Extra cellular gut nematodes

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Th1/Th2 cell development

Dendritic cell 

a. IL-12 from macrophages -> Th1 Cells. -> IFN gamma, inflammation, IL-12, TNF-Beta

b. IL-4 -> Th2 cells. -> B cells and antibodies, IL-4, IL-5, -6, -9 and -13.

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Helminth infections

Large, extracellular. Mucosal surfaces or tissues.

Mucosal immune response: IgA, Mast cells/IgE, Macrophages, eosinophils.

Characteristics of helminth infections: CD4+ Th2 response.

1. High IgE/IgG1 in mouse, IgG4 in man.

2. Mucosal mastocytosis (IL-4)

3. Eosinophils (IL-5)

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Trichuris Muris life cycle

1. L1 hatch in caecum and invade epithelial cells - front of worm burries.

2. L1 to L2 days 9-11 post infection

3. L2 to L3 21 days post infection

4. L3 to L4 days 24-28 post infection

5. L4 to adult, days 28 - 34 post infection

female lays 10,000 eggs per day which are passed out in faeces into external environment. Infective L1 ingested by mice.

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Th2 protects

BALB/c and AKR mice infected with T muris.

mesenteric lymph nodes measured.

BALB/c: IL-4, IL-9, IL-13 -> expulsion

BALB/c: Anti IL-4 -> IFN-gamma -> NO EXPULSION

AKR: IFN-gamma -> NO EXPULSION

AKR: anti IL-12 anti-IFN gamma -> IL-4, IL-9, IL-13 -> Expulsion

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IL-13 IL-4 and TNF alpha

IL-13

IL-13 produced by T cells (Th2). Shares many biological activities with IL-4.

IL-13 KO mice on a resistant background are susceptible to infection -> delayed Th2 response.

Goblet cell hyperplasia - increased resistance like molecule beta - impairs chemosensory function

increased gut permeabilit

increased epithelial cell turnover

increased muscle contraction

IL-14

C57B1/6 WT -> IL-4, -9, -13 -> T muris expulsion

C57B1/6 IL-4 KO -> IFN- gamma -> No expulsion.

Both IL-4 and IL-13 play important roles in resistance.

TNF-alpha

female BALB/c mice with IL-4 KO and anti-TNF also susceptible. Anti-TNF given to resistant mouse delays worm expulsion. 

TNF-alpha may function through regulation of IL-4 and -13.

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IL-27

Chronic T muris infection associated with IL-27p28 expression in cecum. Inolved with Th1 response and proliferation of IFN-gamma secretion

In WSX-1/TCCR KO mice, IFN-gamma repsonse was reduced in Leishmania major infection 2 weeks post infection. Worms expelled. Decreased levels of Th1 cytokines and increased levels of Th2 cytokines.

WSX is a cytokine receptor that drives T1 and IFN-gamma

in a C57BL/6 WT mouse, worms not expelled.

IL-27/WSX-1I Inolved in the initiation of IL-12 cascade.

AKR mice susceptible.

Treatment of WSX-1/ KO mice with IL-12 after infection did not change susceptibility. Meaning WSX-1 is critical to the Th1 response.

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What is the Th2 effector mechanism?

Different KO mice.

IL-5 KO (eosinophils) - expulsion. Not them

scid KO with CD4+ T cells added (antibodies) - expulsion. Not them

Anti-C-kit - expulsion

Muc5ac KI - no expulsion. Goblet cell derived muc5ac essential. also epithelial cell turnover in Th2 environment.

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Why do worms induce a strong Th2 response?

  • Cytokine environment
    • mucosal surfaces, mast cells, IL-4, Th2 response
  • High antigen dose
    • Swiches off Th1 cells
  • APCs induce Th2 cell development preferentially
  • Worm proteases preferentially trigger Th2 response
  • Th2 antigens
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Trichuris trichuria

1 out of 5 people infected

Age intensity profile peaks between ages 5-8

IgE is negatively correlated with infection intensity

similar to Ascaris lumbracoides infection graph

therefore, negaive correlation between Th2 cytokines and intensity of infection

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