Basic Skin Immunology 2011

8/2/2019 Basic Skin Immunology 2011

1/22

Basic Skin Immunology

Julie Woods PhD

Photobiology UnitReviews 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


2/22

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 functionand inappropriate immune response such ashypersensitivity and autoimmunity.


3/22

Immune System

Non-specific (innate) immunity

Ancient,invertebrates

No memory

Non-specific

First line

Specific (adaptive) immunity

Vertebrates

Memory

Highly specific

Tolerance Self-limiting

Defence

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

(antibody generator)


4/22

Normal Immune Response

Infection controlled

Hypersensitivity

Overreaction to antigen

Immunodeficiency

Infection not controlled

Autoimmunity

Reaction to host tissue

Normal & Pathogenic Immune

Responses


5/22

Skin is a functional immunological

system Structure

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


6/22

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


7/22

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 ofmediators.


8/22

T Cells (Lymphocytes)

Produced in bone marrow Sensitised in thymus

Basis ofcell-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


9/22

Mast CellsLocation :

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.


10/22

School of Medicine, University of Virginia


11/22

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


12/22

B Cells (Lymphocytes)

Produced in bone marrow (act. Bursa of fabricus) Produce antibodies (Ab or Ig =immunoglobulin)

Basis ofhumoral 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 withthe help of a TH cell, to proliferate and mature into memorycells and Ab-secreting plasma cells.


13/22

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.

-


14/22

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


15/22

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 cellsinvolved in pathogenesis.


16/22

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


17/22

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.


18/22

Type I (immediate) hypersensitivity

(Allergy)

Antibody mediated: IgE. Early exposure to allergen causes the production of IgE, which

binds to FcR1 receptor on the MC. Later exposure causes

rapid crosslinking of the receptors, signal transduction and

degranulation of the MC. Ag binding causes degranulation ofmast 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)


19/22

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


20/22

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


21/22

Some Factors Affecting Skin Immune

Response/System

Organ transplant Immunosuppression

Sunlight/UV

Immunosuppression

Structure

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


22/22

Immune Response

Immune response elicited depends on how the immune

This impacts on the chemical mediators (cytokines,chemokines, leukotrienes etc) which are released by thecell.

These mediators influence the behaviour of theneighbouring cells and other immune cell types (eg.attracting neutrophils to site of infection), and thus thetype of immune response which is launched.

Inappropriate activation of the immune system can result inchronic inflammation seen in some skin conditionsincluding psoriasis, atopic eczema and some skin cancers.

Basic Skin Immunology 2011

Documents

Transcript of Basic Skin Immunology 2011