Gut immunity & allergy

plenty mucosal tissue

mucosal immune system: lymphoid organs & cells associated with the intestine, respiratory tract, urogenital tract,… and glands associated with these tissues (salivary glands & lachrymal glands)

favored site for pathogens to attack

mucosal infections comprise one of the biggest health problems worldwide

respiratory infections, diarrheal diseases, HIV/AIDS, tuberculosis, measles, whooping cough, hepatitis B

infect mucosal surfaces or enter the body through these routes

most deaths occur in children under 5 years old in the developing world —> no effective vaccines

different composition of bacteria at different mucosal sites

colon contains the greatest number of different species

the primary function is metabolic activity (generates important metabolites) -> without microbiota not metabolic healthy

but also in the set-up of the immune system

-> germ-free mice: no bacteria in the gut, microbiota important for the mature immune system

-> gnotobiotic (germfree reconstructed with specific bacteria (single strain)), segmented filamentous bacteria favor Th17 generation, clostridial strains favor Treg

mucosal immune cells

binding of IgA to a receptor on the basolateral face of epithelial cell ->endocytosis

transcytosis to the apical face of epithelial cell, release of IgA dimer at apical face

gut place where most Ab are made daily (all IgA), along the epithelium secreted by plasma cells

IgA can’t exit tight junction -> no IgA in gut lumen -> don’t affect commensal bacteria

IgA dimer recognized by pIgR (polarized transport from basal to apical face) -> can interact with commensal bacteria (polymeric Ig receptor)

copping with microbiota

secreted IgA on the gut surface can bind & neutralize pathogens & toxins

the main way to control commensal load

IgA adsorbs on the layer of mucus covering the epithelium where it can neutralize pathogens & toxins

prevents their access to tissues & inhibits their function

homeostasis between host & microbiota

local immune responses activate protective mechanisms that stabilize the epithelial barrier

apical mucus forms a physical barrier (glycoproteins)

paneth cells stimulated by IL-22 produce anti-microbial proteins (IL-22 from ILC3 & CD4 Th17)

ways to control commensal bacteria:

barrier, Abs & antimicrobial proteins

high load of non-self in gut but need to react to gut infection

antigens presented induce IgA-switched B cells that localize in the lamina propria as IgA-producing plasma cells

IgA binds commensal bacteria & alters their gene expression

->limits access to epithelium & blocks binding to the surface

-> interference with penetration of epithelium assisted by presence of this layer of mucus (mucin glycoproteins with antibacterial properties & PRR on Paneth cells)

->induce production of antimicrobial peptides

intestinal lymphocytes are found in organized tissues where immune responses are induced & scattered throughout the intestine where they carry out effector functions

in epithelium & lamina propria immune cells (IgA+ plasma cells) -> constitutively present

peyer’s patch: SLO -> T-cell & B-cell zone that can generate adaptive immune responses, migrate to mesenteric LN & then common process

peyer’s pathc & isolated lymphoid follicles

need to sense gut pathogens through tight junction

nonspecific transport across epithelium: via M-cells (microfold), shorter villi & thinner glycocalyx (less mucus)

FcRn-dependent transport: IgG opsonized pathogen transported to lamina propria, MHCI-like, binds IgG by FcRN

antigen capture by macrophages: CX3CR1 macrophage below epithelial cells & extends to lumen to sense pathogens->internalization, degradation & transfer to DC

T-cells enter Peyer’s patches from blood vessels directed by the homing receptors CCR7 & L-selectin (naive T-cells)

HEV = high endothelial venules for extravasation

T-cells in the Peyer’s patch encounter antigens transported across M-cells & become activated by DC

activated T-cells drain via mesenteric LN to the thoracic duct & return to the gut via the bloodstream

activated T-cells expressing α4:ß7 integrin & CCR9 home to lamina propria & intestinal epithelium of the small intestine ->homing back to the gut infected site

IEL lie within the epithelial lining of the gut & are CD8+ T-cells —> 2 types

T-cell like function CD8α/ß

NK-like function CD8α/α

act like T-cell

stimulated via TCR, express CD8α/ß

effector memory T-cells

sense infection & react to peptides presented in MHCI by epithelial cells & kill via Fas & perforin/granzyme

epithelial cells undergo stress as a result of infection, damage or toxic peptides & express MIC-A & MIC-B

NKG2D on IEL binds to MIC-A,B & activates IEL

activated IEL kills the stressed call via perforin/granzyme pathway

much lower response to injected antigen if it was taken up with oral route before

-> Lower specific systemic immune response

predisposition to develop IgE responses to allergen

similar to triggers of auto-immune reaction but more known environmental factors

hygiene concept: the clearer the environment in early life & high genetic susceptibility -> favor IgE production in allergy

exposure to some infections & common environmental microorganisms in childhood drives the immune system toward a general state of non-atopy

gene susceptibility: many genes defined as related risk factors

cytokine IL4/5/13 -> produced by Th2

receptor for mast-cell degranulation

antigen presentation

mediated by IgE

airborne & food antigen

drugs

IgG Abs against drug-modified proteins on the surface of RBCs or platelets

generation of immune complex (IgG) of small size in immune individuals not eliminated by phagocytes

mediated by Th1 or CD8+ cytotoxic T-cells

T-cell response to non-self proteins, hapten-modified self-proteins, enzyme-modified food proteins

promote the priming of Th2 cells that drive IgE responses

protein (often with carbohydrate side chains) -> protein antigens induce T-cell responses

low dose: favors activation of IL-4-producing CD4 T-cells (favors Th2 over Th1)

low molecular weight: allergen can diffuse out of particles into the mucose (penetrate the body)

highly soluble: allergen can be readily eluted from particle

stable: allergen can survive in desiccated particle (pollen grains)

contains peptides that bind host MHCII -> required for T-cell priming

other origin of allergens

proteins from animals or plants

resistant to denaturation: heating (cooking) & enzymatic digestion in the gut

cow milk, egg, soybean, tree nut, fish, shell fish = 90% of food allergy

previous exposure via another mucosa (skin) leading to IgE production instead of oral tolerance

Derp-1 (enzyme from house dust mite) common allergen

cleaves occludin in tight junction & enters mucosa -> penetrated the body

Derp-1 is taken up by DC for antigen presentation and Th2 priming

DC primes T-cell in LN -> Th2 induces B-cell switch to IgE production

IL-4/5/13 favor Th2 proliferation & IgE switch

plasma cell travels back to mucosa & produces Derp-1 specific IgE Abs

->IgE binds FcεRI receptor on mast cells -> triggers mast-cell degranulation

-> Mast-cell granule contents cause allergic symptoms

Basophils act at the place of T-cells at the site of the allergic reaction (no SLO involved)

IgE secreted by plasma cells binds to a high-affinity Fc receptor (FcεRI) on basophils

activated basophils provide contact & secreted signals to B-cells to stimulate IgE production

-> CD40L not only on activated T-cells but also on activated basophils & secretion of IL-4

-> local IgE switch

two IgE receptors FcεR1-like high affinity & CD23C-type lectin

resting mast cell has granules that contain histamine & other inflammatory mediators

multivalent antigen cross-links bound IgE Ab causing the release of granule contents

first exposure to allergen makes humoral response for IgE very high-affinity receptor on mast cells

toxic compounds & immune activating compounds of the granules secreted

IgE mediated (FcεRI independent, CD23 dependent)

-> lower affinity receptor

cytokine IL-3/5 for eosinophil activation & increased production by bone marrow

degranulation inducers

common & specific compounds

2 phases

immediate: mediated by resident mast cells already coated with IgE from previous exposure

late phase: mast cells + memory Th2 + eosinophils

->Th2 cytokines IL3/5 act as degranulation factors

inhibit effects of mediators or inhibit synthesis of specific mediators

class 1: chemical molecule interfering with histamine binding to H1, H2, H3, H4

class 2: blocks mastocyte degranulation

class 3: inhibits L-histidine decarboxylase (inhibits histamine production)

mediator action

in allergy reaction bronchoconstriction (difficult to breath)

ß-adrenergic agonist: broncho-dilator

act on ß-adrenoreceptor

natural ligand = epinephrine

use chemical analogs

general anti-inflammatory effects (inflammation triggered in allergy)

natural corticosteroid: glucocorticosteroid

steroid made in the cortex to regulate glucose metabolism

glucocorticosteroid receptor also expressed on immune cells induce the expression of anti-inflammatory genes

chemical analogs used in clinics: dexamethasone

injection of specific antige

induction of regulatory T-cells (instead to Th2 response)

omalizumab

bind to IgE Fc region & prevent IgE binding to Fc receptors on mast cells

allergy to penicillin

penicillin binds to bacterial transpeptidase & inactivates it but can also modify proteins in human erythrocytes to create foreign epitopes

red blood cells: hemolytic anemia

platelets: thrombocytopenia

polymeric Ag on cell surface

T-cell independent responses (mostly IgM)

Arthus reaction

injection of an Ag in the skin of a sensitized individual with IgG

if Ag is in excess, small immune complexes are formed that are not cleared by macrophages

more Abs: larger complexes -> opsonization by complement & clearance by phagocytes

production of C5a by complement -> binds & sensitizes the mast cell to respond to immune complexes

activation of FcγRIII on mast cells induces their degranulation

T-cell dependent

delayed-type hypersensitivity: not in minutes but 1-3 days, proteins (insect venom, mycobacterial proteins (tuberculin, lepromin)

contact hypersensitivity: haptens (modified self to create analogs of non-self) pentadecacatechol (poison ivy), DNFB or small metal ions (nickel, chromate)

gluten-sensitive enteropathy (celiac disease): gliadin

CD4+ T-cells

antigen is processed by tissue macrophages & stimulated Th1 cells

tuberculin test: intradermal injection of M. Tuberculosis extract without adjuvant

insect bites & venom intradermal delivery

recruits more immune cells ->directed by chemokine & cytokine release of antigen-stimulated Th1 cells

recruit macrophages & other leukocytes, affect local blood vessels (TNFα & lymphotoxin), stimulate the production of macrophages (IL-3 & GM-CSF), macrophage activation (IFNγ, TNFα)

CD4+ & CD8+ T-cells

mediated by a hapten: non-immunogenic molecule by itself, immunogenic when bound to a carrier protein

contact sensitizing agent binding a self-protein to create a new T-cell epitope

poison ivy: chemical soluble in lipids, crosses the plasma membrane, covalent binding to intracellular antigens-> recognized as non-self by CD8+ T-cells

picryl chloride: react with extracellular protein & presented by MHCII -> recognize as non-self by CD4+ T-cells

nickel: binds directly to MHC

Th1

peptides naturally produced from gluten don’t bind to MHCII molecules

enzyme tissue transglutaminase (tTG) modifies the peptides -> processed & bind MHCII in epithelial cells (converts glutamine to glutamic acid binding HLA-DQ2)

bound peptide activates gluten-specific CD4 T-cells

activated T-cells can kill mucosal epithelial cells by binding Fas & secretion of IFNγ ->activates epithelial cell to produce cytokines & chemokines that recruit other inflammatory cells

-> cytotoxic CD4+ T-cells

gluten peptides activate mucosal cells to express MIC molecules

direct activator of epithelial cells -> stimulate proinflammatory cytokines IL1 & induction of MIC proteins

intraepithelial lymphocytes IELs express NKG2D which binds to MIC molecules & activates IELs to kill the epithelial cells

NK like