Gut Immunology (Shnyra) Flashcards
1
Q
- the largest immune organ in the body
- consists of multi-follicular Peyer’s patches and isolated lymphoid tissue (ILT)
- cross-talk between host immune system and microbiota is critical for this organ and ILT development that in turn regulates the microbiota
A
gut-associated lymphoid tissue (GALT)
2
Q
Describe the role of GALT in the host-microbiota mutualism in intestines:
A
- after birth, bacteria immediately colonizes neonatal intestine initiating events that affect development and maturation of mucosa and GALT
- GALT consists of isolated lymphoid follicles (ILFs) and Peyer’s patches (PPs)
- GALT is primary route by which body is exposed to Ags (microbial and diet)
3
Q
Describe the role of ILFs in the host-microbiota mutualism in intestines:
A
- ILFs develop after birth in SI and LI, showing dynamic response of gut immune system to microbiota
- ILFs are single B-cell follicles that act as inductive site for IgA prod
- ILFs lack afferent lymphatic vessels and receive Ags directly from epithelial surface via Ag-transporting DCs
4
Q
Describe the role of Peyer’s patches (PPs) in the host-microbiota mutualism in intestines:
A
- along w/ ILFs, make up GALT
- lack afferent lymphatic vessels and therefore receive Ags directly from epithelial surface via Ag-transporting DCs
- microbes also cross epithelium and enter PPs through M cells, from which they are endocytosed by DCs in subepithelial dome
- Ag-loaded DCs in the PPs interact w/ local lyphocytes to induce differententiation of T cells and T cell dependent B cell maturation in the germinal center to induce the development of IgA-producing plasma cells
- after the plasma cells hone into the lamina propria, they release secretable dimeric IgA for transport into the intestinal lumen
5
Q
Describe the role of microbe-associated molecular patterns (MAMPs) in the host-microbiota mutualism in intestines:
A
- MAMPs recognized by pattern-recognition receptors (PRRs) on intestinal epithelial cells, DCs adjacent to crytopatches stim the recruitment of B cells and T cells, causing cryptopatches to develop into mature ILFs
- PRR-mediated recognition of MAMPs stim proliferation of intestinal epithelial cells in crypts, resulting in their increased depth and density of Paneth cells in SI
- MAMPs also stim intestinal epithelial cells for release of antimicrobial peptides (defensins)
6
Q
How does the intestinal epithelium provide a barrier to exogenous materials?
A
- subpopulations of intestinal epithelial cells (IECs) are integrated into a continuous, single layer
- goblet cells: prod mucin, organized into a dense, more highly cross-linked inner proteoglycan gel and a less densely cross-linked outer mucous layer
- enterocytes (SI), colonocytes (LI), and Paneth cells (base of SI crypts): continually sense the microbiota (MAMPs) to induce prod of antimicrobial peptides (AMPs)
- secretory IgA (sIgA): maintains peaceful bacteria-host interaxn; does not active complement sys; does not active phagocytes in Fc-receptor dependent manner; resistant to proteolysis by peptidases prod in stomach, SI, and pancreas
- AMPs: contibute to mucosal host defense in GI
- defensins: prod by IECs, major class of AMPs in GI which represent innate immunity
7
Q
How do bactericidal defensins protect against pathogens?
A
- high density/conc of defensins within inner mucous layer makes in largely impervious to bacterial colonization/penetration
- have clusters of positively charged AA side chains (pink) and hydrophobic AA side chains (green)
- polarity allows defensins to interact w/ microbial membranes that results in form of membrane “wormholes” or pores
- est that innate immune system provides protection against ~98% of pathogens that encountered by the body
8
Q
Describe the role of adaptive immune responses within the GI:
A
- most commensal bacteria reside outside layer of mucus that covers IECs
- commensal and pathogenic bacteria that penetrate enterocyte epithelial layer are rapidly killed by Mφ in lamina propria
- bacteria can also penetrate specialized follicle-associated epithelium, containing M cells that lie over PPs, which are rapidly killed by Mφ; however some can be picked up by DCs
- DCs interact w/ T and B cells in PPs and/or migrate to mesenteric lymph nodes (LNs), and induce IgA producing plasma cells
- DCs loaded w/ commensal bacteria can traffic to mesenteric LNs, however the LNs function as a barrier, meaning loaded DCs cannot penetrate farther to reach systemic circulation
- following activation, Ag-activated B and T cellsleave mesenteric LNs through efferent lymph, enter the BS at the thoracic duct and hone back to intestinal mucosa
9
Q
What is the role of Treg cells in the GI?
A
- recall: Treg cells are T cells w/ high affinity for self-Ags that express transcription factor Foxp3 and become natural T regulatory cells
10
Q
What is the role of diet, environment, and genetics in gut microbiota?
A
- changes in these factors effect microflora
- balanced microbial composition results in symbiosis > immune regulation and homeostasis
- microbial imbalance results in dysbiosis > immune dysregulation and inflammation in susceptible host (genetics)
- dysbiosis can occur due to changes in diet and other environmental factors
11
Q
- produced by colonic microbial fermentation of undigested or partially digested dietary fibers/carbs
- have broad effects on host immune system development
- examples: butyric acid (butyrate), propionic acid (propionate), acetic acid (acetate)
A
short-chain fatty acids (SCFAs)
12
Q
What is the role of diet in the GI microbiota and immune system?
A
- diet shapes gut microbiota (structurally/functionally), microbiota adapts to promote nutrient processing
- microbiota and IS co-evolve: malnutrition affects both IS and microbiota
- undernutrition: a/w defects in innate/adaptive immunity
- recurrent enteric infections: predispose to nutrient deficiencies and impaired intestinal mucosal barrier function
- increase susceptibility to infection and worsening nutritional status
- microbiota acts as barrier to enteropathogen infection, the barrier may be disrupted by malnutrition
13
Q
What is SCFAs role in cell differentation in the GI?
A
- SCFAs promote differentation of Treg and sIgA production
- acetate stim accumulation of IL-10 producing colonic Tregs
- butyrate either directly acts on Tregs or modulates DC function to enhance Treg-inducing ability
- capsular polysaccharide A (PSA) derived from B. fragilis and MAMPs can directly act on Tregs through TLR2 to promote Treg function by enhancing expression of effector molecules (IL‐10 and TGF‐β)
- SCFAs help support effective IgA-mediated response to gut pathogens and stim prod of mucus
14
Q
What are the different types of food tolerances and what is the clinical/immunological relevance?
A
- immune tolerance: sustained immune unresponsiveness to self-Ags, beneficial Ags, and commensal bacteria
- oral tolerance: suppression of immune responses to Ags that have been administered by oral route
- failure to induce food tolerance to through to result in food allergy and celiac dz (most prevenlant food-induced pathology)
15
Q
type of immune tolerance
immature lymphocytes specific for self Ags may encounter these self Ags in the generative lymphoid organs and are either:
- deleted (apoptosis)
- change BCR specificity (B cells only)
- develop into Treg cells
A
central tolerance
16
Q
type of immune tolerance
mature self-reactive lymphocytes in peripheral tissue may be either:
- inactivated (anergy)
- deleted (apoptosis)
- suppressed by Treg cells
A
peripheral tolerance
17
Q
What is the role of peripheral tolerance in the GI?
A
- central tolerance of T cells and nTreg cell differentiation require interaction of TCR w/ its cognate Ag in the thymus
- since the intestinal Ags are not available in the thymus, central tolerance cannot prevent responses against Ags in the lamina propria
- peripheral tolerance is needed to ensure tolerance to Ags such as food Ags and commensal organisms
18
Q
What is the mechanism of oral tolerance?
A
- Mφ, DCs, and Treg cells play crucial role in OT
- DCs: take up Ags from intestinal lumen by sending cellular processes into lumen across epithelial barrier
- Mφ: transfer acquired Ags to DCs in lamina propria (LP)
- Ag loaded DCs move from LP to mLNs in a chemokine dependent manner
- in mLNs, DCs stim naive CD3+ T cells to differentiate into induced CD4+CD25+Foxp3+ Treg cells via release of retinoic acid (RA), TGF‐β, and indoleamine 2,3‐dioxygenase (IDO)
- RA: directly induced Treg-cell differentiation
- TGF-β: mediates Foxp3 upregulation in Treg differentiation
- IDO: exerts immunosuppresive functions causing anergy of effector T cells and induces proliferation of Treg cells
24
Q
What is the IgE-mediated mechanism of food allergies?
A
- primary encounter and subsequent exposure
- allergic sensitization: when IgE-associated food allergies develop early in childhood
- allergen contact via GI tract, resp tract, and skin induces IgE production (primary sensitization) in genetically predisposed individuals
- repeated allergen contact activates allergen-specific T cell and induces IgE-dependent secondary immune response
- factors that affect integrity of epithelial barrier and extent of allergen digestion are important for primary sensitization and boosting of secondary responses
- after allergen ingestion/degradation, fragments and internalized from GI and distributed throughout body
- thus, allergic response develops not only in intestine, but also organs such as skin, resp tract, circulatory sys (which leads to anaphylaxis)
25
Q
What are mast cell mediators in a food allergy reaction?
A
- histamine: causes SM contraction and vascular permeability
- TNF-α and IL-1: targets endothelial cells and causes inflammation
- tryptase: causes trypsin-like activity, anaphylaxis, and urticaria
- prostaglandin E2 (PGE2): causes pain and vascular permeability
- PGD2 and leukotrienes (C4, D4, E4): cause SM contraction and vascular permeability
- bradykinin: causes SM contraction and vasodilation
- IL-5: targets sputum eosinophils
26
Q
What are the local and systemic effects of food allergies?
A
- mast cells central to both effects
- Ag disseminated systemically triggers distal rxns (urticaria, bronchospasm) through mechanisms dependent on histamine and platelet activating factor (PAF)
- GI sx dependent on Th2-derived cytokines (IL-4, IL-13, and IL-9)
- mastocytosis necessary for local (GI) sx
- PAF and serotonin mediate local acute GI response (diarrhea) to allergen exposure
27
Q
What is the role of Treg cells in controlling food allergies?
A
- allergens are taken up by DCs which migrate to regional LNs, where they induce Treg cells by presenting the allergen Ags within the MHC and secreting of cytokines such as TGF-β
- IL-10 and TGF-β (secreted by Treg) suppress Th2 immunity, inhibit mast cell reactivity, reduce IgE synthesis, and increase IgG and IgA synthesis
28
Q
What is the role of environmental factors on allergic sensitization?
A
- vit D, vit A, and folate suppress inflammatory responses
- high fat diet promotes inflammation
- gut microbiota/constituents suppress allergic immune response through induction of Treg cells and/or direct suppression of basophils and mast cells; Tregs suppress Th2 cells that are central to generating IgE/allergic effector cells
29
Q
What are the 4 routine clinical tests that can be used to detect presence of specific IgE allergy?
A
1) skin prick test: can provide immediate info as to presence of IgE sensitization; SPT for anaphylaxis should be performed in facilities capable of resuscitation
2) serum-specific IgE test: blood lab test performed using allergen extracts or individual alergen components
3) atopy patch: test to understand relationship between IgE sensitization and cell-mediated response of atopic eczema; not widely used
4) basophil activation test: used in research setting; clinical use still in development
31
Q
- classic type of food allergy (IgE plays central role)
- most important allergens: alpha-amylase inhibitors, agglutinin, and peroxidase
- usually affects skin, GI, and resp tract: wheat-dependent exercise induced anaphylaxis (WDEIA), occupational asthma (baker’s asthma), rhinitis, contact urticaria
- producing IgE to wheat increases w/ age from 2% to 9% in central European countries
- FDA est 0.4% prevelance of wheat/gluten allergy in US
A
wheat allergy
32
Q
- urticaria or angioedema w/ upper resp obstruction and hypotension precipitated by exercise
- in susceptible persons, ingestion of certain foods/meds before physical activity may be predisposing factor
- usually occurs within 2 hours of eating allergic food
- onset occurs during physical activity
- drugs: aspirin and NSAIDs have been most frequently implicated
- foods: seafood, celery, wheat, cheese
A
food-dependent exercise-induced anaphylaxis (FDEIA)
34
Q
What type of immune mediated rxn is peanut allergy?
A
mixed IgE-mediated food allergy (both)
35
Q
Compare and contrast IgE-mediated and non-IgE mediated allergic reactions to peanuts:
A
- IgE mediated: mast cells activated by IgE cross-linking of FCεRI plays central role in nut-induced anaphylaxis
- non-IgE mediated: peanut induced anaphylaxis also mediated by IgG1-induced activation of macrophages; mucosa contains everything needed to penetrate plasma cells that produce IgG1
- both: contribute to nut-induced allergy/anaphylaxis
- mediators (histamine and PAF): released by mast cells, induce sx
36
Q
Describe the non-IgE mediated allergic reaction to peanuts in terms of the C3aR-dependent manner:
A
1) peanuts/nuts can contribute to shock by prod C3a
2) C3a stim macrophages, basophils, mast cells to release PAF and histamine in a C3aR-dependent manner (non-IgE pathway)
3) PAF and histamine increases vascular permeability and SM contractility
37
Q
How do nuts induce anaphylaxis?
A
- IgE: FcεRI crosslinking activates mast cells > release of histamine and PAF
- IgG1 (non-IgE): Ag-Ab complexes activate macrophages via FcγRI > release of PAF
- complement activation (C3a, non-IgE): activation of mast cells via C3aR and C5aR > release of histamine
*regarding peanut allergies, study this card if nothing else; it has all the peanut allergy concepts summarized*
39
Q
Why does gluten make a good antigen to elicit an immune response?
A
- gluten is proline-rich protein that is poorly digested in SI due to lack of prolyl endopeptidases
- also rich in glutamine residues
- gluten peptides of 10-50 AAs in length are formed and left incompletely digested
- some glutamines in peptides can be deaminated by tissue enzyme TG2; results in form of negatively charged glutamic acid residues
40
Q
What is the relationship between gluten peptide and HLADQ2.5?
A
- peptides w/ specific spacing of proline and glutamic acid bind to HLA class II on APCs
- negatively charged glutamate residues serve as anchor residues of peptide that is loaded onto HLADQ2.5
- majority of CD patients express HLADQ2.5 heterodimer encoded by the HLA‐DQB1*02 (β‐chain) and HLA‐ DQA1*05 (α‐chain) alleles
41
Q
What is the role of T lymphocytes in celiac disease?
A
- gluten-specific T cells are generated which trigger cell-mediated immune mechanisms
- tissue damage occurs in a type IV hypersensitivity manner
- chronic inflammatory occurs in proximal SI that damages mucosa and leads to malabsoption, response continues as long as patient ingests gluten
42
Q
What is the pathogenesis of celiac disease?
A
- gluten peptides that are highly resistant to intestinal proteases reach the lamina propria
- cross-linking and deamidation of gluten peptides by TG2 creates potent immunostimulatory epitopes that are presented by HLADQ2.5 or HLADQ8 on APCs
- activated gluten-specific CD4 T cells secrete mainly Th1 cytokines such as IFN-γ that in turn induces release of MMPs by myofibroblasts resulting in mucosal remodeling and villus atrophy
- Th2 cytokines prod driving prod of auto-antibodies to gluten and TG2
- other cytokines (IL-18, IFN- γ, IL-21) seem to play role in polarizing/maintaining Th1 response
- IL-15 links adaptive immune system to innate immune responses serving as growth factor for T cells causing their proliferation
