Th1/Th2 cell development
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.
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)
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.
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
IL-13 IL-4 and TNF alpha
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
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.
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.
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.
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.
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
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