Induction of protective IgA responses in enteric inflammation

Question 1

What are the characteristics of inflammatory bowel diseases (Crohn’s disease and ulcerative colitis)?

Answer 1

• Chronic gut inflammation
• Affects quality of life
• Affects young people
• Often leads to complications later on

It is incurable and the incidence is on the rise

Question 2

How many Crohn’s disease patients require surgery?

Answer 2

50-80%

Question 3

How many Crohn’s disease patients require a permanent stoma?

Answer 3

15%

Question 4

What is the goal of IBD treatment?

Answer 4

Goal of treatment is to prevent the complications and improve the quality of life

Question 5

What is the etiology of IBD?

Answer 5

It is a very heterogenious group of diseases with a complex etiology. Crohn’s disease and ulcerative colitis is an accentuated immune response to lumenal antigens like microbes. It is not a monogenic disease, influence of genetics is about 20%
o >240 genes are associated with either Crohn’s disease or ulcerative colitis

Question 6

What is a mouse model for ER stress?

Answer 6

Mice that lack Xbp1ΔIEC in the intestinal epithelium. These mice have Paneth cell abnormalities and develop spontaneous ileitis and intestinal inflammation. The inflammation is microbiota dependant, which is very similar to Crohn’s disease. If compensatory autophagy gene is also knocked out, this leads to severe Crohn’s disease-like transmural inflammation.

Question 7

What is the relevance of ER stress in intestinal inflammation?

Answer 7

• ER stress is involved in the etiology of (subgroups of) inflammatory bowel diseases
• ER stress in the intestinal epithelium leads to spontaneous intestinal inflammation
• ER stress-induced inflammation does not develop in Germ-Free mice, indicating that microbiota play a crucial role in the development of inflammation

Question 8

How can we restore homeostasis in IBD?

Answer 8

Add more of the anti-inflammatory part

Question 9

What are the functions of IgA?

Answer 9

IgA plays a crucial role in intestinal health
Functions:
o Antigen entrapment in mucus –> immune exclusion
o Reducing bacterial virulence
o Assisting in excretion of antigens from lamina propria

Question 10

What is the link between ER stress and IgA?

Answer 10

ER stress in the intestinal epithelium leads to increased numbers of IgA plasma cells. This interesting because basal plasmacytosis (more plasma cells) is a hallmark of IBD
ER stress selectively induces IgA and not other Ig classes

Question 11

What are the differences between IgA and IgG?

Answer 11

IgA coats disease-driving microbiota (in Crohn’s disease and UC). IgA is the dominant isotype in Crohn’s disease. CVID and IgA deficiency increases in Crohn’s disease.

IgG plasma cells are increased in human biopsies of Crohn’s disease. There is evidence of anti-commensal IgG (serum and luminal) in ulcerative colitis.

Question 12

What is the influence of IgA or B-cell loss on small intestinal inflammation?

Answer 12

Loss of IgA or B-cells aggravates small intestinal inflammation

Question 13

Where does IgA function and how does it get there?

Answer 13

IgA functions in the intestinal lumen, and is transported through the polymeric immunoglobulin receptor (Pigr). IgA coats epithelial cells and hinders epithelial interaction with the epithelium, and protects through so called ‘immune exclusion’. IgA protection is dependent on transcytosis to the lumen

Question 14

What are the three types of IgA?

Answer 14

“Natural” IgA, “Primitive” IgA and “classical” IgA

Question 15

What is natural IgA?

Answer 15

Natural IgA is microbiota independent.

Question 16

What is primitive IgA and what is its function?

Answer 16

Primitive IgA:
T-cell independent, microbially induced, no somatic hypermutation (SHM). It requires follicular structures. It is useful for buffering of commensals and buffering and protection from pathobionts.

Question 17

What is classical IgA and what is its function?

Answer 17

Classical IgA:
T-cell dependent, microbially induced, somatic hypermutation (SHM). Classical IgA requires follicular structures. Germinal center formation.

Classical IgA is useful for buffering, protection and neutralization of pathogens and buffering and protection from pathobionts

Question 18

Which type of IgA is a possible target if ER stress is an important factor in IBD?

Answer 18

ER stress-induced IgA does not require GALT or T cell help. This means that the target is “natural” IgA.

Question 19

What types of cells produce natural antibodies?

Answer 19

Peritoneal B-1 cells produce natural antibodies

Question 20

Where do B-1 cells reside?

Answer 20

B-1 cells reside mostly in pleural and peritoneal cavity, 1-2% in spleen

Question 21

When are natural antibodies produced by B-1 cells?

Answer 21

Natural antibodies are produced in ‘absence’ of foreign antigen exposure. IgM B-1 cells preferentially switch to IgA in the intestine
There is no somatic hypermutation, no T-cell help –> polyreactive. They don’t bind specifically to one antigen

Question 22

Where is small intestinal B-1 cell derived IgA important?

Answer 22

Small intestinal B1 cell-derived IgA coats commensals. Really important in the small intestine and not so much in the colon. This is also where we see our whole phenotype! B1 cells are programmed to home to the small intestine.

Question 23

Are peritoneal-derived B cells the source of IgA in response to enteric inflammation?

Answer 23

Intestinal epithelial ER stress leads to activation of peritoneal B1 cells. GF Xbp1ΔIEC have similar peritoneal B1b responses as SPF mice. Epithelial ER stress-induced IgA is microbiota independent. scRNA-Seq demonstrates that B1 cells are the only peritoneal cells that respond to epithelial ER stress.

Question 24

Is there a circulating factor released from ER stressed epithelium that activates peritoneal B1 cells?

Answer 24

Parabiosis experiments reveal the existence of a transmissible factor.
The mice will share bloodstream, but you can still distinguish their immune cells from each other because they have an immune marker that is a little different. Epithelium of sick mice also activated B1 cells of attached, healthy mice! This means that there is a transmissible/circulating factor!

Question 25

Where is classical IgA induced?

Answer 25

Classical IgA is induced in lymphoid structures such as Peyer’s patches, which requires T cell help

Question 26

What is the influence of peritoneal derived IgA+ plasma cells on inflammation?

Answer 26

Peritoneal derived IgA+ plasma cells dampen inflammation in mouse models of Crohn’s disease