198 were observed at a weekly dose of 125 mg/kg. Together, these results justify the clinical investigation of NM26-2198 as a treatment for moderate-to-severe AD.