Flashcards in 13. Mucosal Immune System Deck (71):
the mucosal immune system is divided into two distinct sites, inductive sites and effector sites - explain?
1. inductive sites for mucosal immunity (ie where immune response are induced) = organized mucosa-associated lymphoid Tissue (MALT)
2. effector sites (ie whre the immune system acts against a pathogen) are the mucosal epithelia and underlying lamina propria
what are the 2 genera (overarching)l functions of the mucosal immune system? (hint: think about the bacteria/pathogens in the gut)
1. first line of defense against microbial pathogens (induction, amplification of local immune responses; preserve intestingal barrier, prevent organisms from entering into circulation)
2. tolerance: prevent undesired host reaction vs food and commensals (IMMUNE REGULATION)
the mucosal immune system containst ___-% of all lymphocytes?
70% and produces the largest amount of immunoglobulins
what are 4 distinct features of the mucosal immune system compared to the systemic immune system?
1. intimate association with epithelial cells
2. defined (ILF and PP = isolated lymphoid follicles and peyer's patches) and diffuse lymphoid structures
3. secretory antibodies
4. unique regulatory mechanisms
what are the mucosal secondary lymphoid tissues?
peyer's patches (GALT), appendix, tonsils and adenoids (NALT) and mesenteric lymph nodes
the GI tract's first line of protection is what?
mucus that covers the epithelial cells
what is the major immune compartment?
the mucosal compartment (60-70% of total lymphocytes in the body)
what are the 2 major effector cells of the mucosal immmune system?
plasma cells and CD4 Th2 cells
(M = microfold or membranous) - specialized epithelial cells lacking microvilli They are located selectively over lymphoid tissue and have a major role in transport of substances between the mucosal lumen and underlying lymphoid tissue. They are responsible for ~90% of uptake of larger, antigenic substances (both soluble and particulate) from lumen, the remainder is done by absorptive epithelia
located near the base of the crypts adjacent to or surrounding the multipotent stem cells. They represent a relatively stable cell population in the intestine and exhibit a secretory phenotype, releasing anti-microbial peptides such as defensins.
secrete mucins and epithelial cell-protective peptides and are scattered among absorptive epithelial cells of the villus associated epithelium
connective tissue region that underlies the epithelium. The lamina propria includes abundant numbers of lymphoid and myeloid cells and is considered an immune effector site.
lymphoid tissue embedded in the lamina propria is in which region?
follicle associated epithelium
develops only over lymphoid tissue, such as a Peyer’s patch. The FAE does not contain mucus-secreting goblet cells, but it does contain M cells. The M cell microfolds are readily observed microscopically due to the relatively sparse distribution of mucus over the apical surface of these cells.
the overlaying mucous layer of the GI tract has a viscous, gel-like consistency, due to the presence of what?
mucins - long, fibrous peptides decorated with oligosaccharides. The precise biochemical composition of mucus is specific to each site, due to variations in the locally synthesized peptides and oligosaccharides
A ______ region lies under the mucous layer of the GI tract, but over the microvilli of epithelial cells.
glycocalyx region - a dense layer of glycoproteins, comprised in part of mucins that remain anchored in epithelial cell membranes (the epithelial cell microvilli extend into an aqueous region below the glycocalyx)
how does Shigella work?
taken up by M cells and infects underlying macrophages causing apoptosis. Bacteria released from apoptotic macrophages can infect epithelial cells from the basolateral side and spread through the epithelial cell barrier.
isolated lymphoid follicles (ILF) are present throughout the intestine. What do they contain? When are they induced?
They contain germinal centers but few T cells and no distinct T cell-zones. They are induced after birth by the colonizing microflora –which is then controlled by the IEL (intraepithelial lymphocytes).
peyer's patches - where are they present (ie which part of GI tract), what do they consist of?
present in the small intestine. They consist of B follicles with germinal centers.
how are PP and ILF connected to the lymphatics?
draining mesenteric lymph nodes
development of PP depend on the presence of what?
the presence of lymphoid tissue inducer cells which produce Lta and Ltb and stromal cells, which secrete IL-7
outer vs inner mucus layer?
outer: non sterile, microbes
inner: relatively sterile, rich in antimicrobials, antibodies
what are the epithelial cell-derived antimicrobial proteins of the mucosal immune system? (think innate function of mucosal immune system)
defensins, cathelicidins, C-type lectins
intestinal epithelial stem cell
crypt intestinal epithelial stem cell niche contains epithelial, stromal and haematopoietic cells, controls continuous renewal of epithelial cells. Differentiated IEC (except paneth cells) migrate up the crypt-villus axis
Action of M cells?
are actively pinocytotic, and much of what they take up is transported to the underlying lymphoid area. Once transported through the M cell, these substances become directly available to existing dendritic cells and macrophages, some of which are present just below the surface of the invaginated, basal-lateral pocket of the M cell
DC action re: gut epithelia (physical action of DCs as it corresponds to gut epithelium)
a specialized subset of dendritic cells (DCs) that can extend their dendrites through the epithelial cell tight junctions into the lumen of the corresponding tract. The antigen-laden dendrites of the DCs cells can then return their load directly into the lymphoid area, where the constitutive proteins and peptides can be presented to lymphocytes.
peyer's patches compared to lymph nodes and the spleen
in contrast to peripheral lymph nodes, B cells predominate in Peyer’s patches as in the spleen. However, unlike the spleen where B cells are rich source of IgG, the Peyer’s patches represent a major source of B cells programmed to secrete IgA in the intestine.
Also, in contrast to peripheral lymph nodes, Peyer’s patches and other mucosal lymphoid tissues have no afferent lymphatic and no outer capsule. Instead, such sites represent aggregates of lymphocytes, dendritic cells and macrophages that are organized into follicular and interfollicular regions--essentially B cell and T cell zones, respectively--and embedded in the lamina propria.
what is the major lymphocyte population in the lamina propria?
B cells, most secrete IgA
what are three functions of the epithelial cells of the gut (and mucosal immunity) besides the barrier function?
1. production of cytokines/chemokines (anti and pro-inflammatory/to attract lymphocytes and DC) to provide signals to the underlying mucosal cells
2. express MHC I and II and can present Ags to CD4 T cells
3. transport of polymeric IgA
When stimulated, mucosal DCs form projections that go through the epithelial cell barrier to grab antigens and pathogens - typically express CX3CR1 - capture and transfer antigens to DCs
CD103 and CD11c
DCs in the gut (can go to mesenteric lymph node even in the absence of inflammation, or can go to peyer's patches, or can go to pre-stimulated lymphocytes to help them proliferate/activate)
IgA is produced where?( ie which part of GI system)
although B cells activated in mucosal tissues like Peyer's patches are already programmed to produce IgA, immunoglobulin class switching to IgA is further faciliated how?
by TGF-beta, a key cytokine in the mucosa where it has both activating and inhibiting effects (usually inhibits Th1, Th2, and CD8 cytotoxic T cells, but plays a pivotal role in the differentiation of naive CD4T cells to suppressive T reg cells, which could otherwise develop into Th17 cells that are associated with inflammation
how do you dist secretory IgA from plasma IgA?
After transport across the epithelial cell—but before release into the lumen—the immunoglobulin is proteolytically clipped from its receptor, leaving a remaining fragment of the receptor called “secretory piece”. By contrast, IgA produced in non-mucosal (i.e. systemic) sites can be either a dimer or a monomer, but without a secretory piece. Thus, mucosally produced IgA can be distinguished from plasma IgA by the presence of an associated secretory piece.
which subtype of IgA (IgA1 or IgA2) predominates?
In the gut IgA2 because it is particularly resistant to proteolysis
In the respiratory tract, IgA1 predominates and is thought to contribute to the invasiceness of Haemophilus influenzae and Streptococcus Pneumoniae because they can release IgA1 specific proteases
what are 3 ways IgA works in the gut?
1. immune exclusion (keeps pathogen from entering the gut)
2. intracellular neutralization (inactivates intracellular viruses and gets them out of epithelial cells and back into lumen via exocytosis)
3. antigen excretion (binds antigen in submucosal space and carries it though epitelial cell and out to lumen via exocytosis)
intraepithelial lymphocytes - skin, epithelial bound organs, and the mucosal epithelia contain this specialized subset of lymphoctyes between the epithelial cells. Most express integrin alphaEbeta7, which binds E-cadherin (impt re: tight junctions). They are activated effector cells (continually make cytolytic mediators like granzymes)
conventional IELs are CD8 T cells which express abTCR (activated so suggests that previously this happened in secondary lymphoid site)
features common to unconventional IELs (eg abTCR, CD8aa and some with also CD4 = double positive; gdTCR, CD8aa; gdTCR, CD4-/CD8- = double negative)
- enriched at epithelial surfaces
- activated/memory phenotype
- recognize self antigens (T cells with CD8aa)
- antigen recog is not restricted by conventional MHC I or II. Instead, these unconventional subsets bind MHC-like molecs called MIC-A or B, induced on activated or stressed epithelial cells
- protein recognition doesn't require prior processing into peptides and there is no evidence that APCs are required
- diversity of TCR repertoire is limited
TCR gammadelata IELs?
• The proportion of TCR gammadeltaIELs in the human intestine is relatively small (~10%), however, this proportion increases during certain inflammatory intestinal diseases—e.g. celiac disease .
overall function of IELs is controversial, but likely what?
protecting against pathogen entry, maintain the integrity of the epithelial layer by destroying damaged or stressed epithelial cells.
IgA is the major Ig produced in mucosal sites, but when mucosal pathogens are associated with an inflammatory response, IgG can also be found in mucosal secretions. It is transported by what?
FcRneonatal (FcRn) from the lamina propria into the intestinal lumen (same receptor transports maternal IgG across the placenta to the lumen)
Retinoic acid stimulates the induction of what type of lymphocytes?
Treg cells (along with TGF-beta it does this)
Bacterial products or Ag that cross the epithelium and prime Th1 cells to do what?
produce IFN-gamma and TNF-alpha and increased leakage
Naive B and T cells enter peyer's patches and mesenteric lymph node through the HEV. Entry is controlled by which chemokines?
CCL21 and CCL9, which bind CCR7. If lymphocytes become activated, they lose CCR7 and L-selectin and acquire receptors CCR9 and alpha4beta7
T-dependent pathway of IgA induction?
Ag-loaded APC activate CD4+Th cells, which stimulate IgM+IgD+Bcells through CD40L and TGF-beta production. In the presence of RA they migrate to the LP, where they differentiate into plasma cells. high affinity, monoreactive IgA against pathogens and toxins that occurs in the peyer's patches
T-independent pathway of IgA induction?
DC (esp plasmacytoid DC) and IEC can directly initiate class switch recombination through BRAFF, APRIL, TGF-Beta, RA, and NO (and others). Low affinity, polyreactive IgA against commensals that occurs in the peyers patches and ILF.
what cytokine is important for IgA class switching?
what cytokines are important for differentiation to plasma cells?
IL-4, IL-5, IL-6, IL-10
Transport of IgA through the epithelium?
IgA-producing plasma cell secretes IgA with J chain
dimerized IgA with J chain
binds Poly-Ig receptor
endocytosed complex of IgA and poly-Ig receptor
secreted with SC, the former extracellular domain of poly-Ig receptor
how does the secretor piece help IgA?
helps anchor IgA to mucus by binding mucins
anti-inflammatory role of IgA?
sIgA-immunocomplexes = tolerogenic profile early in life
IgA in breastfeeding = actively stimulates the offspring immune system
mucosal sIgM and IgG?
sIgM is the 2nd most abundant Ig in secretions = potentially inflammatory, activates complement
IgG is a minor component of mucosal plasma cells and leads to neutralization; potentially inflammatory, activates complement and phagocytes
FcRn allows IgG transport in both directions
FcRn is expressed by what cells in adult intestines?
enterocytes and lamina propria APC
mucosal T cells in the lamina propria express what in the small intestine? in the colon?
a4B7 (integrin, binds to MAdCAM-1 in gut lamina propria), CCR9(chemokine receptor binds to CCL25 expressed by epithelial cells) in small intestine
CCR10 in colon
IEL's have a cytotoxic function. They express what? Their development depends on what?
express CD103 and CCR9
development depends on EC-derived IL-7 and IL-15
most don't need priming and express perforin and granzyme to kill infected, malignant cells
which DC promotes gut-tropic effector T cells and Tregs?
CD103+ DC cells ....in the presence of Vit A they get activated go to the secondary lymphoid tissues where they produce RA which does 2 things...
1. activate T cells to have increased expression of CCR9 and a4B7 (gut-tropic T cells)
2. RA amplifies TGF-B-mediated generation of foxP3 Tregs (also maintain Th17 cells in steady state)
what three general things does RA do in the gut?
promotes cell migration, IgA generation, and mucosal tolerance
Commensals signal IEC (intestinal epithelial cells) to produce what molecules? These activate FoxP3+ regulatory T cells (iTregs) which are critical to maintain homeostasis and coincides with induction of IgA
TSLP (thymic stromal lymphopoietin) and RA
following mucosal inflammation due to infection , vaccination, or chronic infection what happens to CD103+ DCs?
RA (from stromal cells and IECs) and Il-15 stimulate CD103+ DC cells to release inflammatory cytokines (IL-6, IL-1) to induce activation of Th1 and Th17 to lead to inflammation (via IL-17 and IFN-gamma). Inflammatory cytokines also produced by CX3CR1+ APCs.
During homeostasis, Treg cells, Cx3CR1, and IECs produce what to inhibit Th1 or Th17 cellds?
IL-10 and TGF-Beta
beneficial commensals tend to have anti-inflammatory properties. What do they upregulate?
in inflammation there is dysbiosis of the microbiota resulting in what regulation of T cells?
increased Th1 and Th17 (inflammation)
decreased Treg cells
what cytokines from IECs and DCs are released (thanks from stimulation by gut microbiota) to increase AID and class switching to IgA (thus increasing sIgA)?
BAFF, APRIL, RA
which molecule is involved in the following:
- imprints gut-homing specificity on T and B lymphocytes
- regulates the differentiation of Treg and Th17 cells
- promotes gut-homing B cells, induces IgA synthesis
also (increases Th2 differentiation, decreases Th1 and Th17 differentiation)
Vitamin A (retinoic acid)
effects of Vit D on the immune system?
- stabilizes cell tight junction
- decreases Th1/Th17 CD4+ T cell and cytokines
- increase Treg
low vitamin D reported in pts with IBD and colitis
vitamin A and D deficiency?
decreased numbers of a4B7 T cells in the lymph node (cells fail to migrate), inflammation increases, decreased synthesis of IgA
mucosal vaccines: pros? what do they induce? examples? problems?
they are vaccines vs pathogens that enter through mucosal surfaces
pros: ease of delivery (oral drops or nasal spray - but involve multiple doses and adjuvant)
induce local antibodies (sIgA) and locall cell-mediated immunity (T cells)
eg: poliovirus, flu
problems: poor performance in developing countries (materal Abs, vitamin and micronutrient deficiencies, other pathogens, etc)
Mucosal DC induce T cell tolerance or protective immunity depending on environmental cues from what?
EC and antigen
why is sIgA constitutively produced?
to keep inflammatory stimuli out of the mucosa
mucosal tolerance is an active, inhibitory process facilitated by what?
microbiome, vit A, vit D