Mucosal immunity Flashcards
GI immunity
- epithelial layer w/ mucus
- commensal bacteria
- paneth cells secrete defensins and stuff that keeps pathogenic species at bay
- Peyers patch- important for antigen presentation
M cell– bridge between innate and adaptive immunity. Resp. for uptake of antigens - dendritic cells embedded in the epithelium take up antigens from there and the lamina propria
- mesenteric lymph node
- Plasma cells- differentiated B cells- embedded in the lamina propria secreting antibodies
Mucins
Gastrointestinal mucins are O-linked oligosaccharides
Include secreted and membrane-bound forms (glycocalyx)
Rapid turnover and inducible expression
Epithelial Host Defense- Regulated Expression of TLRs and NLRs
PAMP: pathogen-associated molecular pattern
TLR: toll-like receptor
NLR: Nod-like receptors
Expression of TLRs and NLRs 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.
Paneth Cells and Defensins
Small cationic peptides (29-34 aa) that contain three intrachain disulfide bonds
Defensins have anti-microbial properties and can act to activate other immune cells
Small bowel
α-defensins produced by Paneth cells (HD5 and HD6)
Neutrophils are also a source of α-defensins
Colon
β-defesin produced by absorptive epithelial cells
C-type lectins- REG3 and REG3β
Peyers patches vs. lymph nodes
. Peyer’s patches are not encapsulted and have a higher percentage of B cells. However, the general structure contains B-cell rich follicles where IgM and IgD-expressing naïve B cells reside. Interspersed between the follicles are T-cell rich zones and the dome region which contains T cells, B cells, DCs and macrophages.
M cells
flattened epithelial cells transport material to the follicular dome areas to interfollicular areas distinguished by ability to pinocytose material transport material in an intact form express MHC class II but no not act as antigen-presenting cells possibly some specificity involved normal flora not transported
deficiency in T cells leads to
widespread inflammation in the gut
Homing signals
α4β7 on lymphocytes binds MAdCAM-1 on postcapillary venule endothelial cells in the gut lamina propria
Chemokine receptor CCR9 on lymphocytes binds the chemokine ligand on intestinal epithelial cells (in small intestine)
Chemokine receptor CCR10 binds chemokine CCL28 expressed by colon and breast tissue
Dendritic cells promote the expression of α4β7 and CCR9 through retinoic acid synthesis (mechanism for this transition is unknown). Only DCs in the gut express retinal dehydrogenases (RALDH) which is necessary for the synthesis of retinoic acid from vitamin A.
IgA Function
Protective role of secretory-IgA (s-IgA)
neutralize biologically active antigens
viruses, toxins and enzymes
prevent uptake of antigens by the intestinal tract
inhibit adherence of bacteria to epithelial surfaces
Enhancement of innate immune factors
IgA structure
Serum IgA
Physiologic role of IgA in the blood is unclear
humans is mainly monomeric
Amount transported from serum to secretions is very low
Does not fix complement
will not induce an inflammatory response
Mucosal antigen gets into circulation will not induce a sytemic inflammatory response
Prevents colonization without inflammation
Allows for clearance of circulating antibody antigen complexes without inducing systemic inflammation
Kupffer cells in liver filter out IgA-antigen complexes
what’s important about IgA?
does not induce inflammation
Cell-mediated Immunity
Intraepithelial cells are mostly CD8+ T cells
10% of intraepithelial cells are γδ T cells
Intraepithelial cells have a limited T cell repertoire
Lamina propria cells are mostly CD4+ T cells
CD4+ T cell Subsets
Th17
- Murine models indicate that Th17 cells play a role in colonization and protection of the gut
- IL-17 and IL-22 characteristic cytokines
Th2
Th2 cells protect against helminthic infections
- IL-4 and IL-13 characteristic cytokines
Regulation of Immunity in the GI Tract
The lamina propria has a higher percentage of FoxP3+ Tregs than any other tissue in the body
CD103+ DC, retinoic acid, and TGF-β all play a role in the development of Tregs
TGF-β, IL-10, and IL-2 are characteristic cytokines
commensal bacteria vs. pathogenic bacteria
The human gut hosts trillions of microorganisms referred to as the microbiota
Beneficial species include Lactobacillus spp., Bifidobacterium spp., and Escherichia coli Nissle 1917
The is evidence showing beneficial bacteria can protect against pathogenic species including: Salmonella Typhimurium and Clostridium difficile
mechanisms of colonization resistance
adhesion exclusion carbon source limitation micronutrient limitation secretion of antimicrobials delivery of toxins
Diseases related to immune responses in the gut
Inflammatory bowel disease (IBD):
- Crohn’s disease (affects the entire thickness of the bowel wall and most frequent, but not restricted, to the terminal ileum)
- Ulcerative colitis (restricted to the colonic mucosa)
Celiac disease- gluten-sensitivity
Food allergies
Tumor development in response to prolonged immune responses
Immunologic abnormalities in IBD
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 regulatory T cell function
- FoxP3 and IL-2 or IL-2R deficiencies result in inflammatory bowel disease
Defective autophagy
Celiac disease
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
when do we think celiac disease?
weight loss, anemia
Food allergies- IgE mediated
food-specific IgE
Acute or chronic cutaneous symptoms or anaphylaxis
Most prevalent in young children
Non-IgE mediated food allergies: Th2-cell mediated
Chronic skin and/or GI symptoms
Eosinophilic disorders
Childhood food allergies
Very Common: milk, eggs, etc.
Most are “outgrown”
Theory: mucosal barrier not complete
until around 4 yeas of age.
Symptoms: GI, skin
Anaphylactic responses: not outgrownAdult food allergies: innapropriate digestion
Normal: di and tri-peptides, non-immunogenic
Abnormal: longer peptides, some maybe immunogenic
Caused by: diet, drugs, toxins, age?
Other hypotheses re: food allergies
Hygiene Hypothesis Environmental Microbial Exposure and Protection against Asthma (NEJM 373;26) December 24, 2015 Dietary Fat Hypothesis Antioxidant Hypothesis Vitamin D Hypothesis Dual-allergen-exposure Hypothesis Emerging Hypothesis(es)
Allergy treatments
No Cure Avoidance diets Sub-Q IT: systemic reactions Anti-IgE: anaphylaxis (non-specific) IT with adjuvants: bacterial products as modulators of Th1 response
what cell type would be induced in order to bring about oral tolerance
T reg cells
prolonged immune responses to GI microbes can lead to…
tumors arising in the gastrointestinal tract. Esp. H Pylori.
Innate immunity in the GI tract
Goblet cells- Mucus secreting- barrier function and antibacterial
Epithelial cells- Barrier and antibacterial functions
Paneth cells - Antibacterial secreting cells
M cells- Antigen sampling
Adaptive immunity in the GI tract
Humoral immunity and IgA
Th17 dominant cell-mediated immunity
Suppression of cell-mediated immunity
Perianal fistulas as a symptom….
think IBD
