Mucosal immunity Flashcards
Most pathogens gain access by passing through
mucosal surfaces
Challenge in the GI tract
Eliminate pathogenic organisms
Limit the growth of commensals, but don’t kill them
Don’t mount an immune response to food
differences in the gut immune responses Vs. the “traditional” immune responses
traditional immune responses:
- Healthy tissue protected by systemic immunity
- surface wound introduces bacteria that activate macrophages to make inflammatory cytokines
- Cytokines released by macrophages produce an inflammatory immune response
- Infection is terminated, leaving a damaged and distorted tissue for repair
- Repaired and healthy tissue
Gut immune response:
- Healthy tissue protected by mucosal immunity
- Bacteria gain access to lamina propria by endocytosis, activate macrophages but do not cause inflammation
- local effector cells respond to limit infection, dendritic cells travel to mesenteric lymph node to activate adaptive immunity
- Effector B Cells and T cells that are highly specific for the invading bacteria colonize the infected area
- infection is terminated with either minor tissue d amage or no need for repair
Lamina Propria of the Gut:
Population is dynamic
- size depends on the antigenic environment
- Germ free animals have very few lamina propria cells
- Animals in highly infectious environments the
population greatly expanded
Antigen presenting cells:
- Chief APCs are the dendritic cells
- Macrophages also abundant in the diffuse
Natural Killer (NK) and Lymphokine-Activated Killer (LAK) cells
Mast cells
Contribute to local host defense by producing important mediators of inflammation
Induce chemoattraction of inflammatory cells to mucosal tissues
Goblet cells in GALT
Mucus secreting- barrier function and antibacterial, mucin glycoproteins
Epithelial cells in GALT
Barrier and antibacterial functions
Paneth cells in GALT
Antibacterial secreting cells
M cells in GALT
Antigen sampling
Microfold cells (M cells): Specialized epithelial cells Do not secrete mucus or have microvilli Take up microorganisms and antigens from the gut and transfer them to the Peyer’s patches (basal surface) DCs inside can take up and present Ag T cells and B cells activated locally
GALT stratification
minimize direct contact between bacteria & epithelial surface
Mucins, Anti-bacterial proteins, IgA
GALT compartmentalization
confine bacteria to intestinal sites and limit systemic exposure
Action of phagocytic cells in the lamina propria
Homing of activated lymphocytes to mucosal surfaces
Small intestine is heavily invested with lymphoid tissue
Peyer’s Patches
- 5-200 B cell follicles with - - Germinal centers
- Only in small intestine
Isolated Lymphoid follicles
- Single follicle, mostly B cells
- Small and large intestine
Appendix
Intra-epithelial lymphocyte
Special type of CD8+ T cell (1 per every 10 epithelial cells)
Limited range of antigen specificities
CD8+ T cell binds MHC 1 to see if the item is foreign or not
Dendritic cells resident in lamina propria
Capture pathogens independently of M cells
Less likely to activate Th1 response
Lymphocytes return to mucosal tissue as effector cells
Occurs in ways that minimize inflammation
These effector cells can now recirculate to any mucosal tissue
In nursing mothers, plasma cells from other mucosal sites will migrate to mammary glands.
This ensures that breast milk IgA represents all the antibody responses from all mucosal tissues
Adaptive Immunity in the mucosa
Humoral immunity and * IgA
- Neutralizing
- Enhance innate immune factors
- Th17 dominant cell-mediated immunity
- Th17 plays a role in gut colonization
- IL-17 and IL-22 are characteristic cytokines
Suppression of cell-mediated immunity
- High percentage of *** FoxP3+ Tregs
- Presence of regulatory CD103+ DCs
- TGF-β, IL-10, and IL-2 are characteristic cytokines
Food allergies
Food potentially immunogenic, inflammatory reaction ensues
Sometimes allergen can be transported to another part of the body causing a skin reaction
IgE mediated: food-specific IgE
- Acute or chronic cutaneous symptoms or anaphylaxis
- Most prevalent in young children
Non-IgE mediated: Th2-cell mediated
- Chronic skin and/or GI symptoms
- Eosinophilic disorders
Mixed: both
IgE mediated allergic reactions
Anaphylaxis (Edema)
Urticaria (increase in blood flow/ vascular permeability)
Seasonal allergies (sneezing)
asthma (bronchoconstriction, mucus, inflammation)
food allrgy (vomiting, diarrhea, pruritis, etc.)
Sensitization (Priming) and repeat exposures to allergen
1st time: no allergic symptoms
2nd time: sensitized. mild
3rd and more: hypersensitized, overt allergic symptoms
Immediate hypersensitivity
Cross linking of FcR1 on mast cells by IgE causes mast cell activation
Immediate hypersensitivity
Varying severity - runny nose to asphyxiation
Early phase (minutes after repeat exposure to allergen)
and late phase (6-24 hours after repeat exposure to allergen)
Why Do Food Allergies Arise?
Inappropriate Digestion Hypothesis
- Normal: di & tri-peptides, non-immunogenic
- Abnormal: longer peptides, some maybe immunogenic
- Caused by: genetics, diet, drugs, toxins, age?
Hygiene Hypothesis
Microflora Hypothesis
Hygiene Hypothesis
Lack of early childhood exposure to infectious agents, including parasites, increases susceptibility to allergic diseases
“Poorly developed” immune systems – can’t perceive real danger
Fail to induce Th1 polarized responses early in life, grow up more prone to Th2 responses
Increase due to better hygiene, vaccination, increased use of drugs and antibiotics
Some studies have shown that children exposed to more infections at a younger age have reduced propensity for allergic reactions
IBD
Autoimmune disease partially mediated by the absence of Treg cells
Inflamed, ulcerated, damaged bowel
* Crohn’s disease
affects the entire thickness of the bowel wall
most frequent, but not restricted, to the terminal ileum
* Ulcerative colitis
restricted to the colonic mucosa
Recent study demonstrated that Celiac and Crohn’s share genetic risk loci
Differences between Crohns and Ulcerative colitis
Crohns: anywhere along the digestive tract
inflammation may occur in patches
pain commonly in RLQ
colon may be thickened and may have a rocky appearance
ulcers along the digestive tract are deep and may extend into all layers of the bowel wall
Bleeding from the rectum during bowel movements is NOT common
Ulcerative colitis: large intestine is typically the only affected site
inflammation continuous
pain common in LLQ
colon wall thinner, continuous inflammation
mucus lining may have ulcers, but they do not extend beyond the inner lining
bleeding from rectum during bowel mvts
IBD treatment
IBD and colitis result from autoreactive T cells in the lamina propria
The disease can be treated by transfer of CD4 CD25 Treg cells, which home to mesenteric lymph nodes and the colon
CD4 CD25 Treg cells proliferate and inhibit the pathogenic effector T cells
After inflammation resolves, CD4 CD25 Treg cells remain in clusters with dendritic cell and pathogenic effector T cells
Immunologic Abnormalities in IBD
Defective Treg cell function
- FoxP3 and IL-2 or IL-2R deficiencies result in inflammatory bowel disease
Dysregulated innate immune response
- Defective defensin expression
- Inadequate negative immune regulation to commensal organisms
Abnormal cell-mediated immunity
- Overactive Th17 response
- Granulomatous inflammation by IFN-γ-producing Th1 cells
Defective autophagy
Epithelial Host Defense- Regulated Expression of TLRs and NLRs
The first susceptibility gene identified for Crohn’s disease was a NOD family member NOD2, a receptor for the muramyl dipeptide structural unit of bacterial peptidoglycan.
Expression of TLRs and NLRs (nod-like receptor) is restricted in the gut and the location of receptors is altered. Furthermore, the functional response of these receptors is biased towards an anti-inflammatory response. The purpose of these alterations is to limit inflammation in the gastrointestinal tract.
Celiac Disease - Introduction
Celiac disease is an immune-mediated disease mediated by T cells
Estimated frequency 1:100 to 1:150
Associated with other autoimmune diseases
Type 1 diabetes, autoimmune thyroid
- Clinical symptoms can vary from abdominal pain, diarrhea, growth failure, anemia, osteoporosis, or asymptomatic
celiac disease antibodies and triggers
Antibodies to tissue transglutaminase (IgA) are seen in individuals with celiac disease
- 10% of type 1 diabetics will develop celiac disease autoantibodies
Gluten is the environmental trigger
- Found in wheat, rye, and barley
Treatment is lifelong dietary avoidance of gluten (gluten-free diet)
- Found in pastas, bread, most marinated meats, salad dressings, & beer
Gluten-free diet completely reverses clinical and histological findings
Celiac Disease is an autoimmune disease
Inflammatory autoimmune disease of gut mucosa
Genetic and environmental factors
CD4 T cells, chronic inflammation, atrophy of intestinal villi, malabsorption of nutrients, diarrhea
Genetic predisposition
- 75% monozygotic twins
- Strong association with HLA-DQ2 or 8
Gluten specific T cells found in gut of celiacs but not healthy controls
BUT peripheral blood T cells from celiac and non-celiac patients contain cells that react to gluten in culture
What happens to gluten in the gut
gluten is degraded in the gut lumen to give a resistant fragment
gluten fragment enters gut tissue and is deaminated by transgluatminase
In celiac: Naive CD4 T cell responds to deaminated peptides presented by HLA-DQ
inflammatory effector T cells cause villous atrophy
one of the first thing that starts to damage tissue in celiac disease
intra-epithelial lymphocytes
genetics of celiac disease
All Celiac disease patients have HLA - DQ2 or DQ8
30% of the Caucasian population has DQ2
3-5% of DQ2/DQ8 individuals develop Celiac disease
HLA genes are necessary but not sufficient to develop disease
Gluten is broken down into
Gliadin (alpha, gamma and omega)- alcohol soluble
Glutenins (alcohol insoluble)
Tissue Transglutaminase (TTG)
TG recognizes certain motifs: QXXF and QXPF → EXXP and EXPF
Deamidation creates a negative charge on specific aa residues to better
fit in DQ pockets.
No evidence that TG antibodies cause disease.
Celiac Disease Antibodies
Tissue Transglutaminase
- IgA – sensitive and specific
- IgG – check if IgA deficiency
Endomysium (IgA)
Gliadin (IgA & IgG)
Deamidated Gliadin
Gluten Free Diet
Very difficult to maintain a completely gluten free diet
“Hidden Gluten” – protein filler in sausage, soups, soy sauce, & ice cream
Cross-contamination – gluten free products encounter gluten during milling & storage
50 mg/day of gluten for 3 months can cause intestinal changes (this amount can come from 250 grams of gluten free food)
- No change in clinical symptoms or autoantibodies levels
Novel Therapies for Celiac disease
Enzyme Therapy
- Bacterial prolyl endopeptidase can digest the 33-mer of gliaden
- Pretreatment of gluten containing food with these peptidases
Zonulin Antagonists
- Zonulin is a protein that increases intestinal permeability
- Zonulin antagonist (AT-1001) has been used in a small clinical trial resulting in no increased intestinal permeability after a gluten challenge (Paterson BM, Aliment Pharmacol Ther 2007)
Inhibiting DQ2/DQ8 antigen presentation
- Small molecules to block basic binding pockets of gluten peptides
Immunodeficiencies that can affect the GI tract
Selective IgA deficiency
IPEX
Selective IgA deficiency
Most common primary immunodeficiency Majority are asymptomatic People are relatively healthy - - Compensated for by IgM, IgG - Could reflect developed countries, few parasitic infections
Caucasians: 1/500 persons little or no IgA
African-Americans: 1/10,000
Japanese: even lower
Immune dysregulation, polyendocrinopathy, enteropathy X-linked disease (IPEX)
Arises due to mutations in the transcription factor Foxp3
The phenotype in humans results in a loss of functional Treg cells
Lack of T cell inhibitory activity results in widespread autoimmunity
Symptoms include intractable watery diarrhea, failure to thrive, dermatitis, and autoimmune diabetes
Immunoglobulin levels are normal with the exception of IgE which is elevated
Building on hygiene hypothesis – “microflora hypothesis”
Western lifestyle alters gut microflora which leads to allergies and other inflammatory diseases
