GI immunology

Question 1

Function of type 1 helper T cells

Answer 1

Th1 recognize antigen and make IFNgamma which activates M1 macrophages, and IL-2 which helps CTL get activated.

Question 2

Th17 helper T cells function

Answer 2

Make IL-17 and cause focused inflammation, important in resistance to listeria and candida also in forms of autoimmunity. Is expanded by IL-23

Question 3

Type 2 helper T cells function

Answer 3

Make IL-5 and IL-4 which attracts macrophages and eosinophils. Also stimulates macrophages to become M2 (alternatively activated). Important in parsite immunity

Question 4

M1 vs M2 macrophages

Answer 4

M1: inflammatory, destructive, angry macrophages. M2: Wall off pathogens and promote healing after M1/ Th1 response. Important in parasite immunity of M1 cant kill invader

Question 5

Follicular helper T cells function

Answer 5

Migrate from T cell area of lymph nodes into B cell follicles where they help activate B cells

Question 6

Regulatory T cells function

Answer 6

Make Il-10 and TGFbeta which suppresses activation and funciton of Th1, Th17 and Th2. Keeps immune response in check.

Question 7

Cytotoxic T cells function

Answer 7

Destroy any body cell that bears foreign or abnormal antigen on surface, presented on class I MHC. Also make IFNgamma which attracts macrophages to eat the cells

Question 8

T helper cells molecular marker

Answer 8

CD4- increases affinity for antigen, helps in activation

Question 9

CTL molecular marker

Answer 9

CD8

Question 10

MHC classes for Thelper and CTL

Answer 10

Th: MHC class II, located on APCs macrophages, dendritic cells and B cells. CTL: MHC class I, located on all nucleated cells.

Question 11

Describe T cell development in thymus

Answer 11

Pre-T cells in the thymus begin proliferating rapidly and express a randomly assembled (from T-cell receptor V(D)J libraries) T cell receptor (TCR). They then examine the surfaces of stromal cells and can undergo non-selection, negative selection or positive selection.

Question 12

What is T cell non-selection

Answer 12

No affinity btw TCR and MHC containing self peptide

Question 13

Negative selection

Answer 13

If there is high affinity for a self-peptide in MHC, the developing T cell is autoimmune, and dies by apoptosis. OR some of them will turn into Tregs (tTreg) and will suppress Th1/2/17 that are mistakenly recognizing self tissues.

Question 14

Positive selection

Answer 14

If there is low affinity btw TCR and MHC containing self peptide (above a certain threshold, but not high enough to activate the T cell) it is selected to mature and become part of the T cell repertoire. CDR1 and CDR2 of the TCR alpha and beta chains interact with MHC, but not CDR3 (which would result in activation of the T cell)

Question 15

T cell development in lymph nodes

Answer 15

T helpers begin as undecided precursor, Th0, in paracortex of lymph node. When correct Ag is presented by dendritic cells, Th0 divides and differentiates into Th1, Th17, Th2, Tfh or Treg.

Question 16

What determines the fate of a Th0 cell

Answer 16

The previous experience of the DC—the conditions in the periphery when it was stimulated, what TLR were engaged, what cytokines and chemokines predominated

Question 17

Located of Peyers patches

Answer 17

submucosa of gut

Question 18

2. Describe the cytokine/cell milieu in a Peyer’s patch under normal conditions, and the consequences for the development of Th subsets.

Answer 18

TGFbeta and IL-10 (from DC): induces Th0 into Treg which prevents immune reactions to food and non-pathogenic bacteria. Tfh: drive B cells to make IgA which makes mucus layer sterile. Tfh and Treg may be interchangeable.

Question 19

2. Describe the cytokine/cell milieu in a Peyer’s patch under stress/infection conditions, and the consequences for the development of Th subsets.

Answer 19

IL-6 is produced by epithelial and other cells in response to stress or damage. The combo of IL-6 and TGFbeta downregulates Treg and upregulates Th1 and Th17.

Question 20

Method of recognition of non-pathogenic organisms

Answer 20

innate immunity- PRRs bind PAMPs. Examples of PRRs include TLRs and NOD2 which detects muramyl dipeptide, a component of bacterial cell walls, and triggers cytokine production by activating NF-kB

Question 21

Compare Treg in gut to those in thymus

Answer 21

The Treg in the gut are different from those generated in the thymus, so they’re called iTreg (induced, by exposure to normal flora). They prevent chronic inflammation that would result from Th1/2/17 recognizing normal commensal flora; if they are knocked out in mice, IBD results, but not systemic autoimmunity.

Question 22

How is apoptosis involved in IBD

Answer 22

Macrophages eating apoptotic cells make insufficient TGFβ

Question 23

How is endoplasmic reticulum involved in IBD

Answer 23

ER stress may release damage-associated molecular patterns (DAMPs)

Question 24

How is oxidative stress involved in IBD

Answer 24

may release DAMPs

Question 25

How is cell migration involved in IBD

Answer 25

Affects how T and inflammatory cells move through gut

Question 26

How is the epithelial layer involved in IBD

Answer 26

Leaky, allows gut enzymes and defensins back through, causing inflammation

Question 27

How is immune cell recruitment involved in IBD

Answer 27

Abnormal differentiation, attraction of inflammatory cells

Question 28

How is Th17 involved in IBD

Answer 28

Activated too easily

Question 29

How is antigen presentation involved in IBD

Answer 29

Excessive presentation of commensal antigens

Question 30

How is innate immune defense involved in IBD

Answer 30

Does not adequately direct Th0 to Treg differentiation

Question 31

How are serious gut infections linked with IBD

Answer 31

An infection with listeria, e. coli, etc, will cause strong TH1 response to pathogen and during the infection, commensal bacteria can penetrate the gut. Now, a Th1 response is made against commensal bacteria. Following resolution of the original infection, some people will have a decrease in Th1 against commensals and Treg will again become dominant. In others, they are not able to suppress the Th1 against the commensals and IBD can develop.

Question 32

Genetic predisposition for celiac disease

Answer 32

Celiac is seen almost exclusively in people with the HLA-DQ2 or -DQ8 allele. This Class II MHC is uniquely able to present immunodominant peptides derived from gliadin (the gluten protein) to Th1/Th17 cells. These peptides are too bulky to fit into othe MHC AP grooves.

Question 33

Significance of tissue transglutaminase (TTG2)

Answer 33

TTG2 tries to cleave the highly branched and charged molecule gliadin, it may get “stuck” and become unable to release its substrate. Then you have a foreign molecule linked to a self-molecule. , This is the setup for “illicit help:” A B cell that’s anti-TTG2 (that never normally gets helped) takes up the complex, and presents foreign gliadin peptides to Tfh (specific for gliadin on DQ2 or DQ8), which then help the B cell make antibody to…TTG2.

Question 34

What is non-celiac gluten sensitivity

Answer 34

Negative blood tests for celiac disease and no sign of damage on an intestinal biopsy. ■ Symptom improvement when gluten is removed from the diet. ■ Recurrence of symptoms when gluten is reintroduced. ■ No other explanation for the symptoms.

Question 35

Proposed sensitivity in non-celiac gluten sensitivity

Answer 35

sensitivity to “Fodmaps” which are “fermentable oligosaccharides, disaccharides, monosaccharides and polyols.” These sugars are known to be a part of standard gluten preparations. This syndrome is not HLA-DQ2 or –DQ8 associated, and may be a form or food allergy,

Question 36

Meat sensitivity

Answer 36

Sudden intolerance to red meat- IgE Ab specific to galactose-α-1,3-galactose. Causes delayed mild to severe anaphylaxis. Avoiding mammalian meat will prevent symptoms, and avoiding ticks leads to gradual loss of the sensitivity.