Short peptides to phospholipase A2

1 - Thymus derived (tTregs or natural Tregs): characterized as CD4+CD25+T cells that constitutively express thetranscription factor Foxp3. These are important in autoimmunity and are unlikely to be involved in allergy as presentation to the thymus must occur for production (allergens are not presented to the thymus).

2 - Peripherally derived (pTregs or inducible Tregs): pTregs can differentiate from preexisting T-effector lymphocytes or circulating naïve T cells and may or may not express Foxp3 and CD25. This subset is thought to be important in the allergic syndrome and especially the response to allergy immunotherapy.

-PCA is an immediate dermal response to an allergen-IgE interaction

-It is based on a passively transferred anaphylactic reaction from antiserum

-Subjects are sensitized with antiserum and following a latent period subjects are injected with Evans blue dye bound to antigen

-Xerosis (dry skin) occurs which leads to allergens penetrating skin which produces subclinical inflammation and activates skin alarmins (IL-25, IL-33 and TSLP)

-Alarmins activate ILC2 cells to secrete Type 2 cytokines (IL-5 and IL-13) which promotes eosinophil inflammation but also activates TH2 cells that are migrating into the tissue and they will further release Type 2 cytokines (IL-4 and IL-13)

-Alarmins also activate intra-epidermal dendritic cells (Langerhan cells) and dermal dendritic cells)

-Alarmins will also activate Basophils which produce IL-4 which further activate ILC2 to promote the release of more type 2 cytokines (IL-5 and IL-13) to stimulate eosinophils and mast cells

-Staph superantigens (enterotoxins) can also directly stimulate Basophils to make IL-4 (many cells are contributing)

-Starting to develop overt inflammation, proteins and lipids in the skin barrier are decreasing, amplified TH2 driven inflammation, increased itch signaling, and increased S.aureus colonization

-Cytokine release of IL-4, IL-31, and IL-13 which can bind to cutaneous nerves to promote itch

-Erythema, papules, papulovesicles, and pruritus occur

-Continued pruritus and scratching promotes chronic stage

-Varied inputs from Th1, Type 22, and Type 17 depending on the phenotype and endotype of the individual (ie. European American AD have big Th2 and Th22, Asian American AD have th2, TH22, and Th17 input, but African Americans have less Th17, etc----> this likely occurs in dogs as well but we need large numbers of individual breeds to understand phenotypes and endotypes in dogs better)

-Lichenification and excoriation occur

-Dermal thickening and fibrosis result

-Perpetuated skin inflammation

-Very Early phase (within first few days to weeks): Mast cells and basophils get desensitized to degranulation

-Days to months (T cell tolerance): T regulatory cells and Altered ratio of Th2:Th1 and cytokines

-Months to years: Increase in blocking antibodies (allergen-specific IgG4 and IgG1) and decrease in allergen-specific IgE

Longterm effects: Decreased numbers of inflammatory cells (eosinophils, basophils, and mast cells)

-sublingual mucosa is very similar to skin which is why immunotherapy can be successful

-Antigen travels through sublingual duct and is absorbed across and activates macrophages/dendritic cells and then those cells will travel via the afferent lymphatic vessel to the submandibular L.N. and take those Naive CD4+ T cells and convert them to FoxP3+ Treg cells

-Result is local and systemic tolerance

• Atopic-Th2- cytokines IL4, 5, 6, 10, 13, 31
• Non-Atopic- Th1- cytokines IL2 and interferon

-Arabians and Thoroughbreds

-Absorb allergen through skin

-Defective barrier function?

-mRNA IL13 elevated in lesional and nonlesional skin in affected horses

-Increased numbers and imbalance of T cells (CD4/CD8 and FoxP3+ T reg cells)

• Histamine
• PAR2
• TRPM8- menthol
• TRPV1- capsaicin
• Cannabinoid receptors
• Opioid receptors
• Substance P-NK1 and GABA
• IL31

-Can be hard to find

-Trial therapy

-IgG Elisa

-Sarcoptes PCR-uses skin scrapings

-Good specificity and sensitivity

-Can be used to monitor therapy

• FCER1: high affinity IgE receptor

• Type IV hypersensitivity, T-cell mediated and delayed reaction
• 1) Sensitization phase: allergens captured by Langerhan cells (dendritic epidermal cells) and migrate to LN's and process the antigen to naive, antigen-specific T cells (6-10 days or prolonged for years).
• 2) Naive T cells recognize antigen and expand clonally to differentiate into memory/effector T cells. During the differentiation phase, sensitized T cells express cutaneous homing antigens (cutaneous lymphocyte antigens) and enable them to migrate from cutaneous capillaries to the epidermis
• 3) Antigen-presenting cells present antigen to sensitized T cells to expand and trigger an inflammatory reaction in that location (elicitation) and result in symptoms and signs of contact dermatitis

• Filaggrin gene defects result in epidermal barrier defects
• Filaggrin gene located on 1q21.3 chromosome and leads to truncation of profilaggrin and loss of filaggrin expression will lead to increased skin permeability, allow allergens, irritants, and microbes to pass the barrier, and initiate the inflammatory cascade
• PTPN22 encodes for lymphoid tyrosine phosphatase involved in the prevention of spontaneous activation of T and B cells

• Th2 and group 2 innate lymphoid cell (ILC2) activation drives type 2 inflammation and express master transcription factor (GATA3)
• Type 2 inflammation is associated with AD in dogs and produce type 2 cytokines (IL-4, IL-5, and IL-13) which mediate and elicit pruritus and inflammation, increase IgG1 and IgE production, decrease skin barrier integrity and drive AD pathogenesis
• Transcripts for Type 2 cytokines (IL-4, IL-13, IL-31, and IL-33) are upregulated in the skin and peripheral blood of allergic dogs
• Type 2 effector cells (eosinophils, mast cells, and CD4+ T cells) infiltrate the inflamed epidermis and dermis of atopic dogs

• 40%

• Pheochromocytoma
• Drug reaction
• Mast cell tumor
• CAEDE

• FCER1: high affinity IgE receptor

• Known food allergies 10-70kDa in animals
• Hydrolyzed proteins in elimination diets must have MW less than 5kDa to prevent allergic reactions (eg. Ultamino is likely <3kDa)

• TH2 and group 2 innate lymphoid cell (ILC2) activation drives type 2 inflammation and express master transcription factor GATA3
• Type 2 inflammation is associated with AD in dogs and produce type 2 cytokines (IL-4, IL-5, and IL-13) which mediate and elicit pruritus and inflammation
• IgG1 and IgE production and decreased skin barrier integrity drive AD pathogenesis
• Transcripts for type 2 cytokines (IL-4, IL-13, IL-31, and IL-33) are upregulated in the skin and peripheral blood in allergic dogs
• Type 2 effector cells (eosinophils, mast cells, and CD4+ T cells) infiltrate the inflamed epidermis and dermis of atopic dog

• Increase in circulating CD4+FOXP3+Treg cells
• pre-immunotherapy Treg numbers did not differ from those of healthy control dogs
• Presence of normal or even slightly supranormal FOXP3 expression suggests that clinical disease in canine AD may be associated with a functionally decreased regulatory capability of cells expressing transcript or protein

• AD canine skin exhibits increased transcription of thymic stromal lymphopoietin (TSLP) compared with healthy skin
• Dendritic cell activation in the presence of TSLP appears to foster a Th2 promoting phenotype
• production of TSLP by primary canine keratinocytes is induced by stimulation with ligands for Toll-like receptors 3 and 4 (TLR3 and 4), but not TLR2 and TLR7

• IL-4 is commonly considered the archetypical Th2 cytokine
• Produced by some T-cells, mast cells, and possibly basophils
• Gene and protein expression of IL-4 has been variably found in dogs with AD
• IL-4 mRNA transcripts were found in the skin of both healthy and atopic dogs
• Another study found overexpression of IL-4 in atopic relative to healthy skin

• Both healthy and atopic dogs mount an IgG response to proteins derived from the mite

• Think Type 1 hypersensitivity reactions
  • Insect bites
  • Adverse drug reactions
  • Ectoparasitism

• CAEDE: Canine acute eosinophilic dermatitis with edema
• Vomiting and hematochezia
• Before, after or concurrent with skin lesions
• IBD, pancreatitis, ADR
• Resolves GI over 5 days; Skin- 20 days

• Unknown but associated with recent GI disease/treatment
• Many patients have had recent drug therapy with metronidazole, antiemetics, antidiarrheals, antibiotics or heartworm preventatives, vaccines, etc
• May or may not result in mild pyrexia, hypoalbuminemia, anemia, thrombocytopenia, pruritus

• Wells-like (CAEDE)
  • Macular erythema +/- plaques
  • Diffuse to ventral
  • Systemic signs: GI disease
  • Suspected drug triggers: Metronidazole, other GI drugs
  • Recurrence uncommon
  • Strongly eosinophilic
  • May be pruritic
• Sweet's like
  • Plaques/nodules more prominent
  • May be regional/limbs
  • Systemic signs: lameness, fever, IMPA
  • suspected drug triggers: NSAIDs, vaccination
  • Possible recurrence
  • <12% eosinophils intradermal

• Filaggrin (FLG)

• Reprogrammed Th2?
• induced by IL4 and TGFβ
• repressed by IFNγ
• produce IL-9 and IL10
• perpetuate chronic inflammation in allergy

• epidermal immunity
• infiltrate epidermis in inflammatory skin disease
• produce IL-22, TNF-α (w/o IL-17, FGFs)
• inflammatory skin diseases
• epidermal hyperplasia and wound repair
• amplify TNFα
• induce IL-3, IL-6, TNF-α in KC

• IL-1β
• IL-6
• IL-8
• TNF-α in normal human keratinocytes