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Murine Anaphylaxis to Food Requires Cysteinyl Leukotriene-Mediated Absorption of Allergens in the Gut
Murine Anaphylaxis to Food Requires Cysteinyl Leukotriene-Mediated Absorption of Allergens in the Gut
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103022
- ISBN
- 9798286437733
- DDC
- 616.079
- 저자명
- Hoyt, Laura.
- 서명/저자
- Murine Anaphylaxis to Food Requires Cysteinyl Leukotriene-Mediated Absorption of Allergens in the Gut
- 발행사항
- [Sl] : Yale University, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 127 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Eisenbarth, Stephanie.
- 학위논문주기
- Thesis (Ph.D.)--Yale University, 2025.
- 초록/해제
- 요약Food-specific IgE triggers life-threatening anaphylaxis; however, some people with food-specific IgE are asymptomatic upon allergen consumption. Using a murine model of food allergy, we discovered an unexpected pathway regulating the ability of food allergens to trigger anaphylaxis. C57BL/6 mice are uniquely resistant to anaphylaxis when challenged orally. Here we show that goblet cells from C57BL/6 mice transport less food allergens into the underlying mucosa and systemic circulation than anaphylaxis-susceptible strains, even prior to allergic sensitization. In a forward genetic screen using oral anaphylaxis resistant C57BL/6 and susceptible C3H/HeJ mice, we have found that resistance to oral challenge displays an autosomal dominant inheritance pattern that we have mapped to a distal portion of chromosome 8. Within this region, we identified Dpep1 as a gene of interest as it is both highly expressed in the intestinal epithelium and encodes the enzyme dipeptidase-1 (DPEP1) that converts leukotriene D4 (LTD4) into leukotriene E4 (LTE4). LTC4, LTD4 and LTE4 are a group of inflammatory mediators termed cysteinyl leukotrienes that are derived from arachidonic acid and are important mediators of allergic responses. LTC4 and LTD4 signal through their G-protein coupled receptors Cysltr1 and Cysltr2, while LTE4 is significantly more stable and signals primarily through its newly discovered receptor Gpr99 (Oxgr1). Oral anaphylaxis susceptible C3H/HeJ and Balb/c mice possess two separate point mutations in DPEP1 (H109Q and N358S respectively) and decreased DPEP1 enzymatic activity relative to C57BL/6 mice, leading to a buildup of LTC4 and LTD4 within the proximal small intestine. Blocking DPEP1 with the drug cilastatin, genetically deleting Dpep1, or oral administration of LTD4 enhanced allergen transport in C57BL/6 mice. Conversely, pre-treatment of C3H/HeJ mice with a leukotriene synthesis inhibitor, zileuton, abrogated allergen absorption from the gut and subsequent oral anaphylaxis. Taken together our data implicate DPEP1 as a major modulator of gut permeability, with diminished DPEP1 activity leading to increased gut permeability and concomitant susceptibility to oral anaphylaxis. Further work studying the role of DPEP1 in oral challenge susceptibility could lead to a paradigm shift in food allergy management by identifying treatments that not only mitigate the symptoms of an allergic reaction; but through the inhibition of food allergen absorption from the intestine, prevent the initiation of an allergic reaction altogether.
- 일반주제명
- Immunology
- 일반주제명
- Microbiology
- 일반주제명
- Public health
- 일반주제명
- Food science
- 일반주제명
- Health sciences
- 키워드
- Food allergy
- 키워드
- Dipeptidase-1
- 키워드
- Anaphylaxis
- 기타저자
- Yale University Immunobiology in MD/PhD Program
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■1001 ▼aHoyt, Laura.
■24510▼aMurine Anaphylaxis to Food Requires Cysteinyl Leukotriene-Mediated Absorption of Allergens in the Gut
■260 ▼a[Sl]▼bYale University▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a127 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Eisenbarth, Stephanie.
■5021 ▼aThesis (Ph.D.)--Yale University, 2025.
■520 ▼aFood-specific IgE triggers life-threatening anaphylaxis; however, some people with food-specific IgE are asymptomatic upon allergen consumption. Using a murine model of food allergy, we discovered an unexpected pathway regulating the ability of food allergens to trigger anaphylaxis. C57BL/6 mice are uniquely resistant to anaphylaxis when challenged orally. Here we show that goblet cells from C57BL/6 mice transport less food allergens into the underlying mucosa and systemic circulation than anaphylaxis-susceptible strains, even prior to allergic sensitization. In a forward genetic screen using oral anaphylaxis resistant C57BL/6 and susceptible C3H/HeJ mice, we have found that resistance to oral challenge displays an autosomal dominant inheritance pattern that we have mapped to a distal portion of chromosome 8. Within this region, we identified Dpep1 as a gene of interest as it is both highly expressed in the intestinal epithelium and encodes the enzyme dipeptidase-1 (DPEP1) that converts leukotriene D4 (LTD4) into leukotriene E4 (LTE4). LTC4, LTD4 and LTE4 are a group of inflammatory mediators termed cysteinyl leukotrienes that are derived from arachidonic acid and are important mediators of allergic responses. LTC4 and LTD4 signal through their G-protein coupled receptors Cysltr1 and Cysltr2, while LTE4 is significantly more stable and signals primarily through its newly discovered receptor Gpr99 (Oxgr1). Oral anaphylaxis susceptible C3H/HeJ and Balb/c mice possess two separate point mutations in DPEP1 (H109Q and N358S respectively) and decreased DPEP1 enzymatic activity relative to C57BL/6 mice, leading to a buildup of LTC4 and LTD4 within the proximal small intestine. Blocking DPEP1 with the drug cilastatin, genetically deleting Dpep1, or oral administration of LTD4 enhanced allergen transport in C57BL/6 mice. Conversely, pre-treatment of C3H/HeJ mice with a leukotriene synthesis inhibitor, zileuton, abrogated allergen absorption from the gut and subsequent oral anaphylaxis. Taken together our data implicate DPEP1 as a major modulator of gut permeability, with diminished DPEP1 activity leading to increased gut permeability and concomitant susceptibility to oral anaphylaxis. Further work studying the role of DPEP1 in oral challenge susceptibility could lead to a paradigm shift in food allergy management by identifying treatments that not only mitigate the symptoms of an allergic reaction; but through the inhibition of food allergen absorption from the intestine, prevent the initiation of an allergic reaction altogether.
■590 ▼aSchool code: 0265.
■650 4▼aImmunology
■650 4▼aMicrobiology
■650 4▼aPublic health
■650 4▼aFood science
■650 4▼aHealth sciences
■653 ▼aFood allergy
■653 ▼aMucosal immunology
■653 ▼aDipeptidase-1
■653 ▼aCysteinyl leukotrienes
■653 ▼aAnaphylaxis
■690 ▼a0982
■690 ▼a0566
■690 ▼a0410
■690 ▼a0359
■690 ▼a0573
■71020▼aYale University▼bImmunobiology in MD/PhD Program.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0265
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17356712▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
