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BEE VENOM ALLERGY

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

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BEE VENOM ALLERGY

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  1. IN THE NAME OF GOD BEE VENOM ALLERGY BEE VENOM ALLERGY 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 consobrina

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

  13. Dried bee venom composition

  14. B.V. SUBSTANCES AND THEIR EFFECTS:

  15. B.V. SUBSTANCES AND THEIR EFFECTS(continued)

  16. 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)

  17. 1) Non-IgE mediated dried venom, 2.850 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

  18. Factors involved in bee venom allrgy High dose IL-12 Allergen dose 1) PLA2 IL4/IFNγ Lowe dose IL-4 HLA DR4 & HLADQW3(decrease) Beevenom 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)

  19. Epidemiology • ميزان مرگ ومير:0.09-0.45مرگ 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 سرم51 - 79درصد 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.

  20. 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 asprogressive 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)

  21. 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

  22. Local reaction to a fire ant sting

  23. Large local reaction to a yellow jacket sting

  24. Systemic reaction

  25. 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.ivictas.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:

  26. 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 (0.1mg/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 βآدرنرژيک(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).

  27. 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) داشتهاندوتست 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 40-60 تا کمتر از 5 درصد در افرادي که واکنشهاي سيستميک نشان مي دهند،کاهش مي دهد. History :1911Freeman&Noon(pollen toxin,hay fever) 1925Braun (insect sting allrgy) 1940-1956 Benson( prepared a venom extract derived from powdered whole bodies of the insects) 1976-1978Hunt etal .demonstrated that the constituent proteins in the venoms of these insects where the allergens responsible for the immediate hypersensitivity reactions to their sting

  28. SELECTION OF THE VENOM • The selection of the venom to be used for immunotherapyis based on the clinical history and on the positive results of the diagnostic tests with the various different venoms. • Difficultiesmay arise if the tests have been positive to more thanone venom. • the greatest problem being to establish whetherthese positive results represent true allergy to all the venomsor whether they simply indicate cross-reactivity betweenthem. IMMUNOTHERAPY PROTOCOLS Thetherapy protocol is initiated with very low doses, usually 0.01 to 0.1 µg, which are then gradually increased untilthemaintenance 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.

  29. Recombinantallergens 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. Thenthe first recombinant allergen variants with reduced allergenic activity were reported and suggested as hypoallergenic candidate molecules for safer forms allergen-specific immunotherapy.

  30. 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

  31. 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-inflammatoryagents! • 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 .

  32. Diseases and Apitherapy There are over 500 diseases and/or conditions which may be prevented or treated through the use of apitherapy.

  33. Diseases and Apitherapy

  34. The exuded sting with a small drop of venum on it

  35. The sting and its poison gland attached

  36. 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.

  37. 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

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

  39. 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.

  40. 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.

  41. ازتوجه شما متشکرم

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