Flashcards in GI immunology Deck (36):
Function of type 1 helper T cells
Th1 recognize antigen and make IFNgamma which activates M1 macrophages, and IL-2 which helps CTL get activated.
Th17 helper T cells function
Make IL-17 and cause focused inflammation, important in resistance to listeria and candida also in forms of autoimmunity. Is expanded by IL-23
Type 2 helper T cells function
Make IL-5 and IL-4 which attracts macrophages and eosinophils. Also stimulates macrophages to become M2 (alternatively activated). Important in parsite immunity
M1 vs M2 macrophages
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
Follicular helper T cells function
Migrate from T cell area of lymph nodes into B cell follicles where they help activate B cells
Regulatory T cells function
Make Il-10 and TGFbeta which suppresses activation and funciton of Th1, Th17 and Th2. Keeps immune response in check.
Cytotoxic T cells function
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
T helper cells molecular marker
CD4- increases affinity for antigen, helps in activation
CTL molecular marker
MHC classes for Thelper and CTL
Th: MHC class II, located on APCs macrophages, dendritic cells and B cells. CTL: MHC class I, located on all nucleated cells.
Describe T cell development in thymus
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.
What is T cell non-selection
No affinity btw TCR and MHC containing self peptide
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.
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)
T cell development in lymph nodes
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.
What determines the fate of a Th0 cell
The previous experience of the DC—the conditions in the periphery when it was stimulated, what TLR were engaged, what cytokines and chemokines predominated
Located of Peyers patches
submucosa of gut
2. Describe the cytokine/cell milieu in a Peyer’s patch under normal conditions, and the consequences for the development of Th subsets.
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.
2. Describe the cytokine/cell milieu in a Peyer’s patch under stress/infection conditions, and the consequences for the development of Th subsets.
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.
Method of recognition of non-pathogenic organisms
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
Compare Treg in gut to those in thymus
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.
How is apoptosis involved in IBD
Macrophages eating apoptotic cells make insufficient TGFβ
How is endoplasmic reticulum involved in IBD
ER stress may release damage-associated molecular patterns (DAMPs)
How is oxidative stress involved in IBD
may release DAMPs
How is cell migration involved in IBD
Affects how T and inflammatory cells move through gut
How is the epithelial layer involved in IBD
Leaky, allows gut enzymes and defensins back through, causing inflammation
How is immune cell recruitment involved in IBD
Abnormal differentiation, attraction of inflammatory cells
How is Th17 involved in IBD
Activated too easily
How is antigen presentation involved in IBD
Excessive presentation of commensal antigens
How is innate immune defense involved in IBD
Does not adequately direct Th0 to Treg differentiation
How are serious gut infections linked with IBD
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.
Genetic predisposition for celiac disease
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.
Significance of tissue transglutaminase (TTG2)
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.
What is non-celiac gluten sensitivity
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.
Proposed sensitivity in non-celiac gluten sensitivity
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,