Eosinophil in health and disease

Eosinophil in health and disease
Malgorzata Karawajczyk
Täby March 2013
Eos är gryningens gudinna i grekisk mytologi
Mature eosinophil
• Paul Ehrlich - 1879
• Acidophilic dyes -eosin
Structure
• Bilobed nucleus
• secretory granules
with cristal core
• Lipid bodies
Content of eosinophil granules
• Cationic proteins
(ECP,EPX,EPO,MBP)
• Chemokines(Rantes,
Eotaxin)
• Cytokines
Life and death of an eosinophil
Maturation in bone marrow
Il-3
Il-5
GM-CSF
5 days
Eosinophil trafficking
3- 26 hours
Helene Rosenberg et al
.
Trafficking of human eosinophils in postcapillary venules of the rabbit mesentery. (A)
labeled eosinophils were injected into the terminal mesentery artery bloodstream
6 h after interleukin-1 (IL-1) administration. intravital microscopy (IVM).)
Rolling of a single fluorescently labeled eosinophil in an IL-1-stimulated venule (blood flow
from right to left).
Emigration of adherent, CFDASElabeled eosinophils in response to complement component C5a (10
7 M) at 5 min (F) and 30 min (G)..16 Reproduced with
permission, Copyright 1994 and 1999, The American Association of Immunologists, Inc.
Chemokine-induced migration of eosinophils in lungs.
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Eosinophil migration from the vascular supply to the
airway is probably dependent on sequential
chemokine gradients, which allow the cells to
extravasate through the various compartments of the
lung. There are several eosinophil-active chemokines
that are produced primarily by activated
macrophages in the interstitium. These include
macrophage inflammatory protein-1 (MIP-1)/CCL3,
monocyte chemoattractant protein 3 (MCP-3)/CCL7
and macrophage-derived chemokine (MDC)/CCL22.
Other chemokines, such as eotaxin/CCL11 and
RANTES (regulated on activation, normal T-cell
expressed and secreted)/CCL5, are highly expressed
in epithelial cells of the airway. The localized
responses of these particular chemokines would
allow the eosinophils to migrate to the airway using
different chemokine receptors, therefore avoiding
desensitization of migratory responses
Nicholas W. Lukacs
Homing of eosinophil progenitors
•
Systemic hemopoietic processes involving
active communication among upper and
lower airways tissue sites, the BM, and the
bloodstream are depicted schematically,
highlighting key cytokines and chemokines.
Both differentiative and migratory events are
critical in the participation of hemopoietic
and, specifically, eosinophilopoietic
progenitors in allergic diseases and asthma
Eosinophil progenitors are now emerging as effector cells
that can migrate to inflamed tissue where they rapidly
proliferate in response to allergic stimuli. Understanding
communication between eosinophil progenitors and the
innate immune system will require further exploration
CHEST. November 2008;134(5):1037-1043. doi:10.1378/chest.08-0485
Eosinophil development and tissue localization. The eosinophil is formed in the bone marrow under the regulation of the transcription factors GATA-1, GATA-2, and c/EBP.
With the influence of IL-5, adhesion molecules, and eotaxin 1, eosinophils subsequently relocate into the peripheral circulation and finally traffic to specific tissues,
predominantly the gastrointestinal (GI) tract, thymus, hematopoietic organs, and mammary gland (during pubertal development
Eosinophil funtions
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adhesion
migration
secretion
phagocytosis
direct communication with other cells
(antigen presentation)
Eosinophil secretion
Piecemeal degranultion
exocytosis
Photomicrograph of an eosinophil incubated with 100 micrograms/ml of an Alternaria extract for 4 hours. Notice extensive degranulation of nearly all of the granules (see arrows for examples).
Melo et al, 2005
ECP makes pores in membranes
100 Å
Courtesy Prof .Per Venge
Injection of ECP into the brain
of a rabbit causes vast destructions
Courtesy Prof .Per Venge
Extracellular traps
the process of DNA release occurs rapidly in a catapult-like
manner—in less than one second. In the extracellular space,
the mitochondrial DNA and the granule proteins form
extracellular structures able to bind and kill bacteria.
These data suggest a previously undescribed mechanism of
eosinophil-mediated innate immune responses that might be
crucial for maintaining the intestinal barrier function after
inflammation-associated epithelial cell damage,
preventing the host from uncontrolled invasion of bacteria.
Eosinophils (in green with red nucleus) catapult their mitochondrial DNA out of the cell, forming tangled traps (red) that ensnare foreign bacteria.
(Photo credit: Hans-Uwe Simon, Institute of Pharmacology, University of Bern, Switzerland)
Jacobsen EA et al J Allergy Clin Immunol 2007;119:1313
Eosinophil role
• Pro-inflammatory
• tissue remodeling
• immunomodulatory
• microbial defense
Eosinophil secretory products and potential actions (bold) (From Hogan SP, Foster PS, Rothenberg ME.
Experimental analysis of eosinophil-associated gastrointestinal diseases. Curr Opin Allergy Clin Immunol
2002;2:239–48;
Dr. Jekyll eller Mr.Hyde
How eosinophils are influenced
to make life or death decisions
Steven J Ackerman 2007
Eosinophil death
• Apoptosis
• Cytolisis
• Necrosis
Ann M. Dvorak, M.D.
N Engl J Med 1999; 340:437February 11, 1999
Eosinophil apoptosis in sputum
Allergol Immunopathol (Madr). 2005;33:105-11.
Am. J. Respir. Crit. Care Med. October 1, 2004 vol. 170 no. 7 742-747
Eosinophil apoptosis
Transmission electron micrographs of purified blood eosinophils demonstrating a normal in vitro eosinophil (a), an eosinophil at an early stage of apoptosis with typical nuclear chromatin condensation
(b), an apoptotic eosinophil with pyknotic nucleus with extensive blebbing at the nuclear envelope (c), apoptotic eosinophils undergoing secondary necrosis with chromatolysis (d), and an eosinophil in
which the nucleus is completely lysed in a late phase of secondary necrosis (e).
Eosinophil in disease
Primary hypereosinophilia
Secondary eosinophilia
Homing of eosinophil progenitors
•
Systemic hemopoietic processes involving
active communication among upper and
lower airways tissue sites, the BM, and the
bloodstream are depicted schematically,
highlighting key cytokines and chemokines.
Both differentiative and migratory events are
critical in the participation of hemopoietic
and, specifically, eosinophilopoietic
progenitors in allergic diseases and asthma
Eosinophil progenitors are now emerging as effector cells
that can migrate to inflamed tissue where they rapidly
proliferate in response to allergic stimuli. Understanding
communication between eosinophil progenitors and the
innate immune system will require further exploration
CHEST. November 2008;134(5):1037-1043. doi:10.1378/chest.08-0485
Diseases and conditions with reactive eosinophilia
•Infections
Viral infection; e.g. Human immunodeficiency virus,
Respiratory syncytial virus
Bacterial infections; e.g. Mycobacterium tuberculosis
and other chronic infections
Parasitic disease; almost any
Rickettsial infections
Ticks
Post-acute infection (post-acute inflammation)
•Allergy
Asthma
Rhinitis
Atopic dermatitis
Eczema
Urticaria
•Connective tissue disease
Rheumatoid arthritis
Polyarteritis nodosa
Scleroderma local or systemic, eosinophil fasciitis
Systemic vasculitis e.g. Wegener´s granulomatosis
•Cancer
Solid cancers e.g. colorectal, lung, kidney, breast,
female genital tract, Hodgkin and non-Hodgkin lymphoma
•Cardiac disease
Eosinophilic myocarditis
Löffler´s endomyocarditis
Davies´ (tropical) endomyocardial fibrosis
•Pulmonary disease
Non-allergic asthma
COPD
Bronchiectasis
Acute and chronic eosinophil pneumonia
ARDS
Cystic fibrosis
Idiopathic pulmonary fibrosis
Churg-Strauss syndrome
Löffler´s syndrome
•Skin diseases
Bullous pemphigoid
Psoriasis with arthropathy
Well´s syndrome
Episodic angioedema (Gleich´s syndrome)
Eosinophilic pustulosis
Eosinophilic folliculitis
Kimura disease
•Gastrointestinal diseases
EGID (Eosinophil GastroIntestinal Disorders); esophagitis,
gastritis, gastroenteritis, colitis
Inflammatory bowel disease; Crohn´s disease, Ulcerative colitis
Food hypersensitivities e.g. celiac disease
•Drug-induced
Drug hypersensitivities
Cytokines; IL-2, GM-CSF
•Other
Eosinophilia-myalgia syndrome
Toxic oil syndrome
Transplant rejection
Eosinophil and Asthma
Eosinophil and asthma
Innan kortison
Jean -Martin Charcot
Ernst von Leyden
Eosinophils in Asthma.
Allergic
asthma
EG2
p = 0.019
p = 0.0004
p = 0.0027
Positive cells/mm
2
300
200
100
0
HC
Non-allergic
asthma
AA
NAA
Eosinophil in astma
Asthma and Eosinophil
• Late phase reaction
• Bronchial hyperresponsivness
• Tissue remodeling
• Anti IL-5 treatment
Anti Il-5 treatment Eosinophil and risk for
exacerbations
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Anti Il-5 treatment The cumulative
number of severeexacerbations that
occurred in each study group over
thecourse of 50 weeks.
The mean number of exacerbations
persubject over the course of the
50-week treatment period was2.0 in
the mepolizumab group, compared
with 3.4 in theplacebo group
relative risk, 0.57; 95% confidence
interval,0.32 to 0.92; p ¼ 0.02).
(Reproduced with permission from
Haldar P, et al.77)
Eosinophil and airways
hyperesponsivnes
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FIGURE 13.4.6 Relationship between
changes in EG2
þeosinophils and changes in methacholine
PC20 (the dose of
the inhaled antagonist that provokes a 20%
drop in FEV1,
the forced expiratory volume in one second)
during 2 yearsof treatment according to the
reference and airway hyperresponsiveness
(AHR) strategies. The greater the decreasein
number of EG2þ eosinophils, the greater the
improvementin AHR to inhaled
methacholine. EG2, antibody
marker for activated esinophils. (Reproduced
with permission
from Sont JK, et al.80)
Eosinophil and parasite
ECP kills larvae of Schistosoma Mansoni
Courtesy Prof .Per Venge
Schistosomiasis/ Bilharzia
Trematode parasite infection, five different species
Approx. 200 million people infected worldwide
Infection is transmitted via fresh water snails.
Biomphalaria Glabrata, one of several fresh
water snails that act as intermediate hosts of the
schistosomes.
Courtesy Prof .Per Venge
Eosinophil-rich granuloma in liver
Hypereosinophila
>1,5 x109/L
Eosinophil infiltration in a tissue
Chronic eosinophil leukemia
Gleich syndrome
Facial angioed
Eosinophil infiltrate of
myocardium
H&E stains of endomyocardial biopsy at 100x (panel A) and 400x (Panel B) magnifications
notable for paucity of eosinophils. Staining of same sectionn with antibody to MBP1
(panels C and D) demonstrate striking MBP1 deposition.
Eosinophil
• No reports of humans with eosinophil
deficiency
• Eosinophil deficient mouse show no
symptoms of disease
Eosinophil and infection
• Antiviral – EPX är ribonucleas.
– In mice models reduction of viral content
observed in sensitized animals
(Adamko DJ 1999
• anti bacterial- release of eosinophil traps
(
)
• antiparasite - complex interaction
yousefi S 2008
Eosinophil
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In blood
in urine
in BAL
in ascites
in pleural fluid
Lahja Sevéus, Dept of Medical Sciences,
Uppsala University
Jori Soukka, Laboratory of Biophysics,
Turku University