PLENARY SESSION ABSTRACTS Theme: IMMUNITY AND AUTOIMMUNITY State-of-the-Art Address Supporting Review What’s new in autoimmune blistering diseases? Epithelial, immune cell and microbial cross- D. F. MURRELL talk in homeostasis and atopic dermatitis Department of Dermatology, St George Hospital, and T. KOBAYASHI UNSW Faculty of Medicine, Sydney, New South Wales, Laboratory for Innate Immune Systems, RIKEN Center Australia for Integrative Medical Sciences (IMS), Yokohama, There are several blistering diseases which occur natu- Japan rally in other species as well as in humans; for example, Skin is a complex and dynamic ecosystem, wherein the pemphigus occurs naturally in dogs and horses and the epithelial cells, immune cells and microbiota engage in inherited blistering disease, epidermolysis bullosa, also active dialogues and maintain barrier integrity and occurs in dogs. Several new validated scoring systems functional immunity. Alterations of the peaceful coexis- to measure the severity of autoimmune blistering dis- tence with the resident microbiota, referred to as dys- ease (AIBD) have been developed which assist in biosis, lead to dysregulation of host immunity. It has demonstrating efficacy of new treatments, such as the been long debated whether the dysbiosis in the skin of Pemphigus Disease Area Index (PDAI) for pemphigus atopic dermatitis is merely a consequence of chronic and Bullous Pemphigoid Disease Area Index (BPDAI) skin inflammation or whether it is actively involved in for pemphigoid. Pemphigus is due to autoantibodies to driving skin inflammation. Microbiome analysis by 16S desmogleins 1 and 3 in human pemphigus foliaceus and rRNA sequencing in humans and dogs with atopic der- vulgaris and desmocollin1 in canine pemphigus foli- matitis showed the shifts in microbial diversity repre- aceus, generated by the late onset activation of the sented by increased proportion of Staphylococcus spp. adaptive immune response. Paraneoplastic pemphigus, Direct evidence has been found in mice deficient in a in which there are also antibodies to plakin proteins in disintegrin and metalloproteinase 17 (ADAM17), which the skin and mucosae, also has occurred in canines. spontaneously developed eczematous dermatitis with The B-cell CD-20 inhibitor, Rituximab, with short- dysbiosis that was predominated by S. aureus and course steroids has been shown to be more effective Corynebacterium spp. Targeting the dysbiotic flora with and safer than traditional high-dose steroids alone in a an antibiotic cocktail reversed dysbiosis and extin- large human pemphigus RCT. guished eczematous inflammation, suggesting crucial Pemphigus also involves the innate immune response, roles of dysbiotic flora during atopic inflammation. with induction of interleukin (IL)-1 and IL-6. A canine Symbiotic relationships between the host and micro- version of the PDAI has been developed and used in a biota must be constitutively maintained. Detailed mech- pivotal study of the first Bruton Tyrosine Kinase Inhi- anisms on how host immunity regulates commensal bitor (BTKI), which can inhibit both the innate and bacteria in the steady state are now being revealed. adaptive immune response, to be used in an AIBD, in Skin harbours a myriad of tissue-resident immune cells dogs, as solo open-label treatment. Two BTKIs given which include both innate and adaptive immune cells. orally once daily demonstrated excellent efficacy and Recent studies have highlighted a fundamental role of safety, as proof-of-concept for trials in patients with innate lymphoid cells (ILCs) in the maintenance of bar- pemphigus. Open-label Phase 2 studies in pemphigus rier functions and tissue homeostasis. A study in mice have shown rapid responses with rilzabrutinib and the revealed that ILCs and T lymphocytes differentially reg- phase 3 PEGASUS trial is recruiting. CAR-T cell trials ulate skin microbiota. In particular, epidermal ILCs reg- in pemphigus are also ongoing. Bullous pemphigoid ulate production of antimicrobial lipids from sebaceous (BP) is increasing in incidence, particularly in patients glands to maintain homeostatic balance of skin micro- over 70 years. Case control studies have shown that biota. Cross-talk between epithelial cells and immune prior neurological damage, particularly multiple sclero- cells determines immunological tones in the barrier tis- sis, and also dementia and Parkinson disease, increase sue. ILCs directly respond to tissue-derived signals and the risk. Multiple medications increase the risk of trig- play an essential role in barrier immunity. Epithelial cells gering BP, particularly gliptins used to treat diabetes produce alarmins such as thymic stromal lymphopoietin mellitus. Eotaxin 1, IL-17 and IL-4/13 are pathways (TSLP), interleukin (IL)-33 and IL-25, all of which acti- which are increased in BP and trials of new therapies vate group 2 ILCs (ILC2s), which produce type 2 cytoki- targeting these pathways are underway. Epidermolysis nes such as IL-5 and IL-13, and boost type 2 immune bullosa acquisita (EBA) develops due to autoantibodies reactions against parasitic infections, allergens, mites and to collagen VII, the anchoring fibril protein present in toxins. Dysregulation of epithelial–ILC cross-talk results skin and stratified mucosae. Inflammatory forms of in allergic inflammation. Single cell RNA-sequencing EBA have been reproduced in mice and respond to analysis uncovered unique characteristics of skin ILCs complement inhibitors and inhibition of the Fli-1 path- and the regulatory mechanisms in the context of atopic way, which is increased in the EBA mouse and in inflammation. Understanding active interactions between hereditary dystrophic EB, a disease with gene defects in the host epithelial and resident immune cells and micro- collagen VII. biota provides a foundation of novel therapeutic strate- Source of funding: Self-funded. gies of inflammatory skin diseases. Conflict of interest: None declared. Source of funding: Self-funded. Conflict of interest: None declared. © 2020 The Authors. Veterinary Dermatology © 2020 ESVD and ACVD, Veterinary Dermatology, 31 (Suppl. 1), 6–109 Abstracts 7 Theme: ALLERGY AND ATOPIC DERMATITIS State-of-the-Art Address syndrome, and that different genetic alterations play a A world of inflammation: ecological solutions role in certain breeds and geographical locations and for people, place and planet not in others. Disease development is modulated by the interaction between skin barrier alterations, lifestyle S. L. PRESCOTT conditions, microbiome and immunological responses. School of Paediatrics and Child Health, University of As is the case in people, dogs living on a farm with Western Australia, Perth, Western Australia, Australia increased exposure to the outdoors and other dogs have The ecology of the early environment determines life- decreased risk of development of disease. This likely long health, including microbial diversity, nutrition, results from a modulation of immunological response nature, social interactions and the wider “exposome”. by increased exposure to beneficial bacteria and Almost all of these factors impacting immunity had increased biodiversity. Skin barrier impairment plays a have implications for all aspects of health and reliance. role in promoting cutaneous dysbiosis, increased aller- In particular, the emergence of “microbiome science” gen penetration and excessive T helper 2 (Th2) provides new evidence of vital relationships between response. It is under investigation whether primary biodiversity and health at every level. Allergy was the defects exist in dogs, as reported in people, or whether first discipline to link adverse changes in early life ecol- alterations are purely secondary to inflammation. Doc- ogy with the epidemic of immune disease – with much umented abnormalities range from ultrastructural (e.g. wider implications for other systems. New perspectives disorganized lipid lamellae) to chemical (e.g. decreased of ecological interdependence connect personal and ceramide levels) and functional (e.g. increased transepi- planetary health; the human health crisis cannot be sep- dermal water loss). These alterations are present in clin- arated from the social, political and economic “ecosys- ically normal atopic skin and are intensified in lesional tems” otherwise driving “dysbiosis” (life in distress) at atopic skin. It is important to stress that clinically nor- every level. Changes in macroscale ecology – of food mal atopic skin is not the same as normal skin and that systems, lifestyle behaviours, socioeconomic disadvan- low-grade inflammation is present in atopic skin, thus tage and environmental degradation – all impact the making possible that these changes are secondary. microbial systems sitting at the foundations of all Future studies should include control groups with ecosystems. In particular, changes in the function and inflammatory diseases that are not AD (besides healthy composition of the human-associated microbiome has controls) to distinguish between changes that are simply been implicated in the mounting global burden of non- consequences of inflammation and those that are speci- communicable diseases (NCDs), exacerbating inflam- fic signatures of atopic disease. Decreased transepithe- mation and metabolic dysregulation through multiple lial electrical resistance of monolayers of atopic pathways along lifespans. This underscores the need for keratinocytes in culture suggests a role of tight junctions ecological approaches aimed at restoring symbiosis,