Hypereosinophilic%20syndrome:%20a%20historical%20overview

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Japanese Society for Dermatoallergology33rd.
Annual Meeting
President Prof. Kiyoshi Nishioka MD
PhD Secretary General Dr. Takahiro Satoh
MD Tokyo Medical and Dental University

• Tokyo, 6 July 2003

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Diagnosis and management of patients with
eosinophilia new concepts and treatment

• Prof. Christopher Spry
• FRCP FRCPath FESC DPhil
• St. Georges Hospital Medical School
• London UK

Eosinophils
Tokyo, 6 July 2003
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Overview

• Eosinophils are often present in skin diseases
• Eosinophils may protect or injure in areas of
  inflammation
• Eosinophils may induce oedema, pruritus, fibrosis
  and thrombosis
• New forms of treatment are becoming available

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Eosinophils were defined in 1879 by Paul Ehrlich
(1854 1915)
1879
c 1900
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Eosinophilic (polymorphonuclear)
leukemiaShapiro, (1919) L.G. Proc. New York
Path. Soc. 18, 13-83
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The primary role of eosinophils is to release
stored and newly formed molecules in tissues
Nuclear hyper-segmentation
Reduced granules
Vacuoles
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Eosinophil stored constituents
Granule
Crystalloid Major basic protein, MBP
Matrix Eosinophil ribonucleases, ECP
EDN Lysophospholipase, CLC protein Eosinophil
peroxidase, lysosomal enzymes etc. Cytokines,
chemokines eotaxins
Lipid bodies Eicosanoid mediators, LTC4 etc.
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Eosinophil newly formed products

• Stimulated eosinophils generate
• High respiratory burst activity glucose
  metabolism
• Reactive oxygen species, superoxide H2O2
• Leukotrienes, LTC4 and LTD4
• Prostaglandins thromboxane
• Platelet-activating factor, PAF
• Cytokines, IL-2, IL-3, IL-5, IL-8, IL-13, GM-CSF
  etc.
• Chemokines, CCR3 etc.

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Normal skin

• There are very few eosinophils in normal human
  skin.

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Eosinophils in skin diseases localization
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Eosinophils degranulate in skin diseases

• Degranulated eosinophils
• Electron microscopy

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Eosinophil degranulating onto a heart cell
Eosinophil
Heart cell
Electron-dense material
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Eosinophils degranulate in skin diseases

• Degranulated eosinophils
• Electron microscopy
• Activated eosinophils
• Antibody EG2-stained eosinophils

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Activated (EG-2 stained) eosinophils in the heart
Heart cells
Activated eosinophils
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Eosinophils degranulate in skin diseases

• Degranulated eosinophils
• Electron microscopy
• Activated eosinophils
• Antibody EG2-stained eosinophils
• Eosinophil granule proteins
• MBP
• EDN
• CLC protein
• Serum levels of granule proteins raised

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Effects of eosinophil supernatants on isolated
rat heart cells and mitochondria
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Eosinophils in human skin diseases diagnoses

• Dermatitis
• Atopic dermatitis
• Urticarias
• Episodic angioedema with eosinophilia
• Skin eruptions in pregnancy and infancy
• Scleroderma syndromes
• Eosinophilic fasciitisEosinophilia-myalgia
  syndrome
• Bullous skin diseases
• Bullous pemphigoid
• Dermatitis herpetiformis
• Linear IgA disease
• Incontinentia pigmenti
• Eosinophilic pustular folliculitis (Ofujis
  disease)
• Psoriasis
• Erythema nodosum
• Lymphomatoid papulosis
• Erythema annulare
• Drug reactions
• Angiolymphoid hyperplasia with eosinophilia

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Atopic dermatitis Eosinophils in dermal tests

• Atopic dermatitis 15 patients
• Asthma rhinitis without dermatitis 10
• Non-atopic - 10

Dermal eosinophils at 2 hours Epidermal
eosinophils in 24 hours Dermal, but not epidermal
eosinophils were activated (EG2-stained) Eosinophi
ls were adjacent to Langerhans cells
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Margination emigration from venules
Rothenberg ME. Eosinophilia. N Engl J Med. 1998
283381592-600.
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Atopic dermatitis - localization

• Patients studied at Tokyo Medical Dental
  UniversityBlood eosinophils bound soluble
  P-selectin, but not soluble E-selectin.Eosinophil
  s expressed large amounts of a(1,3)fucosyltransfer
  ase-IV mRNA.They may act in eosinophil
  extravasation in atopic dermatitis

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Atopic dermatitis - deposits

• Patients studied at the Mayo Clinic
• Dense deposits of eosinophil major basic protein
  in a fibrillar pattern, similar to lichenified
  lesions of untreated onchocerciasis. Few adjacent
  eosinophils seen.
• Deposits from cytolytic eosinophils

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Urticarias

• Intact eosinophils only seen when inflammation is
  present, such as in delayed pressure urticaria
• Urticarial vasculitis 14 patients, 7 had
  activated eosinophils and 12 deposits of ECP
• Chronic urticaria pressure urticaria MBP
  deposits in spontaneous induced lesions
• MBP, ECP and EDN produce a dose-related wheal and
  flare in normal human skin and are deposited in
  late phase reactions
• MBP, ECP and EDN deposited in late phase reactions

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Episodic angioedema with eosinophilia

• 1984 Four patients described by Gleich et al.
• MBP raised in serum and present in skin biopsies
• Blood eosinophils degranulated
• Note IL-2 can induce eosinophilia and oedema

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Episodic angioedema with eosinophilia
Pruritic skin lesions
Nail ridges
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Lymphomatoid papulosis hypereosinophilia
T-lymphocytes may be malignant and secrete
eosinopoietic factors causing hypereosinophilia
1.5 cm
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Eosinophilic fasciitis

• Inflammation in distal forearm and legs, variable
  eosinophilia
• Induration of skin and subcutis
• Limitation of movement
• Deposits of collagen between dermis muscle
• No Raynauds phenomenon no autoantibodies
• Overlap with systemic sclerosis
• Response to steroids

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Eosinophilia-myalgia syndrome

• Toxins toxic oil, L-tryptophan
• Variable damage to joints, muscle, skin etc.
• Poor response to treatment
• Eosinophil activation and secretion
• IL-5 TGF-beta involved

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Eosinophilic endomyocardial diseaseThrombosis in
the late fibrotic stage
Left ventricle
Fibrosis
Thrombus
Thrombus liquefaction
Hypertrophy
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MBP in the heartin eosinophilic endomyocardial
disease
Endocardium
Adjacent sections
Fluorescent anti-MBP
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T lymphocytes that induce eosinophiliain rats
with trichinosis
Normal
Infected
Large pyroninophilic lymphocytes
Thoracic duct lymph
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Eosinopoietic factors

• Interleukin-5
• GM-CSF (stimulated by IL-2)
• IL-3
• Genes on chromosome 5.
• Genetic control of eosinopoiesis shown in mice.

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Suppression of eosinophil apoptosis by IL-5
GM-CSF
Ladder pattern of DNA cleavage
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Eosinophilia inhaematological malignancies

• Lymphoma leukaemias may produce IL-5
• Monoclonal T-lymphocytes produce IL-5
• M4-eo myeloid leukaemias breakpoints in
  chromosome 16 at 16p13 16q22
• Hypereosinophilic syndrome tyrosine kinase
  created by PDGFRA and FIP1L1 on chromosome 4

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Skin lesions in HES

• Pruritus
• Erythematous lesions
• Dermal vascular occlusions

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Skin lesions in patients with HES
Painless necrotic ulcers
Pruritic areas on the legs
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Retinal vascular occlusion in HES
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Survival of 54 patients with HES
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Defect of chromosome 4 in HES Cools et al. N
Engl J Med 2003, 348, 1201-14
Deletion, creatingFIP1L1-PDGFRaan active
tyrosine kinase Imatinib mesylate inhibits
tyrosine kinase and PDGFRalpha
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Imatinib is an effective treatment of HES

• Imatinib was effective in 4 of 11 patients with
  skin lesions and the myeloproliferative form of
  the hypereosinophilic syndrome
• D. Garry Gilliland et al. 2003
• Brigham Womens Hospital, Boston

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Summary

• Eosinophils are often present in skin diseases
• Eosinophils may protect or injure in areas of
  inflammation
• Eosinophils may induce oedema, pruritus, fibrosis
  and thrombosis
• New forms of treatment are becoming available

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Finally, thank you to all those present and many
others!
Particularly My colleagues and friends in the
eosinophil world, especially those who have
contributed to the observations and discoveries I
have discussed today. President, Prof. Kiyoshi
NishiokaSecretary General, Dr. Takahiro
Satoh BIOMEDIS International Ltd. for inviting my
wife and me, their hospitality and kindness
during our visit to Tokyo
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