Mucosal Immunity Flashcards
Combined area of mucosal surfaces
Greater than that of the skin
- small intestine has a surface area 200x the skin
Body’s lymphocytes
3/4 are in secondary lymphoid tissues serving mucosal surfaces
- similar proportion of all antibodies made by the body is secreted dimeric IgA
GIT
Continuous contact with large populations of commensal microorganisms and substantial quantities of proteins derived from animals and plants (food)
Challenge of mucosal immunity
Making immune responses to eliminate pathogens, limit the growth and location of commensal microorganisms, and to NOT attack food
Gut-associated lymphoid tissues
- lamina propria
- mesenteric lymph nodes
- palatine tonsils
- adenoids
- lingual tonsils
- Peyer’s patches
- M cells
- isolated lymphoid follicles
- intestinal epithelium
Peyer’s patch
T cell and B cell rich areas
- function like secondary lymphoid tissues
M cells
Microfold (multifenenestrated)
- specialized to transport microorganisms to GALT
- surface is designed for microbes to fall into sunken area
Antigen uptake and transport by M cells
M cells are interspersed between enterocytes and in close contact with DC –> take up antigens from gut lumen via endocytosis –> antigens are released beneath M cells and taken up by APCs (DC) –> DC dendrites span the gut wall and engulf antigens
Dendritic cell periscopes
Extend processes across the epithelial layer to capture antigen from the lumen of the gut
Most immune system cells in the mucosal tissues are activated ________
Effector cells
- have already been primed by antigens against certain pathogens
- ex: CD8 T cell, plasma cell, IgA, DC, mast cell, macrophage, CD4
Naive lymphocytes
Naive lymphocytes activated in Peyer’s patch give rise to effector cells that travel in the lymph and blood to gain access to the lamina propria of the mucosal tissue (return to tissue as effector cells)
Secretory IgA
Export toxins and pathogens from the lamina propria while being secreted –> IgA is able to bind and neutralize antigens internalized in endosomes –> secreted IgA on the gut surface can bind/neutralize pathogens and toxins –> secreted IgA binds pathogens on M cell surface and takes it to lymphoid tissue –> IgA picks up antigen in endosomes of M cell and takes it to lymphoid tissue
Cytoplasmic NOD-like receptors
Are a type of signaling PRRs
- binding of PAMPs to their signaling PRRs promotes synthesis and secretion of intracellular regulatory molecules (cyto/chemokines, defensins) to initiate innate and adaptive immunity
NOD2 proteins are found ____
In the cytosol of enterocytes
- respond to bacterial products by activating NFkB
Naive CD4 T cells activated during helminth infection can differentiate to ____ or _____ effector cells
Th1; Th2
Th2 cells produce IL-13, which induces _____
Epithelial cell repair and mucus
- increased cell turnover and movement helps shedding of parasitized epithelial cells
- mucus prevents adherence and accelerates loss of parasite
Th2 cells produce IL-5, which recruits/activates ____
Eosinophils
- produce MBP, which kills parasites and mediate ADCC using parasite-specific Ig
Th2 cells drive B cells to produce ___
IgE
- arms mast cells and eosinophils to recognize parasite antigens
Th2 cells drive _____ via IL-3, IL-9
Mast cell recruitment
- produce mediators (histamine, TNF-alpha, and MMCP) to recruit inflammatory cells and remodel the mucosa
Th2 is _____
Protective for the host!
Th1 cells activate _____
Macrophages
- products of activated macrophages cause tissue damage and tissue remodeling
Th1 cells activate B cells to produce ______
IgG2a
- complement fixing antibodies
Th1 is _____
Host damaging!
- can not kill helminths, macrophages will damage tissues while trying to get rid of helminth
Features of helminth-induced immune resonpse
- helminth infected populations exhibit lower levels of immunological diseases
- helminth infection is a feature in developing countries, while allergy is an issue of developed/industrialized countries
Helminth hypothesis
Immune system has coevolved to operate in the presence of helminths, while in the absence or exposure to helminths, the immunoregulatory components that would normally prevent allergy and autoimmunity become weakened
Helminths have unique evolutionary dialogue with hosts immune system due to
- longevity within the host
- complex life cycle
- multicellular nature
Th2 type immune responses
- inflammation
- wound repair
- resistance to helminths
Key players of helminth induced immune response
- dendritic cells
- CD4+ Th2
- IL-4,5,9, 10, 13
- IgE
- chemokines
= recruitment of eosinophils, basophils, mast cells, and expansion of alternatively activated macrophages (AAM)
Modified Th2 type response
Induced by helminths to limit a possibly detrimental Th2 immunity
- helps restrain extreme symptoms (allergy, fibrosis, etc)
Mechanisms of helminth immune responses lead to
- attenuation of pathology
- tolerance and persistance of the worm = long term survival of parasite within the host
- sustained parasite feeding
- completion of life cycle, successful reproduction
Helminth/host immune interaction summary
- helminth infection induces a protective Th2 immune response
- helminths induce immunoregulation via modulation of immune cells (AAM, Treg, and B cells = inhibitory antibodies)
- allergic inflammation may be suppressed by spill over effect of immunomodulatroy mechanisms of helminth infection
What kind of cells are helminths targeting to protect themselves?
- induced alternatively activated macrophages, Tregs (stop Th17), and B cells
Antibody dependent cell mediated cytotoxicity
IgE coats large parasites –> Fc receptor of eosinophil recognizes IgE –> interaction between Fc receptor and Fc portion of helminth-bound IgE signals eosinophil to degranulate
Mucosal barrier and mucus
- 1st arm of innate immunity
- goblet cells + antibodies, defensins, etc release protective agents that produce a hostile environment, reducing chances of microorganisms from reaching host epithelium
Mucins
Essential anti-parasitic effector molecules due to importance in mucus structural integrity
How are type 2 inducing stimuli sensed?
- pathogens/allergens are sensed by PRRs
- proteolytic cleavage of host proteins by the protease activity of allergens, tissue damage, and metabolic changes are sensed by DCs
Anatomical features of mucosal immune system
- intimate interactions between mucosal epithelia and lymphoid tissues
- discrete compartments of diffuse lymphoid tissue and more organized structures (peyer’s patches, isolated lymphoid follicles, tonsils)
- specialized antigen-uptake mechanisms provided by M cells in Peyer’s patches, adenoids, and tonsils
Effector mechanisms
- activated effector T cells predominate even in absence of infection
- plasma cells are in the tissues where antibodies are needed
Immunoregulatory environment
- dominant and active downregulation of inflammatory immune responses to food and other innocuous environmental antigens
- inhibitory macrophages and tolerance-inducing DC
____ of the immune system’s cells are dedicated to the mucosal surfaces defense
75%
________ continuously sample the gut’s luminal contents and stimulate adaptive immune responses to pathogens, commensals, and food
Secondary lymphoid tissues
Healthy gut
Chronic adaptive immune response, which is not inflammatory
- ensures that microorganisms are confined to the lumen of the gut and prevented from breaching the mucosal barrier
