Role of the NLRP1 inflammasome in skin cancer and inflammatory skin diseases.

Inflammasomes are cytoplasmic protein complexes that play a crucial role in protecting the host against pathogenic and sterile stressors by initiating inflammation. Upon activation, these complexes directly regulate the proteolytic processing and activation of proinflammatory cytokines interleukin (IL)-1ß and IL-18 to induce a potent inflammatory response, and induce a programmed form of cell death called pyroptosis to expose intracellular pathogens to the surveillance of the immune system, thus perpetuating inflammation. There are various types of inflammasome complexes, with the NLRP1 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-1) inflammasome being the first one identified and currently recognized as the predominant inflammasome sensor protein in human keratinocytes. Human NLRP1 exhibits a unique domain structure, containing both an N-terminal pyrin (PYD) domain and an effector C-terminal caspase recruitment domain (CARD). It can be activated by diverse stimuli, such as viruses, ultraviolet B radiation and ribotoxic stress responses. Specific mutations in NLRP1 or related genes have been associated with rare monogenic skin disorders, such as multiple self-healing palmoplantar carcinoma; familial keratosis lichenoides chronica; autoinflammation with arthritis and dyskeratosis; and dipeptidyl peptidase 9 deficiency. Recent research breakthroughs have also highlighted the involvement of dysfunctions in the NLRP1 pathway in a handful of seemingly unrelated dermatological conditions. These range from monogenic autoinflammatory diseases to polygenic autoimmune diseases such as vitiligo, psoriasis, atopic dermatitis and skin cancer, including squamous cell carcinoma, melanoma and Kaposi sarcoma. Additionally, emerging evidence implicates NLRP1 in systemic lupus erythematosus, pemphigus vulgaris, Addison disease, Papillon-Lefèvre syndrome and leprosy. The aim of this review is to shed light on the implications of pathological dysregulation of the NLRP1 inflammasome in skin diseases and investigate the potential rationale for targeting this pathway as a future therapeutic approach.

Immune checkpoint inhibitor-induced epidermal necrolysis: A narrative review evaluating demographics, clinical features, and culprit medications.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but can cause immune-related adverse events (irAEs). Severe cutaneous irAEs, including epidermal necrolysis, are rare but potentially life-threatening. There is limited understanding of the clinical features and management of ICI-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), so we aimed to analyze 95 cases of ICI-induced SJS/TEN (35 cases of SJS, 26 cases of TEN, two cases of SJS/TEN overlap, and 32 cases of unspecified) to increase knowledge of this condition among oncologists and dermatologists. We conducted a comprehensive search of PubMed for all relevant case reports published until the end of December 2022, and collected data on patient demographics, cancer type, ICI regimen, time to onset of SJS/TEN, clinical presentation, management strategies, and outcomes. PD-1 inhibitors were the most common ICIs associated with SJS/TEN (58.9%), followed by the combination of PD-1 and CTLA-4 inhibitors (11.6%), and PD-L1 inhibitors (6.3%). Lung cancer and melanoma were the most frequent malignancies treated (35.8% and 25.4%, respectively). SJS/TEN occurred most frequently within the first 4 weeks (51.7%), and corticosteroid monotherapy was the most commonly chosen systemic treatment (56.4%). The overall mortality rate of ICI-induced SJS/TEN was 30.8%. Our findings highlight the frequency and severity of ICI-induced SJS/TEN and the urgent need for predictive molecular biomarkers aimed at preventive measures and early intervention.

Relationship between α-genus human papillomavirus and non-genital seborrheic keratosis: Report of new cases and updated review.

BACKGROUND: Seborrheic keratoses (SK) are the most common acquired benign tumor that affects middle-aged or older adults with great cosmetic concern. Clinical and histopathological similarities of SK and common warts have been addressed by investigating the possible presence of human papillomavirus (HPV) DNA in SK. Previous studies suggested the association between α-genus HPV and SK located on genital skin, whereas the causal relationship between α-HPV and non-genital SK remains controversial. AIM: This study aimed to clarify the pathogenic involvement of α-HPV in the development of non-genital SK. METHODS: We analyzed α-HPV DNA prevalence and HPV genotypes using a PCR-based microarray on 51 skin samples presenting with histologically confirmed SK without any malignant changes. Correlation between the histological subtype of SK and their HPV DNA-positive reactivity was also evaluated. RESULTS: Of 51 non-genital SK, two (3.9%) skin samples were positive for α-HPV DNA; high-risk HPV 31 and low-risk HPV 42 were found. Evaluation of HPV prevalence in different histological types of SK showed that both HPV-positive cases were acanthotic type; 14.3% of acanthotic SK lesions were positive, while all of the other types were negative for α-HPV. CONCLUSIONS: This study demonstrates that α-HPV positivity is very rare in common non-genital SK. The rare α-HPV-positive SK lesions histologically belonged to the acanthotic type, implying a potential impact of HPV infection on epidermal hyperproliferation. Although a possible association cannot be excluded, our findings suggest that α-HPV is not a major causative factor for non-genital SK.

New-generation diagnostics in inflammatory skin diseases: Immunofluorescence and histopathological assessment using ex vivo confocal laser scanning microscopy in cutaneous lupus erythematosus.

Ex vivo confocal laser scanning microscopy (CLSM) offers real-time examination of excised tissue in reflectance, fluorescence and digital haematoxylin-eosin (H&E)-like staining modes enabling application of fluorescent-labelled antibodies. We aimed to assess the diagnostic performance of ex vivo CLSM in identifying histopathological features and lupus band test in cutaneous lupus erythematosus (CLE) with comparison to conventional histopathology and direct immunofluorescence (DIF). A total of 72 sections of 18 CLE patients were stained with acridine orange (AO), anti-IgG, anti-IgM and anti-IgA; 21 control samples were stained with AO. Subsequently, ex vivo CLSM examination of all samples was performed in reflectance, fluorescence and digital H&E-like staining modes. Superficial and deep perivascular inflammatory infiltration (94.4%), interface dermatitis (88.9%), spongiosis (83.3%) and vacuolar degeneration (77.7%) were the most common features detected with ex vivo CLSM. Kappa test revealed a level of agreement ranging within "perfect" to "good" between ex vivo CLSM and conventional histopathology. ROC analysis showed that the combination of perivascular infiltration, interface dermatitis and spongiosis detected by ex vivo CLSM has the potential to distinguish between CLE and controls. Basement membrane immunoreactivity with IgG, IgM and IgA was identified in 88.8% (n = 15), 55.5% (n = 10) and 55.5% (n = 10) of the CLE samples using ex vivo CLSM, respectively, whereas DIF showed IgG, IgM and IgA positivity in 94.4% (n = 17), 100% (n = 18) and 88.9% (n = 16) of patients, respectively. In conclusion, ex vivo CLSM enables simultaneous histopathological and immunofluorescence examination in CLE showing a high agreement with conventional histopathology, albeit with a lower performance than conventional DIF.

Ex vivo confocal laser scanning microscopy: An innovative method for direct immunofluorescence of cutaneous vasculitis.

Ex vivo confocal laser scanning microscopy (ex vivo CLSM) offers an innovative diagnostic approach through vertical scanning of skin samples with a resolution close to conventional histology. In addition, it enables fluorescence detection in tissues. We aimed to assess the applicability of ex vivo CLSM in the detection of vascular immune complexes in cutaneous vasculitis and to compare its diagnostic accuracy with direct immunofluorescence (DIF) microscopy. Eighty-two sections of 49 vasculitis patients with relevant DIF microscopy findings were examined using ex vivo CLSM following staining with fluorescent-labeled IgG, IgM, IgA, C3 and fibrinogen antibodies. DIF microscopy showed immunoreactivity of vessels with IgG, IgM, IgA, C3 and Fibrinogen in 2.0%, 49.9%, 12.2%, 59.2% and 44.9% of the patients, respectively. Ex vivo CLSM detected positive vessels with the same antibodies in 2.0%, 38.8%, 8.2%, 42.9% and 36.7% of the patients, respectively. The detection rate of positive superficial dermal vessels was significantly higher in DIF microscopy as compared to ex vivo CLSM (P < .05). Whereas, ex vivo CLSM identified positive deep dermal vessels more frequently compared to DIF microscopy. In conclusion, ex vivo CLSM could identify specific binding of the antibodies in vessels and showed a comparable performance to conventional DIF microscopy in diagnosing vasculitis.

Mast cells play a key role in host defense against herpes simplex virus infection through TNF-α and IL-6 production.

The essential contribution of mast cells (MCs) to bacterial host defense has been well established; however, little is known about their role in viral infections in vivo. Here, we found that intradermal injection with herpes simplex virus 2 (HSV-2) into MC-deficient Kit(W/Wv) mice led to increased clinical severity and mortality with elevated virus titers in HSV-infected skins. Ex vivo HSV-specific tetramer staining assay demonstrated that MC deficiency did not affect the frequency of HSV-specific cytotoxic T lymphocytes (CTLs) in draining lymph nodes. Moreover, the high mortality in Kit(W/W-v) mice was completely reversed by intradermal reconstitution with bone marrow-derived MCs (BMMCs) from wild-type, but not TNF(-/-) or IL-6(-/-) mice, indicating that MCs or, more specifically, MC-derived tumor necrosis factor (TNF) and IL-6 can protect mice from HSV-induced mortality. However, HSV did not directly induce TNF-α or IL-6 production by BMMCs; supernatants from HSV-infected keratinocytes induced the production of these cytokines by BMMCs without degranulation. Furthermore, IL-33 expression was induced in HSV-infected keratinocytes, and blocking the IL-33 receptor T1/ST2 on BMMCs significantly reduced TNF-α and IL-6 production by BMMCs. These results indicate the involvement of MCs in host defense at HSV-infected sites through TNF-α and IL-6 production, which is induced by keratinocyte-derived IL-33.

Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM. METHODS: Clinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab. RESULTS: Seven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb-IV). CONCLUSIONS: While less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy.

A case of lymphoepithelioma-like carcinoma of the skin associated with Epstein-Barr virus infection.

Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare cutaneous neoplasm with histopathologic similarities to nasopharyngeal carcinoma. The association of nasopharyngeal carcinoma with Epstein-Barr virus (EBV) is well documented. EBV has also been reported to be associated with LELC in only four sites (the stomach, salivary glands, lung, and thymus), but not in the skin. We report herein a case of EBV-positive LELCS. An 82-year-old female presented with a red nodule on the right cheek. Histologically, the entire dermis was occupied by atypical tumor cell nests with dense lymphocytic infiltration. Neoplastic cells were strongly positive for cytokeratin 14 but were negative for cytokeratins 19 and 20. EBV genomes in neoplastic cells were detected by polymerase chain reaction analysis and in situ hybridization for EBV-encoded RNA, suggesting an association with EBV.

Favourable prognosis with modified dosing of docetaxel and cisplatin in Japanese patients with ovarian cancer.

BACKGROUND: The long-term efficacy and safety of docetaxel/cisplatin as first-line chemotherapy in Japanese patients was evaluated in order to find an optional regimen for ovarian cancer. PATIENTS AND METHODS: Women with surgically resected stage Ic-IV epithelial ovarian cancer were treated with docetaxel 70 mg/m2 and cisplatin 60 mg/m2 every 4 weeks. RESULTS: Ninety women were enrolled of whom 89 (median age, 54 years) received a median of 6 cycles (range 1 to 9). With a median 38 months'follow-up, median progression-free survival was 28 months (95% lower confidence interval, 24 months) in 60 patients with stage III-IV disease. The overall response rate for 20 patients was 45%. Neutropenia was the most common (67%) grade 3/4 toxicity. Major grade 3/4 nonhaematological toxicities were gastrointestinal toxicities (< or = 11%) and fatigue (8%). No grade 3/4 neurotoxicity was observed. CONCLUSION: The combination of docetaxel/cisplatin is a regimen with favourable progression-free survival for ovarian cancer.

Gap junction-mediated intercellular communication between dendritic cells (DCs) is required for effective activation of DCs.

Gap junctions, formed by members of the connexin (Cx) family, are intercellular channels allowing direct exchange of signaling molecules. Gap junction-mediated intercellular communication (GJIC) is a widespread mechanism for homeostasis in organs. GJIC in the immune system is not yet fully understood. Although dendritic cells (DC) reportedly form cell-to-cell contact between DCs in nonlymphoid and lymphoid organs, GJIC between DCs remains unknown. In this study we examined whether DCs form GJIC. XS52 and bone marrow-derived DCs (BMDCs) were tested for GJIC by counting intercellular transfer of Lucifer Yellow microinjected into a cell. Either DC became effectively dye-coupled when activated with LPS plus IFN-gamma or TNF-alpha plus IFN-gamma. LPS- plus IFN-gamma-induced dye-coupling was mediated by DC-derived TNF-alpha. In addition, CpG plus IFN-gamma induced dye-coupling in BMDCs, which was also mediated by DC-derived TNF-alpha. LPS- plus IFN-gamma-induced activation of DCs (assessed by CD40 expression) was observed when there was cell-to-cell contact and was significantly blocked by heptanol, a gap junction blocker. These results indicate that cell-to-cell contact and GJIC are required for effective DC activation. In addition, heptanol significantly inhibited the LPS- plus IFN-gamma-induced up-regulation of the other costimulatory (i.e., CD80 and CD86) and MHC class II molecules expressed by BMDCs, and it significantly reduced their allostimulatory capacity. Among Cx members, Cx43 was up-regulated in dye-coupled BMDCs, and Cx mimetic peptide, a blocker of Cx-mediated GJIC, significantly inhibited the dye-coupling and activation, suggesting the involvement of Cx43. Thus, our study provides the first evidence for GJIC between DCs, which is required for effective DC activation.