Immunological DiseasesImmunological Diseases

Spectrums and MechanismsSpectrums and Mechanisms

Assistant Professor Kiat Ruxrungtham, M.D.Assistant Professor Kiat Ruxrungtham, M.D.

Division of Allergy and Clinical ImmunologyDivision of Allergy and Clinical Immunology

Department of Medicine, Faculty of MedicineDepartment of Medicine, Faculty of Medicine

Chulalongkorn UniversityChulalongkorn University

Principles of Immunology

• Key roles of immune responsesKey roles of immune responses

• TerminologyTerminology

• Primary and Secondary Immune RespoPrimary and Secondary Immune Responsesnses

• Cells and Molecules involvedCells and Molecules involved

• Immunological DisordersImmunological Disorders

• Mechanisms and Clinical ImplicationsMechanisms 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 lymphocytesC’, barriers APCs

Primary and Secondary ImmuPrimary and Secondary Immune Responsesne 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 ImmunityAcquired Immunity

• CellsCells: APCs (macrophages), T (CD4+, : APCs (macrophages), T (CD4+, CD8+) and B lymphoctyes (plasma cellsCD8+) and B lymphoctyes (plasma cells), monocytes), monocytes

• MoleculesMolecules: HLA, cytokines, immunoglo: HLA, cytokines, immunoglo

bulins, adhesion molecules bulins, 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 DiseasePathogenesis of Allergic Disease

Genetic Susceptibility

Allergic Sensitzation

Upper/lower airway or Skinhyperresponsiveness

Allergic Diseases

Allergen Exposure

Adjuvant factors:• Tobacco smoke• Air pollutants

Lack of protective factors:• Infection ?• Immunization ?• Nutrition ?

PollutantsInfectionExcercise

Modified from Ulrich Wahn 1998

Vary in spectrum and severity

Principle Pathogenesis of Allergic Diseases Principle Pathogenesis of Allergic Diseases

Th-2Th-1

IL-12

IFN-gIL-5IL-3GM-CSF

Eosonophil

Mastcell

IL-4 IgE

B-cell

APCAllergenCD4+ T-cell

Late Phase Reaction

_ +

IgG

Durham and Till 1998, Lu 1998, Drazen 1996

CD8+ cell

AllergyChula

IL-5

B-cell

Allergen

Tryptase, LTs

MBPECP, LTs

Other cells

Pathogenesis of Pathogenesis of Allergic DiseasesAllergic Diseases

Cells & MoleculesCells & MoleculesInvolved in Involved in

AllergicAllergicInflammationInflammation

Modified from Modified from Robert DaviesRobert Davies

Mediators of Mast Cells and Basophils

Histamine

Tryptase

Chymotryptase

Heparin/Chondroitin

Kininogenase

Chemotactic Factors

ProstaglandinsLeukotrienes

PAFHistamine RFs

IL-3, 4, 5, 6, 7, 8GM-CSF, TNF

Chemokines -MCP1, MIP1

Oxygen radicals

Primary Mediators Secondary Mediators

Sim TC, Grant JA 1996 AllergyChula

Mediators of Mast Cells and AllergyMediators of Mast Cells and Allergy

Mast CellMast CellBasophilBasophil

Blood VesselsBlood VesselsBlood VesselsBlood Vessels

Smooth MusclesSmooth MusclesSmooth MusclesSmooth Muscles

Mucus GlandsMucus GlandsMucus GlandsMucus Glands

Sensory NervesSensory NervesSensory NervesSensory Nerves

LeukocytesLeukocytesLeukocytesLeukocytes

H, PGDH, PGD22, , LTs, PAFLTs, PAF

KininKinin

HH

H, PGDH, PGD22, , LTs, PAFLTs, PAF

LTB4LTB4PAFPAFIL3, IL5IL3, IL5ChemokinesChemokines

Urticaria, AngioedemaUrticaria, AngioedemaLaryngeal edema, ShockLaryngeal edema, Shock

BronchospasmBronchospasmAbd. pain, VomitingAbd. pain, Vomiting

Diarrhea, RhinorheaDiarrhea, RhinorheaBronchial secretionBronchial secretion

ItchingItching

Inflammation - LPAR Inflammation - LPAR

AllergyChula

โรคภู�มิ�แพ้ที่� พ้บบ�อยโรคภู�มิ�แพ้ที่� พ้บบ�อย โรคภู�มิ�แพ้ที่างจมิ�ก โรคภู�มิ�แพ้ที่างจมิ�ก Allergic Allergic

RhinitisRhinitis โรคหื�ดจากภู�มิ�แพ้ โรคหื�ดจากภู�มิ�แพ้ Allergic Asthm Allergic Asthm

aa โรคภู�มิ�แพ้ที่างผิ�วหืนั�ง โรคภู�มิ�แพ้ที่างผิ�วหืนั�ง Atopic Atopic

DermatitisDermatitis โรคลมิพ้�ษโรคลมิพ้�ษ UrticariaUrticaria โรคโรค แพ้อาหืาร แพ้อาหืาร Food AllergyFood Allergy การการแพ้ยาแพ้ยา Drug AllergyDrug Allergy

Allergy Chula 1999

Epidemiology of Allergic Diseasesin Thai Children

13

17.9

40

4.2

13

0 10 20 30 40

Prevalence (%)

AtopicDermatitis

AllergicRhinitis

Asthma1990 1995

พยนต์� บุ�ญญฤทธิ พงษ์� และมนต์รี� ต์��จิ นดา 2533; ปกิ ต์ วิ ชยานนท� และคณะ 2541

Skin Prick TestSkin Prick Test

สิ่� งแวดลอมิ ก�บ โรคภู�มิ�แพ้ สิ่� งแวดลอมิ ก�บ โรคภู�มิ�แพ้

ต์!วิไรี#ฝุ่�%น ท�&กิ!กิฝุ่�%นเกิสรี

ฝุ่�%นบุ�าน เช)*อรีาฝุ่�%นบุ�&นอน ส!ต์วิ�เล�*ยง

อาหารี

ส &งเหล#าน�*ม�อย�#รีอบุต์!วิเรีา ม�ท!*งในบุ�านและนอกิบุ�าน แต์#ม�หลายอย#างท�&เรีาหล�กิเล�&ยงได� หากิเรีารี� �วิ ธิ�ท�&ถู�กิต์�อง

คว�นับ หืร� คว�นับ หืร� คว�นัธู�ปคว�นัธู�ป

Factors Affecting Clinical OutcomesFactors Affecting Clinical Outcomes of Allergic Diseases of Allergic Diseases

AllergyChula

Enivronmental• Allergens• Irritants• Westernization

Infection• Viral• Bacterial

Treatment• Anti-inflammatory• Anti-allergic• Relievers

Compliance• Avoidance• Medication uses

Allergic DiseasesAllergic Diseases

RemissionRemission ModerateMild SevereSevere

Allergen Immunotherapy

Genetic Degree of atopy

Future Therapy ?

Clinical Uses of H1 AntagonistsGeneration 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 AdultsTreatment of Allergic Rhinitis in Adults

Allergy 1994; suppl. 19

Drug Itch/sneezing

Rhinorrhea Blockage Anosmia

Antihistamines +++ ++ + -Topical CS +++ +++ ++ +

Oral CS +++ +++ +++ ++

Topicaldecongestants

- - +++ -

Ipratropiumbromide

- +++ - -

Sodiumcromoclycate

+ + + -

Treatment of Allergic Asthma

Allergy 1994; suppl. 19

Treatment Mildintermittant

Mildpersistant

Moderatepersistant

Sverepersistant

Avoidnace + + + +

Beta-2Agonist, prn

+ + + +

Inhaled steroid - +/- + +

Long-actingbeta-2 agonist

- no +/- +

Slow releasetheopphylline

- - +/- +

Anti-leukotrienes - + +/- +/-

Type II Hypersensitivity• Cytotoxic antibodies: IgG, IgMCytotoxic antibodies: IgG, IgM• Mechanisms of cytolysis: Fix complement and/Mechanisms of cytolysis: Fix complement and/

or ADCCor ADCC• Clinical spectrums:Clinical spectrums:

– Autoimmune Hemolytic anemia (AIHA)Autoimmune Hemolytic anemia (AIHA)– ABO Miss-matchedABO Miss-matched– ITPITP

• Stimulatory antibody: Stimulatory antibody: Grave’s diseaseGrave’s disease

• Inhibitory antibody: Inhibitory antibody: Myasthenia gravis (anti-Ach Rc)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