Pathomechanisms in Hypersensitivity

Erika Jensen-Jarolim

Dept. of Pathophysiology

Medical University Vienna

Turn of the 19th century: Infectious diseases

Cholera

TetanusTuberculosis

Diphteria Polio

Pocks

Diphteria: a major health threat

Corynebacterium diphteriae (Klebs-Loeffler bacillus) produce phage-encoded toxin

E. von Behring and S. Kitasato (1890): passive immunotherapy

with antitoxin

Diphteria treated with immune serum from horse

The production of antiserum from jugular vein Dialysis of precipitate

Antitoxin was the first major success of therapeutic immunology

Ammon sulfate precipitate of anti-toxin

1902: Paul Portier and Charles R. Richet discover anaphylaxisDogs surviving small doses of Actinaria (sea anemone) toxin were reinjected a few weeks later: death from dyspnea, diarrhoea and vomiting.

1903: M. Arthus describes Arthus phenomenonDaily intracutaneous injection of horse serum in rabbits induced no obvious local response for the first few days but leads, subsequently, to foci of oedema, inflammation and eventually tissue necrosis

1906: Clemens Freiherr von Pirquet defines allergy

Death-rate after passive immunotherapy with „Antitoxin“ 1890: 60 % 1894: 30 %1910: 10 %

In: Reports of the Metropolitan Asylums in 1910

…soon reports of side effects upon antitoxin

Vienna: Clemens Freiherr von Pirquet

HARMFUL EFFECTS OF SERUM TREATMENT1. Delayed

serum sicknessdevelops after one week: fever, joint pains, rashes

2. Immediatesudden collapse, sometimes followed by rapid death. Anaphylaxis.

Ant

itoxi

n in

ject

ion

Diagnosis for (hyper-)immune state

Intracutaneous inoculation of antigen:

• Pirquet test for tuberculosis

• Schick test for diphteria

Definition of „Allergy“ and Allergen(allos – changed; ergos – action).

In: Münchner Med. Wochenschrift 1906

Novel DoctrineSpecific interaction of pathogen and organism determines disease course

Repeated application – reaction between allergen and antibody

Dept. of Juvenile Medicine in Vienna, University Vienna

Hypersensitivity – an immune reaction

1.) Sensitization phase

2.) Memory

phenomena

antigen contact secondary contact

Interval

repeated contact1st contacts

hypersensitivity

IgM IgGIgAIgE

sensitivity

R.R.A. Coombs & P.H.G. Gelldefined „Hypersensitivity reactions“ in 1963

Immediate type reaction: „Allergy“

IgEI.

Cytotoxic reaction

CIgM,IgGII.

Immune complex reactionIgG, IgAIII.

Delayed type reactionIV.Gell PGH, Coombs RRA. Clinical Aspects of Immunology. London: Blackwell, 1963.

R.R.A. Coombs & P.H.G. Gelldefined „Hypersensitivity reactions“ in 1963

Cytotoxic reaction

CIgM,IgGII.

Immune complex reactionIgG, IgAIII.

Delayed type reactionIV.Gell PGH, Coombs RRA. Clinical Aspects of Immunology. London: Blackwell, 1963.

Immediate type reaction

IgEI. 1966/67 T&K. Ishizakas, S.G.O. Johannsson

1974: H. Metzger et al.

Turn of the 20th century: allergic diseases

Birch pollen

milk

mites

harmlessagents

Weed pollen

Grass pollen

danderfish venom

Symptoms

Rhinoconjunctivitis

OAS

Urticaria

Asthma bronchiale

Anaphylactic shock

Immediate type reaction: „Allergy“

IgEI.

What is special about allergen molecules ?

Effector phase:Multivalent antigen crosslinks bound IgE….

In: Immunobiology, by Janeway & Travers 1997.

Repetetive epitope display

IgE

Allergen

multivalent

Allergen

multivalent repetitive:

Tropomyosin

Multimeric:

Ara h 1

mast cell

Allergen dimers-oligomers-multimersABA 1 (Ascaris) McGibbon et al. Mol Biochem Parasitol. 39: 163. 1990.Tropomyosin Gimona et al. PNAS 92: 9776 . 1995. Phl p 1 Petersen et al. in: Progr. Allergy Clin Imm, 4: 139. 1997.Ara h 1 Shin et al. JBC 273: 13753. 1998.Tropomyosin Reese et al. IAAI 119: 247. 1999.Equ c 1 Gregoire et al. Acta Cryst D Biol Cryst 55: 880. 1999.Equ c 1 Lascombe et al. JBC 275: 21572. 2000. ABA-1 Xia et al. Parasitology 120: 211. 2000.Ara h 1 Maleki et al. JI 164: 5844. 2000.Ves v 5 Suck et al. IAAI 121: 284. 2000.Profilin Wopfner et al. Biol Chem. 383:1779-89 2002.Parvalbumin Das Dores et al. Allergy 57, Suppl 72: 79; 2002.Ara h 2 Sen et al. JI 169:882. 2002.Phl p 5b Rajashankar et al. Acta Cryst D Biol Cryst 58: 1175; 2002.Phl p 7 Verdino et al. EMBO J 21: 5007. 2002.Fel d 1 Grönlund et al. J. Biol Chem 278 (41): 40144. 2003.Bet v 1 Schöll et al. J. Immunol. 175 (10): 6645. 2005.

Many allergens are multimers

Also B-cell triggering depends on epitope display

mast cell

effector cell

Schöll et al, J. Immunol. 2005

B-cell

B-lymphocyte

0.4

0.3

0.2

0.1

0

OD

405-

490n

m

1 2 3 4 5

*0.4

0.3

0.2

0.1

0

OD

405-

490n

m

1 2 3 4 5

**

Sensitization Memory boost

Immunization of BALB/c mice

Dimer

Monomer

Isotype switch supported by cytokines

Rezeptor-Recycling

HLA II mit Allergen-Peptid

Allergen-Dimer

r

LysosomalerVerdau

Endozytose

Präsentation

Segmente für variable Domänen IgDIgM IgG1 IgA1IgG3 IgG2 IgG4 IgE IgA2

Segmente für die konstante (CFc) Domänen der schweren Immunglobulinkette

SchnittSchnitt

„Looping out“

Segmente für variable Domänen IgA2IgE

Segmente für variable Domänen

IgD

IgM

IgG1 IgA1IgG3

IgG2

IgG4

IgE IgA2

Programmed and sources of preformed IL-4 and IL-13:

• CD4+ Th-cells

• Basophils, eosinophils, mast cells (Mohr et al., JI 2005)

• CD1-restricted gammadelta T-cells (Russano et al, JACI 2006)

Sources of early IL-4:

• conventional, naive CD4+(Noben-Trauth et al, JI 2000)

• Basophils (Koh et al, Blood 2006)

• TLR-activated DCs inhibit early IL-4 by CD4 T cells(Sun et al, JI Feb. 2007)

IL-13

IL-4

Moy et al, JMB 310, 2001

IL4 and IL-13 are switch factors for IgE

B-cell

AllergenDimer

B-lymphocyte

Take home: Allergens can trigger

mast cell

Allergen Dimer

effector cell

Schöll et al, J. Immunol. 2005

…if they present several identical epitopes

Respiratory allergens Food allergens

Degrading: pH and enzymesNon-degrading

Natural factors: Pollen carry lipid mediators with „adjuvant properties“: PALMsTraidl-Hoffmann et al, J.Exp. Med. 2005.

Pollution – Nitrogen oxides and ozone: Nitration of allergens enhances allergenic potentialGruijthuijsen et al, Int Archs Allergy Imm. 2006

Respiratory allergens Food allergens

Degrading: pH and enzymesNon-degrading

PALMs: Traidl-Hoffm. J.Exp.Med 2006

B-cell

AllergenDimer

B-lymphocyte

Food allergens must stay intactStability during transit

mast cell

Allergen Dimer

Effector cell

HClPepsin

Untersmayr et al, JACI 2003; Schöll et al. Am J Clin Nutr 2005

Peptic digestion is pH-dependent

Richter C et al. Biochem J 1998.

Non-digested

Acidic gastric juice:digested

The gate-keeping function of the stomach depends on acid

Hypoacidic:non-digested

gastritis

ulcus

• PPIs

• H2-blocker

• Sucralfat

Food allergens resist or persist

Diagnosis in Allergy• Anamnesis• Serology• Skin test• Food: Provocation test: DBPCFC

Therapy• Allergen-avoidance• Antihistamines• Beta-Mimetics for Asthma• Glucocorticoids

Allergen immunotherapy

Subcutaneous immunotherapy (SIT)• 1911 in EU (Noon & Freeman, Lancet 1911)• 1915 in US (Cooke, Laryngoscope 1915)• Current standard of care: rhinitis, asthma, venom

Oral immunotherapy• 2005 no published data to support clinical efficacy.

Medical Policy & Technology Assessment Committee (MPTAC) Review(04/18/2005; http://medpolicy.unicare.com)

Sublingual immunotherapy (SLIT) • 1986 (Scodding & Brostoff, Clin Allergy 1986,

Warner, Clin. Allergy 1986)• > 20 double blind, placebo-controlled studies

confirm clinical efficacy in rhinitis(Canonica & Passalacqua, JACI 2003)

Mechanisms I.• Activation of Tregs

Clark & Cupper, JID 2005: „Immature dendritic cells are polarized by the binding of type 1, type 2, or regulatory PAMP and differentiate into mature dendritic cells that induce the formation of Th1, Th2, or T regulatory T cells, respectively. In general, viral-associated PAMP give rise to Th1 responses, and PAMP from parasitic organisms favor Th2 responses….“

Mechanisms II.

• (Trapping and) Blocking antibodies: IgG1, IgG4

R.R.A. Coombs & P.H.G. Gelldefined „Hypersensitivity reactions“ in 1963

Cytotoxic reaction

CIgM,IgGII.

Immune complex reactionIgG, IgAIII.

Delayed type reactionIV.Gell PGH, Coombs RRA. Clinical Aspects of Immunology. London: Blackwell, 1963.

Immediate type reaction

IgEI.

Cytotoxic reaction

CIgM,IgGII.

Diseases:

• Thrombocytopenic purpura

• Immune-hemolytic anemia

drug

Red blood cell Hemolysis

Mediated by cytotoxic cells or complement: ADCC or CDC

Immune complex reaction IgG, IgAIII.

Disease type I:

• Arthus reaction: preformed IgG - local precipitation

and inflammation

Examples:

Vaccination and farmer lung

injection

inhalation

Immune complex reactionIgG, IgAIII.

Disease type II:

• Serum sickness: patient slowly forms IgG - systemic precipitation and inflammation

Examples:

Passive immunotherapy with serum or antibodies

Delayed type reactionIV.

• Allergens: anorganic molecules, metal ions, peptides

• T-cells: cytotoxic and strong inflammatory component

Direct destruction by cytotoxic cells

Combined hypersensitivity reactions

Atopy: genetic predisposition for IgE production

and chronic eczema

Exacerbation upon exogen triggers, e.g. food

Atopic dermatitis: Type I and Type IV

IgE and T-lymphocytes

Combined hypersensitivity reactions• Celiac disease: Type III and IV

Symptoms• growth inhibition• Fe-deficiency• Hypocalcemia• Osteomalacia, tetany• Hypoproteinemia, edema• Diarrhoea

Celiac disease • Exogen trigger: Gluten• Endogen factor: tTG

(tissue transglutaminase)

• Genetic predisposition

Basal membrane

normaleMukosa

Nullniveau

Mukosa bei Zöliakiehealthy

celiac

Nutritional uptake of gluten

Gastrointestinaldigestion

gluten peptides

desamidated gluten peptides

CELIAC patients: HLA-DQ2, DQ8, DR4

activation of T-helper cells

Effector T-cells

tTG

B-cells

IgA, IgG

IL-2

T-cells

Type IV Type IIIPathophysiology of celiac disease

pollen

food

mites

cosmetics

harmlessagents

drugs

gluten

Pathomechanisms in Hypersensitivity

Erika Jensen-Jarolim

Dept. of Pathophysiology

Medical University Vienna