A Derp a day, keeps the allergy away.

Oral tolerance:  local and systemic immune unresponsiveness that is induced by oral
administration of harmless antigen such as food proteins.
oral tolerance=orally administered soluble antigens
mucosally induced tolerance：可能才是有包含細菌在內的詞彙

例子：commensal bacteria in the large intestine

功能：prevent intestinal disorders such as food allergy, celiac disease, and inflammatory bowel
diseases
機制：specialized populations of mucosal dendritic cells and the unique microenvironment of
draining mesenteric lymph nodes→generate regulatory T cells that undergo subsequent
expansion in the small intestinal lamina propria.→systemic effect：prevent hypersensitivity
reactions
Active immune responses directed against the microbiota can result in inflammatory bowel
diseases such as Crohn's disease and ulcerative colitis，目前 IBD 發生率越來越高，也會 food
allergy and celiac disease

◎tolerance 的分類
1. negative selection or central tolerance：對於自體抗原的清除(所以腸子裡面的不在此
機制)，使 developing T and B cells in the thymus and bone marrow 被 eliminated。此外，
這些 T cell 還會變成 Natural Treg
2. peripheral tolerance：對於 foods and commensal organisms

腸子要兼顧正常菌叢和真正有害的，其實是件困難的事
其實要分成兩部分，一個是對於細菌的 tolerance(對於 systemic 沒有用)，一個是對於
protein antigen 的(local and systemic 免疫作用都能減弱)(對於 protein antigen 的研究較透
徹)

100 年前最早開始有吃 orally administered antigen to suppress immune response(local 和

systemic effect)
Wells, H.G. & Osborne, T.B. The biological reactions of the vegetable proteins. I:
Anaphylaxis. J. Infect. Dis. 8, 66–124 (1911).
Oral tolerance: Scope and Effects，怎麼知道有 oral tolerance 呢？
在人類身上也有經過實驗證實了，會 reductions in systemic delayed-type hypersensitivity, T-cell
proliferation, and cytokine production，也能藉由測 IgE、T helper type 1-dependent IgG2a
production、mucosal T-cell and immunoglobulin A

oral tolerance attenuates a broad range of immune responses and appears to play a central role in
immune homeostasis.跟自體免疫疾病其實都有關係，可以減緩一些自體免疫疾病的症嚴重
度

接著討論
1. antigen 是如何被 take up、tolerance 在哪裡被 induce 的，
2. mechanisms that underlie local and systemic tolerance to orally administered antigens
3. future mechanistic studies

(一) Mechanisms of Antigen Uptake in the Intestine

1. Inductive site：gut-associated lymphoid tissues (GALT) (如 Peyer’s patch、gut-
draining mesenteric lymph nodes (mLNs))
2. effector sites(如：lamina propria (LP) and epithelium)，裡面有大量 activated T cell
跟 plasma cell
3. LP may also contribute to the induction of tolerance, as a site of antigen uptake and
loading of the migratory dendritic cells (DCs) that encounter naïve T cells in the mLNs

在 GALT 上方的 epithelium 層的 M cells 帶著 microbial antigen 給 DC/或是一些 soluble antigen 擴散(目
前未知怎進來的)到 epithelium 內由 LP 的 DC 抓住，然後 DC 再去 APC，引發 tolerance

nature of the antigen determines its route of uptake. Particulate material and microbiota
mostly enter into GALT by M-cell-mediated transcytosis, whereas soluble antigens induce
oral tolerance after being taken up by DCs in the LP and, to a lesser extent, the GALT.
1. M cell
2. 小分子：diffusion through pores in the tight junctions
3. 大分子： transcytosis
4. 也可透過 MHC class II–expressing enterocytes 釋出 exosome 給 DC
5. LP myeloid cells(V)伸出 dendrite 去 sample(他不算是 dendritic cell 因為不會抗原呈現)，
但可能釋出給 DC(參與 microbial 或 protein)

Beyond the Gut: Dissemination of Intestinal Antigen

這些 soluble antigen 也可能透過循環再全身流動，造成全身性效果
antigen-specific tolerance：
1. 經由 portal vein 到肝的(antigen presentation in the liver by sinusoidal endothelial cells, tolerogenic
conventional dendritic cells (DCs)&Kupffer cell or plasmacytoid DCs (pDCs) (三種 APC)
2. 或是以再 lamina propria 的 CD103+ DCs 帶著經由 mesenteric lymph nodes(mLN)，到達胸管、再
進到血液， 對 oral tolerance induction 最重要，，因為實驗移除老鼠的 mLN 就抑制了 oral
tolerance induction。下面詳述！
3. Spleen / peripheral lymph nodes: also induce tolerance

Migratory CD103+ DCs and Local Conditioning Create a

Tolerogenic Environment in the mLNs—induce Treg 產生

CD103+ (αvβ8 integrin) DCs carry antigen 前往 mLN 可以產生 retinoic acid (RA)，能夠
induce Treg 產生。這種 CD103+ DCs 的功能只在腸道有這樣的功能，由以下物質造成他
的特異性 unique phenotype(thymic stromal lymphopoietin, TGF-β, and RA)。stromal cells of
the mLNs(因此腸道的 LN 才行)也是參與幫助 DC induce Treg 的重要因素。非常重要。

Mechanisms of Oral Tolerance

1. active regulation by Tregs(重要)，種類包含 Foxp3+ Tregs(包含 natural Foxp3+ Tregs
(nTregs) and induced Foxp3+ (Tregs (iTregs))、IL-10-producing Tr1 T cell、Th3 T cells
→nTreg 是 thymus 裡對自體抗原有反應的變成的，iTreg 才是這裡重要的，造成長期
的 tolrerance
2. clonal deletion and clonal anergy of T cells

A framework for the generation and maintenance of oral tolerance

讓他回 mucosa 進行 secondary expansion

induction and maintenance of oral tolerance may reflect a multi-step process involving
both lymphoid organs and the mucosal tissues 

oral tolerance requires the β7-integrin-dependent gut homing of iTregs after their initial
generation in the mLNs.
induced tolerance are initiated in the draining LNs, but are then expanded and sustained
in the LP
β7 integrin(R)、MadCAM-1(Ligand)、和 CCR9 都是把 T reg 帶來 mucosa 的重要分子，這樣
才能 tolerance。Recruit 來 mucosa 後，secondary expansion 會被 IL-10 induce(gut-resident
macrophages)，造成數量能夠 maintain。
至於 systemic 的 tolerance，可能是因為 Tregs that have undergone secondary expansion in the
LP may exit the tissue and enter the circulation either via the draining lymphatics, or directly via
the bloodstream.跑到全身個個組織。
dissemination of iTreg-dependent tolerance only seems to occur with soluble antigens, whereas
tolerance to microbiota is limited to the intestinal tissues.(如果是 microbiota 跑到身體裡面了，
那就是 infection，所以不會 tolerance 他，身體神奇地考慮到這點！)

最後跟一開始提幾個問題問大家
有過敏嗎？有對什麼食物過敏嗎？所以可以吃 antigenic tomato 有用嗎？

Reference:
Pabst, O., and A. M. Mowat. "Oral tolerance to food protein." Mucosal immunology (2012): 232.

◎食物過敏的種類：
hygiene hypothesis: Strachan: cause of the recent rapid rise in atopic disorders could
be a lower incidence of infection in early childhood, 因為這造成 Treg 的產生減少。但是新
的說法是 protection against allergy is mediated by broad exposure to a wealth of
commensal, non-pathogenic microorganisms early in life , rather than by
infections，所以應該叫做“microbial deprivation” hypothesis(&food antigen 也很重要)
過敏原：
cow's milk, peanuts, eggs, seafood, soy, wheat, rice, and fruit(mango, kiwi)
In recent decades, the prevalence of food allergy in general has increased by 0.60 %

 the timing and balance of cutaneous and oral exposure determine whether a child will
have allergy or tolerance
 late introduction of potential food allergens or cutaneous exposure might be associated
with allergy, while early oral exposure might contribute to tolerance
目前 debate 是否抗過敏的原則要改由 deliberate exposure
(Ben-Shoshan M, Turnbull E, Clarke A (2012). "Food allergy: temporal trends and
determinants". Curr Allergy Asthma Rep. 12 (4): 346–72.)

因素舉例：
1. higher socioeconomic populations
2. In adults, anaphylaxis is more common in females，因為雄性激素的產生抑制過敏反
應
3. In children, 男>女
4. Breastfeeding 其實沒有影響

Treg 可以抑制 TH2

TH2 lymphocyte,→ IL-4→B cells→IgE→mast cell→第二次以後會 degranulation( histamine、cytokines)

Prevalence:
(source: CDC, national center for health statistics)
◎Burks, A. Wesley, Susan Laubach, and Stacie M. Jones. "Oral tolerance, food allergy, and
immunotherapy: implications for future treatment." Journal of Allergy and Clinical
Immunology 121.6 (2008): 1344-1350.
In general, soluble antigen is more tolerogenic than particulate antigen

◎Oral immunotherapy with the ingestion of house dust mite extract in a murine model of allergic
asthma
Oral immunotherapy with HDM extracts ingestion was demonstrated to have a partial
therapeutic effect in the murine model of allergic asthma. This study may serve as the
basis for the further development of oral immunotherapy with HDM extracts in allergic
asthma.
→有用

◎Dust mite allergen-specific immunotherapy increases IL4 DNA methylation and induces Der p-specific T
cell tolerance in children with allergic asthma
These results suggest that decreased IL-2 production and increased IL-4 cytokine promoter
methylation is a potential mechanism of Der p-specific allergen desensitization immunotherapy.
Dermatophagoides pteronyssinus (Der p) allergen-SIT(Allergen-specific immunotherapy )
lower levels of IL-4, IL-5 and IL-2
治療有用
但是預防目前沒找不太到研究。
所以吃 DerP 有用！

An apple a day, keeps the allergy away.

我不喜歡番茄，蘋果好像比較好吃！