new pathomechanisms in hypersensitivity · 2010. 10. 15. · allergen dimers-oligomers-multimers...
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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