mucosal immunity Flashcards
mucosal immunity normal vs abnormal
normally- physiologic inflammation- usually tolerated and innate barriers limit immune responses to bacteria, viruses, fungi, parasites and ingested Ags
abnormal- pathophysiologic inflammation disease
Acute- infection
Chronic/recurring- ibd, celiac, food allergy
Host defense 3 phases
Immediate- an existing physical, chemical, and ecoogical barrier
Early: Existing innate, immune cells and inflammatory messengers
late- activation of adaptive immune cells (T cells and or b cells ) and messengers
Immediate host defenses in the epithelium
Epithelium- Tight junctions maintain integrity between external and internal compartments
Pattern Recognition receptors- activate immune response
Anti microbial peptide secretion
Epithelial shedding and repair
Epithelial ion transpoert and muscle contractions- diarrhea
immediate host defenses- microbiota
Compete for resources with virulent organisms, produce their own anitmicrobial peptides (AMPs)- bacteriocidins
Keep innate immune cells in a n attentive state
Peyers patches
Specialized immune tissue located in the gut
Follicle associated epithelium covers it, in the follicle epithelium contains M cells- attraction of bacteria, acts as an APC to present the gut bacteria to a Dendrtitic cell- and take it to the follicle to potentially activate T cells
Under neath the single layer of epithelium is a follicle
Parafollicular cortex (on the edge)- contains lots of T cells
In the germinal center (center)- contains lots of B cells
Early host defense- recognition of pathogens
innate receptors for bacterial PAMPs (recognized by PRRs) expressed in cytoplasm and on basolateral membrane, but not on lumenal surface
Dendritic cells in the lamina propria express low levels of TLRs
Cell associated pattern recognition receptors
TLRs on the plasma membranes of epithelial cells, Dcs, Macrophages, PMNs, they recognize PAMPs- bacterial, virla and fungal structures
Nod-like receptors- in the cytoplasm of epithelial cells, macrophages, and PMNs, they recognize- Bacterial wall components (peptidoglyans), and viral RNA
Mannose receptors on the membrane receptors on phagocytes- recognize bacterial cell wall carbohydrates and fungal wall glycans
Secreted pattern recognition receptors
CRP - in the plasma- recognizes Microbial cell wall components
Mannose binding lectin (MBL)- in plasma) recognizes bacterial cell wall carbohydrates
Complement C3- in plasma recognizes cell wall
IGM- in the plasma and gut lumen- recognizes BActerial cell walls
intestinal bacterial infections categories
Minimally invasive- Campylobacter, clostridium, candida, cryptococcus
Invasive- Listeria, enteroinvasive E coli, (opportunistic)-clostridium and shigella
Toxigenic- Enterotoxigenic E coli, vibrio cholerae, clostridium, shigella
PRRs that recognize bacteria: TLRs 2 4 5, Nod 1 2, Complement
Prrs that recognize fungi- TLRs 3 4 5, C3b, IgM
Early innate response phase
Bacteria gain entrance to interior, taken up by DCs, DC makes IL2 to activate macrophages, DC leaves the epithelium and goes to the lymphatics – goes to peyers patches, makes ILs and activate inflammaotry cells in endothelium (IL6 TFB
How the adaptice response phase is acitvated
DC enters presnts pathogen via MHC 2
CD4 cells get activated make TGFB and IL6–> make Th17 or Th1 cells
The Th 17 and Th1 cells either go back to the gut mucosa or they secrete IFNg to differentiate a Naiive B cell to a plasma cell to secrete IgG or IgA
in the gut mucosa IL 17 andIL 22 strengthen the defense mechanisms and clear the bacterial infection-> increased immune cell trafficking leads to an inflammed gut
anti viral host defense
Viral PRRs- TLRs 3 7 9, RIG 1 and IgM
Enteric viruses- rotavirus, norwalk virus, enteroviruses
DC cells phagocytoze the virus, activation, MHC 1 –> effector cytoxic cells, NK cells (making IFNg)– or IgA/IgG Plasma cell
Anti parasite host defense
not phagocytosed, Trematodes (schistisoma, nematodes (strongyloides), Cestodes (taenia saginata)
Granulocytes defend against parasites- granulocyes (eosinophils, basophils, mast cells defend the host by releasing their granule contents)- enzymatically digest tegument- stimulate propulsive muscle
Granulocytes are acitvated by Ag- bound IgE binding cell surface FceRI- require prior Ag exposure (sensitization)
Produce chemokines and cytokines to recruit and activate macrophages and lymphocytes to site of infection
Why do we not mount an immune response against food or microbiome bacteria
Immunogen- a molecule that induces an immune response
Anitgen- a molecule that is recognized and binds to antibody on B cells or T cell receptors on T cells
Tolerogen a molecule that induces immune unresponsiveness to subsequent doses of the molecule
tolerance
Self or Non self
Self?–> suppress immune response (tolerance)
Non- self?–> activate the immune response (Immunity)
Immunologic tolerance= Specific unresponsiveness to an individuals SELF antigen
Both T cells and B cells can immunologically tolerate antigenic molecules
in mucosa- the decision is a little complicated
Respond or not respond to self, food, microbiota
Respond= immunity
Not respond= tolerance
What makes something an immunogen?
Things that will increase immune response: large molecule, intermediate does, Sub G (vs intragastric), complex composition, comes with bacteria, interaction with MHC is effective
mucosal tolerance
Oral tolerance- the state of local and systemic immune unresponsiveness that is induced by oral administration of innocuous Ags such as food proteins
Mucosal tolerance: state of local and systemic unresponsiveness induced by the commensal microbiota
Mucosal induced tolerance helps prevent intestinal disorders (Celiac, IBS, food allergy)
Humoral NEUTRALIZING IGA is the most prevalent form of adaptive immunity in the gut
Th17 cytokine response is the most predominant cell-mediated immune response
Non responsiveness to food and microbiota is mediated by tolerogenic DCs and regulatory T cells
Mucosal Trafficking and retinoic acid
Gut homing traffic signals- Immune cells a4B7 integrin an dCCR9, Endothelium- mucosal addressin MadCam, Epithelium- mucosal trafficking signal CCL25
Mucosal DCs produce REtinoic acid from dietary Vitamin A through expression of REtinal Dehydrogenases
Intestinal epithelial cells also express retinal dehydrogenase–> elevated Retinoic acid in gut tissues
Retinoic Acid, TGFB etc establish these as tolerogenic mucosal DCs
Gut dendrtitic cells Take up Ags from the gut (food microbiota), travel to MLN present Ag to naive T cells
These cells produce retinoic acid and TGF B–> drive differentiation of CD4 naive T cells to become regulatory T cells (FoxP3+)- absent proinflammatory signals
IgA Class switching
T dependent: Soluble Ag, Activate B cell, Phagocytosed presented to T cells, DCs in peyers patch present Ag and activate naive T cells to Th1 cells, CD40 on Th1 cells and TGFB from DCs activates naive B cells
T- independent- soluble Ag recognized by B cell, TLR on DC stimulate release of TGF B, with IL6 and Retinoic Acid
Th17 T cells promote mucosal protection
MHC 2 restricted, Naive CD4 t cells differentiate into effector CD4 Th17 Cells in response to CD40L, IL6, IL 23, and TGFB
Effector CD4+ Th17 cells secrete IL 17 and Il22-> increased barrier function, anti microbial peptide secretion, Production of inflammatory cytokines, for macrophages and neutrophils
autoimmunity- loss of immunologic tolerance
the principle factors in autoimmunity are:
Over activation of immune system to typically innocuous Ags (hypersensitivity)
Inheritance of susceptibility genes
environmental triggers may activate self reactive or tolerized lymphocytes
Hypersensitivity
Excessive or aberrent immune responses following challenge wiht ag
Caused by- dysregulated or uncontrolled response to foreign Ags resulting in tissue damage and injury. OR failure of self tolerance followed by immune responses directed at self Ags (Autoimmunity)
Heterogenous group of disorders (type of immune response B cells vs Tcell)- nature and location
Hypersensitivity types
Type 1: Allergy immediate- IgE mediated, mast cells and eosinophils, vasoactive amines, and cytokines
Type 2: antiBody mediated, IgM and IgG, surface Ags–opsonization/phagocytosis, complement, Fc recruitment of leukocytes
Type 3- immune Complex mediated- IgM and IgG soluble Ag- complement and FC recruiment of leukocytes
Type 4- Delayed cell mediated- T cells- CD4 macrophages activation and inflammation
Autoimmunity Genetics
Multiple genes predispose to autoimmune diseases
HLA genes are linked
Non HLA genes- additional non-MHC genes (Nod 2 (a PRR) and ATG16 (autophagy gene in inflammation)
Mutations in MHC may contribute to autoimmune disease through- inefficient in displaying self ags or poorly stimulate regulatory T cells
celiac disease
Loss of tolerance to wheat- glutn) increased levels of deamidated gliaden peptide- loaded in MHC molecule
Autoimmune disorder- associated with HLA DQ 2 and DQ8 presence of auto antibodies to tissue transglutaminase (diagnostic), endomysium and gliadin peptide
Type 4 hypersensitivty- Th1 t cells and inflammatory damage to gut tissues
IBDs
loss of tolerance to microbiota- mutations in Nod PRR gene, mutations in ATG autophagy (cellular homeostasis) genes
Autoimmune disorders (Associated with HLA Dr adn HLA B27
type 4 Hs- th1 (crohns) or th2 (ulcerative colitis)–> inflammatory damage
food allergy
loss of tolerance, not autoimmunity,
type 1 HS0 sensitized to food Ag, immediate response, eosinophilic esophagitis, food protein induced enterocolitis syndrom (rare cell mediated
treating AI diisease
eliminating symptoms by suppressing the Immune response
