Skin Immune Mechanisms in Health and Disease

Transcription

1 Skin Immune Mechanisms in Health and Disease by Barbara S. Baker Published by Garner Press ( Copyright 2006 Garner Press All rights reserved. This book, or parts thereof, may not be reproduced or redistributed in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the Publisher. ISBN: ISBN: (From 1st January 2007) G P Garner Press

2 Contents Preface... iii List of Colour Plates... v PART I: Immune Components of Skin 1. Skin Immune System: Cellular 1.1 T lymphocytes T cell subpopulations Intraepidermal and dermal T cells TCR and Antigens/Superantigens Restricted TCR Vβ families in skin Restricted TCR δ families in skin T lymphocyte homing to skin Tethering and rolling Firm adhesion Transmigration/Extravasation Antigen-presenting cells Langerhans cells Surface markers associated with antigen presentation Immune receptors Birbeck granules/langerin Proinflammatory cytokines Langerhans cell precursors Dermal dendritic cells Macrophages Keratinocytes Cytokines and Cytokine receptors Proinflammatory cytokines Immunomodulatory cytokines Suppressors of cytokine signalling Growth factors Colony stimulating factors Interferons Chemokines Response to cytokines Proliferation/Differentiation vii

3 viii Skin Immune Mechanisms in Health and Disease Up-regulation of surface molecules Cytokine/chemokine production Integrins Antigen/Superantigen Presentation Apoptosis Mast cells Mast cell activation Mediators and cytokines Dermal endothelial cells Leukocyte recruitment Cytokines and cytokine receptors Proinflammatory cytokines Th-2 cytokines/growth factors Colony stimulating factors Chemokines Antigen presentation Fibroblasts Cytokines, growth factors and chemokines Summary References Skin Immune System: Humoral 2.1 Complement components C3 and B Complement regulatory proteins Polyunsaturated fatty acid metabolites Linoleic acid Arachidonic acid Prostaglandins HETE and Leukotrienes Secretory immunoglobulins Cytokines and Chemokines Interaction between keratinocytes and Langerhans cells Interaction between keratinocytes and T cells Interaction between keratinocytes and endothelial cells Interaction between keratinocytes and fibroblasts Leukocytes attracted by keratinocyte-derived chemokines Cytokine inhibitors Neuropeptides Substance P... 45

4 Contents ix Cutaneous neuroinflammation Modulation of immune cell function Calcitonin gene-related peptide Cutaneous neuroinflammation Modulation of immune cell function Neuropeptide Y Somatostatin VIP PACAP POMC-derived peptides Modulation of immune cell function Modulation of cutaneous cell function Proteinase-activated receptors PAR PAR Vanilloid receptor Summary References PART II: Immune Responses in Skin 3. Skin Immune System: Innate Immunity 3.1 Alternative Complement Pathway Components of Innate Immunity: PAMPs and PRRs Phagocytic cells Inflammatory Response Pattern-Recognition Receptors in Normal Skin Toll-like Receptors TLR Structure and Signalling TLR Ligands TLR Expression by Peripheral Blood Leukocytes TLR Expression by Resident Skin Cells Responses by Skin Cells to TLR Activation Nod proteins Dectin CD C-type Lectin Receptors Macrophage C-type Lectin Macrophage Mannose Receptor (CD206) DEC-205 (CD205) Integrins... 70

5 x Skin Immune Mechanisms in Health and Disease 3.6 Antimicrobial molecules in skin Antimicrobial peptides Defensins Cathelicidins Dermcidin Adrenomedullin Antimicrobial proteins Bactericidal permeability-increasing protein (BPI) Psoriasin (S100A7) and Calprotectin (S100A8/S100A9) Antimicrobial molecules with enzyme/enzyme inhibitor activity RNase Antileukoprotease (ALP) Elafin (skin-derived serine protease inhibitor) Antimicrobial Lipids Palmitoleic acid Sphingosine NK cells Interaction between Innate and Acquired Immunity Summary References Acquired immune Responses: Immunological Hypersensitivity Reactions 4.1 Type I Hypersensitivity Mechanism Initial exposure to allergen Subsequent exposure to allergen Late Reactions IgE detection and measurement ELISA/RAST Skin prick test Examples of type I hypersensitivities Anaphylaxis Food allergy Asthma and Hayfever Treatment Modulation of the immune response to allergens Alleviation of clinical symptoms Type II Hypersensitivity Mechanism Phagocytosis/Antibody-dependent cellular cytotoxicity... 90

6 Contents xi Complement-mediated cytotoxicity Examples of Type II hypersensitivity Autoantibody-induced diseases Natural antibody-induced transfusion reactions Antibody-induced haemolytic reactions requiring previous sensitisation Drug-induced blood cell destruction Treatment Type III Hypersensitivity Mechanisms for phagocyte recruitment Complement-dependent mechanisms Complement-independent mechanisms Phagocyte-induced tissue damage Examples of type III hypersensitivity Arthus reaction Serum sickness Farmer s lung/bird fancier s lung Treatment Immunosuppressive drugs Immunomodulation Type IV Hypersensitivity Generation of a cell-mediated immune response Th-1 cytokine response Th-2 cytokine response Response to microorganisms Microbial stimuli Histology of reaction Granuloma formation Contact hypersensitivity In vivo tests for type IV hypersensitivity Detection of infection Function of the immune system Patch testing In vitro tests for type IV hypersensitivity Macrophage migration inhibition assay Lymphocyte transformation assay Cytokine assays Treatment Overlap of hypersensitivity types in an immune response Summary References Further Reading

7 xii Skin Immune Mechanisms in Health and Disease PART III: Immunological Mechanisms of Skin Disease 5. Antibody-Mediated Skin Diseases 5.1 Urticaria Acute and chronic forms Pathogenesis of urticaria Causes of urticaria Histology of skin lesions Mast cell mediators Kinins Complement activation Neuropeptides Protease inhibitors Other cell types Types of urticaria Acute idiopathic urticaria Acute allergic urticaria Pseudo-allergic (Non-immunological) urticaria Contact urticaria Physical urticarias Chronic Idiopathic Urticaria Hereditary Angioedema Urticarial vasculitis Urticaria Pigmentosa/Mastocytosis Treatment H 1 -antihistamines Other treatments Pemphigus Pemphigus vulgaris Clinical features Autoantibodies to desmoglein Autoantibodies to desmoglein Autoantibodies to other keratinocyte surface molecules T cell autoreactivity to Dsg 3 in PV patients MHC restriction/antigen specificity/tcr usage of autoreactive CD4 + T cells T cell autoreactivity to Dsg 3 in normal individuals Pemphigus foliaceous Clinical features Autoantibodies to desmoglein T cell autoreactivity to Dsg 1 in PF patients

8 Contents xiii Paraneoplastic pemphigus Clinical features Autoantibodies to desmogleins and plakins Treatment Bullous pemphigoid Clinical features Autoantibodies to hemidesmosomal proteins T cell autoreactivity to BP180 antigen Treatment Summary References Systemic Lupus Erythematosus 6.1 Clinical features Joints and skin Kidneys Lungs/Heart Central nervous system Haematological changes Aetiology Genetic factors Chromosomal linkage sites Candidate genes Mouse genetic models Environmental Hormonal factors Immune Dysregulation Defective T cell signalling Increased protein tyrosine phosphorylation and Ca 2+ influx TCR/CD3ζ chain deficiency Mechanisms involved in decreased transcription of CD3ζ chain Overexpression of FcRγ Altered T cell function Decreased proliferative/cytotoxic response Decreased IL-2 production Th-1 and Th-2 cytokines Autoreactive helper T cells Apoptosis Defective B cell signalling Autoantibodies

9 xiv Skin Immune Mechanisms in Health and Disease Nuclear antigens Intracellular proteins Phospholipids Immune complexes Normal clearance of immune complexes Defective clearance of immune complexes in SLE Model of Pathogenesis Pathogenesis of skin lesions Treatment Anti-inflammatory and immunosuppressive drugs New approaches to treatment Immunosuppressant Immunoablation B cells as targets Blocking of costimulatory molecules Anti-IL-10/TNF-α therapy Modulation of hormone system Gene therapy Summary References Allergic Contact Dermatitis 7.1 Clinical features Genetics Nickel-induced ACD Paraphenylenediamine-induced ACD Immunopathology of skin lesions Sensitisation to allergens Langerhans cell migration to lymph nodes Regulation of Langerhans cell migration to lymph nodes Antigen presentation within lymph nodes Elicitation of ACD Non-specific proinflammatory effects of haptens Activation and recruitment of T cells to the skin Amplification of T cell response T cell-mediated keratinocyte damage Immunoregulation of the contact sensitivity response IL-10-producing Tr1 cells CD4 + CD25 + regulatory T cells Treatment

10 Contents xv Summary References Atopic dermatitis 8.1 Clinical features Aetiology Genetics Genetic linkage Linkage sites shared by AD and psoriasis Candidate genes Environmental factors IgE-mediated allergy Food allergens Aeroallergens Secondary microbial infections The Hygiene Hypothesis Innate immune system Innate immune factors Anti-microbial peptides IL-8 and induced nitric oxide synthetase TLR and CARD/Nod proteins Immunological abnormalities T lymphocyte responses in vitro and in vivo Leukocyte function Dysregulation of IgE synthesis Increased total and allergen-specific IgE Impaired regulation of IgE production by cytokines Defects of the epidermis Impairment of the skin barrier Keratinocyte defects Immunopathology of AD Immunohistology of skin lesions Epidermal dendritic cells Model for pathogenesis of AD Antigen presentation Biphasic Th-2/Th-1 cytokine pattern Chemokines S.aureus and AD Colonisation of AD skin Staphylococcal superantigens

11 xvi Skin Immune Mechanisms in Health and Disease Malassezia and AD Auto-allergens Treatment Prevention Topical corticosteroids ± antibiotics Topical tacrolimus and pimecrolimus UV light Systemic treatments Biological response modifiers Summary References Further Reading Psoriasis 9.1 Clinical Features Histology of skin lesions Aetiology Genetics Evidence for a genetic basis Genomic imprinting HLA Associations Genetic linkage/positional candidate genes Other candidate genes Global gene expression in psoriatic skin Environmental factors Infections Koebner reaction (trauma) Hormones/drugs Innate immunity response Altered TLR expression Anti-microbial peptides/proteins NK-T cells/ keratinocyte CD1d expression Dendritic cell CD91 expression Peripheral blood T lymphocyte abnormalities T cell responses in vitro and in vivo T cell homing T cell cytokine profile Keratinocyte defects Response to IFN-γ Chemokine profile

12 Contents xvii Resistance to apoptosis Immunohistology of skin lesions T cell subpopulations Epidermal dendritic cells Dermal dendritic cells Endothelial cells Role of T cells in psoriasis Evidence that psoriasis is T cell-mediated Immunosuppressive treatments Psoriasis xenograft model in SCID mice Bone-marrow transplantation Stimulatory T cell supernatants Low CD4+ T cells/hiv infection T cell antigen specificity T cell clonality Microbial antigens Autoantigens Antigen presentation Cytokines/Chemokines in skin lesions Cytokines T cell cytokines Dendritic cell cytokines Keratinocyte cytokines Chemokines Model for pathogenesis of psoriasis Treatment Established treatments for psoriasis Steroid hormones Immunosuppressive drugs PUVA, Dithranol and Fumaric acid esters Current and emerging biological therapies for psoriasis Blocking T cell activation/costimulation Inhibiting T cell proliferation Cytokine blockade Immune deviation New systemic therapies for psoriasis Summary References Further Reading

13 xviii Skin Immune Mechanisms in Health and Disease Glossary Index Colour Plates