Gut Immunology Flashcards
what does the gut-associated lymphoid tissue (GALT) consist of?
multi-follicular Peyer’s patches and isolated lymphoid follicles (ILF)
what is critical for the GALT and ILT development that in turn regulates the microbiota?
cross-talk between the host immune system and the microbiota
what are isolated lymphoid follicles (ILFs)?
they are single B-cell follicles that act as an inductive site for IgA production
what is the primary route by which the body is exposed to Ags (microbial and diet)?
the GALT
how do the Peyer’s patches and ILFs receive Ags since they lack afferent lymphatic vessels?
they receive Ags directly from the epithelial surfave and via Ag-transporting DCs
what is another way that microbes can cross the epithelium and enter the peyer’s patches?
through M cells, from which they are endocytosed by DCs in the subepithelial dome
Ag-loaded dendritic cells in the peyer’s patches interact with what to do what?
they interact with local lymphocytes to induce differentiation of T cells and T-dependent B cell maturation in the germinal center–> leads to the induction of the development of IgA producing plasma cells
what do goblet cells produce and how is their product organized?
they produce mucin, which is organized into a dense inner proteoglycan gel (inner mucous layer)
what cells continually sense the microbiota (MAMPs)?
enterocytes in the small intestine, colonocytes in the large intestine and specialized Paneth cells
what do the enterocytes, colonocytes, and Paneth cells induce the production of?
antimicrobial peptides (AMPs)
how does the secretory IgA maintain a peaceful bacteria-host interaction?
IgA does not activate complement, IgA does not activate phagocytes, and IgA is resistant to proteolysis
what is the major class of AMPs in the GI which represent innate immunity?
defensins
why is the inner mucous layer largely impervious to bacterial colonization or penetration?
due to its high density and high concentration of bactericidal defensins
describe the structure of defensins?
they have clusters of positively charged amino acid side chains and hydrophobic amino acid side chains
what do defensins cause in microbial membranes due to their structure?
membrane “wormholes” or pores
what are defensins produced by?
epithelial cells
what happens when commensal and pathogenic bacteria penetrate the enterocyte epithelial layer?
they are rapidly killed by macrophages in the lamina propria
what is lying over the peyer’s patches? and what happens if bacteria penetrate this?
a specialized follicle-epithelium, containing M cells. these bacteria are also rapidly killed by macrophages, but some bacteria can be picked up by DCs
once the DCs pick up antigen, where do they travel?
to the draining mesenteric lymph nodes
what do DCs that engulf bacteria induce?
IgA producing plasma cells
Although the DCs loaded with commensal bacteria can traffic to the mesenteric LNs, what do the LNs function as?
as a barrier, the loaded DCs cannot penetrate further to reach the systemic circulation
following activation, Ag-activated B and T cells leave the mesenteric LNs through the efferent lymph, enter the bloodstream at the thoracic duct and then do what?
home back to the intestinal mucosa
in the mesenteric lymph node, the dendritic cell interacts with a naive and does what?
stimulates their proliferation
where is the T cell differentiation taking place?
in the environment where stromal cells produce a significant amount of TGF-beta
what does the limited expression of pro-inflammatory cytokines by APCs and an excess of TGF-beta result in?
differentiation of naive T cells into Tregs
what do T regs suppress?
Th1 cells, Th2 cells, and Th17 cells
what has a major effect on gut microflora?
changes in diet, environmental factors, and host genetics
what happens to undigested dietary carbohydrates in the gut?
they are fermented by gut commensal bacteria to produce SCFAs
what are some examples of SCFAs produced by commensal gut bacteria?
acetate, propionate, and butyrate
what is the function of acetate?
it stimulates the accumulation of IL-10-producing colonic Tregs
why are SCFAs important?
they help to support an effective IgA-mediated response to the gut pathogens and they stimulate the production of mucus
some T cells with high affinity for self antigens will express what?
the Foxp3 transcription factor and they will become natural t regulatory cells
since the intestine Ags are not available in the thymus, what can be said about central tolerance?
it does not prevent responses against antigens in the lamina propria; therefore additional layers of peripheral tolerance are needed
what group of immune cells have been shown to play a crucial role in induction of oral tolerance?
macrophages, dendritic cells, and T regulatory cells
in the mesenteric lymph node, what do DCs stimulate?
the naive CD4+ T cells to differentiate into induced CD4+ CD25+ Foxp3+ T regulatory cells
how do DCs stimulate the development of T reg cells?
via the release of retinoic acid, TGF-beta, and IDO
what is the role of retinoic acid (RA)
it directly induces Treg cell differentiation
what is the role of TGF-beta?
it mediates Foxp3 up-regulation in Treg differentiation
what is the role of IDO?
it has important immunosuppressive functions, which cause anergy of effector T cells and it induces the proliferation of T reg cells
what are the categories of non-immune mediated food adverse reactions?
pharmacological, enzymatic, psychosomatic, and irritant
what are the categories for immune-mediated food adverse reactions?
IgE-mediated (type I) and non-IgE-mediated (type III/IV)
what is the most common form of immune-mediated adverse reactions to foods?
type I hypersensitivity
how is type I hypersensitivity always characterized?
by the development of IgE against food allergens
how can a patient with an IgE-associated food allergy be identified?
based on the detection of food allergen by measuring in vivo IgE-mediated skin reaction to allergen
what do type III and type IV hypersensitivities involve?
the activation of macrophages by allergen-Ab complexes
what might abrogate oral tolerance leading to food allergy?
genetic and environmental factors
what is sensitization?
when the allergen induces IgE production in genetically predisposed individuals
what does repeated allergen contact activate?
the allergen-specific T cells and induces the IgE dependent secondary immune response
after allergen ingestion and degradation, what happens to the allergen fragments?
they are internalized from the GI and distributed throughout the body
Ag disseminated systemically can trigger distal reactions (urticaria and bronchospasm) through mechanisms dependent on what?
histamine and platelet activating factor (PAF)
the GI manifestations of food allergy are dependent on what?
the Th2- derived cytokines including IL-4, IL-13, and IL-9 (these cause increase in mast cells)
what mediates the local acute GI response (diarrhea) to allergen exposure?
PAF and serotonin
treg cell derived what and what supress what immunity?
treg cell derived IL-10 and TGF-beta suppress Th2 immunity and inhibit mast cell reactivity
in a person with a food allergy, what happens to their Th2 levels?
they are increased
what effect do vitamin d and vitamin a have on inflammatory responses?
they suppress inflammatory responses
what effect does a high fat diet have on inflammatory responses?
it promotes inflammation
how does the gut microbiota or its constituents suppress allergic immune responses?
through the induction of Treg cells and/or direct supression of basophils and mast cells
what are central to generating IgE and allergic effector cells?
Th2 cells
what is the primary tool for assessing immediate hypersensitivity reactions?
the patient’s history
what type of allergy is wheat allergy?
type I hypersensitivity
what are the most important allergens involved in wheat allergy?
alpha-amylase inhibitors, wheat germ agglutinin, and peroxidase
what is the correlation of IgE to wheat with age?
the prevalence of IgE to wheat progressively increases with age
what is a common symptom of wheat allergy?
food-dependent exercise-induced anaphylaxis (FDEIA)
what is FDEIA?
urticaria or angioedema with upper respiratory obstruction and hypotension precipitated by exercise after ingestion of certain foods in susceptible persons
what drugs could cause FDEIA?
aspirin and NSAIDs
what are some common foods that have caused FDEIA?
seafood, celery, wheat, and cheese
what is the mechanism behind FDEIA?
exercise/aspirin enhance the absorption of undigested immuno-reactive allergens into the circulation; related to permeability
non-IgE mediated reactions are delayed and take how long to develop?
up to 48 hours
what is an example of a non-IgE mediated food allergy?
Cow’s milk allergy (CMA)
what is the dietary management of a non-IgE CMA?
involves removal of all dairy products from diet
what is an example of a mixed IgE-mediated food allergy?
peanut allergy
what is non-IgE mediated allergic reaction to peanuts?
it is peanut-induced anaphylaxis mediated in part by IgG-induced activation of macrophages
What contributes to a nut-induced allergy and anaphylaxis?
IgE-mediated (mast cells) and non-IgE-mediated (IgG induced activation of macrophages)
how do peanuts and other nuts in general contribute to shock?
by causing production of C3a (complement activation)
what does C3a stimulate?
macrophages, basophils, and mast cells to release PAF and histamine in a C3aR-dependent manner
what are the effects of histamine and PAF?
they increase vascular permeability and smooth muscle contractility
what are the main genetic predisposing factor for celiac’s diease?
the HLA-DQ2 and DQ8 molecules
what antibodies are specifically associated with CD?
serum autoantibodies against the ubiquitous enzyme tissue transglutaminase 2 (TG2)
what is CD strongly linked to?
autoimmunity
what type of protein is gluten?
proline-rich protein that is poorly digested in the small intestinal tract due to a lack of prolyl endopeptidases
what is gluten rich in?
glutamine residues
what does it mean when it is said “deamination of gluten”?
some of the glutamines in the peptides can be deaminated by tissue enzyme TG2
what happens when gluten is deaminated?
the formation of negatively charged glutamic acid residues
what serves as the anchor for residues of the peptide that is loaded into HLADQ2.5?
the negatively charged glutamine residues
in CD, how does tissue damage occur?
in a type IV hypersensitivity manner
what triggers the cell-mediated immune mechanism in CD patients?
gluten-specific T cells that are generated
In CD patients, gluten causes a T-cell mediated inflammatory response that generates what?
an inflammatory environment and it produces IgA antibodies against gluten (anti-TG2 Abs)
what is the result of inflammatory response when T cells are activated and release IFN and TNF?
matrix degradation and mucosal remodeling
activated gluten-specific CD4 T cells secrete mainly what?
Th1 cytokines (IFN)
what do Th1 cytokines (IFN) induce?
the release of MMPs by myofibroblasts
what is the effect of MMPs?
mucosal remodeling and villus atrophy
what are produced that drive the production of auto-Abs to gluten and TG2?
Th2 cytokines
other cytokines seem to play a role in polarizing and maintaining the Th1 response. What are they?
IL-18, IFN-gamma, or IL-21
what is the role of IL-15?
it links the adaptive immune system to innate immune responses serving as a growth factor for T cells causing their proliferation
what is recommended to be the initial testing for CD?
the measurement of IgA antibody to human tissue transglutaminase (tTG)
about 95% of patients with CD have which one of the celiac disease associated HLA alleles?
DQ2
