EGFR Inhibition by Erlotinib Rescues Desmosome Ultrastructure and Keratin Anchorage and Protects Against Pemphigus Vulgaris IgG-Induced Acantholysis in Human Epidermis.

Pemphigus is a severe blistering disease caused by autoantibodies primarily against the desmosomal cadherins desmoglein (DSG)1 and DSG3 which impair desmosome integrity. Especially for the acute phase, additional treatment options allowing to reduce corticosteroids would fulfill an unmet medical need. Here, we provide evidence that epidermal growth factor receptor (EGFR) inhibition by erlotinib ameliorates pemphigus vulgaris immunoglobulin G (PV-IgG) -induced acantholysis in intact human epidermis. PV-IgG caused phosphorylation of EGFR (Y845) and SRC in human epidermis. In line with that, a phosphotyrosine kinome analysis revealed a robust response associated with EGFR and SRC family kinase signaling in response to PV-IgG but not pemphigus foliaceus autoantibodies. Erlotinib inhibited PV-IgG-induced epidermal blistering and EGFR phosphorylation, loss of desmosomes as well as ultrastructural alterations of desmosome size, plaque symmetry, keratin filament insertion and restored the desmosome midline considered as hallmark of mature desmosomes. Erlotinib enhanced both single molecule DSG3 binding frequency and strength and delayed DSG3 fluorescence recovery supporting that EGFR inhibition increases DSG3 availability and cytoskeletal anchorage. Our data indicate that EGFR is a promising target for pemphigus therapy due to its link to several signaling pathways known to be involved in pemphigus pathogenesis.

Highly diverse cuticular hydrocarbon profiles but no evidence for aggression towards non-kin in the ambrosia beetle Xyleborinus saxesenii.

Animal societies use nestmate recognition to protect against social cheaters and parasites. In most social insect societies, individuals recognize and exclude any non-nestmates and the roles of cuticular hydrocarbons as recognition cues are well documented. Some ambrosia beetles live in cooperatively breeding societies with farmed fungus cultures that are challenging to establish, but of very high value once established. Hence, social cheaters that sneak into a nest without paying the costs of nest foundation may be selected. Therefore, nestmate recognition is also expected to exist in ambrosia beetles, but so far nobody has investigated this behavior and its underlying mechanisms. Here we studied the ability for nestmate recognition in the cooperatively breeding ambrosia beetle Xyleborinus saxesenii, combining behavioural observations and cuticular hydrocarbon analyses. Laboratory nests of X. saxesenii were exposed to foreign adult females from the same population, another population and another species. Survival as well as the behaviours of the foreign female were observed. The behaviours of the receiving individuals were also observed. We expected that increasing genetic distance would cause increasing distance in chemical profiles and increasing levels of behavioural exclusion and possibly mortality. Chemical profiles differed between populations and appeared as variable as in other highly social insects. However, we found only very little evidence for the behavioural exclusion of foreign individuals. Interpopulation donors left nests at a higher rate than control donors, but neither their behaviours nor the behaviours of receiver individuals within the nest showed any response to the foreign individual in either of the treatments. These results suggest that cuticular hydrocarbon profiles might be used for communication and nestmate recognition, but that behavioural exclusion of non-nestmates is either absent in X. saxesenii or that agonistic encounters are so rare or subtle that they could not be detected by our method. Additional studies are needed to investigate this further.

Different ecological demands shape differences in population structure and behaviour among the two generations of the small pearl-bordered fritillary.

The population structure and behaviour of univoltine butterfly species have been studied intensively. However, much less is known about bivoltine species. In particular, in-depth studies of the differences in population structure, behaviour, and ecology between these two generations are largely lacking. Therefore, we here present a mark-release-recapture study of two successive generations of the fritillary butterfly Boloria selene performed in eastern Brandenburg (Germany). We revealed intersexual and intergenerational differences regarding behaviour, dispersal, population characteristics, and protandry. The observed population densities were higher in the second generation. The flight activity of females decreased in the second generation, but remained unchanged in males. This was further supported by the rate of wing decay. The first generation displayed a linear correlation between wing decay and passed time in both sexes, whereas the linear correlation was lost in second-generation females. The proportion of resting individuals in both sexes increased in the second generation, as well as the number of nectaring females. The choice of plant genera used for nectaring seems to be more specialised in the first and more opportunistic in the second generation. The average flight distances were generally higher for females than for males and overall higher in the first generation. Predictions of long-distance movements based on the inverse power function were also generally higher in females than in males but lower in the first generation. Additionally, we found protandry only in the first but not in the second generation, which might correlate with the different developmental pathways of the two generations. These remarkable differences between both generations might reflect an adaptation to the different ecological demands during the flight season and the different tasks they have, i.e., growth in the spring season; dispersal and colonisation of new habitats during the summer season.

Unveiling CXCR2 as a promising therapeutic target in renal cell carcinoma: exploring the immunotherapeutic paradigm shift through its inhibition by RCT001.

BACKGROUND: In clear cell renal cell carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study explored the potential of enhancing ccRCC treatment by concurrently using CXCR2 inhibitors alongside immunotherapies. METHODS: We analyzed ELR + CXCL levels and their correlation with patient survival during immunotherapy. RCT001, a unique CXCR2 inhibitor, was examined for its mechanism of action, particularly its effects on human primary macrophages. We tested the synergistic impact of RCT001 in combination with immunotherapies in both mouse models of ccRCC and human ccRCC in the presence of human PBMC. RESUTS: Elevated ELR + CXCL cytokine levels were found to correlate with reduced overall survival during immunotherapy. RCT001, our optimized compound, acted as an inverse agonist, effectively inhibiting angiogenesis and reducing viability of primary ccRCC cells. It redirected M2-like macrophages without affecting M1-like macrophage polarization directed against the tumor. In mouse models, RCT001 enhanced the efficacy of anti-CTLA4 + anti-PD1 by inhibiting tumor-associated M2 macrophages and tumor-associated neutrophils. It also impacted the activation of CD4 T lymphocytes, reducing immune-tolerant lymphocytes while increasing activated natural killer and dendritic cells. Similar effectiveness was observed in human RCC tumors when RCT001 was combined with anti-PD-1 treatment. CONCLUSIONS: RCT001, by inhibiting CXCR2 through its unique mechanism, effectively suppresses ccRCC cell proliferation, angiogenesis, and M2 macrophage polarization. This optimization potentiates the efficacy of immunotherapy and holds promise for significantly improving the survival prospects of metastatic ccRCC patients.

Cuticular Hydrocarbon Profiles of Himalayan Bumble Bees (Hymenoptera: Bombus Latreille) are Species-Specific and Show Elevational Variation.

Bumble bees are important pollinators in natural environments and agricultural farmlands, and they are in particular adapted to harsh environments like high mountain habitats. In these environments, animals are exposed to low temperature and face the risk of desiccation. The Eastern Himalayas are one of the recognized biodiversity hotspots worldwide. The area covers subtropical rainforest with warm temperature and high precipitation as well as high mountain ranges with peaks reaching up to 7,000 m, shaping a diverse floral and faunal community at the different elevational zones. To identify possible adaptation strategies, we investigated the cuticular hydrocarbon profiles of four bumble bee species occurring at different elevational ranges in Arunachal Pradesh, the northeastern most state in India. At 17 locations along an elevational gradient, we collected workers of two species from lower elevations (B. albopleuralis and B. breviceps; ~ 100 m - 3,000 m asl) and two species from higher elevations (B. prshewalskyi and B. mirus; ~ 2,800 m - 4,500 m asl). The CHC profiles of all four species showed a significant degree of variation in the composition of hydrocarbons, indicating species specificity. We also found clear correlation with elevation. The weighted mean chain length of the hydrocarbons significantly differed between the low and high elevation species, and the proportion of saturated hydrocarbons in CHC profiles significantly increased with the elevational range of the bumble bee species. Our results indicate that bumble bees living at high elevations reduce the risk of water loss by adapting their CHC composition on their cuticle, a phenomenon that has also been found in other insects like ants and fruit flies.

Biology, ecology, and biogeography of eremic praying mantis Blepharopsis mendica (Insecta: Mantodea).

Background: Blepharopsis mendica (Fabricius, 1775) is a large mantid species found from the Canary Islands across North Africa, the Middle East, and Pakistan. Research on this species has been limited, especially in Iran, despite the country's potential significance for studying its biology and distribution. Adults of this species are easily recognizable by their marble-white pattern and rhomboidal leaf-like pronotum. They are sit-and-wait predators that inhabit various open environments. Methods: Field observations were conducted across various regions of the Egyptian Flower mantis (Blepharopsis mendica) global distribution, with a focus on Morocco, Tunisia, and Iran. Distribution data for B. mendicawere gathered from fieldwork, museum collections, online biodiversity databases, and publications, totaling 593 occurrence points. Ecological niche modeling was performed using environmental data, and various models were evaluated for suitability. Phylogeographic analyses involved DNA sequencing and construction of a haplotype network to examine genetic relationships between populations. Divergence time estimation and biogeographical range expansion models were applied to explore historical distribution shifts of the species across different regions. The study provided comprehensive insights into the biology, distribution, and genetic history of B. mendica. Results: We provide information on the life cycle, ootheca, defense behavior, habitat, and biogeography of the Egyptian Flower mantis Blepharopsis mendica. This mantid is an overwintering univoltine species with nymphs emerging in summer and becoming adults in spring. In the wild, females start oviposition in April and can lay their first ootheca within a week after mating. The species is distributed from the Canary Islands to Pakistan in the dry belt. Thus, its distribution is associated with xeric areas or desert and semi-desert habitats. Phylogeographic analyses revealed three major genetic lineages, (i) in the Maghreb, (ii) from Egypt via Arabia to Iran (with internal substructures), and (iii) likely in Pakistan; the estimated onset of differentiation into these lineages is of Pleistocene age. Defense behavior involves flying away or extending wings broadly and lifting forelegs. Performing laboratory breeding, we documented life cycle and color changes from first instar to adulthood. Due to overwintering, the last larval instar needs considerably longer than the others. At 25 °C (±2), average adult life span was 118 days (±6 SD) for females (range: 100-124) and 46 days (±5 SD) for males (range: 39-55), with a significant difference among sexes. On average, oothecae contained 32.3 eggs (±10.1 SD) and the mean incubation period was 36.8 days (±2.9 SD). We did not find evidence of parthenogenesis. In general, the biology of B. mendica shows a variety of adaptations to its often extreme and little predictable type of habitat.

Species- and sex-specific chemical composition from an internal gland-like tissue of an African frog family.

Intraspecific chemical communication in frogs is understudied and the few published cases are limited to externally visible and male-specific breeding glands. Frogs of the family Odontobatrachidae, a West African endemic complex of five morphologically cryptic species, have large, fatty gland-like strands along their lower mandible. We investigated the general anatomy of this gland-like strand and analysed its chemical composition. We found the strand to be present in males and females of all species. The strand varies in markedness, with well-developed strands usually found in reproductively active individuals. The strands are situated under particularly thin skin sections, the vocal sac in male frogs and a respective area in females. Gas-chromatography/mass spectrometry and multivariate analysis revealed that the strands contain sex- and species-specific chemical profiles, which are consistent across geographically distant populations. The profiles varied between reproductive and non-reproductive individuals. These results indicate that the mandibular strands in the Odontobatrachidae comprise a so far overlooked structure (potentially a gland) that most likely plays a role in the mating and/or breeding behaviour of the five Odontobatrachus species. Our results highlight the relevance of multimodal signalling in anurans, and indicate that chemical communication in frogs may not be restricted to sexually dimorphic, apparent skin glands.

Active around the year: Butterflies and moths adapt their life cycles to a warming world.

Living in a warming world requires adaptations to altered annual temperature regimes. In Europe, spring is starting earlier, and the vegetation period is ending later in the year. These climatic changes are leading not only to shifts in distribution ranges of flora and fauna, but also to phenological shifts. Using long-term observation data of butterflies and moths collected during the past decades across northern Austria, we test for phenological shifts over time and changes in the number of generations. On average, Lepidoptera adults emerged earlier in the year and tended to extend their flight periods in autumn. Many species increased the annual number of generations. These changes were more pronounced at lower altitudes than at higher altitudes, leading to an altered phenological zonation. Our findings indicate that climate change does not only affect community composition but also the life history of insects. Increased activity and reproductive periods might alter Lepidoptera-host plant associations and food webs.

The de novo genome of the Black-necked Snakefly (Venustoraphidia nigricollis Albarda, 1891): A resource to study the evolution of living fossils.

Snakeflies (Raphidioptera) are the smallest order of holometabolous insects that have kept their distinct and name-giving appearance since the Mesozoic, probably since the Jurassic, and possibly even since their emergence in the Carboniferous, more than 300 million years ago. Despite their interesting nature and numerous publications on their morphology, taxonomy, systematics, and biogeography, snakeflies have never received much attention from the general public, and only a few studies were devoted to their molecular biology. Due to this lack of molecular data, it is therefore unknown, if the conserved morphological nature of these living fossils translates to conserved genomic structures. Here, we present the first genome of the species and of the entire order of Raphidioptera. The final genome assembly has a total length of 669 Mbp and reached a high continuity with an N50 of 5.07 Mbp. Further quality controls also indicate a high completeness and no meaningful contamination. The newly generated data was used in a large-scaled phylogenetic analysis of snakeflies using shared orthologous sequences. Quartet score and gene concordance analyses revealed high amounts of conflicting signals within this group that might speak for substantial incomplete lineage sorting and introgression after their presumed re-radiation after the asteroid impact 66 million years ago. Overall, this reference genome will be a door-opening dataset for many future research applications, and we demonstrated its utility in a phylogenetic analysis that provides new insights into the evolution of this group of living fossils.

Improving Agri-environmental Schemes: Suggestions from Farmers and Nature Managers in a Central European Region.

Agri-environmental schemes (AES) are important policy instruments within the Common Agricultural Policy (CAP) of the European Union for environmental protection. Due to the voluntary nature of AES, their attractiveness to farmers and stakeholders involved in nature management and protection (nature managers) is essential for high participation levels. This study aims to assess farmers' and nature managers' ideas to improve agri-environmental schemes. We analyzed suggestions of 825 farmers and 118 nature managers for improvements of AES collected in a large-scale survey in Bavaria, Germany. A content analysis was applied to categorize and compare suggestions by farmers (differentiated into two groups through a cluster analysis) and nature managers. The results reveal that stakeholders were highly willing to share ideas and made detailed suggestions for improvements and individual measures. They were aware of the importance of protecting nature and promoting biodiversity in agricultural landscapes and acknowledged the necessity of (financial) support programs. Farmers placed more emphasis on the practicability and profitability of measures on arable land, while nature managers tended to propose policy-related ideas focusing on nature protection, biodiversity, and specific species. Among farmers, suggestions differed with farm characteristics such as the operation mode (full-time, part-time). These findings can support the design of future AES, accounting for different background situations and thereby increasing acceptability. This includes considering perspectives from different stakeholder groups and creating regionally adapted programs with varying levels of flexibility and practicability.

Targeted treatment of injured nestmates with antimicrobial compounds in an ant society.

Infected wounds pose a major mortality risk in animals. Injuries are common in the ant Megaponera analis, which raids pugnacious prey. Here we show that M. analis can determine when wounds are infected and treat them accordingly. By applying a variety of antimicrobial compounds and proteins secreted from the metapleural gland to infected wounds, workers reduce the mortality of infected individuals by 90%. Chemical analyses showed that wound infection is associated with specific changes in the cuticular hydrocarbon profile, thereby likely allowing nestmates to diagnose the infection state of injured individuals and apply the appropriate antimicrobial treatment. This study demonstrates that M. analis ant societies use antimicrobial compounds produced in the metapleural glands to treat infected wounds and reduce nestmate mortality.

Metabolomics evaluation of the photochemical impact of violet-blue light (405 nm) on ex vivo platelet concentrates.

INTRODUCTION: Microbicidal violet-blue light in the visible spectrum (405 nm) has been under evaluation for pathogen inactivation in ex vivo human plasma and platelets (PLTs) stored in plasma. Results to date have demonstrated that several blood-borne infectious disease-causing pathogens can be successfully reduced to significantly low levels in the light-treated plasma and PLTs. METHOD: In order to evaluate whether the microbicidal 405 nm light is safe for the treatment of PLT concentrates for pathogen inactivation, LC/MS-based metabolomics analyses were performed to evaluate the overall impact of 405 nm violet-blue light treatment on ex vivo PLT concentrates suspended in plasma and on plasma itself, and to identify metabolome changes in intra-platelet and extra-cellular medium (i.e., plasma). RESULTS: The metabolomics data identified that platelet activating factors (PAFs), agonists and prostaglandins, which can influence PLT basic functions such as integrity, activation, and aggregation potential were unaltered, suggesting that 405 nm light illumination is safe regarding PLT basic functions. Distinct increases in hydroxyl fatty acids and aldehydes, as well as decreases in antioxidant metabolites indicated that reactive oxygen species (ROS) were generated at high levels after only one hour of exposure to 405 nm light. Distinctly changed endogenous photosensitizer metabolites after 1 h of light exposure provided good evidence that 405 nm light was an effective microbicide acting through ROS mechanism and no external additive photosensitizers were required.

Life history and biogeography of the enigmatic mantid Nilomantisfloweri (Mantodea, Nanomantidae).

The biology and distribution patterns of the Sahelian mantid species Nilomantisfloweri are still insufficiently known. For the first time, records are confirmed of this species from Iran and the distribution map of its native range is updated. Records are compiled from the Sahel zone of North Africa, the Arabian Peninsula, and Iran. Detailed information on its biology, oothecal characteristics, male genitalia variation, and intraspecific molecular diversity in the mitochondrial gene cytochrome c oxidase are provided, and ecological niche modelling was used to gain insight into the overall species distribution and understand its climatic niche limits. Genetic analysis revealed only one haplotype shared between Iran and Oman. The Iranian populations likely represent two distinct clusters, both more related to the diverse Oman haplotypes than to each other. Based on new data, N.floweri appears to be mostly associated with coastal areas in southwestern Asia, with the vast majority of records found along the Red Sea, Persian Gulf, and Oman Gulf coasts. This distribution contrasts markedly with N.floweri records in the Sahel, where most collections have been reported in the transitional zone between the southern Sahara and arid thorn savannah, far off the coast. This study contributes to a comprehensive understanding of this still enigmatic mantid species.

Behavioural individuality determines infection risk in clonal ant colonies.

In social groups, infection risk is not distributed evenly across individuals. Individual behaviour is a key source of variation in infection risk, yet its effects are difficult to separate from other factors (e.g., age). Here, we combine epidemiological experiments with chemical, transcriptomic, and automated behavioural analyses in clonal ant colonies, where behavioural individuality emerges among identical workers. We find that: (1) Caenorhabditis-related nematodes parasitise ant heads and affect their survival and physiology, (2) differences in infection emerge from behavioural variation alone, and reflect spatially-organised division of labour, (3) infections affect colony social organisation by causing infected workers to stay in the nest. By disproportionately infecting some workers and shifting their spatial distribution, infections reduce division of labour and increase spatial overlap between hosts, which should facilitate parasite transmission. Thus, division of labour, a defining feature of societies, not only shapes infection risk and distribution but is also modulated by parasites.

Moderate mobility and high density in a small area: the population ecology of the marsh fritillary Euphydryas aurinia in Transylvania (Romania).

The Natura 2000 network is one of the most important tools for nature conservation in the EU. Therefore, knowledge of the ecology of the species listed on the Habitats Directive annexes is of particular relevance. One of these species is the butterfly Euphydryas aurinia. Much is already known about the ecology of this species at the European level, but information on Romania is scarce. Therefore, in a study area northwest of Cluj, the species was intensively studied in a mark-release-recapture study over its entire flight period. The investigated population harboured many individuals and had a high density. The dispersal behaviour of the individuals was somewhat more pronounced than in Mediterranean and partly also high alpine populations, but roughly comparable to other populations of the nominotypic subspecies. Overall, the ecological differences to Central and Western European populations were not very pronounced, and many of the conservation-relevant statements on this species in Central Europe should also be largely valid in Romania.

Global change drives phenological and spatial shifts in Central European longhorn beetles (Coleoptera, Cerambycidae) during the past 150 years.

Temperature increases and land-use changes induce altered annual activity periods of arthropods. However, sufficiently resolved long-term data sets (> 100 years) are mostly missing. We use a data set of longhorn beetle records (71 species) collected in Luxembourg 1864-2014. Increase of annual temperatures was significantly correlated with an earlier annual appearance. Forty-four species present before and after 1980 appeared on average 8.2 days earlier in the year in the more recent period. Since 1950, the estimated shift was 0.26 days per year. Increase of temperature in spring (March-June) preponed the first appearance of beetles by on average 9.6 days per 1 °C. We found significant changes in the composition of beetle communities, with a net gain in species richness during the last 40 years. Eleven species recorded only after 1997 were characterized by comparatively early annual appearance. Smaller beetles tended to appear earlier in the year in comparison to large-bodied species. Shifts in phenology did not correlate with species Red List status. As also demonstrated by our data, climate change in general affects insect phenologies and changes species composition. However, land-use change has taken place in parallel with climate change. Both aspects of global change are influencing the changes in longhorn beetle occurrences in Luxemburg in their combination. This might be most clearly reflected in the strong decrease of species with continental climate niches dwelling in old-growth deciduous forests that apparently are threatened by the loss of these habitats and increasing spring temperatures.

Northern Richness, Southern Dead End-Origin and Dispersal Events of Pseudolycoriella (Sciaridae, Diptera) between New Zealand's Main Islands.

Sciaridae (Diptera) is a widespread insect family of which some species can reach high abundances in arboreal habitats. This trait, together with their (passive) mobility, enables them to quickly colonise suitable habitats. To reveal the biogeographic history of the New Zealand members of the sciarid genus Pseudolycoriella, we analysed three molecular markers of selected species and populations in a Bayesian approach. At the intra- and interspecific levels, we detected a pattern of northern richness vs. southern purity, which has probably developed as a result of Pleistocene glacial cycles. Since the late Miocene, we identified 13 dispersal events across the sea strait separating New Zealand's main islands. As nine of these dispersal events were south-directed, North Island can be considered the centre of radiation for this genus. An unequivocal re-colonisation of North Island was only observed once. Based on the inclusion of three undescribed species from Tasmania and on previously published data, three colonisations of New Zealand are likely, all of them assumed to be of Australian origin. One of these most probably took place during the late Miocene, and the other two during the late Pliocene or at the Pliocene-Pleistocene boundary.

Olfaction is essential for nest recognition in solitary Hymenoptera.

Flying insects are believed to rely primarily on visual cues for orientation, with chemical cues often being overlooked. In the case of solitary bees and wasps, being able to return successfully to their nests and provision their brood cells is paramount for the survival of the species. While vision has been shown to be involved in pinpointing the nest location, our results confirm that olfaction is important in nest recognition. The large diversity in nesting strategies observed among solitary Hymenoptera makes them an excellent model to comparatively study the use of olfactory cues from the nesting individual for nest recognition. We have analyzed the chemical profiles of three nesting bees (Osmia spp.) and one wasp (Sceliphron curvatum) and that of their nest entrances. A striking match in the identified chemicals was revealed between each nest and its occupant. When the chemicals were removed from the nest, a clear behavioral response could be observed for Osmia cornuta. This shows the importance of olfactory cues in complementing visual orientation for precise homing in a solitary species, thereby opening up various promising biological questions in the fields of sensory perception and complementation, or the trade-offs of nest aggregation and associated costs.

Dsg3 epitope-specific signalling in pemphigus.

Introduction: Pemphigus is an autoantibody driven disease that impairs the barrier function of the skin and mucosa by disrupting desmosomes and thereby impeding cellular cohesion. It is known that the different clinical phenotypes of pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are dependent on the autoantibody profile and target antigens that, amongst others, are primarily desmoglein (Dsg)1 and/or Dsg3 for PV and Dsg1 for PF. However, it was reported that autoantibodiesagainst different epitopes of Dsg1 and Dsg3 can be pathogenic or not. The underlying mechanisms are very complex and involve both direct inhibition of Dsg interactions and downstream signalling. The aim of this study was to find out whether there is target-epitope-specific Dsg3 signalling by comparing the effects of the two pathogenic murine IgGs, 2G4 and AK23. Methods: Dispase-based dissociation assay, Western Blot analysis, Stimulated emission depletion microscopy, Fura-based Ca2+ flux measurements, Rho/Rac G-Protein-linked immunosorbent assay, Enzyme-linked immunosorbent assay. Results: The IgGs are directed against the EC5 and EC1 domain of Dsg3, respectively. The data show that 2G4 was less effective in causing loss of cell adhesion, compared to AK23. STED imaging revealed that both autoantibodies had similar effects on keratin retraction and reduction of desmosome number whereas only AK23 induced Dsg3 depletion. Moreover, both antibodies induced phosphorylation of p38MAPK and Akt whereas Src was phosphorylated upon treatment with AK23 only. Interestingly, Src and Akt activation were p38MAPK-dependent. All pathogenic effects were rescued by p38MAPK inhibition and AK23-mediated effects were also ameliorated by Src inhibition. Discussion: The results give first insights into pemphigus autoantibody-induced Dsg3 epitope-specific signalling which is involved in pathogenic events such as Dsg3 depletion.