CLINICAL IMMUNOLOGY
TOPIC 2: IBD & CELIAC DISEASE
LECTURE 1: MOLECULAR BASIS OF CELIAC DISEASE Wednesday, 13/11/2019
What is wrong in CD? With influence of wheat, villi are damaged → poor absorption of nutrients (diagram
see slide)
a. Genetic influence: HLA-DQ2 and/or HLA-DQ8 → *is it also present in “healthy” individuals? YUP.
HLA-DQ2/8 likes peptides that contain AA with
negative charge in certain positions
E = glutamic acid (negative-charged); X = any other
AA
Actually, the affinity of HLA-DQ/gluten peptide
bonds is very low, but there are hecking T cells that
are reactive to this weak bond
b. Environment: gluten peptides
Gluten characteristics: water-insoluble, non-digestible (amylase – pepsin – trypsin can’t break it down)
for some people
But gluten doesn’t contain any negative-charged amino acid → how the heck does it affect HLA-DQ2/8
then? It is hella modified hey. What modifies the molecule?
First, these are the important peptides:
- GLIADIN (fragment of pepsin) → HLA-DQ8 restricted; doesn’t contain any negative-charged AA
either (no E’s)
- GLUTAMINE (Q) → transformed into glutamic acid with negative charge (by tissue
transglutaminase/TTG); exerts the noxious effect; Q→E modification exerts T cell response
TTG is highly specific to gluten, released in stress condition/acidic pH → modify glutamine into
glutamic acid (creating new epitope by deamidation – posttranslational modification) & amplify the
binding of gluten to HLA-DQ2/8
Why is TTG very specific to gluten in
intestines? → QXP/QXPY/QXPF are
the tissue-specific sequence of
gluten-induced intestinal villi
damage, 30% of gluten contain
that sequence
c. Effector: CD4+ T cells
From intestinal biopsy tissues of CD patients → Case = patients with CD; Controls = relatively healthier
individuals, mostly not age-matched; consider the risk of intestinal perforation, thus procedure has to be
undertaken accordingly
- T cell clones 2/5 are restricted via HLA-DQ → responds to gluten ONLY when it’s bound to HLA-
DQ2/8 (see slide)
- T cell recognizes multiple gluten peptides → CD patients can be intolerant to more than 1 type of
gluten; Characteristic: PRO-inflammatory
, CLINICAL IMMUNOLOGY
TOPIC 2: IBD & CELIAC DISEASE
- Gluten-reactive T cells are primed after the child is weaned/more solid food is introduced → various
T cells reacting to various gluten epitopes are generated early in life, some can break the individual’s
tolerance to gluten
d. Impact: tissue damage in intestines
*How does some people realize their gluten
intolerance later in life if the priming occurs very
early in life? → Not everyone has similar symptoms,
tolerance is varied among individuals - mild
symptoms can be ignored/misdiagnosed
Conclusion: there is a PERFECT BUT FATAL
MATCH between HLA-DQ molecule and TTG-
modified gluten → causing tissue damage
Paradox: 95% of patients is HLA-DQ2 (+) but 95% of HLA-DQ2 (+) individuals DO NOT DEVELOP CD; WHY?
a. High affinity T cell responses to immunodominant gluten peptides (gluten-reactive T cells) are only
found in CD patients
b. T cell repertoire among CD patients (as well as non-CD individuals) are unique to the individual → no
one is 100% the same, even among CD patients themselves, however, there are some some similarity
among the individuals with CD
- TRAV26-BV9 bias → …?
- CDR3 alfa/CDR3 beta regions of the T cell receptors are the same in 2 different CD patients; Arginine
in the middle of CDR3 alfa sequence (inserted later, non-germline) → arginine is in contact with
gluten particle, induce the T cell recognition of gluten peptide as foreign
If arginine is replaced/removed → no recognition by gluten-reactive T cell
Blue = gluten, grey = HLA
- Some people’s T cell are not primed to react against gluten in thymus → may explain why some
people don’t develop intolerance to gluten at all
c. Deamidated gluten peptide induce B cell response → create auto-antibodies
Conclusion: biased TCR repertoire is
structurally conserved → expansion of T
cells is necessary for CD development
*Does it impact Dx & Tx? PROBABLY
, CLINICAL IMMUNOLOGY
TOPIC 2: IBD & CELIAC DISEASE
Mass cytometry (next gen flowcytometry) can work with multiple markers (>12 markers) simultaneously w/o
spectral overlap
a. Benefit: more extensive, dimensionality reduction techniques possible
Visible markers: CD3, CD7
Other benefits: localize T cells, differentiate various cells in biopsy sample
b. t-SNE → …?
Grouping the cells based on their similarities; green = Treg, others = conventional T cells
Through t-SNE we can see that gluten-specific CD4+ T cells are present since early life & 28 distinct
subsets (for …?) in gluten-specific CD4+ T cells especially in gastrointestinal organs (when analysis is
combined with heat map)
t-SNE can also distinguish the source of samples → healthy control/patients, not just the location from
which the sample is taken
c. unknown cells between NK cells & ILCs → plastic, it differentiates into NK cells/ILC depending on the
administered interleukins
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller oddsters. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $4.27. You're not tied to anything after your purchase.