Induction of IgA responses In enteric inflammation

Question 1

What is the relevance of ER stress in intestinal inflammation?

Answer 1

• 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 2

What is the link between ER stress and IgA?

Answer 2

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

Question 3

What are the three types of IgA and their function?

Answer 3

• Natural IgA: is microbiota independent.
• 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.
• Classical IgA: T-cell dependent, microbially induced, somatic hypermutation (SHM). Classical IgA requires follicular structures. Germinal center formation. It is useful for buffering, protection, and neutralization of pathogens and pathobionts.

Question 4

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

Answer 4

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

Question 5

What types of cells produce natural antibodies?

Answer 5

Peritoneal B-1 cells produce natural antibodies.

Question 6

Where do B-1 cells reside?

Answer 6

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

Question 7

When are natural antibodies produced by B-1 cells?

Answer 7

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

Question 8

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

Answer 8

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 9

Where is classical IgA induced?

Answer 9

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

Question 10

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

Answer 10

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