Lecture 15 - B Cells in Celiac Disease Flashcards
is celiac disease reversible? when?
yes, when gluten-free diet
where in the body does celiac disease occur?
duodenum
who does celiac disease occur in?
occurs in ppl who are genetically susceptible –> carry HLA-DQ2 or HLA-DQ8
what does celiac disease do to the SI? (2)
- Villous atrophy –> destroys epithelium
- Infiltration of intraepithelial lymphocytes btwn enterocytes
what type of cytokines are produced? where?
pro-inflammatory cytokines (like IL15) in gut below and within epithelium
what is gluten made of?
long filament rich in protein residues that make them resistant to proteolytic degradation in the gut
describe how gluten causes celiac disease (8)
- gluten is rich in glutamine residues which are substrate for TG2 when they cross epithelium
- TG2 converts glutamine to glutamate
- now gluten has good binding ability to MHC made of HLA-DQ2/DQ8
- APC presenting gluten can migrate to secondary lymphoid organ and present to naive T cells
- T cells make pro-inflammatory cytokines
- the CD8 intraepithelial T cells (CTLs) expand and express NK receptor to kill epithelial cells
- B cells are activated to make anti-gluten peptide Ab and anti-TG2 autoAb
- increased plasma cells in mucosa
what allows gluten to become antigen?
the post-translational modification by TG2 that deamidates glutamine to glutamate
describe Ab production in celiac patients who eat gluten vs don’t eat gluten
eat gluten = huge production of Ab
don’t eat gluten = less Ab
describe correlation btwn Ab and severity of disease. how do we know?
no correlation btwn amount of Ab produced and severity of disease
can have moderate infiltration of epithelial lymphocytes with and without Ab production
how do we measure severity of celiac disease?
infiltration of epithelial lymphocytes
are Ab pathogenic?
probably not! no correlation btwn production and severity
what happens when anti-TG2 Ab is active?
TG2 enzymatic activity is NOT inhibited by the anti-TG2 Ab –> therefore no direct role on the enzyme itself
what deposits in epithelium with celiac disease?
anti-TG2 IgA and TG2 form a complex that deposits in tissue and accumulates over time to impair tissue function
why might IgA Ab actually be pathogenic? but why is this disproven?
the IgA-TG2 complex brings in more gluten peptides into mucosa and induce tissue damage
IgA deficient patient can still have celiac disease so IgA might not be pathogenic
is there lots of plasmacytosis in celiac disease?
yes
how do we know there is high level of plasmacytosis in celiac?
10% of total plasma cells recognize TG2 –> huge influx of plasma cells in the gut
what can plasma cells bind? (2)
- TG2
- Gluten peptide
plasma cells possess all machinery of __________
plasma cells possess all machinery of antigen presentation
do plasma cells contribute to pathogenesis? how do we know?
probably not
ppl thought maybe act as APC to activate T cells but if you remove plasma cells = no effect on pathogenesis
what happens to patients with celiac + other autoimmune disease treated with anti-CD20?
Clinical GI symptoms improved so removing B cells may help what’s happening in the gut BUT this study only looked at symptoms, not molecular immunology
what happens to mice treated with anti-CD20? significance?
B cells depleted = improvement in celiac disease when exposed to gluten
anti-B cells does not deplete plasma cells, so other B cells may be involved in pathogenesis
what is the villous to crypt ratio?
indication of tissue damage
what does a high villous to crypt ratio mean?
villi are restored
what does a low villous to crypt ratio mean?
tissue damage
what is the model that they use to explain the formation of Ab against gluten and TG2?
Hapten-Carrier Model
describe the Hapten-Carrier Model
TG2 deamidates gluten peptide and crosslinks peptides to form complex of TG2-gluten which binds BCR and gets presented to T cells to activate T cells and activate B cells to make anti-TG Ab
are B cells APC for TG2 or gluten? why?
both! hapten-carrier model
experiment that evidence for Hapten-Carrier Model in T cell line
T cell line expressing gluten-specific TCR in co-culture with B cells –> T cells can recognize TG2-gluten complex
look at IL2 release to see if T cells activated
results: only in presence of TG2-gluten complex will promote activation of CD4 T cells with IL2 release
where do B cells with TG2-gluten complex interact with T cells? (2)
- in Peyer’s Patches
- isolated lymphoid follicles with spontaneous development of T and B cells in gut
what determines whether CD4 T cells get activated?
MAGNITUDE of B cells with TG2-gluten that can activate CD4 T cells in gut
what is amount of CD4 T cells in gut correlated to?
tissue damage
tissue damage is correlated to: (2)
- number of plasma cells in gut
- number of CD4 T cells in gut
what causes death of epithelial cells? how?
intraepithelial CTLs
TCR recognizes MHC on epithelial cells to induce cytotoxicity
infiltration of B cells in epithelium when normal mouse is fed gluten:
HUGE increase of B cells in epithelium when normal mouse is fed gluten
infiltration of B cells in epithelium when B cell deficient is fed gluten:
reduced infiltration of B cells
what is the consequence of having reduced infiltration of B cells?
CD4 T cells are less cytotoxic –> express less NK receptor –> express less cytotoxic molecules
describe what they found when they sequenced Ig heavy chain of TG-specific plasma cells (2)
compared to other plasma cells:
1. TG-specific plasma cells have selection for specific type of antigen
2. much less SHM
what can we conclude about the fact that there is much less SHM in TG-specific plasma cells
since SHM occurs in germinal center, fewer B cells are going in germinal center to interact with T cells
if fewer B cells are interacting with T cells in germinal center, where are they interacting instead?
extra-follicular pathway
