花粉アレルギーが生じるメカニズム
約 10 年前，花粉症の研究を始めた頃，アレル ギーの発症機構は，教科書に次のように書かれて いた．
- ①粘膜下に侵入したアレルゲンを貪飲した マクロファージ系細胞が，所属リンパ節でリンパ 系細胞に抗原提示する．
- ②ヘルパー T 細胞が，侵入物が異物であり，アレルゲンであることを認識， サイトカインを分泌し，
- ③ B 細胞は，形質細胞に 分化して抗体のクラススイッチが起こり，抗原特 異的 IgE を産生する．
- ④抗原特異的 IgE は血中に 分泌され，末梢組織の常在性細胞の一つである肥 満細胞の上の FcεR に結合し，感作が成立する．その後，
- ⑤体内の所謂アレルギーコップに長期間かけて徐々に発症原因が貯まり，コップが一杯になって抗体が抗原によって架橋されると，種々の化学伝達物質が分泌され，アレルギーが突然発症する．
10 年後の今も，教科書に書かれている内容 はほとんど変わっていない．(マウスの IgE 産生機構―アレルギー疾患が重なり合う理由を求めて アレルギー 59（ 12）， 1619―1624，2010（平22）)
アレルギー反応（過敏反応）はI型からIV型までの4種類に分類されており、花粉症などIgEが関係するアレルギーは、I型と呼ばれています。I型アレルギーが発症するメカニズムを説明した英語論文の文例を集めておきます。
論文１
Effect of neuromedin U on allergic airway inflammation in an asthma model (Review) December 4, 2019
- In allergic eosinophilic airway inflammation, specialized dendritic cells present allergens
- to steer the differentiation of naive T lymphocytes
- towards the formation of Th2 cells,
- which produce cytokines such as interleukin-4 (IL-4), IL-5, IL-9 and IL-13
- that result in IgE switching in B cells.
- The released IgE molecules bind to the Fc epsilon receptor I (FcεRI) on mast cell surfaces.
- Exposure to allergens
- and the cross-linking of receptors by allergens, which bind to high-affinity IgE
- result in mast cell degranulation.
- Type 2 innate lymphoid cells (ILC2s) are activated by cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) secreted by activated mast cells.
- Once activated, ILC2s rapidly expand and secrete large amounts of IL-5 and IL-13.
- ILC2s contribute to allergic airway inflammation by directly interacting with Th2 cells to promote the release of cytokines, mucus production and airway eosinophilia.
論文２
T-Cell Response to Allergens Chem Immunol Allergy. Basel, Karger, 2010, vol 95, pp 22–44
- Antigen-presenting cells introduce processed allergens to T-helper lymphocytes, where a decision of developing different types of T-cell immunity is given under the influence of several cytokines, chemokines, costimulatory signals and regulatory T cells.
- Among Th2-type cytokines, interleukin (IL)-4 and IL-13
- are responsible for class switching in B cells,
- which results in production of allergen-specific IgE antibodies
- that bind to specific receptors on mast cells and basophils.
- After re-exposure to the sensitized allergen, this phase is
- followed by activation of IgE Fc receptors on mast cells and basophils
- resulting in biogenic mediator releases responsible for the symptoms and signs of anaphylaxis.
論文３
次の論文は、出来事の順では書かれておらずIgEを中心にした説明。
Triggers of IgE class switching and allergy development Lars K. Poulsen &Lone Hummelshoj Pages 440-456 | Published online: 08 Jul 2009
- IgE is produced by B lymphocytes and plasma cells, but in order to become an IgE‐producing plasma cell the naive B cell needs a number of molecular signals, most importantly provided by a Thelper lymphocyte with a specialized cytokine secretion profile—the so‐called Th2 type (Th2) which can produce the cytokines necessary for stimulation of the B cell to IgE class switch (interleukin (IL‐) 4, IL‐13), for stimulation and recruitment of eosinophils (IL‐5, IL‐9, granulocyte/macrophage‐colony stimulating factor (GM‐CSF) and for other inflammatory tissue reactions (IL‐9, IL‐13).
- Undifferentiated Th cells on the other hand also need signals to develop into the Th2 phenotype, and it is likely that specialized dendritic cells are responsible for this process.
次に、起こる順でも、再度まとめています。
- Thus three steps are crucial to mount an IgE immune response:
- 1) differentiation of dendritic cells to ‘DC2’ promoting
- 2) the formation of allergen‐specific Th2 cells which subsequently
- 3) induce the differentiation of B lymphocytes to IgE isotype switch and transformation to an IgE‐producing plasma cell. The molecular background of these processes is discussed in more detail in the second part of this paper.
論文４
CD4 T Helper Cell Subsets and Related Human Immunological Disorders Int. J. Mol. Sci. 2020, 21(21), 8011
- Th2 cells are mainly involved in host defense against large extracellular pathogens, such as helminths.
- Naïve CD4 T cells after receiving signals from DCs
- may differentiate into Th2 cells after their activation.
- IL-2 and IL-4 are two important cytokines during Th2 cell differentiation, particularly in vitro.
- IL-2 and IL-4 activate STAT5 and STAT6, respectively,
- and the latter induce the expression of the Th2 master transcription factor GATA3 in activated CD4 T cells.
- Differentiated Th2 cells secret lineage cytokines including IL-4, IL-5, and IL-13.
- During a classic type 2 immune response, IL-4 promotes B cell antibody class switching to immunoglobin E (IgE),
- IL-5 recruits eosinophilia to the inflammation sites,
- and IL-13 promotes mucus production and goblet cell hyperplasia.
- Th2 cells and ILC2s also express chemokine receptors on the cell surface, including CCR3, CCR4, and CCR8, to receive migration signals from ligands (CCL11 for CCR3, CCL17 and CCL22 for CCR4, and CCL1 for CCR8) secreted by epithelial cells.
- In addition to recruiting Th2 cells and ILC2s, these chemokines can also recruit other cells, such as DCs, eosinophils, basophils, and mast cells to the damaged epithelial sites caused by helminth infection or protease allergens.
参考
- 好酸球性気道炎症のメカニズム アレルギー 70（2）， 100―106， 2021（令3）アレルギー疾患において好酸球性炎症を発現せしめ る基本的な調節機構は，T ヘルパー（Th）2 細胞なら びにグループ 2 自然リンパ球（type 2 innate lymphoid cells，ILC2）が参画するいわゆる 2 型免疫反応系であ る．‥ 感作アレルゲン曝露により活性化されるマ スト細胞は，ヒスタミンなどの貯蔵性分子などのみな らず，Prostaglandin D2（PGD2）あるいは CysLT など の脂質メディエーターを豊富に産生・放出する．
- 専門医のためのアレルギー学講座 34．免疫学における基礎と新たな展開 3．アレルギー発症と制御における B 細胞の役割 アレルギー 68（6）， 661―667， 2019（令1）アレルギー反応は I～IV 型に 分類されるが，IgE 依存的な即時型アレルギー反応が I 型アレルギーである．IgE を介した免疫反応は寄生虫 に対する感染防御において重要である一方，様々なア レルギー疾患に関与している．
- Multi-faceted regulation of IgE production and humoral memory formation Allergology International Volume 70, Issue 2, April 2021, Pages 163-168 IgE antibody (Ab) is produced by plasma cells (PCs) derived from B cells having undergone class-switching (CS) to IgE isotype during type 2 immune responses. IgE plays a pivotal role in protection against parasite infection and environmental toxins by activating mast cells and basophils through binding FcεRI, a high-affinity Fc receptor for IgE. On the other hand, IgE is best known as a mediator of allergic responses through the same mechanism. IgE産生に関する詳細なレビュー論文
- Biology and dynamics of B cells in the context of IgE-mediated food allergy 03 December 2020 B cells play a pivotal role in IgE-mediated food allergies, as a result of their unique ability to produce allergen-specific IgE antibodies that sensitize mast cells and basophils by binding to their high-affinity IgE receptors (FcεRI). Subsequent allergen cross-linking of FcεRI-bound IgE on mast cells and basophils initiates the release of pro-inflammatory mediators resulting in a type I hypersensitivity reaction.
- IgE GENERATION AND MAST CELL ACTIVATION Vol. 12, no. 1,21-25 (2014)