Immunology of Skin Flashcards
Cutaneous Immunology
The skin is a first line barrier defense
Epidermal dendritic cells capture antigens entering the epithelium.
Continual traffic of immune cells between skin, draining lymph nodes, and circulation provide immunosurveillance
Site for active surveillance of basal and squamous cell carcinoma development
Imbalance of immune defensive and tolerance pathways to various challenges leads to inflammatory skin disorders
Skin Cells with Immune Function In Dermis
Dendritic cells (mDC and pDC) help induce anti-viral (herpes) skin responses
CD4+ T (Th1, TH2, TH17) and CD8+T in equal numbers, mostly memory cells expressing cutaneous lymphocyte–associated antigen (CLA)
gamma-delta T cells: role in anti-tumor responses and wound repair
Natural killer T (NKT) cells, macrophages, mast cells
Keratinocytes
Innate barrier function
Antimicrobial peptide release
Cytokine/chemokine release in response to infection, UV radiation, or wounds/injury
Pro-inflammatory functions (IL-1, IL-18)
Chemokine recruitment of immune cells (IL-8)
Regulation of APC function:
IL-10 (suppressive, UVB inducible), TGF-b (inhibit APCs)
IL-12, GM-CSF, TSLP (promote APC function)
Non-professional APC function (tolerance induction)
Differential Antigen Presentation by Skin Dendritic Cells (Langerhans cells)
Dendritic APC are recruited (“home”) to the epidermis
Immature LC capture antigen, migrate to regional lymph nodes, and present antigen to naïve T cells
Inflammatory (microbial) antigens trigger costimulator and cytokine (IL-12) expression by LC that promote Th1 responses.
Innocuous antigens induce costimulators + cytokines by LC that promote Th2 or Treg responses
Urticaria
Acute urticaria is caused by drugs, chemicals, and foods in association with IgE–dependent mast cell degranulation Intracutaneous edema (wheal) is surrounded by an area of redness (erythema) that is typically pruritic Chronic urticaria can be autoimmune, mediated by anti-IgE-receptor (anti-FcR) antibodies
Lupus Erythematosus (LE)
Autoimmune disorder
Anti-nuclear antibodies, anti-dsDNA, anti-ribonucleoproteins, plus non-LE-specific autoantibodies
Immune dysregulation or defects Poor clearance of apoptotic cells (source of autoantigen) Poor clearance of Immune complexes due to C1q deficiency Treg defects (alters self-tolerance) Increased skin IFN-a (promotes T cell infiltration)
Multiple Cutaneous (CLE) and/or Systemic (SLE) clinical manifestations: dermatitis, nephritis, arthritis; heart, lung, and nervous system problems
Type II CLE Reactions
Localized photosensitive rashes (such as malar/butterfly rash) in acute CLE are a Type II (cytotoxic autoantibody) immune reaction
UVB-induced cell death (apoptosis) of keratinocytes exposes nuclear autoantigens on the apoptotic cells
Anti-nuclear autoantibodies bind to the exposed nuclear antigens on the apoptotic cells and promote inflammatory responses in the skin
Examples of Type III Hypersensitivity Skin Reactions
Anytime you have excess immune complexes and body has a hard time getting rid of them
Generalized Vasculitic skin lesions in systemic autoimmune diseases such as SLE caused by vascular deposition of circulating autoantibody/autoantigen immune complexes
Arthus-type skin reaction (post vaccination, or post allergy shots) to antigens injected subcutaneously in pre-immune person
Post-infection vasculitis (post-viral H-S-purpura, meningococcemia, RMSF, syphilis,plus others)
Type IV Sensitivity Examples
Allergic Contact Dermatitis, example: poison ivy allergy
Delayed onset inflammation (24-72 hr post contact)
Transient redness to severe swelling with bullae (blisters) and pruritus (itching). Usually limited to site of allergen contact
Skin contact allergens: Highly reactive small chemical allergens penetrate the skin and covalently modify (haptenate) self proteins such as ingredients in topical drugs (bacitracin), plant substances (poison ivy), chemicals in leather, clothing, metal compounds (nickel), dyes, cosmetics.
Th1, Tc, and macrophage infiltration
TB PPD
Atopic Dermatitis (Eczema)
Chronic, relapsing, inflammatory pruritic skin disease
Disrupted epidermal barrier function promotes infection and allergen sensitization
Mutations in filaggrin genes are genetically linked with AD
Heightened Th2 cytokines, IL-17, eosinophils, mast cells, and DC in skin
IgE-associated (extrinsic atopic dermatitis) with IgE sensitization to food, environmental allergens, M. furfur, S. aureus
Reduced Treg, decreased production of AMPs (defensins) further reduces barrier function
Increased rate of S. aureus colonization and eczema activation by superantigens
Th22 activation in chronic stages
IL-22 inhibits KC terminal differentiation, promotes KC hyperplasia & acanthosis
Psoriasis
Inflammatory disease with high Th1 and Th17 cytokines driving:
Keratinocyte proliferation
Elevated AMPs (human beta-defensins and cathelicidin LL-37)
Effective biologic therapies (neutralizing antibodies):
Anti-TNF-a
Anti-IL-23 (in clinical trials)
Psoriasis Pathogenesis
Defensins (Cathelicidin LL-37) complex with self DNA generated by injury or infection of skin and may initiate an autoimmune inflammatory response
Defensin-DNA complexes stimulate (via TLR9) pDC release of IFNa to activate mDC
Activated DC present autoantigen plus cytokines (TNF-a, IL-12, IL-23) that promote Th17,Th1, and Tc differentiation and inflammatory responses.
The resulting cytokine milieu (TNF-a, IFN-gamma, IL-17, IL-22) increase keratinocyte proliferation, increase AMP levels, and amplify cytokine cascade.
Immunosuppressive Effects of UV
Keratinocytes recover better from DNA damaging effects of UV than T cells or macrophages.
Keratinocyte-derived cytokines might suppress local immune responses
Keratinocytes + UV = IL-10 (inhibits APCs) and suppressed delayed T cell response
Summary
The skin is a physical barrier to infection but also is a major site of antigen contact for initiation of immune responses.
Langerhans cells are critical APC in initiating and regulating primary and secondary T cell responses to contact antigens.
Cytokine release by immune cells and keratinocytes regulate specific immunity, local inflammation, and keratinocyte proliferation or death.
DC promote TH2 and TH22 responses in atopic dermatitis
DC promote TH1 and TH17 responses in psoriasis
