Lecture 15 - B Cells in Celiac Disease

Question 1

is celiac disease reversible? when?

Answer 1

yes, when gluten-free diet

Question 2

where in the body does celiac disease occur?

Answer 2

duodenum

Question 3

who does celiac disease occur in?

Answer 3

occurs in ppl who are genetically susceptible –> carry HLA-DQ2 or HLA-DQ8

Question 4

what does celiac disease do to the SI? (2)

Answer 4

1. Villous atrophy –> destroys epithelium
2. Infiltration of intraepithelial lymphocytes btwn enterocytes

Question 5

what type of cytokines are produced? where?

Answer 5

pro-inflammatory cytokines (like IL15) in gut below and within epithelium

Question 6

what is gluten made of?

Answer 6

long filament rich in protein residues that make them resistant to proteolytic degradation in the gut

Question 7

describe how gluten causes celiac disease (8)

Answer 7

1. gluten is rich in glutamine residues which are substrate for TG2 when they cross epithelium
2. TG2 converts glutamine to glutamate
3. now gluten has good binding ability to MHC made of HLA-DQ2/DQ8
4. APC presenting gluten can migrate to secondary lymphoid organ and present to naive T cells
5. T cells make pro-inflammatory cytokines
6. the CD8 intraepithelial T cells (CTLs) expand and express NK receptor to kill epithelial cells
7. B cells are activated to make anti-gluten peptide Ab and anti-TG2 autoAb
8. increased plasma cells in mucosa

Question 8

what allows gluten to become antigen?

Answer 8

the post-translational modification by TG2 that deamidates glutamine to glutamate

Question 9

describe Ab production in celiac patients who eat gluten vs don’t eat gluten

Answer 9

eat gluten = huge production of Ab

don’t eat gluten = less Ab

Question 10

describe correlation btwn Ab and severity of disease. how do we know?

Answer 10

no correlation btwn amount of Ab produced and severity of disease

can have moderate infiltration of epithelial lymphocytes with and without Ab production

Question 11

how do we measure severity of celiac disease?

Answer 11

infiltration of epithelial lymphocytes

Question 12

are Ab pathogenic?

Answer 12

probably not! no correlation btwn production and severity

Question 13

what happens when anti-TG2 Ab is active?

Answer 13

TG2 enzymatic activity is NOT inhibited by the anti-TG2 Ab –> therefore no direct role on the enzyme itself

Question 14

what deposits in epithelium with celiac disease?

Answer 14

anti-TG2 IgA and TG2 form a complex that deposits in tissue and accumulates over time to impair tissue function

Question 15

why might IgA Ab actually be pathogenic? but why is this disproven?

Answer 15

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

Question 16

is there lots of plasmacytosis in celiac disease?

Answer 16

yes

Question 17

how do we know there is high level of plasmacytosis in celiac?

Answer 17

10% of total plasma cells recognize TG2 –> huge influx of plasma cells in the gut

Question 18

what can plasma cells bind? (2)

Answer 18

1. TG2
2. Gluten peptide

Question 19

plasma cells possess all machinery of __________

Answer 19

plasma cells possess all machinery of antigen presentation

Question 20

do plasma cells contribute to pathogenesis? how do we know?

Answer 20

probably not

ppl thought maybe act as APC to activate T cells but if you remove plasma cells = no effect on pathogenesis

Question 21

what happens to patients with celiac + other autoimmune disease treated with anti-CD20?

Answer 21

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

Question 22

what happens to mice treated with anti-CD20? significance?

Answer 22

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

Question 23

what is the villous to crypt ratio?

Answer 23

indication of tissue damage

Question 24

what does a high villous to crypt ratio mean?

Answer 24

villi are restored

Question 25

what does a low villous to crypt ratio mean?

Answer 25

tissue damage

Question 26

what is the model that they use to explain the formation of Ab against gluten and TG2?

Answer 26

Hapten-Carrier Model

Question 27

describe the Hapten-Carrier Model

Answer 27

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

Question 28

are B cells APC for TG2 or gluten? why?

Answer 28

both! hapten-carrier model

Question 29

experiment that evidence for Hapten-Carrier Model in T cell line

Answer 29

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

Question 30

where do B cells with TG2-gluten complex interact with T cells? (2)

Answer 30

1. in Peyer’s Patches
2. isolated lymphoid follicles with spontaneous development of T and B cells in gut

Question 31

what determines whether CD4 T cells get activated?

Answer 31

MAGNITUDE of B cells with TG2-gluten that can activate CD4 T cells in gut

Question 32

what is amount of CD4 T cells in gut correlated to?

Answer 32

tissue damage

Question 33

tissue damage is correlated to: (2)

Answer 33

1. number of plasma cells in gut
2. number of CD4 T cells in gut

Question 34

what causes death of epithelial cells? how?

Answer 34

intraepithelial CTLs

TCR recognizes MHC on epithelial cells to induce cytotoxicity

Question 35

infiltration of B cells in epithelium when normal mouse is fed gluten:

Answer 35

HUGE increase of B cells in epithelium when normal mouse is fed gluten

Question 36

infiltration of B cells in epithelium when B cell deficient is fed gluten:

Answer 36

reduced infiltration of B cells

Question 37

what is the consequence of having reduced infiltration of B cells?

Answer 37

CD4 T cells are less cytotoxic –> express less NK receptor –> express less cytotoxic molecules

Question 38

describe what they found when they sequenced Ig heavy chain of TG-specific plasma cells (2)

Answer 38

compared to other plasma cells:
1. TG-specific plasma cells have selection for specific type of antigen
2. much less SHM

Question 39

what can we conclude about the fact that there is much less SHM in TG-specific plasma cells

Answer 39

since SHM occurs in germinal center, fewer B cells are going in germinal center to interact with T cells

Question 40

if fewer B cells are interacting with T cells in germinal center, where are they interacting instead?

Answer 40

extra-follicular pathway