Basic Skin Immunology

Julie Woods PhD Photobiology Unit

Reviews Of Interest: Basic Background: NEJM 2000 343 (1) pp 37-49; & pp 108-117 NEJM 2001 344 (9) pp 655-664 Psoriasis: Nature 2007 455 pp 866-873 Autoimmunity: Nature 2005 435 pp 583-627

Learning Objectives
Knowledge of innate (passive) and adaptive (active) immunity, barrier properties of the skin, key cell types involved, how different pathogens trigger immune responses. How skin structure, immunosuppression, ageing and sunlight affect the immune response. Understand the pathophysiology of the skin immune system in relation to barrier function and inappropriate immune response such as hypersensitivity and autoimmunity.

Immune System

Defence
Non-specific (innate) immunity Specific (adaptive) immunity

Ancient, invertebrates No memory Non-specific First line

Vertebrates Memory Highly specific Tolerance Self-limiting

Antigen (Ag) = Usually a protein/peptide or polysaccharide that elicits an immune response (antibody generator)

Normal & Pathogenic Immune Responses

Normal Immune Response Infection controlled

Hypersensitivity Overreaction to antigen

Immunodeficiency Infection not controlled

Autoimmunity Reaction to host tissue

Skin is a functional immunological Structure system Stratum corneum

Blood & lymphatics Stratified Adhesion molecules Cells Dendritic cells T lymphocytes Mast cells Keratinocytes Cytokines, eicosanoids IL-1, 2, 10, IFN Complement Genetics Major histocompatibility complex Melanin DNA recognition & repair

Innate immunity Adaptive immunity

Stratum Corneum/Keratinocytes
Outer layer of the skin. Formed by terminal differentiation of keratinocytes (KC) to corneocytes. Filaggrin/Involucrin/keratin Antimicrobial peptides
Eg. defensins

Lipid-rich barrier

Dendritic Cells (DC)

Antigen Presenting Cell Langerhans cells (LC) Located in epidermis (Dermal) Myeloid DC Plasmacytoid DC ROLE Initiate adaptive IR by antigen presenting to T cells. Modulate neutrophil recruitment via production of mediators.

T Cells (Lymphocytes)
Produced in bone marrow Sensitised in thymus Basis of cell-mediated immunity
Many subgroups exist , including: Helper T Cells: CD4+ Th1: Activate macrophages to destroy microorganisms IL2, IFN Th2: Help B cells to make Ab IL4, IL5, IL6

Cytotoxic T Cells: CD8+ Kill infected cells directly

Mast Cells
Location : Dermis especially

Activated by: IgE-Ag binding (allergy) Physical trauma, drugs Microbes, fungi & parasites
Granules: Preformed mediators include: Tryptase, chymase, TNF, histamine Newly synthesised mediators include: IL (3,5,6,8,13,16,18), TNF, TGF , IFN , PGD2, PGE2, LTB4, LTC4, VEGF, bFGF, IP-10, MIP-1 , MIP-1 .

School of Medicine, University of Virginia

Neutrophils
Recruited to the sites of injury/bacterial infection and some cancers by chemotactic mediators released by other cell types (IL-8, IFN- ).
Cytokines Phagocytes Reactive intermediates

Predominant cells in pus

School of Medicine, University of Virginia

B Cells (Lymphocytes)
Produced in bone marrow (act. Bursa of fabricus) Produce antibodies (Ab or Ig =immunoglobulin) Basis of humoral immunity
B cells make Ab molecules with a unique Ag binding site Abs are initially inserted into the B cell plasma membrane, where they act as Ag receptors.

Ag binding to the receptors activate the B cell, usually with the help of a TH cell, to proliferate and mature into memory cells and Ab-secreting plasma cells.

Major Histocompatibility Complex

Chromosome 6 Class I: Found on almost all cells Present Ag to cytotoxic T cells Present endogenous Ag Class II: Found on APC (B cells, macrophages) Present to Th cells Present exogenous Ag Immunological recognition & transplant rejection. -

Skin Conditions Associated with Immune System Dysfunction/Inappropriate Immune Response

Psoriasis Atopic dermatitis Bullous pemphigoid Contact dermatitis Morphea/Systemic sclerosis Urticaria Systemic lupus erythematosus Skin infections Skin tumours

Psoriasis
Common & complex (2-3% globally). Genetic & environmental factors involved
(Twin studies; Koebner phenomenon; infection; interferon therapy; drugs).

T-cell dependent disease. Hallmark of skin lesions is inflammation. Plaques are reversible. Adaptive and innate immune system cells involved in pathogenesis.

Psoriasis
CD4+ Th1 cells (INF ) CD4+ Th17 (IL-17) Keratinocytes DC MC Neutrophils Macrophages

Activation of T cells and their secreted products. Aberrant KC terminal differentiation: failure of corneocytes to stack. Neutrophils & inflammatory cells infiltrate the SC, epidermis & dermis. Dilated blood vessels: erythema. Factors produced by KC directly affect Tcells & DC...and vice versa.

Corneocyte = terminally differentiated keratinocytes

Atopic Eczema
Commonest in children. Genetic & environmental factors involved
(Twin studies; Koebner phenomenon; infection; drugs).

Histologically different. from psoriasis. Impairment of skin barrier function.

Tcells DC KC

No cure.

Antibody mediated: IgE. Early exposure to allergen causes the production of IgE, which binds to Fc R1 receptor on the MC. Later exposure causes rapid crosslinking of the receptors, signal transduction and degranulation of the MC. Ag binding causes degranulation of mast cells and basophils Very rapid early response: minutes (wheal & flare) Late response: hours (cellular infiltration, nodule) Pollen (birch, oilseed rape) Drugs (penicillin) Food (nuts, eggs, seafood) Insects & animals (bee sting, cat hair)

Type I (immediate) hypersensitivity (Allergy)

Type II & III hypersensitivity

Antibody mediated: IgG, IgM Type II mechanisms important in autoimmunity & transplantation
Haemolytic disease of the newborn Blood transfusion recipients

Skin testing in type III hypersensitivity leads to an Arthus reaction, which is slower than a type I skin response, but faster than a type IV skin response

Type IV hypersensitivity
Cell mediated: TH1 cells Delayed type hypersensitivity is based on a Tcell/Ag interaction, which then recruits other cells to the site
Tuberculin reaction Contact allergy

Peaks at 24-48h after contact with Ag Metals (nickel, chromate), drugs

Some Factors Affecting Skin Immune Response/System

Organ transplant
Sunlight/UV
Immunosuppression Structure

Immunosuppression

Ageing
Changes in skin structure (access) Decreased ability to detect malignant cells- Cancer Decreased ability to detect Ag- Infection risk - - Autoimmunity Vaccinations (eg. flu) less effective and not as long lasting

Immune Response
Immune response elicited depends on how the immune This impacts on the chemical mediators (cytokines, chemokines, leukotrienes etc) which are released by the cell. These mediators influence the behaviour of the neighbouring cells and other immune cell types (eg. attracting neutrophils to site of infection), and thus the type of immune response which is launched. Inappropriate activation of the immune system can result in chronic inflammation seen in some skin conditions including psoriasis, atopic eczema and some skin cancers.