GI Immunology (continue w/ handout on page2) Flashcards
Th1
type I helper T cells
recognize antigen and make a lymphokine that attracts thousands of
macrophages
-make IFN gamma, attracts and activates M1 mac and IL2 which helps CTL get activated
-M1 mac are aggressive; “classically activated”
mistakenly activated in IBD, RA, T1D
Th17
- more powerful than Th1
- make IL17
- DC make IL23 that helps differentiation into Th17
- imp for CANDIDA, Listeria, and other org
- IL-23 is imp in IBD, psoriasis
important cytokine in crohns, uc
IL-23
Th2
stimulate mac to become M2 alternatively activated
- help wall off pathogens and promote healing
- imp in parasite immunity if Th1 M1 can’t kill invader
- Th2 makes IL-4 (attracts mac and eosinophils)
-involved in asthma
Follicular helper T cells
Tfh
stimulated by antigen and migrate from T cell areas of lymph nodes into the B cell follicles, where they help B cells get activated and make the IgM, IgG, IgE
and IgA antibody subclasses.
Treg
-make cytokines (IL10, TGF-beta) that suppress activation and function of Th1, Th17, and Th2– keep immune response in check
CTL
Cytotoxic or killer Tcells
-destroy any body cell bearing a foreign or abnormal antigen on its surface, presented on Class I MHC.
They can also make IFNγ which attracts macrophages
CD8 on surface
look for antigen on MHC Class I
CD4
marker on TH1, 2, 17, fh, reg -these all look for antigen on MHC class II on mac, DC, and B cells
CTL have CD8, look for antigen on MHC Class I on all nucleated cells
Th0
In thymus:
- binds peptide/MHC with HIGH affinitiy:
- dies by apop or turns into a Treg cell (tTreg)
Th0 in gut:
binds peptide/MHC in presence of TGF-beta ONLY turns into a Treg (iTreg)
but in presence of TGFbeta and IL-6 turns into a Th1, Th2, or Th17
**gut should be Treg dominant
T cell development
Pre-T cells in the thymus proliferate rapidly and express a randomly assembled (from T-cell receptor V(D)J libraries) (TCR). Then
examine the surfaces of stromal cells.
Non-selection: If there is essentially no affinity between the TCR and the MHC on the stromal
cells (which are always loaded with a self-peptide of some sort).
Negative selection: If there is high affinity for a self-peptide in MHC, the developing T cell is
autoimmune, and dies by apoptosis. ►BUT A significant proportion of these cells
can turn into Tregs! They are called tTreg, and they serve to suppress Th1/2/17 as well as CTL
that are mistakenly recognizing self tissues.
Positive selection: If there is low affinity (above a certain threshold, but not high enough to
activate the T cell) it is selected to mature and become part of the T cell repertoire. ( takes place usually when the CDR 1s and CDR2s of both the TCR α and β chains interact adequately with amino acid residues on the alpha-helical sides of the peptide-binding MHC groove)
–>then in periphery, strong contacts with CDR3s leads to T cell stimulation
T cells involved in celiac
Th1 and Th17 against gliadin peptides
Are there TTG2 self reactive B cells?
yes, but it is ok if there isn’t self reactive T cells to react.
Gliadin:TTG2 could serve as stimulus for antiTTG2 autoantibody by formation of hybride self-foreign antigen.
(IgA)
Tfh then may help B cell, and then there is Ab against TTG2
-binds to TTG2 in gut, but then cross rxn with TTG3 by epitope spreading–> dermatitis herpetiformis
In the gut, what T cell is highly abundant and why?
Treg
B/c abundance of TGFbeta in the submucosal Peyer’s patches and DC make IL-10.–> both stim Treg devel
(Tfh are also common in Peyer’s patches and drive B cells to make IgA creating an almost sterile mucus layer)
What happens with combination of TFGbeta AND IL-6?
Downregulation of Treg and upreg of Th1 and Th17
-IL6 produced by epi cells in resp to stress/damage
Treg in thymus vs gut
thymus: tTreg
gut: iTreg (induced by exposure to normal gut flora)
Celiac Disease
-HLA-DQ2 or DQ8 allele
-These Class
II MHC are uniquely able to present immunodominant peptides derived from gliadin to Th1/Th17 cells.
-gliadin peptides
-TTG2 tries to cleave highly branched gliadin (proline, glutamine, glutamic acid side chains), but could “get stuck” and be unable to release substrate.
-B cell that is anti-TTG2 takes up the complex and presents foreign gliadin peptides to Tfh (specific for DQ2 or DQ8).
-This helps B cell make ab to TTG2
-common: IgA
-cross reactivity to TTG3 appears (dermatitis herpetiformis)
-celiac isn’t autoimmune, but derm herpetiformis is
-2HLA-DQ allels also confer risk of Type I diabetes
Arthritis and IBD
5-50% of IBD pts report arthritis in one or more joints
Non-Celiac gluten sensitivity
Negative blood tests for celiac disease and no sign of damage on an intestinal biopsy.
Symptom improvement when gluten is removed from the diet.
Recurrence of symptoms when gluten is reintroduced.
No other explanation for the symptoms.
May be sensitivity to Fodmaps “fermentable oligosaccharides,
disaccharides, monosaccharides and polyols”
not HLADQ2 or 8 assoc
may be form of a food allergy
Meat sensitivity
-Sudden intolerance to red meat
-IgE antibody specific to
galactose-alpha-1,3-galactose (alpha-gal)
-sx: delayed mild to severe anaphylaxis (hives, wheezing, coughing)
-Avoiding meat prevents sx
-Lone Start tick makes lots of alpha-gal in its drool
- Its a parasite, the typical response to it will be the Th2 cells, and the Th2-like Tfh that direct B cells to switch to making IgE.
The IgE can then react against alpha-gal coming in with a load of meat.
IBD
GWAS
71 risk loci for Crohn’s
47 for UC
table on phone
Also: a serious gut infection (listeria? e coli?) might make people susceptible for later IBD development. (Th1 response against commensals can’t be suppressed)
