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BEE VENOM ALLERGY BEE VENOM ALLERGY IN THE NAME OF GOD

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1 BEE VENOM ALLERGY BEE VENOM ALLERGY IN THE NAME OF GOD
PRESENTED BY: SHAFI MOJADADI

2 Introduction Taxonomy of the hymenoptra The biology of honey bee Bee venom composition Allergy to bee sting (mechanisms) Factors involved in allergy to bee sting Epidemiology Classification of reactions Diagnosis Treatment Hymenoptra venom immunotherapy(VIT) Recombinant allergens Mechanisms of action of hymenoptra venom immunotherapy apitherapy

3 Introduction

4 TAXONOMY OF HYMENOPTRA
Order Family Apis spp. Bombus spp. Megabombus spp. Pyrobombus spp. Halictus spp. Dialictus spp. Vespula spp. Dolichovespula spp. Polistes spp. Solenopsis spp. Pogonomyrmex spp. Genus

5 Apidae Bombus spp. Bumble Bee

6 Vespidae Vespula spp. Yellow jacket

7 Vespidae Vespula spp. Vespula maculifrons Vespula vidua
Vespula maculifrons Vespula vidua   Vespula consobrina

8 Dolichovespula arenaria Dolichovespula maculata (White-faced hornet)
Vespidae Dolichovespula spp.                               Dolichovespula arenaria (yellow hornet)                                Dolichovespula maculata (White-faced hornet)

9 Vespidae Polistes spp. Paper Wasp

10 Formicidae Solenopsis invicta (Fire ant)

11 The bilogy of honey bee(apis mellifera)
Kingdom:animalia Phylum: arthropoda Class: insecta Family: apidae Genus: apis Species: apis mellifera Apis mellifera(honey bee)

12 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

13 Bee venom composition pH 5-5.5 A:liquid B:Dried Colorless
sharp-bitter tasting B:Dried Yellowish brown LD50:2.8mg/kg (IV) (In mice) Cold resistance Heat resistance (when dry) 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

14 NON-PEPTIDE COMPONENTS
ENZYMES MOL. Wt. % (Dry Venom) Hyaluronidase 38,000 Phospholipase A2 19,000 10-12 Glucosidase 170,000 0.6 Acid Phosphomono-esterase 55,000 1.0 Lysophospholipase 22,000 ACTIVE AMINES Histamine Dopamine Norepinephrine NON-PEPTIDE COMPONENTS Carbohydrates: Glucose & Fructose < 2.0 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 Adolapin 11,500 1.0 Protease inhibitor 9,000 < 0.8 Secarpin 0.5 Tertiapin 0.1 Melittin F 0.01 Procamine A, B 1.4 Minimine 6,000 Cardiopep < 0.7

15 Apamin (a polypeptide with 18 amino acids)
B.V. SUBSTANCES AND THEIR EFFECTS: Phospholipase A (enzyme) 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 Hyaluronidase selectively attacks tissue hyaluronic acid polymers; increase the capillary permeability (Neumann and Habermann); immune response and tissue-spread properties; antigenic; anaphylactogene Apamin (a polypeptide with 18 amino acids) antigenic and; anti-inflammatory properties Mast Cell Degranulating peptide 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. Adolapin analgesic (Shkenderov, 1982); anti-inflammatory (Shkenderov, 1982)

16 B.V. SUBSTANCES AND THEIR EFFECTS(continued)
Melittin (a polypeptide also consisting of 26 amino acids which represents 40-60% of the bee venom) 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 % 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 anti-inflammatory agents known, and it can be useful in treating arthritis and rheumatism. Cardiopep increase both the force of contraction (beta-adrenergic) 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.)

17 آلرژي به زهر زنبور آمريکا: 40-50مرگ در هر سال
استراليا: ساليانه1مرگ در هر ميليون نفر نيوزيلند: 1مرگ در هر 3سال اسپانيا: کمترين ميزان مرگ ومير Non-igE mediated1) زهر زنبور با استفاده از 3مکانيسم باعث بروز آلرژي مي شود: igE mediated2) Histamine&leukotriens3)

18 Major allergens: PLA2, Hyaluronidase,acid phosphatase,melittin
1) Non-IgE mediated dried venom, kd,26 aa٪ Melittin: 50 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

19 Bee venom allergy (increase)
Factors involved in bee venom allrgy High dose IL-12 Allergen dose 1) PLA2 IL4/IFNγ Lowe dose IL-4 HLA DR4 & HLADQW3(decrease) Bee venom allergy (increase) 2) Genetic background: DRB1*07 allels (allergic individals) (faux et al.) 3) CD40 ligand (T cell),CD40(Bcell) & CD28/CTLA4(T cell),CD86/CD80(APC)

20 Epidemiology ميزان مرگ ومير: مرگ در هر ميليون نفر در هر سال(بيشتر مرگ و مير ها در افراد بالاتر از 40 سال) ميزان مرگ ومير درکشورهاي اسکانديناوي به مراتب کمتر از قسمتهاي جنوبي اروپا مي باشد. حساسيت در مردها بيشتر از زنها مي باشد(در کشور فنلاند 80درصد زنبورداران مرد مي باشند) در جمعيت انساني IgE اختصاصي الف:به زهر زنبور عسل:6-17درصد ب:به زهر زنبورهاي غير عسلي:12-21درصد در سرم درصد زنبورداران IgEاختصاصي به زهر زنبورهاي عسل وجود دارد. 31درصد از زنبورداران و اعضاي فاميلشان علاوه بر حساسيت به زهر زنبورهاي عسل ،به ترکيبات بدني زنبورها حساسيت نشان مي دهند(علائم چشمي و بويائي در هنگام کار با کندوي زنبورهاي عسل). واکنشهاي موضعي بزرگ در 31-38درصد و واکنشهاي سيستميک آلرژيک در22-43درصد زنبورداران گزارش شده است. 25-32 درصد افرادي که نسبت به نيش حشرات آنافيلاکسي دارند،افراد اتوپيک مي باشند.

21 Classification of reactions
A:local reaction B:large local reaction C:systemic reaction 1) Immediate reactions(< 4 hrs) 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. Bradykinin Acethylcholin Dopamine Histamine Seretonine Toxic reactions : non immunologic,exogenous vasoactive amines (Bee venom) Fatal toxic reactions from Africanized honeybees(AHB) :may be accompanied by intravascular hemolysis, adult respiratory distress syndrome, renal failure, and diffuse intravascular coagulation(DIC)

22 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. Systemic reaction symptoms: Grade 1: anxiety,malaise,urticaria,pruritus. Grade 2: abdominal cramping, nausea and/or vomiting. Grade 3:hoarseness,dysphagia , stridor,wheezing, palpitation, dyspnea,feeling of impeding doom. Grade4: extensive hypotension, vascular collapse ,death

23 Local reaction to a fire ant sting
                                                          Figure 1. Local reaction to a fire ant sting. Local reaction to a fire ant sting

24 Large local reaction to a yellow jacket sting

25 Systemic reaction

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27 Diagnosis واکنشهاي فوري به نيش حشرات هميشه وابسته به IgE نمي باشد(10 درصد افرادي که تجربه واکنشهاي آنافيلاکتيک داشته اند،هيچ IgE قابل دتکت نداشته اند). A تستهاي پوستي: الف:پيريک تست ب: انترادرمال مزيت: سريع،ارزان و حساس سموم 5 رده هيمنوپترا honey bee,yelllow jacket,yellow hornet,white-faced hornet wasp ترکيبي مساوي از زهر وسپيد شامل: yelllow jacket,yellow hornet,white-faced hornet B تستهاي سرولوژيکي: RAST,RIST,ELISA انواع تستها دردسترس مي باشند. توجه: مي بايست به کراس راکتيويتي بين سموم مختلف توجه کرد! بعنوان مثال بين آنتي ژنها و آلرژنهاي گونه هاي مختلف جنس vespula کراس راکتيويتي وجود دارد(v.germanica,v.vulgaris,v.flovopilosa,v.maculifrons,v.squamous) همچنين بين گونه هاي مختلف جنس polistes (p.exclamans,p.apachus,p.instablis,p.annularis,p.fuscatus) بين سموم solenopsis (s.ivicta s.richteri,)=fire ant نيز کراس راکتيويتي وجود دارد. بين آنتي ژنهاي موجود درزهر زنبورعسل وbumble bee کراس راکتيويتي وجود دارد.همچنين بين هيالورونيداز زنبور عسل وvesid از طرف ديگر بين آلرژنهاي عمده فاميلهاي مختلف حشرات کراس راکتيويتي وجود ندارد. 1- افرادي با تست پوستي منفي با سم حشرات گزارش شده اند که بعد از نيش زدگي دچار آنافيلاکسي گرديده اند. 2- حدود 40 درصد افراد ايمن نشده داراي تست پوستي مثبت ممکن است بعداز نيش زدگي دچار آنافيلاکسي نشوند. نکات:

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29 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 خاصي ندارد.رعايت نکات فوق مي تواند کمک کننده باشد. واکنشهاي موضعي بزرگ: با يک کمپرس آب يخ بموقع درمان مي شوند.اگر چه ممکن است در چنين مواردي آنتي هيستامينها و گلوکوکورتيکوئيدها نيز تجويز شوند. واکنشهاي سيستميک: اپي نفرين مايع 1000/1 (0.1 mg/kg وزن بدن IM or IV.ماکزيمم 0.3ميلي ليتر براي کودکان و0.5 ميلي ليتر براي بزرگسالان) مکانيسم اثر اپي نفرين : خواص α آدرنرژيک(افزايش مقاومت رگي سيستميک و افزايش فشار دياستوليک) خواص β آدرنرژيک(برونکوديلاسيون) همچنين استفاده از آنتي هيستامينهاي بلوک کننده گيرنده H1 (Dyphenhydramine) بعنوان مکمل،براي پايين آوردن خارش و کهير. توجه: افراد بسيار حساس را مي بايست با Epipen وآنتي هيستامينها مجهز کرد.(اين افراد مي بايست ايمونوتراپي شوند).

30 Hymenoptra venom immunotherapy(VIT)
VIT براي چه کساني توصيه مي شود؟ با توجه به اين که ايمونوتراپي مشکل وپر خرج مي باشد،توصيه مي شود درافرادي که تاريخچه واکنشهاي سيستميک(علائم قلبي وعروقي وتنفسي) داشته اندوتست پوستي آنها مثبت مي باشد يا IgE درسرمشان قابل دتکت مي باشد، صورت گيرد. نکته: در مورد زنان حامله VIT نبايد صورت گيرد. VIT در 80 درصد موارد حساسيت به زنبورعسل و95درصد موارد حساسيت نسبت به ديگر زنبورها موثر است.و خطر آنافيلاکسي را از تا کمتر از 5 درصد در افرادي که واکنشهاي سيستميک نشان مي دهند،کاهش مي دهد. History :1911 Freeman&Noon(pollen toxin,hay fever) 1925 Braun (insect sting allrgy) Benson( prepared a venom extract derived from powdered whole bodies of the insects) 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

31 IMMUNOTHERAPY PROTOCOLS
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.

32 Recombinant allergens
History : 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.

33 VIT Mechanisms of action of hymenoptra venom immunotherapy IgE 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. VIT

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35 Apitherapy Melittin: the most prevalent substance, is one of the most potent anti-inflammatory 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 .

36 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

37 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

38 MUSCULOSKELETAL SYSTEM DISEASES (RHEUMATOLOGY, MYOLOGY, OSTEOLOGY)
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

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41 The exuded sting with a small drop of venum on it

42 The sting and its poison gland attached

43 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.

44 A worker bee trying to get away after stinging
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

45 Two minutes after being stung
Two minutes after being stung. The sting is removed to show the site of sting entry

46 The site of a sting injury after 24 hours
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.

47 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.

48 ازتوجه شما متشکرم


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