what characteristics define mucosal tissue?

mucus-secreting epithelium joined by tight junctions

communicates with external environment

the site of entry for most pathogens

includes linings of GI, respiratory, and urogenital tracts, mammary glands, and conjunctiva of the eye

site of secretion of secretory IgA

what are mucins?

a family of large (10,000 AA) glycoproteins secreted by mucosal epithelium

size forces the glycoprotein into an extended conformation heavily hydrated

various genes code for mucins that each have differences in viscoelastic properties

what is mucus?

slimy, protective secretions composed of glycoproteins, proteoglycans, peptides, and enzymes secreted by goblet cells embedded in internal epithelium; prevents smog/smoke

what are glycoprotein?

glycol (sugar) + proteins; rich in theronine and serine

what are commensal microorganisms?

the digestive tract is approximately 9 meters in length, with each area having its specific function

the GI tract is populated by approximately 750 species of bacteria

what are five of the symbiotic benefits of the microbiome?

synthesis of essential metabolites

breakdown of plant fibers into digestible food

inactive toxic substances in food or from pathogens

prevent access of pathogens to the human gut

interact with epithelium to trigger development of secondary lymphoid tissue

what are examples of secondary lymphoid tissues at mucosal sites?

GUT-associated lymphoid tissue; the most extensive secondary lymphoid tissues in the body; they key antigen sampling and adaptive immune inductive sites within the intestinal wall

GALT consists of...

peyer's patches in the ileum

appendix

isolated lymphoid follicles

tonsils, adenoids

what is the inductive compartment?

directly beneath the mucosal epithelium

where interactions between the antigen, dendritic cells, and lymphocytes induce adaptive immune responses

three steps in the inductive compartment?

antigen is captured by dendritic cells or M cells and lymphocytes are activated

mucosal cells produce retionic acid which - along with other cytokines- drives differentiation and homing

change in homing phenotype `

what is the effector compartment?

connective tissue; lamina propria

the residence of effector cells: plasma cells, effector T cells, macrophages, mast cells, eosinophils

what is systemic immunity?

immunity that occurs at non-mucosal tissues

interactions with microbes are relatively rare

cells are recruited from the blood; DCs migrate to secondary lymphoid tissue

short violent episodes of localized and intense inflammation are the price paid to squash the sporadic infections of non-mucosal tissues

what is mucosal immunity?

immunity that occurs at mucosal tissues

interactions with microbes are close and continual

commensal microorganisms have a symbiotic relationship with their host but can turn pathogenic with any significant breach of the gut

two strategies for avoiding peritonitis

the mucosal response is proactive, constantly making adaptive response against gut microbiota so healthy gut issue already has effector T and B cells ready and available

the mucosal response is sparing in its use of inflammation

what is Crohn's disease?

a chronic inflammatory bowl disease that causes inflammation anywhere in the digestive tract, most commonly in the lower part of the small intestine and the beginning of the large intestine

how does the innate immune response in the gut work?

intestinal epithelial cells express pattern recognition receptors

activation of the two receptor types

thus epithelial cells have a quick and localized inflammatory response that is a sufficient to respond to the infection but not create lasting damage

activation of the two receptor types in the gut innate immune response lead to

formation of the NLRP3 inflammasome leads to expression of NFkB

production of antimicrobial peptides

productions of cytokines and chemokines

what role do intestinal macrophages play?

crucial for maintaining gut homeostasis by tolerating beneficial bacteria while still defending against pathogens. they are structurally and functionally different from blood monocytes due to their origin and lack of certain receptors, which makes them less inflammatory and prevents them from becoming professional antigen-presenting cells

what is the role of NFkB?

functions as a transcription factor to control the expression of genes involved in the immune response, inflammation, cell growth, and survival

what is the role TFGB?

promoting cell proliferation, differentiation, and apoptosis, as well as regulating the immune system by influencing both T and innate immune cells

what are the cell types of the intestinal epithelium?

enterocytes

goblet cells

paneth cells

M cells

lymphoid follicle

follicle-associated epithelium

what are enterocytes?

specialized for the absorption of nutrients

what are goblet cells?

secrete mucus

what are paneth cells?

secretion of anti-microbial peptides and proteins

what are M cells?

important in 'antigen sampling' take up antigen and transport them across the epithelial barrier

what are lymphoid follicle?

a discrete, organized structure within secondary lymphoid tissue; similar to follicles discussed in the lymph node

what are follicle-associated epithelium?

epithelium that overlies follicles

what is the role of microfold cells?

follicle-associated epithelium overlying lymphoid tissue in the small intestine and is poorly defended

microorganisms are funneled towards microfold or M cells that are strategically positioned above the lymphoid follicles

M cells are named because...

they contain fewer folds than adjacent enterocytes; basolateral side is known as the interepithelial pocket

what is oral tolerarnce?

if you eat something first then you are less likely to be allergic to it than if you experience it on your skin first

what types of T cells do CD103+ DCs present to?

T(FH) and T(REG) cells

when T(FH) and T(REG) activate B cell, what antibody isotypes do they produce?

IgM --> IgA

how do CD103+ DCs function in the presence infection?

think escalation

DCs become more mobile and can capture antigen in the absence of M cells by having extended processes

through perpetual sampling T cells specific for pathogens, commensal microorganisms and food antigens are stimulated to become effector cells; T cells then activate IgA

how do CD103+ DCs function in the absence of infection?

think surveillance

in the gut, food antigens are taken up by CD103+ dendritic cells

to ensure that commensal microorganisms remain outside the epithelial barrier, DCs present antigen to CD4+ T cells, leading to activation of B cells and production of microganism-specific IgM -> IgA

where are mucosal lymphocytes activated?

activation at mucosal inductive site imprints a lymphocyte with a homing signal that directs them back to mucosal sites

down regulation of CCR7, upregulation of CCR9 and MAdCAM-1

what is the distribution and nature of lymphocytes in the gut?

at all times, mucosal tissues are populated by antigen-activated effector cells; most other tissues only permit activated effector cells during infection

effector cells primarily stimulated by antigens from commensal bacteria; others are from primary response against pathogens that aren't normally part of the gut

ongoing, low0level antigen exposure continually restimulates them while their high antigen specificity and tissue's regulatory milieu keep inflammation muted

how do B cells in the gut work?

B cells are mostly plasma cells that secrete IgA and IgM

adaptive effectors are not intrinsically noninflammatory

chronic activation converts the normally noninflammatory mucosal state into pathogenic inflammation

mucosal B cells develop and circulate similarly to mucosal T cells

1st wave of B cells in the gut

B cells in the lamina propria secrete IgM

2nd wave of B cells in the gut

most of the B cells in the lamina propria become IgA-secreting plasma cells; dimeric IgA is higher affinity than IgM

antibodies are embedded in the nucleus and help maintain a balanced environment, but...

they DO NOT fix complement

they DO coat the surfaces of bacteria to impede entry into the tissues and then allow antimicrobial peptides to do the killing

what is the role of IgA in maintaining tolerance?

anti-inflammatory antibody that limits the access of pathogens, commensal microorganisms, and food products to mucosal surfaces in a manner that avoids unnecessary damage to these delicate and vital tissues

what are the differences between IgA1 and IgA2?

the major difference between IgA1 and IgA2 is the hinge region

hinge region is twice as long IgA1

longer hinge region allows for greater 'freedom' in binding pathogens

the longer hinge region is also more susceptible to pathogen-secreted proteases

therefore, IgA1 predominates in mucosal areas expect for areas for those that contain protease-secreting microbes

what tare the potential causes of and problems caused by selective IgA deficiency?

selective IgA deficiency results from an inability to class switch from IgM

clinically heterogenous; results from numerous mutations

anatomical features of mucosal immunity

intimate interactions between mucosal epithelia and lymphoid tissues

discrete compartments of diffuse lymphoid tissue and more organized structures such as peyer's patches, isolated lymphoid follicles, and tonsils

specialized antigen-uptake mechanisms provided by M cells in peyer's patches, adenoids, and tonsils

effector mechanisms of mucosal immunity

activated effector T cells predominate even in the absence of infection

plasma cells are in the tissues where antibodies are needed

immunoregulatroy environment of mucosal immunity

dominant and active down regulation of inflammatory immune response to food and other innocuous environmental antigens

inflammation-anergic macrophages and tolerance-inducing CD103+ dendritic cells