Hypersensitivity Notes

Hypersensitivity

Learning Outcomes

• Explain what hypersensitivity is. (解釋什麼是超敏反應。)

• Understand the range of responses, from localized reactions like rashes to systemic anaphylaxis that can lead to death. (了解反應的範圍，從皮疹等局部反應到可能導致死亡的全身性過敏反應。)

• Provide examples of different types of hypersensitivity (Type I – Type IV) resulting from different mechanisms. (提供由不同機制引起的不同類型超敏反應（I 型 – IV 型）的示例。)

• Understand the mechanisms involved in sensitization and allergy. (瞭解致敏和過敏所涉及的機制。)

• Understand key treatment options for different types of hypersensitivity, including anti-inflammatories, antihistamines, and corticosteroids. (瞭解不同類型超敏反應的主要治療方案，包括抗炎葯、抗組胺葯和皮質類固醇。)

• Provide examples of localized anti-inflammatory therapy (e.g., creams, nasal sprays) and systemic therapy (e.g., antihistamine tablets). (提供局部抗炎療法（例如乳膏、鼻噴霧劑）和全身療法（例如抗組胺藥片劑）的示例。)

• Discuss the crossover between control of inflammation and pain. (討論控制炎症和疼痛之間的交叉。)

Summary Theme 1

• Balance is required when deliberately activating or inhibiting the immune system. (當故意啟動或抑制免疫系統時，需要保持平衡。)

• Core Concepts:

  • Innate immunity (先天免疫)

  • Adaptive immunity (適應性免疫)

  • Antigen specificity (抗原特異性)

  • Lymphocytes (淋巴細胞)

  • Effector Mechanisms (效應器機制)

Overview: Therapeutics & Immunology

1. Principles of immunology (免疫學原理)

2. Allergy and hypersensitivity (過敏和超敏反應)

3. Autoimmunity (自身免疫)

4. Therapeutics that activate the immune system (啟動免疫系統的療法)

5. Transplantation and immunosuppression (移植和免疫抑制)

6. Cancer Immunotherapy (癌症免疫療法)

5 Core Concepts & Focus: Interventions

• Innate immunity (先天免疫)

• Adaptive immunity (適應性免疫)

• Antigen specificity (抗原特異性)

• Lymphocytes (淋巴細胞)

• Effector Mechanisms (效應器機制)

• Interventions focus:

  • Infection (Immune Activation): (感染（免疫啟動）:)

  • Vaccines (疫苗)

  • Immune stimulators (免疫刺激劑)

  • Hypersensitivity: (過敏症:)

  • Antihistamines (抗組胺葯)

  • Glucocorticoids + Symptom management (糖皮質激素 + 癥狀管理)

  • Transplantation: (移植:)

  • Glucocorticoids (糖皮質激素)

  • Antiproliferatives (抗增殖藥)

  • Calcineurin inhibitors (鈣調磷酸酶抑製劑)

  • Other immunosuppressants (其他免疫抑製劑)

  • Autoimmunity: (自身免疫:)

  • Analgesics (鎮痛藥)

  • Glucocorticoids (糖皮質激素)

  • Antiproliferatives (抗增殖藥)

  • Calcineurin inhibitors (鈣調磷酸酶抑製劑)

  • Other immunosuppressants + Symptom management (其他免疫抑製劑 + 癥狀管理)

  • Cancer: (癌症:)

  • Checkpoint inhibitors (檢查點抑製劑)

  • Cancer vaccines (癌症疫苗)

  • T cell immunotherapy (T 細胞免疫療法)

Hypersensitivity & Autoimmunity

Immune system is critical for survival (e.g. SCID, AIDS etc.) BUT damage is caused by adaptive immune mechanisms and no hazard can be identified. (免疫系統對生存至關重要（例如 SCID、AIDS 等）但損傷是由適應性免疫機制引起的，無法確定危害。)

Hypersensitivity & Autoimmunity: Classification

• Classify by source of antigen (按抗原來源分類)

  • External = hypersensitivity (外部 = 超敏反應)

  • Internal = autoimmunity (內部 = 自身免疫)

• Classify by effector mechanism causing immunopathology (按引起免疫病理學的效應機制分類)

Hypersensitivity

• There are different types of hypersensitivity. (超敏反應有不同類型。)

• Types are defined by the effector mechanism by which damage occurs. (類型由發生損害的效應器機制定義。)

• Hypersensitivity leads to a range of conditions ranging from irritating (allergy) to life-threatening (anaphylaxis). (超敏反應會導致一系列情況，從刺激性（過敏）到危及生命（過敏性休克）。)

• All have in common: Sensitization to external antigen (所有藥物都有一個共同點：對外部抗原敏感)

Effector Mechanisms

• Types of antibody (抗體類型)

  • Binding and blocking (neutralisation) (結合和封閉 （中和）)

  • Histamine (組胺)

  • Opsonisation, complement activation and phagocytosis (調理作用、補體啟動和吞噬作用)

• Types of T lymphocyte (T 淋巴細胞的類型)

  • Killers: Direct killing of virally infected cells (殺手：直接殺死病毒感染的細胞)

  • Helpers: Cytokine release and inflammation (cell-mediated) (輔助方法：細胞因數釋放和炎症（細胞介導）)

  • Helpers: Control B cell antibody responses (humoral response) (輔助方法：對照 B 細胞抗體反應（體液反應）)

Hypersensitivity Classification

• Classification of Hypersensitivity (超敏反應分類)

  • Class I is by far the most common. (I 類是迄今為止最常見的。)

  • Classification most helpful to understand how it happens. (分類最有助於理解它是如何發生的。)

  • Contrasting different types illustrates that much is known about mechanism (even if cause is sometimes unclear). (對比不同類型的說明對機制瞭解很多（即使原因有時不清楚）。)

• Type I Hypersensitivity (I 型超敏反應)

  • Mast cells are ‘sentinels’ coated with IgE (or basophils) via FceR (肥大細胞是通過 FceR 包被 IgE（或嗜鹼性粒細胞）的“前哨細胞”)

  • Parasite antigen recognition triggers histamine release (寄生蟲抗原識別觸發組胺釋放)

  • Normal role of mast cells and IgE: protection from parasites (肥大細胞和IgE的正常作用：保護免受寄生蟲侵害)

  • Allergen triggers histamine release (過敏原觸發組胺釋放)

  • Swelling, sneezing, itching, swelling, vasodilation, sudden death (腫脹、打噴嚏、瘙癢、腫脹、血管舒張、猝死)

  • Th2 mediated response (T cell response). Evolved manage worm infections. IgE key response. Hygiene hypothesis. (Th2 介導的反應 （T 細胞反應）。進化管理蠕蟲感染。IgE 鍵回應。衛生假說。)

• Th2 Response vs Th1 (Th2 回應與 Th1)

  • Th2 secrete IL-4, IL-5, IL-13 – e.g., activate eosinophils (IL-5), mast cells (IL-4), B cells (antibody IgE, IL-4), M2 macrophage (IL-13, anti-inflammatory) (Th2 分泌 IL-4、IL-5、IL-13 – 例如，啟動嗜酸性粒細胞 （IL-5）、肥大細胞 （IL-4）、B 細胞（抗體 IgE、IL-4）、M2 巨噬細胞（IL-13，抗炎）

  • IFNgIFNg 和 TNFaTNFa(IFNgIFNg 和 TNFaTNFa)

  • IL−4IL−4， IL−5IL−5， IL−13IL−13 (IL−4IL−4， IL−5IL−5， IL−13IL−13)

  • IL−17AIL−17A， IL−17FIL−17F， IL−22IL−22， IL−23IL−23 (IL−17AIL−17A， IL−17FIL−17F， IL−22IL−22， IL−23IL−23)

• Type I Hypersensitivity: Allergy (I 型超敏反應：過敏)

  • Most common, wide range of examples from trivial to fatal, all sharing common mechanism (最常見，從微不足道到致命的廣泛示例，都共用共同的機制)

  • It is not yet fully clear what IgE mediated mast cell immunity is required for (目前尚不完全清楚 IgE 介導的肥大細胞免疫需要什麼)

  • Nor is it clear why some people respond to some antigens – genetic predisposition (HLA-DQ, IL-33R 等), PRR polymorphisms, hygiene hypothesis – skewed response towards Th2 (也不清楚為什麼有些人會對某些抗原有反應 – 遺傳易感性（HLA-DQ、IL-33R 等）、PRR 多態性、衛生假說 – 對 Th2 的反應偏斜)

• Hayfever (花粉症)

  • Allergen (antigen) in upper respiratory tract and eyes: itching and sneezing (上呼吸道和眼睛過敏原（抗原）：瘙癢和打噴嚏)

• Anaphylaxis (過敏反應)

  • If enough mast cells triggered at same time, systemic vasodilation leads to catastrophic loss BP & death (如果同時觸發足夠的肥大細胞，全身性血管舒張會導致災難性的血壓損失和死亡)

• Asthma (哮喘)

  • Allergen (antigen) in lower respiratory tract: air vessel constriction; shortness of breath, wheezing (下呼吸道過敏原（抗原）：氣管收縮;氣短、喘息)

• Type I Hypersensitivity: Allergens (I 型超敏反應：過敏原)

  • Typical external antigens found to sensitise some individuals to IgE responses: (發現典型的外部抗原會使某些個體對 IgE 反應敏感：)

    • Pollen (花粉)

    • Medicines (藥物)

    • Latex (乳膠)

    • Dust mites (塵蟎)

    • Food components (食品成分)

    • Food contaminants (食物污染物)

    • Rodents (啮齒動物)

    • Birds (鳥類)

    • Insect bites (昆蟲叮咬)

  • For many, can detect what the antigen in two ways: (對於很多來說，可以通過兩種方式檢測出什麼抗原：)

    • removal of antigen (去除抗原)

    • skin prick test (皮膚點刺試驗)

• Sensitisation (敏感)

  • （說明敏化過程的圖片）

• Therapeutics: Targeting Histamine (治療學：靶向組胺)

  • ANTI-HISTAMINES (early phase, acute response) (抗組胺葯（早期、急性反應）)

    • Histamine antagonists that act to inhibit the release or action of histamine (組胺拮抗劑，可抑製組胺的釋放或作用)

    • Most are antagonists of the H1 receptor (大多數是 H1 受體的拮抗劑)

    • Used for e.g., allergic rhinitis/hayfever (用於過敏性鼻炎/花粉症等)

    • Can be taken as capsules/tablets (e.g., loratadine), nasal sprays (azelastine), eye drops (azelastine) (可以作為膠囊/片劑（例如氯雷他定）、鼻噴霧劑（氮卓斯汀）、滴眼液（氮卓斯汀）服用)

    • Also available: mepyramine maleate cream e.g., for insect bites/stings (還提供：馬來酸甲吡拉明乳膏，例如，用於昆蟲叮咬/叮咬)

  • SODIUM CROMOGLICATE (色甘列酸鈉)

    • Mechanism not fully understood but it prevents release of histamine from mast cells (mast cell stabilizer) (機制尚不完全清楚，但它會阻止肥大細胞釋放組胺（肥大細胞穩定劑）)

    • Can be taken as capsules/tablets (food allergy), eye drops (e.g., allergic conjunctivitis) (可以作為膠囊/片劑（食物過敏）、滴眼液（例如過敏性結膜炎）服用)

  • Both focus on histamine: a potent proinflammatory molecule BUT many other inflammatory mediators & pathways … (兩者都專注於組胺：一種有效的促炎分子，但還有許多其他炎症介質和途徑…)

• Glucocorticoids and Corticosteroids (糖皮質激素和皮質類固醇)

  • Inhaled antigen (hay fever): Nasal spray (e.g., Beclometasone dipropionate) Solution to adverse effects in hypersensitivity – topical use (吸入抗原（花粉症）：鼻噴霧劑（例如，二丙酸倍氯米松）超敏反應不良反應的解決方案 - 局部使用)

  • ‘Wonder drugs’ used in huge range of conditions: most potent anti-inflammatory BUT major side effects if taken systemically (‘神奇藥物’ 用於各種疾病：最強效的抗炎藥，但如果全身服用，副作用很大)

  • Skin response (e.g., Insect bite): cream (e.g., hydrocortisone) High-dose, long term topical use can of course lead to systemic side effects (皮膚反應（例如昆蟲叮咬）：乳膏（例如氫化可的松）大劑量、長期局部使用當然會導致全身副作用)

  • Effects on immune system: synthetic mimics of endogenous anti-inflammatory steroid molecules (對免疫系統的影響：內源性抗炎類固醇分子的合成類比物)

• Symptom Management (癥狀管理)

  • Non-immune interventions for immune disease: depends on specific disease (免疫性疾病的非免疫干預：取決於特定疾病)

  • Example: Epinephrine (adrenaline) for anaphylaxis (示例：腎上腺素（腎上腺素）用於過敏反應)

    • Autoinjectors – EpiPen, Jext pen, and Emerade* pen (自動注射器 – EpiPen、Jext 筆和 Emerade* 筆)

    • Attempt compensate for massive drop in BP (e.g., histamine and other inflammatory mediators causes vasodilation) (嘗試代償血壓的大幅下降（例如，組胺和其他炎症介質導致血管舒張）)

    • Alpha2-adrenergic R agonist - vasoconstriction (α2-腎上腺素能 R 激動劑 - 血管收縮)

    • Leads to bronchial smooth muscle relaxation (beta 2) (導致支氣管平滑肌鬆弛 （beta 2）)

    • Can also reduce release of inflammatory mediators (還可以減少炎症介質的釋放)

  • Example: Salbutamol for asthma (示例：沙丁胺醇治療哮喘)

    • Beta-2 adrenergic receptor agonist inhalers (β-2 腎上腺素能受體激動劑吸入器)

    • Opens airways, relaxes constricted vessels (打開氣道，放鬆收縮的血管)

• Allergy Summary (過敏總結)

  • Exposure to allergens leads to initial sensitisation (接觸變應原會導致初始致敏)

  • Get Th2 cell response and IgE class switching B cells (獲得 Th2 細胞反應和 IgE 類切換 B 細胞)

  • B cells produce IgE that binds to Fc receptor (FcR) for IgE on mast cells (B 細胞產生的 IgE 與肥大細胞上的 Fc 受體 （FcR） 結合)

  • Subsequent exposure to same allergen leads to activation mast cells (cross-linking IgE:allergen) (隨後暴露於相同的變應原會導致肥大細胞活化（交聯 IgE：變應原）)

  • Release inflammatory mediators (immediate, e.g., histamine) and late-phase (cytokine-mediated) (釋放炎症介質（即刻，例如組胺）和晚期（細胞因數介導）)

• Desensitisation (脫敏)

  • （說明敏化過程的圖片）

  • Allergy Immunotherapy – AIT for IgE-mediated allergic disease (過敏免疫療法 – AIT 治療 IgE 介導的過敏性疾病)

  • Aim: shift to a more protective Type 1 immune response (目標：轉向更具保護性的 1 型免疫反應)

  • Different strategies depending also on allergy type (不同的策略也取決於過敏類型)

• Type II Hypersensitivity (II 型超敏反應)

  • （1）（1） activate ‘complement’ (C1q binds Fc Receptors) lyse cell, （2）（2） opsonise and lead to phagocytosis, （3）（3） ADCC (cytotoxic cell killing) (（1）（1） 啟動“補體”（C1q 結合 Fc 受體）裂解細胞，（2）（2） 調理素並導致吞噬作用，（3）（3） ADCC（細胞毒性細胞殺傷）)

  • Normal role of IgM and IgG: killing pathogens (IgM 和 IgG 的正常作用：殺死病原體)

  • Antibodies bound to drug bound to red blood cells directly kills them and leads to anaemia Also mismatched blood transfusion (與紅細胞結合的藥物結合的抗體會直接殺死他們並導致貧血 還有不匹配的輸血)

  • Diseases: Myasthenia gravis, Grave’s disease…more next lecture (疾病： 重症肌無力， 格雷夫氏病更多 下一場講座)

  • Example: Drug-induced hemolytic anemia (示例：藥物性溶血性貧血)

  • Treatment depends on the type. Can be e.g., steroids (治療取決於類型。可以是類固醇)

• Type III Hypersensitivity (III 型超敏反應)

  • Normal role of IgG: neutralizing toxins and viruses (IgG 的正常作用：中和毒素和病毒)

  • Example: Serum sickness caused by high levels of antibody (IgG or IgM) bound to foreign protein (示例：與外源蛋白結合的高水準抗體（IgG 或 IgM）引起的血清病)

  • Complexes precipitate in tissues, activate complement and trigger inflammatory responses causing tissue damage (複合物在組織中沉澱，啟動補體並觸發炎症反應，導致組織損傷)

  • Treatment: Stop antiserum/drug. Can treat e.g., corticosteroids, anti-histamines (治療：停止抗血清/藥物。可以治療皮質類固醇、抗組胺藥等)

  • Disorders: Rheumatoid arthritis, SLE…more next lecture (疾病： 類風濕性關節炎， 系統性紅斑狼瘡更多 下一場講座)

  • Antivenom: Made by taking venom from snake, then injecting into horses. horse serum is ‘antivenom’ and can then protect individual after snakebite (抗蛇毒血清：從蛇身上取毒液，然後注射到馬身上製成。馬的血清是“抗蛇毒血清”，可以在蛇咬傷後保護個體)

From antivenom to mAbs

MMonoclonal Antibodies: mAbs (單克隆抗體：mAbs)

• 100 millions of B cells (1 億個 B 細胞)

• Single rearranged antibody selected binds desired antigen e.g. human TNF / human HER2 receptor (選擇的單個重排抗體可結合所需抗原，例如人 TNF/人 HER2 受體)

• Can be made to bind any antigen (可結合任何抗原)

• Therapeutic mAbs have been developed to block signals, kill cells, and activate receptors… (已經開發出治療性 mAb 來阻斷信號、殺死細胞和啟動受體……)

• Immune response to therapeutic mAbs (and other therapeutic proteins) is still the most significant challenge for biologic therapies (對治療性 mAb（和其他治療性蛋白質）的免疫反應仍然是生物療法面臨的最重大挑戰)

• Crucially: hypersensitivity to biologics may not lead to serum sickness BUT drug gradually stops working (至關重要的是：對生物製劑的超敏反應不會導致血清病，但藥物會逐漸停止工作)

• Type IV Hypersensitivity (IV 型超敏反應)

  • Delayed hypersensitivity – not antibody mediated, instead cell-mediated (遲發性超敏反應 – 不是抗體介導的，而是細胞介導的)

  • Has sensitisaton step (type I); on re-exposure get T-cell mediated response (CD4 Th1, CD4 Th2 or CD8 CTL) (有致敏階梯（I 型）;再次暴露時獲得 T 細胞介導的反應（CD4 Th1、CD4 Th2 或 CD8 CTL）)

  • Example: allergic contact dermatitis (also test for TB!) (示例：過敏性接觸性皮炎（也要檢測結核病!)

• Why? (為什麼？)

  • Why do we develop antigen specific immunity to so many things that appear to be - and often are - harmless? (為什麼我們會對這麼多看起來 - 而且通常是 - 無害的事物產生抗原特異性免疫力？)

    • Genetic? (遺傳？)

    • Hygiene hypothesis? (衛生假說？)

    • Environmental factors? (環境因素？)

• Interventions (recap) (干預措施（回顧）)

  • Infection (Immune Activation): (感染（免疫激活）：)

    • Vaccines (疫苗)

    • Immune stimulators (免疫刺激劑)

  • Hypersensitivity: (過敏症:)

    • Antihistamines (抗組胺葯)

    • Glucocorticoids + Symptom management (糖皮質激素 + 癥狀管理)

  • Transplantation: (移植:)

    • Glucocorticoids (糖皮質激素)

    • Antiproliferatives (抗增殖藥)

    • Calcineurin inhibitors (鈣調磷酸酶抑製劑)

    • Other immunosuppressants (其他免疫抑製劑)

  • Autoimmunity: (自身免疫:)

    • Analgesics (鎮痛藥)

    • Glucocorticoids (糖皮質激素)

    • Antiproliferatives (抗增殖藥)

    • Calcineurin inhibitors (鈣調磷酸酶抑製劑)

    • Other immunosuppressants + Symptom management (其他免疫抑製劑 + 癥狀管理)

  • Cancer:

    • Checkpoint inhibitors (檢查點抑製劑)

    • Cancer vaccines (癌症疫苗)

    • T cell immunotherapy (T 細胞免疫療法)

• Interventions Summary (干預措施總結)

  • Trade off: severity of disease vs intervention (權衡：疾病的嚴重程度與干預措施)

  • Target site important: topical drug delivery can avoid adverse effects (靶位點很重要：局部給藥可以避免不良反應)

  • Only CURE: AVOID ANTIGEN (唯一的治療方法：避免抗原)

Learning Outcomes: Recap

• Explain how inflammation can result from innate (e.g., irritants, endotoxin) or adaptive (hypersensitivity)

• Explain the range of responses range in severity from rashes (localised responses) to death (systemic anaphylaxis)

• Provide examples of different types of hypersensitivity resulting from different mechanisms (allergy, contact sensitivity)

• Understand the two major classes of anti-inflammatory therapeutics- antihistamines plus corticosteroids

• Provide examples of localised anti-inflammatory therapy (e.g., creams, nasal sprays) and systemic therapy (e.g., antihistamine tablets)

• Briefly discuss the crossover between control of inflammation and pain.

超敏反應分類

從抗蛇毒血清到 mAb