IBD Flashcards
(30 cards)
MALT (mucosal associated lymphoid tissue)
A secondary lymphoid tissue, along with the spleen and lymph nodes. Site of induction of mucosal responses
IBD gut-associated, GALT.
- digestive tract possesses largest mass of lymphoid tissue in the body. is the largest immune system of the body. SA 1 1/2 tennis courts!
- regulates tolerance to commensal (friendly) bacteria
- needs to maintain immune homeostasis. So is stable but constantly dynamic and working
- produces more IgA than IgG. 3-5 grams of IgA secreted/ day. 10^10 plasma cells that produce IgA per metre of intestine. more than other Igs.
Type of MALT Tissues
GALT - in small clusters in terminal ileum region of small intestine. called Peyer’s patches. monitors intestinal bacteria populations and prevent pathogenic growth.
- also in ones and twos. called isolated lymphoid follicles.
- tissue that drains gut. Mesenteric lymph nodes.
all present even without disease
Sites of Expression
MALT area is organized. Has distinct structures with areas where B/T/APC cells reside like a germinal center.
Has other sites of expression that aren’t really part of MALT but still have immune function. Needed because so many antigens and only one epithelial layer separates the outside of the body to the inside.
- cells differentiated in MALT but production of antibodies, of cytokines occur at those other sites
Lamina propria - beneath epithelium. dispersed in it are T/B cells, eosinophils, a big mix of effector cells.
Intra-epithelial compartments - small.
M cells
Follicle associated epithelium (FAE) - rounded area of epithelium between the protruding villus parts where M cells are.
Microfold/membraneous cells
- bring antigens to the lymphoid tissue. Like breaks in the tight barrier of epithelium that connects lumen to MALT
Process - (M cells bring antigens in. Antigens presented by APCs, DCs. DCs activate T cells. T cells split into CD4 and CD8. CD4 activate B cells. B cells proliferate highly to form germinal center. B cells then can class switch to IgA which is particularly associated with mucosal immunity.)
Mucosal homing receptors
Necessary for antigens and cells to hone to specific sites because the gut SA is just too huge compared to the capacity of the immune cells!
GALT DCs also generate retinoic acid from Vitamin A which when bound to a receptor on lymphocytes, induces mucosal homing receptors for cells to move from site of induction (at MALT or germinal center) to site of expression.
(process happens from birth and structures start forming early on)
1) homing occurs when a4b7 on effector cells matured in lymph node is induced by retinoic acid. Travels through blood stream, passes by epithelium, blood vessels that line the gut, will hone onto MAdCAM-1 on the epithelium at sites of immune response. Thus they are ‘imprinted’ with a4b7.
2) CCR9 chemokine that causes cells to move to the intestinal epithelium.
= two levels of homing/recruitment. boundary of epithelial cells (MAdCAM-1) bring cells in.then epithelium themselves make chemokines to attract imprinted cells.
IgA induction
B cells from GALT go to Mesenteric lymph node via lymphatic system and into blood stream and back to gut FAE via homing and MAdCAM where they rapidly turn into plasma cells. They produce dimeric IgA which is transported into gut lumen.
IgA - uncertain function. previously thought binds to antigen and just passes through. now, thought preferentially binds to actual immunologic bodies.
Intestinal T cells
Peyer’s patch and GALT. Although germinal center mostly B cells, have a lot of CD4 T cells. to support B cells. Next to it, have T cell zone where CD4 majority but some CD8.
Lamina propria - CD4
Interepithelial lymphocytes - CD8 predominant
Goblet cells (villus)
Found in the intestinal tract. Secretes mucus. A thick layer on the lumenal surface of the epithelial cells. Mucus limits exposure of epithelial cells to bacteria
Over FAE, mucus much less, defense weaker.
Structure of epithelium
Has the rounded FAE where M cells are and where below is the GALT tissue.
Has villus where lamina propria and effector cells mostly are.
Have crypt where proliferation of epithelial cells occur to renew epithelial layer.
Paneth cells (crypt)
In the small intestine
produce antimicrobial peptides e.g. a-defensins, activated to stimulate defensins.
- an extra defense mechanism in the microbiota of the lumen
Also have NOD-like (nucleotide oligerization domain) receptors to sense microbes PAMPs to activate inflammation or apoptosis
Defectiveness involved in small bowel Crohn’s. Nod2, UPR, autophagy gene polymorphisms affect it.
Microbial sensing
- GALT and M cells bring antigen in
- paneth cells have NOD-like receptors that sense PAMPs
- DC in GALT and lamina propria can reach through epithelial layer to recognize bacteria through TLRs.
Migration
after recognition, DC migrate away from gut to lymph nodes. T cells then differentiate depending on cytokines around it.
- lots of TGFb produced in gut environment. induces Treg. .
- Il-1, Il-6 produces Th17
- IFNy, Il-4
Have all lineages of cells, pro and anti-inflammatory, and regulatory. Balance is KEY!
Oral tolerance
Unresponsiveness to innocuous substances such as food.
Although antigens can’t enter through epithelial except M cells, foods need to be absorbed.
Food enters as peptides. Can go through lymphatics to blood. Can also drain into mesenteric lymph nodes.
- DCs there are associated with oral tolerance. Secrete TGFb and stroma generates retinoic acid. To induce Foxp3 Tregs for the antigen. (retinoic acid also induces homing towards MAdCAM-1) thus Foxp3 Tregs home back to gut and suppresses immune response for oral tolerance towards food.
Intestinal bacteria, microbiota along the intestine.
and in IBD
More bacteria in gut than your own cells. Bacteria is very important for your health.
90% of the bacteria belong to two phyla (rank)
- Gram - bacteriodetes
- Gram + fermicutes
Composition of microbiota will develop early on, often similar to mothers (not genetic, just similar to those you live with). It changes along the gut.
Stomach has lots of HCl that usually sterilizes ingested bacteria, so microbiota is that of bacteria that actually lives there.
- As go along stomach from periphery to distal ileum more inside, there is more bacteria and more of the GALT. That’s where optimal exposure to immune system is.
- go further to colon, even more bacteria. a bioreactor with major metabolic activity - can generate short chain fatty acids
- SCFA butyrate derived from dietary fibre. So bacteria can break down fibrous diet to generate butyrate that binds to G protein coupled receptors that can modulate inflammation (mice that are deficient are more susceptible to inflammation)
In IBD:
bacteria profile changes. Is it the cause? or consequence?
- 90% bacteria decrease. adherent bacteria to mucosal surfaces increase
- butyrate producing population decrease. Loss of anti-inflammatory functions.
Symbiotic relationship between host and microbiota
Host environment isn’t trying to kill all bacteria but fostering their use.
- bacteria can take fibre from diet and generate butyrate from it in the colon for the benefit of the immune system. (mouse model)
- butyrate also can go through epithelium to induce differentiation of naive t cells into Tregs to promote immune suppression.
In health there is an active equilibrium between microbiota and host.
- MicrobeAMPs from microbiota initiates immune responses (ROS, Tregs, cell-mediated, AMPs, inflammation) from the gut that affects the microbiota
FUN FACT
Yakult like mice eating poo. Expose your small intestine to the same microbes the colon sees.
IBD
Common, severe and debilitating inflammatory diseases. (not including Irritable Bowel Syndrome, severe but not serious and immune)
- chronic but not infectious.
- relapsing and remitting, have acute periods
- 1/250 in the UK
- between ages 10 and 40
- global incidence. disease of higher income countries, the global north.
Dysregulation of epithelial cells. makes more susceptible to other diseases and cancer
Crohn’s disease
affects different areas of the colon. Patchy skip lesions wherever even in the small intestine.
Symptoms:
- abdominal pain
- urgent diarrhea
- lack of energy, lack of weight gain
- extra-articular impacts, joints, skin, mouth.
Signs:
- mucosal/bowel wall thickens. cobblestoning and raised bumps
- fat wrapping around the outside of the gut
- fistula forms. gut penetrated and may be stuck to other parts of gut
- granulomas (clusters of macrophages) present
Is transmural so not only an inflammation of the mucosal layer with lymphoid tissues, but also enlarge the connective tissues underneath.
Ulcerative Colitis
affects the rectum and the colon (aka large intestine). degree depends on how much colon affected, just the rectum (proctitis), part of the colon (left-sided colitis) or entire up to appendix (pancolitis)
- continuous small ulcers inside lining of colon
Symptoms:
- bloody diarrhea, pain
‘Cured’ by removal surgery
Signs:
- no thickening but ulcers form on mucosal surface. pseudopolyps
- epithelial cells, crypts are distorted
Antibodies in IBD
Production seemingly increases.
More IgA, but much more IgG, signals a more systemic inflammatory response since it can activate complement system. (IgA is less inflammatory, agglutinates stuff).
UC may produce autoantibodies against neutrophil proteins, but not really pathogenic.
- doesn’t really count as autoimmune unless you consider the bacteria in your gut self-antigens
Pathology
Polygenic - many gene variants related to immune regulation
Microbial flora is altered - affects production of defensins, IgA, makes deficient
Environment - diet, hygiene, smoking
Environment and genetics
Environment important.
- Migrants may take on IBD if country has higher prevalence, esp more westernized countries.
- Smoking - can make more susceptible and exacerbate Crohn’s. but low rates for UC!
- hygiene hypothesis. exposure to infections decrease atopy. - higher helminth less ibd
- Hereditary 5-10%. not much diff between di/monozygotes. Monozygotic twin 50-70% concordance, but only 10-20% concordance UC. (low genetics heritability) Inherited from mother (fetal microchimerism)
Risk alleles. Some shared but many unique to either Crohn’s (to do with innate immune) or UC. It’s an immune disease either way, impacts:
- Innate immune, Th17, Il-10, MHC II
- Il-12, Il-23 axis that regulates IgE inflammation, but promote cell-mediated response. and Th17 inducing.
All modest odds ratio but accumulate
Butyrate
Short chain fatty acid (SCFA) derived from dietary fibre. Produced by bacteria in colon that ferment fibre.
- food for the colonocytes, 70% energy. protective against colon cancer, too much inflammation
Will bind to GPCR to modulate inflammation. Can enter through epithelium to induce T cell differentiation to Tregs.
- Mice with ko that don’t have SCFA cannot resolve inflammation
Genotype study
1) Nod2 gene.
2) Autophagy (destruction of cells) genes
3) Unfolded protein response genes
ultimately all are necessary. Pathway convergence.
- UFR genes XBP1 if knocked out will lead to ER stress, leading to NF-kB and autophagy pathway. Autophagy will try to suppress inflammation
- Autophagy ATG16L1 if knocked out, will also lead to ER stress and make more susceptible to inflammation
- if knock both out, ER stress, autophagy can’t rescue and stop inflammation.
