Immunological Diseases Spectrums and Mechanisms Assistant Professor Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine, Faculty of Medicine Chulalongkorn University

Principles of Immunology Key roles of immune responses Terminology Primary and Secondary Immune Responses Cells and Molecules involved Immunological Disorders Mechanisms and Clinical Implications

Key Roles of Immune System Prevent and control infection Prevent and control autoimmune diseases Prevent and control malignancy Prevent and control allergic diseases Prevent and control graft-versus-host (GVH)

Terminology Antigen, allergen, immunogen and epitope Innate and Acquired Immunity Allergy Autoimmunity, autoimmune diseases

Innate and Acquired Immunity Innate Acquired Ag specificity no yes Magnitude (10, 20) same higher (20 > 10) Memory no yes Key components PMN, NK T, B lymphocytes C’, barriers APCs

Primary and Secondary Immune Responses Primary IR 7-10 relatively low Mostly IgM relatively high Secondary IR 2-5 days relatively high Other class (IgG, IgA, etc) relatively low Lag period Peak response Ig class Antigen [ ]

Cells and Molecules Involved in Immunology Innate Immunity Cells: epithelium, phagocytes (neutrophils, monocyte-macrophages) NK cells, mast cells Molecules: complement, inflammatory mediators, cytokines, chemokines, adhesion molecules

Cells and Molecules Involved in Immunology Acquired Immunity Cells: APCs (macrophages), T (CD4+, CD8+) and B lymphoctyes (plasma cells), monocytes Molecules: HLA, cytokines, immunoglobulins, adhesion molecules

Immunological disorders Hypersensitivity mediated disorders Immunodeficiency : 10 and 20 ID

Classification of Hypersensitivity Gell and Coomb’s Classification: 4 Types Type 1 : IgE-mediated Type 2 : Cytotoxic antibodies Type 3 : Ag-Ab Immune complexes Type 4 : Delayed-type, cell-mediated hypersensitivity

Type I Hypersensitivity Allergen exposure, sensitization and re-exposure IgE antibody, mast cells/ basophils and its’ mediators Target organ immediate reactions Clinical allergy: atopic diseases, drug allergy, insect allergy and anaphylaxis

Pathogenesis of Allergic Disease Genetic Susceptibility Adjuvant factors: Tobacco smoke Air pollutants Lack of protective factors: Infection ? Immunization ? Nutrition ? Allergic Sensitzation Allergen Exposure Upper/lower airway or Skin hyperresponsiveness Pollutants Infection Excercise Vary in spectrum and severity Allergic Diseases Modified from Ulrich Wahn 1998

Principle Pathogenesis of Allergic Diseases Durham and Till 1998, Lu 1998, Drazen 1996 Allergen APC CD4+ T-cell IL-12 Allergen Th-1 Th-2 IL-4 IgE IFN-g IL-5 IL-3 GM-CSF B-cell B-cell CD8+ cell IgG Mast cell IL-5 Other cells _ + Eosonophil MBP ECP, LTs Late Phase Reaction Tryptase, LTs AllergyChula

Pathogenesis of Allergic Diseases Cells & Molecules Involved in Allergic Inflammation Modified from Robert Davies

Mediators of Mast Cells and Basophils Secondary Mediators Primary Mediators Prostaglandins Leukotrienes PAF Histamine RFs IL-3, 4, 5, 6, 7, 8 GM-CSF, TNFa Chemokines -MCP1, MIP1 Oxygen radicals Histamine Tryptase Chymotryptase Heparin/Chondroitin Kininogenase Chemotactic Factors AllergyChula Sim TC, Grant JA 1996

Mediators of Mast Cells and Allergy Blood Vessels Urticaria, Angioedema Laryngeal edema, Shock H, PGD2, LTs, PAF Kinin Bronchospasm Abd. pain, Vomiting Smooth Muscles H, PGD2, LTs, PAF Diarrhea, Rhinorhea Bronchial secretion Mucus Glands H Mast Cell Basophil Sensory Nerves Itching LTB4 PAF IL3, IL5 Chemokines Leukocytes Inflammation - LPAR AllergyChula

โรคภูมิแพ้ที่พบบ่อย โรคภูมิแพ้ทางจมูก Allergic Rhinitis โรคหืดจากภูมิแพ้ Allergic Asthma โรคภูมิแพ้ทางผิวหนัง Atopic Dermatitis โรคลมพิษ Urticaria โรคแพ้อาหาร Food Allergy การแพ้ยา Drug Allergy Allergy Chula 1999

Epidemiology of Allergic Diseases in Thai Children พยนต์ บุญญฤทธิพงษ์ และมนตรี ตู้จินดา 2533; ปกิต วิชยานนท์ และคณะ 2541

Skin Prick Test

สิ่งเหล่านี้มีอยู่รอบตัวเรา มีทั้งในบ้านและนอกบ้าน สิ่งแวดล้อม กับ โรคภูมิแพ้ ฝุ่นบ้าน ฝุ่นบี่นอน สัตว์เลี้ยง เชื้อรา เกสร ตัวไร่ฝุ่น ที่กักฝุ่น อาหาร สิ่งเหล่านี้มีอยู่รอบตัวเรา มีทั้งในบ้านและนอกบ้าน แต่มีหลายอย่างที่เราหลีกเลี่ยงได้ หากเรารู้วิธีที่ถูกต้อง

ควันบุหรี่ ควันธูป

Factors Affecting Clinical Outcomes of Allergic Diseases Treatment Anti-inflammatory Anti-allergic Relievers Enivronmental Allergens Irritants Westernization Genetic Degree of atopy Compliance Avoidance Medication uses Infection Viral Bacterial Allergen Immunotherapy Allergic Diseases Future Therapy ? Remission Mild Moderate Severe AllergyChula

Clinical Uses of H1 Antagonists Generation of Antihistamines Clinical First Second and Third Allergic Rhinitis ++ ++ (better compliance) Urticaria ++ ++ (better compliance) Atopic dermatitis ++/+++ ++ (better compliance) Asthma - -/++ (Meta-analysis= NS)URI/NAR ++ - Itching dermatosis ++/+++ ++ Anti-motion sickness ++ - Antiemetic ++ - Appetite stimulation ++ - (+ for astemizole) Insomnia ++ - AllergyChula

Treatment of Allergic Rhinitis in Adults Allergy 1994; suppl. 19

Treatment of Allergic Asthma Allergy 1994; suppl. 19

Type II Hypersensitivity Cytotoxic antibodies: IgG, IgM Mechanisms of cytolysis: Fix complement and/or ADCC Clinical spectrums: Autoimmune Hemolytic anemia (AIHA) ABO Miss-matched ITP Stimulatory antibody: Grave’s disease Inhibitory antibody: Myasthenia gravis (anti-Ach Rc)

Principle treatments in Type II ABO matching For AIHA, ITP: Steroid, immunosuppressive agents, +/- splenectomy

Type III Hypersensitivity Mechanisms: Ag (protein, drugs) + Ab (IgG, IgM) --> Immune complex --> deposit at subendothelial basement membrane --> fix complement --> chemotaxis ---> PMNs --> vasculitis Immune complex diseases: Serum sickness Autoimmune diseases: prototype-SLE Vasculitis

Principle treatments in Type III Serum sickness: Avoidance of heterogeneous protein injection: ERIG antirabies Autoimmune diseases: SLE Avoidance sun exposure Steroid Immunosupressive agents

Type IV Hypersensitivity Delayed-type cell-mediated reaction Mechanism: Antigen (contactants) --> sensitized T-lymphoctyes --> re-exposure --> T cells activation --> cytokines ---> mononuclear cell recruitment --> DTH Clinical disorder: Atopic contact dermatitis

Principle treatments in Type IV Avoidance Topical steroid Systemic steroid, if severe