Transcript Bee venom allergy

IN THE NAME OF GOD
BEE VENOM ALLERGY
PRESENTED BY: SHAFI MOJADADI
1) Introduction
2) Taxonomy of the hymenoptra
3) The biology of honey bee
4) Bee venom composition
5) Allergy to bee sting (mechanisms)
6) Factors involved in allergy to bee sting
7) Epidemiology
8) Classification of reactions
9) Diagnosis
10) Treatment
11) Hymenoptra venom immunotherapy(VIT)
12) Recombinant allergens
13) Mechanisms of action of hymenoptra venom immunotherapy
14) apitherapy
Introduction
TAXONOMY OF HYMENOPTRA
HYMENOPTRA
Order
Family
Genus
Apidae
Vespidae
Formicidae
Apis spp.
Vespula spp.
Bombus spp.
Dolichovespula spp. Pogonomyrmex spp.
Megabombus spp. Polistes spp.
Pyrobombus spp.
Halictus spp.
Dialictus spp.
Solenopsis spp.
Apidae
Bombus spp.
Bumble Bee
Vespidae
Vespula spp.
Yellow jacket
Vespidae
Vespula spp.
Vespula maculifrons
Vespula vidua
Vespula consobrina
Vespidae
Dolichovespula spp.
Dolichovespula maculata
(White-faced hornet)
Dolichovespula arenaria
(yellow hornet)
Vespidae
Polistes spp.
Paper Wasp
Formicidae
Solenopsis invicta
(Fire ant)
The bilogy of honey bee(apis mellifera)
Kingdom:animalia
Phylum: arthropoda
Class: insecta
Family: apidae
Genus: apis
Species: apis mellifera
Apis mellifera(honey bee)
Queen
Drone
Worker
relative
size
large
medium
small
#/hive
1
~200 or 0
20K-200K
lifespan
2 years
depending on #sperm
21-32 days spring
90 days summer
or until mating
0 winter
20-40 days summer
(worked to death)
140 days winter
sex
female/bisexual
male
sterile female
functions
-kill sisters and mother
-mate with males
-lay 1500 eggs/day
= 200K eggs/year
-secrete pheromone =
9-hydroxydecenoic acid
HOOC=C-C-C-C-C-C-COH-C
-mate with young queen
-tend larvae
-tend young drones
-tend queen
-clean hive
-gather nectar
-gather pollen
-gather propolis
-evaporate nectar
-defend hive
-starve drones
-lay drone eggs
-move larvae for
making new queen
Bee venom composition
pH 5-5.5
PEPTIDES
melittin (family)
melittin F
apamin
mast-cell degranulation peptide 401 (MCD)
secarpin
tertiapin
adolapin
protease inhibitor
procamine A, B
minimine
cardiopep
ENZYMES
phospholipase A2
hyaluronidase
acid phosphomonoesterase
glucosidase
lysophospholipase
ACTIVE AMINES
histamine
dopamine
norepinephrine
leukotriens
NON-PEPTIDE COMPONENTS
carbohydrates like:
Glucose
Fructose
LIPIDS
6 phospholipids
AMINO-ACIDS
r-aminobutyric acid
B-aminoisobutyric acid
A:liquid
Colorless
sharp-bitter tasting
B:Dried
Yellowish brown
LD50:2.8mg/kg (IV)
(In mice)
Cold resistance
Heat resistance
(when dry)
ENZYMES
MOL. Wt.
% (Dry
Venom)
Dried bee venom composition
COMPONENT
MOL. Wt.
% (Dry
Venom)
PEPTIDES
Melittin
2,840
40-50
Apamin
2,036
2-3
MCD-Peptide 401
2,588
2-3
Adolapin
11,500
1.0
Protease inhibitor
9,000
< 0.8
Secarpin
0.5
Hyaluronidas
e
38,000
1.5-2.0
Phospholipa
se A2
19,000
10-12
Glucosidase
170,000
0.6
Acid
Phosphomon
o-esterase
55,000
1.0
Lysophospho
lipase
22,000
1.0
ACTIVE
AMINES
Histamine
Tertiapin
0.1
Melittin F
Cardiopep
0.13-1.0
Norepinephri
ne
0.1-0.7
0.01
Procamine A, B
Minimine
Dopamine
1.4
6,000
2-3
< 0.7
NONPEPTIDE
COMPONEN
TS
Carbohydrat
es: Glucose
< 2.0
B.V. SUBSTANCES AND THEIR EFFECTS:
Phospholipase A (enzyme)
Hyaluronidase
Apamin (a polypeptide with 18 amino
acids)
Mast Cell Degranulating peptide
Adolapin
•radioprotective activity;
•mastocytolitic;
•histamine release;
•blood pressure depressants
•antigenic properties;
it is the major BV allergen ;
•antagonistic effect on staphylococic alfa-toxin and
tetanus toxin;
•antitumoural effect
•acts on biological membranes
•selectively attacks tissue hyaluronic acid polymers;
•increase the capillary permeability (Neumann and
Habermann);
•immune response and tissue-spread properties;
•antigenic;
•anaphylactogene
•antigenic and;
•anti-inflammatory properties
In many animal studies, in comparison studies with
hydrocortisone, this peptide was 100 times more
potent as an anti-inflammatory agent in suppressing
the development of adjuvant-induced arthritis. (Simics
p 13) & quot.
•analgesic (Shkenderov, 1982);
•anti-inflammatory (Shkenderov, 1982)
B.V. SUBSTANCES AND THEIR EFFECTS(continued)
Melittin (a polypeptide also consisting of
26 amino acids which represents 40-60%
of the bee venom)
Cardiopep
•antibacterial;
•antifungal;
•anti-lyme disease (in vitro experiment)
•antitumoural;
•central nervous system inhibitory;
•block nerve muscle and ganglial synapses;
•contraction of the striated and smooth muscles;
•histamine releasing;
•mastocytololysic;
•radio protecting (against X-irradiation; study on
mice, Shipman and Cole, 1967);
•vascular permeability increasing;
•haemolysis;
•lowers blood pressure;
•anti-inflammatory;
•mellitin (which represents 40-60 % from the B.V.
substances) has no antigenic properties (Orlov);
otherwise, according to Artemov, the bee enemies
would have gotten a specific immunity;
•stimulate the pituitary - adrenal axis to release both
cathecolamines and cortisol (Brooks et al.);
•increase plasma cortisol levels
•acts on biological membranes
Presently, it is one of the most potent antiinflammatory agents known, and it can be useful in
treating arthritis and rheumatism.
•increase both the force of contraction (betaadrenergic) and
the heart rate with little or no effect on coronary
circulation (Brooks et al.);
•anti-arrhythmic properties (Brooks et al.);
•stimulate the pituitary - adrenal axis to release both
cathecolamines and cortisol (Brooks et al.)
‫آلرژي به زهرزنبور‬
‫آمريکا‪50-40 :‬مرگ در هر سال‬
‫استراليا‪ :‬ساليانه‪1‬مرگ در هر ميليون نفر‬
‫نيوزيلند‪1 :‬مرگ در هر ‪3‬سال‬
‫‪Non-igE mediated )1‬‬
‫اسپانيا‪ :‬کمترين ميزان مرگ ومير‬
‫زهر زنبور با استفاده از ‪3‬مکانيسم باعث بروز آلرژي مي شود‪:‬‬
‫‪igE mediated )2‬‬
‫‪Histamine&leukotriens )3‬‬
1) Non-IgE mediated
Melittin: 50 ٪ dried venom, 2.850 kd,26 aa
a) effects:histamine releasing,vascular permeability,RBC lysis,low blood pressure
b) Melittin has sequences like CH4 domain of IgE molecule
2) IgE mediated
Major allergens: PLA2, Hyaluronidase,acid phosphatase,melittin
Mast cell,basophil,IgE,IL-4,IL-13
Th0 shift into th2
Preformed synthesized (histamine)
mediators
Newly synthesized(PGD2,LTC4,LTD4.LTE4)&(IL1,4,5,6,13)
3) Histamine&leukotriens
Factors involved in bee venom allrgy
High dose
1) PLA2
Lowe dose
IL-12
Allergen dose
IL-4
HLA DR4 & HLADQW3(decrease)
2) Genetic background:
IL4/IFNγ
Bee venom allergy
(increase)
DRB1*07 allels (allergic individals) (faux et al.)
3) CD40 ligand (T cell),CD40(Bcell) & CD28/CTLA4(T cell),CD86/CD80(APC)
‫‪Epidemiology‬‬
‫‪‬‬
‫ميزان مرگ ومير‪0.45-0.09 :‬مرگ در هر ميليون نفر در هر سال(بيشتر مرگ و مير ها در افراد باالتر از ‪ 40‬سال)‬
‫‪‬ميزان مرگ ومير درکشورهاي اسکانديناوي به مراتب کمتر از قسمتهاي جنوبي اروپا مي باشد‪.‬‬
‫‪‬حساسيت در مردها بيشتر از زنها مي باشد(در کشور فنالند ‪80‬درصد زنبورداران مرد مي باشند)‬
‫‪‬در جمعيت انساني ‪ IgE‬اختصاص ي الف‪:‬به زهر زنبور عسل‪17-6:‬درصد ب‪:‬به زهر زنبورهاي غير عسلي‪21-12:‬درصد‬
‫‪‬در سرم‪79 - 51‬درصد زنبورداران ‪IgE‬اختصاص ي به زهر زنبورهاي عسل وجود دارد‪.‬‬
‫‪31‬درصد از زنبورداران و اعضاي فاميلشان عالوه بر حساسيت به زهر زنبورهاي عسل ‪،‬به ترکيبات بدني زنبورها حساسيت نشان مي‬
‫دهند(عالئم چشمي و بويائي در هنگام کار با کندوي زنبورهاي عسل)‪.‬‬
‫‪‬واکنشهاي موضعي بزرگ در ‪38-31‬درصد و واکنشهاي سيستميک آلرژيک در‪43-22‬درصد زنبورداران گزارش شده است‪.‬‬
‫‪ 32-25‬درصد افرادي که نسبت به نيش حشرات آنافيالکس ي دارند‪،‬افراد اتوپيک مي باشند‪.‬‬
Classification of reactions
A:local reaction
1) Immediate reactions(< 4 hrs)
B:large local reaction
C:systemic reaction
reactions
2) Delayed reactions(>4 hrs) :usually present as
progressive swelling and erythema at the sting site but
may rarely present as serum sickness-like reactions,
Guillain-Barre syndrome, glomerulonephritis
or myocarditis.
Toxic reactions :
Bradykinin
Acethylcholin
non immunologic,exogenous vasoactive amines
(Bee venom)
Dopamine
Histamine
Seretonine
Fatal toxic reactions from Africanized honeybees(AHB) :may be accompanied by intravascular
hemolysis, adult respiratory distress syndrome, renal failure, and diffuse intravascular
coagulation(DIC)
IMMEDIATE REACTIONS
Local reaction symptoms: Transient pain,erythema and swelling at the sting site(2cm
diameter).
Larg local reaction symptoms: erythema and swelling(10 cm diameter) for 24 hrs.
Grade 1: anxiety,malaise,urticaria,pruritus.
Grade 2: abdominal cramping, nausea and/or vomiting.
Systemic reaction symptoms:
Grade 3:hoarseness,dysphagia , stridor,wheezing,
palpitation, dyspnea,feeling of impeding doom.
Grade4: extensive hypotension, vascular collapse ,death
Local reaction to a fire ant sting
Large local reaction to a yellow jacket sting
Systemic reaction
‫‪Diagnosis‬‬
‫واکنشهاي فوري به نيش حشرات هميشه وابسته به ‪ IgE‬نمي باشد(‪ 10‬درصد افرادي که تجربه واکنشهاي آنافيالکتيک‬
‫داشته اند‪،‬هيچ ‪ IgE‬قابل دتکت نداشته اند)‪.‬‬
‫‪ A‬تستهاي پوستي‪ :‬الف‪:‬پيريک تست ب‪ :‬انترادرمال‬
‫انواع تستها‬
‫مزيت‪ :‬سريع‪،‬ارزان و حساس‬
‫سموم ‪ 5‬رده هيمنوپترا ‪honey bee,yelllow jacket,yellow hornet,white-faced‬‬
‫‪ wasp‬دردسترس مي باشند‪.‬‬
‫‪hornet‬‬
‫ترکيبي مساوي از زهر وسپيد شامل‪yelllow jacket,yellow hornet,white-faced hornet :‬‬
‫‪ B‬تستهاي سرولوژيکي‪RAST,RIST,ELISA :‬‬
‫توجه‪ :‬مي بايست به کراس راکتيويتي بين سموم مختلف توجه کرد! بعنوان مثال بين آنتي ژنها و آلرژنهاي گونه هاي مختلف جنس ‪ vespula‬کراس راکتيويتي‬
‫وجود دارد(‪)v.germanica,v.vulgaris,v.flovopilosa,v.maculifrons,v.squamous‬‬
‫همچنين بين گونه هاي مختلف جنس ‪)p.exclamans,p.apachus,p.instablis,p.annularis,p.fuscatus( polistes‬‬
‫بين سموم ‪ fire ant =)s.richteri, s.ivicta( solenopsis‬نيز کراس راکتيويتي وجود دارد‪.‬‬
‫بين آنتي ژنهاي موجود درزهر زنبورعسل و‪ bumble bee‬کراس راکتيويتي وجود دارد‪.‬همچنين بين هيالورونيداز زنبور عسل و‪vesid‬‬
‫از طرف ديگر بين آلرژنهاي عمده فاميلهاي مختلف حشرات کراس راکتيويتي وجود ندارد‪.‬‬
‫‪ -1‬افرادي با تست پوستي منفي با سم حشرات گزارش شده اند که بعد از نيش زدگي دچار آنافيالکس ي گرديده اند‪.‬‬
‫نکات‪:‬‬
‫‪ -2‬حدود ‪ 40‬درصد افراد ايمن نشده داراي تست پوستي مثبت ممکن است بعداز نيش زدگي دچار آنافيالکس ي نشوند‪.‬‬
‫‪Treatment‬‬
‫رعايت نکات زير مي تواند کمک کننده باشد‪:‬‬
‫‪‬محل نيش را با آب و صابون بشوييد‪.‬‬
‫‪‬با گذاشتن يک کيسه يخ يا جوش شيرين در محل مي توان جلوي دردوتورم بيشتر را گرفت‪.‬‬
‫واکنشهاي موضعي‪ :‬احتياج به درمان خاص ي ندارد‪.‬رعايت نکات فوق مي تواند کمک کننده باشد‪.‬‬
‫واکنشهاي موضعي بزرگ‪ :‬با يک کمپرس آب يخ بموقع درمان مي شوند‪.‬اگرچه ممکن است در چنين مواردي آنتي‬
‫هيستامينها و گلوکوکورتيکوئيدها نيزتجويزشوند‪.‬‬
‫واکنشهاي سيستميک‪ :‬اپي نفرين مايع ‪ mg/kg 0.1( 1000/1‬وزن بدن ‪.IM or IV‬ماکزيمم ‪0.3‬ميلي ليتربراي کودکان‬
‫و‪ 0.5‬ميلي ليتربراي بزرگساالن)‬
‫مکانيسم اثراپي نفرين ‪ :‬خواص ‪ α‬آدرنرژيک(افزايش مقاومت رگي سيستميک و افزايش فشاردياستوليک)‬
‫خواص ‪ β‬آدرنرژيک(برونکوديالسيون)‬
‫همچنين استفاده ازآنتي هيستامينهاي بلوک کننده گيرنده ‪ )Dyphenhydramine( H1‬بعنوان مکمل‪،‬براي پايين‬
‫آوردن خارش و کهير‪.‬‬
‫توجه‪ :‬افراد بسيارحساس را مي بايست با ‪ Epipen‬وآنتي هيستامينها مجهزکرد‪(.‬اين افراد مي بايست ايمونوتراپي‬
‫شوند)‪.‬‬
‫)‪Hymenoptra venom immunotherapy(VIT‬‬
‫‪ VIT‬براي چه کساني توصيه مي شود؟ با توجه به اين که ايمونوتراپي مشکل وپرخرج مي باشد‪،‬توصيه مي شود درافرادي که‬
‫تاريخچه واکنشهاي سيستميک(عالئم قلبي وعروقي وتنفس ي) داشته اندوتست پوستي آنها مثبت مي باشد يا ‪ IgE‬درسرمشان قابل‬
‫دتکت مي باشد‪ ،‬صورت گيرد‪.‬‬
‫نکته‪ :‬درمورد زنان حامله ‪ VIT‬نبايد صورت گيرد‪.‬‬
‫‪ VIT‬در‪ 80‬درصد موارد حساسيت به زنبورعسل و‪95‬درصد موارد حساسيت نسبت به ديگر زنبورها موثر است‪.‬و خطرآنافيالکس ي را‬
‫از‪ 60-40‬تا کمتراز‪ 5‬درصد درافرادي که واکنشهاي سيستميک نشان مي دهند‪،‬کاهش مي دهد‪.‬‬
‫)‪History :1911 Freeman&Noon(pollen toxin,hay fever‬‬
‫)‪1925 Braun (insect sting allrgy‬‬
‫‪1940-1956 Benson( prepared a venom extract derived from powdered‬‬
‫)‪whole bodies of the insects‬‬
‫‪1976-1978 Hunt et al .demonstrated that the constituent proteins in‬‬
‫‪the venoms of these insects where the allergens responsible for the immediate‬‬
‫‪hypersensitivity reactions to their‬‬
‫‪sting‬‬
SELECTION OF THE VENOM
The selection of the venom to be used for immunotherapy is based on the clinical history and on the
positive results of the diagnostic tests with the various different venoms.
Difficulties may arise if the tests have been positive to more than one venom .
the greatest problem being to establish whether these positive results represent true allergy to all the
venoms or whether they simply indicate cross-reactivity between them.
IMMUNOTHERAPY PROTOCOLS
The therapy protocol is initiated with very low doses, usually 0.01 to 0.1 µg, which are then
gradually increased until the maintenance dose is reached.
Cluster schedule: involve a few injections given at each visit, usually at intervals of one week
or less.
Rush schedul: can reach the 100-µg maintenance dose within one day, or even within a few
hours.
Recombinant allergens
History
1998-1991: The first allergen-encoding DNA sequences were published.
Shortly thereafter, recombinant allergens were produced by expression of
allergen-encoding cDNAs mainly in prokaryotic (Escherichia coli) expression
systems and then tested for their IgE-binding capacity and for their ability to
induce specific activation of T cells and basophils .
1994–1995: the first recombinant allergens were successfully used for in vivo diagnosis of Type I allergy in patients by skin testing.
1996:The first three-dimensional (3D) allergen structures solved by X-ray
crystallography and NMR were published.
Then the first recombinant allergen variants with reduced allergenic activity
were reported and suggested as hypoallergenic candidate molecules for
safer forms allergen-specific immunotherapy.
Mechanisms of action of hymenoptra venom immunotherapy
IgE
VIT
IgG4
Th2 shift into th1
Increase IL-10 production
(IL-10 blocks CD28-dependent costimulatory
signaling pathways in T cells. IL-10 initiates peripheral T-cell anergy by
blocking tyrosine phosphorylation of CD28 and subsequently the CD28
costimulatory signal.
Apitherapy
Melittin: the most prevalent substance, is one of the most potent antiinflammatory agents known (100 times more potent than
hydrocortisol). Melittin also stabilizes the lysosome cell membrane
to protect against inflammation.
Apamin: inhibits complement C3 activity, and blocks calcium-dependent
potassium channels, thus enhancing nerve transmission.
Melittin and Apamin: found in bee venom have been shown to stimulate
the pituitary gland in humans and animals, releasing a hormone that
causes the adrenal gland to produce cortisol, one of the body's major
anti-inflammatory agents!
Adolapin: is another strong anti-inflammatory substance, and inhibits
cyclooxygenase; it thus has analgesic activity as well.
Peptide 401( MDC peptide): blocks the arachidonic acid and inhibits
prostaglandin synthesis.
Protease inhibitors: inhibit carrageenin, prostaglandin E1, bradykinin,
and histamine induced inflammations .
Diseases and Apitherapy
There are over 500 diseases and/or conditions which may be prevented or treated through the use of
apitherapy.
ALLERGIES (ALLERGOLOGY)
BV Allergy
Bee Pollen Allergy
Hay fever
Ragweed polinosis
CARDIOVASCULAR DISEASES
(CARDIOLOGY)
Acute rheumatic carditis
Angina pectoris
Arrhythmias
Artheritis obliterans
Artheriosclerosis
Atherosclerosis
Atherosclerotic Arteritis of the Inferior Limbs
etc.
Capillary fragility
Cardiac diseases (non-specific)
Cerebral atherosclerosis
Cerebral Trombosis
Coronary Heart Diseases
Flebitis
Heart insufficiences
Haemorrhagies of vascular origin
High Blood Pressure
Liver congestion
Peripheral Ischemic Degenerative Syndrome
Peripheral Vascular Diseases
Raynaud’s Disease
Slow peripheral blood flow
Varicose ulcer
Varicosis
Diseases and Apitherapy
Blood diseases (HEMATOLOGY)
Anaemia
Coagulation diseases with aplasia
Haemorrhagic gingivitis
Hyperlipidaemia
Respiratory apparatus diseases
(PNEUMOLOGY)
Allergic rhinitis (hay fever)
Angina
Asthmatic bronchitis
Bronchial asthma
Bronchiectasis
Bronchitis
Chronically cough
Chronic non-specific diseases of lungs
Cough
Inflammatory diseases of the upper
respiratory tract
Influenza infection
Laryngitis
Non-specific chronic pneumonia
Non-specific endo-bronchitis
Non-specific pneumonia
Pulmonary tuberculosis
Rhinitis
Tracheitis
Tuberculosis
CANCERS (ONCOLOGY)
Basal cell carcinoma
Chemotherapy (during)
Gynaecologic cancer (non-specific)
Lymphoma
Malignant melanoma
Mammary tumours
MUSCULOSKELETAL SYSTEM
DISEASES (RHEUMATOLOGY,
MYOLOGY, OSTEOLOGY)
Acute and Chronic Bursitis
Ankylotic Spondyilarthritis
Ankylotic Spondylitis Deformans
Arthritis
Arthrosis
Fibrositis
Juvenile Arthritis
Lateral Epicondylitis (Tenis Elbow)
Muscle Tonus Problems Ligament Troubles
Myalgia
Osteoarthritis
Periarthritis of the shoulder with
calcifications
Poliarthritis Deformans
Psoriatic Arthritis
Reduced Muscle Force (Weak Muscles =
Hypotonia)
Rheumatic afflictions of muscles, nerves and
articulations, etc.
Rheumatic diseases (non-specific)
Rheumatoid arthritis
Scheuermann’s Disease )osteochondrosis)
Spondyloarthrosis (Clinical Arthrosis)
Traumatic Arthritis
The exuded sting with a small drop of venum on it
The sting and its poison gland attached
Closeup of the sting showing the barbs, which
allows the sting to anchor inside the victim's
flesh, much like the barb on a fishing hook.
A worker bee trying to get away after
stinging. The sting has barbs preventing
the sting to be pulled out, part of her
digestive system is seen dragging behind
her
Two minutes after being stung. The sting
is removed to show the site of sting entry
The site of a sting injury after 24 hours. Light red and
swelling is seen, a small scar tissue is forming at the
site of sting entry.
Urticaria (hives) on a person, who is having a systematic
reaction to a bee sting. This can be a prelude to an
anaphylactic response, which can be fatal if not treated
immediately.
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