Diseases associated with hypersensitivity reactions (HRs) are extremely common and can affect the quality of life of millions of people, sometimes with life-threatening severity. In order to diagnose, treat, cure, or potentially prevent these diseases, clinicians and scientists need a better understanding of the entire immune process, from its initiation through the central mechanism to the effector phase. A new classification is needed, primarily because earlier classifications defined HRs almost exclusively by their effector mechanisms. However, outstanding achievements in immunological science over the past decades have revealed the critical, decision-making roles of initiation and central mechanisms in shaping the well-known effector phases. In addition, a crucially important group of HRs consists of small-molecule drug-induced reactions, which include both immunological and non-immunological pharmacological processes; therefore, the incorporation of these entities represents a key aspect of the revised classification. This review article provides a historical overview of the evolution of the main HR classifications, and proposes a new, expanded classification that (a) considers the initiation, central, and effector phases of HRs as interconnected, equally important processes; (b) highlights the role of peripheral barrier tissues in the breakdown of tolerance, thereby contributing to the development of HRs, and (c) distinguishes between classic and non-classic HRs (e.g., pharmacological interaction with immune receptors [p-i] reactions and pseudoallergies). Adoption of this new classification may expand the possibilities for developing preventive and causal therapies and help physicians appropriately interpret and thus effectively treat the heterogeneous phenotypes of hypersensitivity diseases.

IntroductionB-type natriuretic peptide (BNP) is a well-known cardiac hormone and biomarker of heart failure, but emerging evidence suggests that it also possesses immunomodulatory properties, including a role in inflammatory skin conditions like atopic dermatitis (AD). Langerhans cells (LCs), specialized epidermal antigen-presenting cells, orchestrate cutaneous immunity and are targets of neuropeptides. In the present study, we investigated how BNP treatment during differentiation affects the activation, cytokine profile, and interaction of immune cells with moLCs subsequently activated via Toll-like receptors (TLRs).MethodsMoLCs were differentiated in the presence or absence of BNP, followed by 24-hour activation with the TLR7/8 agonist CL075 and/or the TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)). Cell surface markers of moLCs were assessed using flow cytometry. ELISA was used to analyze the production of cytokines. The T cell proliferation-inducing ability of moLCs was detected through T cell coculture. Transwell migration experiments were conducted to elucidate the migratory capacity of moLCs, as well as the migration of other lymphocytes toward moLCs.ResultsBNP treatment during the differentiation of moLCs did not alter the expression of activation markers; however, it significantly counteracted the robust increase in both pro- and anti-inflammatory cytokine production induced by TLR activation. Combined TLR activation significantly increased T cell proliferation capacity, and this effect was significantly diminished in moLCs differentiated in the presence of BNP. Functionally, BNP pre-treated moLCs exhibited significantly enhanced chemotaxis towards the lymph node chemokines, supporting the previously observed migratory phenotype. Transcriptomic analysis further supported this finding, demonstrating that BNP pre-treatment attenuated the inflammatory gene signature induced by TLR agonism. Furthermore, the supernatant from TLR-activated, BNP-treated moLCs showed a marked reduction in the ability to induce the migration of peripheral blood CD56+ Natural Killer (NK) cells.DiscussionWe found that BNP primes moLCs toward a migratory phenotype and, upon subsequent TLR activation, exerts a potent inhibitory effect on their cytokine and chemokine production, thereby limiting their capacity to drive T cell proliferation and NK cell migration. This dual effect suggests that BNP may play a context-dependent role in skin immunity, potentially restraining inflammation while promoting LC transit to the draining lymph nodes.

Background: Risk assessment models are increasingly being used in oncology to improve therapeutic and follow-up decisions for individual patients. Methods: In our study, we used a university hospital registry database containing data on patients diagnosed with invasive cutaneous melanoma between 2000 and 2019 (training cohort: N = 1402; validation cohort: N = 601). Using multivariate Cox regression models, we identified clinicopathological variables that are independent risk factors for melanoma recurrence at specific sites. We then constructed nomograms to predict the probability of recurrence at 3, 5, and 10 years. Results: Age, sex, primary tumor location, histological subtype, Clark invasion level and AJCC pT category were independent prognostic factors for melanoma recurrence in regional lymph nodes. Age, sex, primary tumor location, Clark level of invasion, AJCC pT stage and regional lymph node metastasis were risk factors for skin/soft tissue (including muscle)/non-regional lymph node metastases. We found that AJCC pT category and sex were also independent prognostic factors for melanoma recurrence in the lung, visceral sites, and brain. Furthermore, the nomogram predicting recurrence in the lung and visceral sites incorporated the presence of regional lymph node and skin/soft tissue/non-regional lymph node metastases. ROC curves showed good performance of the nomograms in both the training and validation cohorts. The calibration curve showed a good fit. Conclusion: Our results support the high prognostic value of AJCC pT stage and patient sex, which remained consistent across all melanoma stages, and demonstrate the feasibility of creating nomogram models to predict recurrence risk in melanoma patients.

Adult skin varies across regions, with differences in chemical, physical, microbiota, and immune barriers. However, data on topographical immune differences in other age groups are limited. This study aimed to explore the chronological maturation of the immune barrier in various skin regions. A TaqMan low-density array and immunohistochemical and immunofluorescence detection of various immune cells and mediators in sebaceous gland-rich (SGR) and gland-poor (GP) healthy skin were performed in children, adolescents, and adults. The maturation of SGR skin showed a general upward trend in the mRNA levels of most Th17-related molecules with a significant increase in IL-1B from childhood to adulthood, but with only a slight elevation between childhood and adolescence. In addition, T cell, Treg, dendritic cell (DC) counts, as well as the levels of several Th17-related proteins (IL-17, IL-10, IL-23, CCL20, S100A8, sfTSLP, LCN2), increased significantly with age. In GP skin, AHR mRNA levels decreased, while Th17-related protein levels increased, although only moderately. When comparing the two regions, SGR and GP skin were similar in childhood, with differences emerging in adolescence and becoming significant in adulthood, particularly in the IL-17 pathway, mainly produced by Th17 cells. Our results show a similarly directed maturation process in GP and SGR regions, with more pronounced development of the SGR skin immune barrier (with more immune cell infiltration and cytokine production) during and after the adolescence. This is likely to be related to the significant changes in the chemical and microbiota barriers of the SGR skin during adolescence, and may explain the high incidence of inflammatory skin diseases on the SGR skin of adolescents, highlighting the need for targeted skin care in this region.

Az atopiás dermatitis az egyik leggyakoribb, krónikus gyulladásos bőrbetegség. A kórkép komplexitása régóta ismert, az elmúlt években pedig a patomechanizmus mellett az érintett populáció és a klinikai kép heterogenitását is jobban megismertük. A betegség hátterének pontosabb megértése által a terápiás lehetőségek is folyamatosan bővültek. A Debreceni Egyetem Bőrgyógyászati Klinikáján évtizedek óta kiemelten foglalkozunk az atopiás dermatitis hátterének kutatásával és a betegcsoport gondozásával. Jelen közlemény célja részben saját kutatási eredményeink, részben az exponenciálisan növekvő új irodalmi adatok összefoglalása. Orv Hetil. 2024; 165(41): 1602–1612.

The skin barrier can be divided into at least four functional units: chemical, microbial, physical and immunological barriers. The chemical and microbial barriers have previously been shown to exhibit different characteristics in topographically distinct skin regions. There is increasing evidence that the physical and immunological barriers also show marked variability in different areas of the skin. Here, we review recent data on the topographical variations of skin barrier components, the contribution of these variations to the homeostatic function of the skin and their impact on the pathogenesis of specific immune-mediated skin diseases (such as atopic dermatitis and papulopustular rosacea). Recognition of these topographical barrier differences will improve our understanding of skin homeostasis and disease pathogenesis and provide a basis for body site-specific targeted therapies.

Prognostic studies can provide important information about disease biology and improve the use of biomarkers to optimize treatment decisions. Methods: A total of 199 patients with advanced melanoma treated with BRAF + MEK inhibitors were included in our single-center retrospective study. We analyzed the risk of progression and death using multivariate Cox proportional hazard models. The predictive effect of prognostic factors on progression-free survival (PFS) was evaluated in ROC analysis. Results: We found that primary tumor localization, Clark level, pT category, baseline M stage and baseline serum S100B are independent and significant prognostic factors for PFS. The discriminative power of the combination of these factors was excellent for predicting 18 month PFS (AUC 0.822 [95% CI 0.727; 0.916], p < 0.001). Primary tumor localization on the extremities, Clark level V, baseline M1c stage or M1d stage, and elevated baseline serum S100B and LDH levels were independently and significantly associated with unfavorable overall survival (OS). Conclusion: Baseline M stage and serum S100B appear to be independent prognostic factors for both PFS and OS in melanoma patients treated with BRAF + MEK inhibitors. We newly identified significant and independent prognostic effects of primary tumor localization and Clark level on survival that warrant further investigation.

Atopic dermatitis is one of the most common chronic inflammatory skin diseases. The complexity of the pathology has been known for a long time and in recent years we have gained a better understanding of the pathomechanism, the heterogeneity of the affected population and the clinical picture. Therapeutic options have also expanded with a better understanding of the disease background. At the Department of Dermatology, University of Debrecen, we have been studying the background of atopic dermatitis and looking after this group of patients for decades. The aim of this article is to summarize the results of our own research and the exponentially growing new data from the literature.

Background: Intestinal symptoms are common in patients with hidradenitis suppurativa (HS). HS patients may experience a broad spectrum of chronic inflammatory intestinal disorders (CIID), not exclusive to inflammatory bowel diseases, which are diagnosed by colonoscopy and intestinal biopsies. The frequency of CIID in patients with HS has not been investigated. Objective: The objectives of this study were to determine the occurrence of CIID in HS and characterize this clinical population. Furthermore, the feasibility of using faecal calprotectin (FC) test or anti-Saccharomyces cerevisiae antibody (ASCA) levels to assess the colonic inflammation of CIID in HS patients was investigated. Methods: All newly diagnosed and untreated HS patients (n = 74) were referred to a gastroenterologist for FC followed by colonoscopy after informed consent. C-reactive protein (CRP), white blood cell count, nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) polymorphism, and ASCA levels were measured. Patients were divided into HS-only and HS with CIID (HS + CIID) groups, based on the absence or presence of CIID. Laboratory and clinical parameters (age, gender, HS onset, clinical stage, family history, body mass index (BMI), smoking) were compared between the groups. Results: Thirteen patients complained gastrointestinal symptoms prior to any examination, including 11 in the HS + CIID group. The CIID frequency in HS was 28.4% (n = 21/74), based on colonoscopy and histology. Significantly more patients had severe disease state in the HS + CIID group compared with the HS-only group, and BMI was significantly lower in the HS + CIID group (28.20 ± 5.58 vs. 32.74 ± 6.45, p = 0.006). FC positivity occurred significantly more in HS + CIID patients compared with HS-only patients (90.48% vs. 3.77%, p < 0.001), and ASCA IgG levels were significantly elevated in HS + CIID patients (22.08 ± 23.07 vs. 8.41 ± 10.94 U/mL, p = 0.001). The FC test identified HS + CIID patients with 96.23% specificity and 91.3% sensitivity, while ASCA displayed 77.8% sensitivity and 76.3% specificity. Blood count, CRP, and the presence of NOD2 polymorphisms were indifferent between the two groups. Conclusion: A high frequency of CIID was detected in the examined HS population. The noninvasive FC test has high sensitivity and specificity for diagnosing CIID in HS patients. Concomitant CIID and HS may indicate the need for an early-start for biological treatment.

As one of our most important barrier organs, our skin has complex functions, both to connect us with the outside world and to protect us from its harmful effects. According to literature data, skin barrier can be divided into 4 functional units: microbial, chemical, physical and immunological barriers. The microbial and chemical barriers have been previously shown to exhibit different characteristics in topographically distinct skin regions. The research group at the Department of Dermatology, University of Debrecen, Hungary, has investigated whether the physical and immunological barriers also show differences in different skin areas. This article summarises the working group’s research on this topic, which demonstrated that, in addition to the microbial and chemical barriers, the other two barriers also differ in distinct skin regions. These differences may explain the characteristic localisation of certain region-specific skin diseases.

Hidradenitis suppurativa (HS) is a Th1/17-driven inflammatory skin disease of the apocrine gland-rich (AGR) skin regions, where keratinocytes seem to be the crucial drivers of the initial pathogenic steps. However, the possible role of permeability barrier alteration in activating keratinocytes during HS development has not been clarified. We compared the major permeability barrier elements of non-lesional HS (HS-NL; n = 10) and lesional HS (HS-L; n = 10) skin with healthy AGR regions (n = 10) via RT-qPCR and immunohistochemistry. Stratum corneum components related to cornified envelope formation, corneocyte desquamation and (corneo)desmosome organization were analyzed along with tight junction molecules and barrier alarmins. The permeability barrier function was also investigated with transepidermal water loss (TEWL) measurements (n = 16). Junction structures were also visualized using confocal microscopy. At the gene level, none of the investigated molecules were significantly altered in HS-NL skin, while 11 molecules changed significantly in HS-L skin versus control. At the protein level, the investigated molecules were similarly expressed in HS-NL and AGR skin. In HS-L skin, only slight changes were detected; however, differences did not show a unidirectional alteration, as KRT1 and KLK5 were detected in decreased levels, and KLK7, KRT6 and DSG1 in increased levels. No significant differences in TEWL or the expression of junction structures were assessed. Our findings suggest that the permeability barrier is not significantly damaged in HS skin and permeability barrier alterations are not the driver factors of keratinocyte activation in this disease.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease of the apocrine gland-rich (AGR) skin areas. Initial molecular events in HS are poorly explored. We aimed to identify the potential driver factors during HS development by comparing 9 HS non-lesional (HSNL) skin to 12 region-matched controls by RNASeq. 611 significantly differentially regulated DEGs were identified, of which 212 were upregulated while 399 were downregulated. In order to identify gene sets with different gene expression patterns, KMeans clustering was carried out by Morpheus, which allowed us to distinguish 6 modules. Two contained downregulated genes while 4 consisted of upregulated genes. To understand the functional characteristics of each module, we performed enrichment analysis on their respective gene sets by String. Downregulated modules were related to cellular metabolism and extracellular matrix organization. Among upregulated modules, the first was associated with keratinocyte differentiation and antimicrobial peptides. The second was related to B cell function, the third consisted of genes connected to IL-17 pathway and chemokine signaling, while no enrichment was found in the last module. According to literature data and our own results, two transcription factors (TFs) (STAT1 and GRHL3) have significant role in the development and progression of HS, therefore, we were curious if genes regulated by these TFs are represented among DEGs between HSNL and control. Therefore, we performed TF analysis by ChEA3 and found that almost 10% (58 of 611) of DEGs were regulated by GRHL3, and 51 were upregulated and only 7 were downregulated. 14% (86 of 611) of DEGs were connected to STAT1. Both TFs have important role in keratinocytes (KCs), STAT1 regulates immune responses to microbes, while GRHL3 promotes KC differentiation. These findings further strengthen KCs' primary role in HS initiation and indicate these TFs as new drug targets.

Atopic dermatitis is an inflammatory skin disease characterized by significant permeability barrier damage. Regulation and maintenance of permeability and antimicrobial skin barriers are strongly connected. There is a lack of comprehensive studies of the expression of all 5 major antimicrobial peptide functional groups in atopic dermatitis. The aim of this study was to investigate the major antimicrobial peptide functional groups in lesional atopic dermatitis, non-lesional atopic dermatitis, and healthy control samples, using real-time quantitative PCR and immunohistochemistry. Lesional psoriatic skin was also examined as a diseased control. No differences in mRNA levels were detected between non-lesional atopic dermatitis and healthy control skin, and, at the protein level, the only change was the significantly decreased LL-37 in non-lesional atopic dermatitis. In lesional atopic dermatitis, several antimicrobial peptides were significantly altered at the mRNA level, while, at the protein level, all antimicrobial peptides were significantly upregulated or unchanged, except for LL-37, which decreased, compared with healthy controls. Antimicrobial peptides were similarly elevated in lesional atopic dermatitis and lesional psoriatic skin, with somewhat higher expression in lesional psoriatic skin, except for LL-37. In conclusion, LL-37 was the only antimicrobial peptide that was impaired in both non-lesional and lesional atopic dermatitis, highlighting its potential pathogenetic or exacerbating role in the initial stages of the disease.

Acne and hidradenitis suppurativa (HS) are region-specific follicular inflammatory skin diseases occurring around puberty (acne on sebaceous, HS on apocrine gland-rich region). Their inflammatory features are also very similar with enhanced innate immune function and Th1/17 activation. On the other hand, teenage acne resolves spontaneously in most cases, while HS shows no spontaneous remission, which has not yet been explained. We aimed to find out at the whole transcriptomic level whether they are indeed closely related diseases, and if so, what might be the reason behind the acne spontaneous resolution that is missing in HS. Lesional samples (HS: own data, acne: data of Kelhala et al) were compared to region-matched controls, and common and we analyzed disease-specific genes by multiple bioinformatics approaches. We found 456 acne-specific, 1786 HS-specific, and 438 common DEGs (FC>2). Enrichment analysis of both common and disease-specific genes pointed out strikingly similar immune activation in the two diseases. These results were confirmed by ChEA3 transcription factor (TF) analyses where the top 25 TFs regulating common and disease-specific gene sets were identified. Prominent overlap was found among TFs when comparing disease-specific and common upregulated genes (10/25 in acne, 6/25 in HS) indicating that disease-specific upregulated genes are also responsible for the common inflammatory events. On the contrary, only one TF, namely GRHL3 turned up when TFs targeting counter-regulated disease-specific gene sets were compared. GRHL3-regulated genes showed increased expression in acne, while decreased in HS. Since GRHL3 is known to activate epidermal differentiation and suppress the expression of alarmins and proinflammatory molecules in keratinocytes, GRHL3 may be a driver TF behind the spontaneous resolution of acne and it may emerge in the future as a potential drug target.

Recent data indicate that distinct skin areas show different microbial/chemical milieu. Keratinocytes (KC) respond to these stimuli by producing cytokine mediators. Therefore, we aimed to determine KC-derived cytokine expression in distinct healthy skin regions (gland-poor [GP], sebaceous gland-rich [SGR] and apocrine gland-rich [AGR]), and their changes in skin diseases of the given regions (atopic dermatitis [AD], papulopustular rosacea [PPR] and psoriasis). Cytokines were analysed at the mRNA and protein levels, and literature analysis was performed for functional categorization. The three regions showed characteristically different cytokine patterns. GP was featured by an IL-25/IL-33/IL-36RA/IL-38/IL-18 cytokine milieu, SGR was characterized by IL-23/IL-17C/IL-18, and AGR skin exhibited a mixed IL-25/IL-33/IL-23/IL-18 profile. Literature analyses revealed different homeostatic and proinflammatory roles of these cytokine patterns (Th2 related in GP, Th17 related in SGR and mixed Th2/Th17 in AGR). In skin diseases which are primarily epidermal cytokine-driven (AD, PPR), the level of the regionally characteristic cytokines were further elevated, in contrast to the autoantigen-driven psoriasis, where the cytokine pattern was independent from the localization. Healthy skin regions are equipped with different KC-derived cytokine profiles, which may influence each region's capability of mediator production in certain types of dermatoses.