Download Mucosal Immunology

FUNDAMENTALS HOUR 2
SEPTEMBER 30, 2010
LORENZ
I.
MUCOSAL IMMUNOLOGY
Scribe: FARAH BUTT
Proof: CALVIN SIMS
Page 1 of 9
Mucosal Immunology [S1]:
a. Will point out differences between the immune response that happens at mucosal surfaces (eye and oral
cavity) and the systemic immune system.
b. A number of the examples we will use almost all come from the GI tract
i. Because that is where almost all of the research has been done.
II. Why Do We Need to Understand How the Mucosal Immune System Works? [S2]
a. Why do we need to learn something specific about the mucosal immune system separate from the rest of
immunology?
i. Mucosa is major site of interaction for almost all antigens and the majority of bacterial or viral challenges
that our bodies have.
ii. It is thought to be the surface where we really need to learn more about how to increase our defenses, be
able to give mucosal vaccines, etc.
iii. Mucosal immunology is a fairly large area of research.
iv. Gastrointestinal diseases kill more than 2 million people every year; a lot of times this is in third-world
countries.
v. We don’t have very good vaccines or ways to increase the immune response to these different infections.
III. The Mucosa is Bombarded by Foreign Antigens [S3]
a. This is your mucosa; can be oral cavity, GI tract, lung.
b. There is a single layer of epithelia cells that protects your body from everything that you eat, all the organisms
that you intake, via breathing, via food, not washing your hands, etc.
c. Your mucosal immune system has to know what to do with all of this.
d. When exposed to various food antigens, you mucosal immune system needs to be able to say “that’s not an
antigen I should respond to, so I want to be tolerant to this food antigen”
e. This is a slightly different type of tolerance than what you learned about in the thymus where you learned to
be tolerant of your own self.
f. You can be exposed to a lot of new food antigens throughout your lifetime.
g. Your mucosal immune system should be able to know to not respond to any of these types of antigens.
h. Foods like shellfish or peanut butter are antigens that the immune system is responding inappropriately to.
i. There are a lot of bacteria in your oral cavity and GI tracts, and your body needs to understand that those are
part of our microcosm.
i. It shouldn’t respond to those either.
ii. There are more bacteria in your GI tract than there are cells in your body.
iii. Mucosal immune system response should know that those are there for good, and shouldn’t respond to
them the same way it would if you got an infectious organism in your GI tract.
j. If you get some sort of infectious organism, then the mucosal immune response needs to respond to this.
k. You don’t want it to respond to the normal lactobacillus that is in your stomach.
IV. Learning Objectives [S4]
a. Know these objectives
b. Read slide
c. Will talk about immunoglobulins because IgA is the primary immunoglobulin at mucosal sites
i. It is one of the only places that it plays a major role in the immune system
V. The Human Gut Flora [S5]
a. One thing you need to think about with the mucosal immune system that you don’t think about with the
systemic immune system:
i. The mucosal immune system is constantly being exposed to various bacteria that are colonizers of your GI
tract.
ii. This means that you’re constantly being exposed to various bacterial antigens, ligands that will bind things
like toll-like receptors that would normally stimulate the immune system, but in the mucosa that has to
actually not occur in order that you can function normally.
b. The mucosal immune system is constantly in a state of activation.
i. It’s not like the spleen that just sits there until it actually gets some kind of antigen or bacteria to stimulate it.
ii. Since these are there always, there is a small amount of activation there continually in your oral mucosa
and intestinal mucosa.
c. Lamina propria- where the activated immune cells live.
FUNDAMENTALS HOUR 2
Scribe: FARAH BUTT
SEPTEMBER 30, 2010
Proof: CALVIN SIMS
LORENZ
MUCOSAL IMMUNOLOGY
Page 2 of 9
d. There’s a lot of interest in using bacteria to shape the health of an individual (e.g. yogurt has probiotics in it)
i. There’s not a lot of data that argues this is actually true.
ii. There is data that shows that for specific diseases, these probiotics can help recover faster
iii. But for overall health, it is debatable.
iv. It doesn’t hurt us
v. We haven’t studied it much.
VI. Bacteria of the Oral Commensal Flora [S6]
a. The concept she wants us to remember:
i. The bacterial component of your oral cavity and GI lumen is not the same in every different space.
ii. There are microcommunities in each of these areas of the mucosa.
iii. If you look at the tongue, Strep salivarius is found in high numbers. But there’s very few Strep mutans.
iv. If you look right next to it on the teeth, Strep mutans is there in high numbers but Strep salivarius is not.
v. Depending on which area you look at, there is different bacteria that would be considered commensal.
vi. Therefore, the host should ignore that bacteria, or if it’s there in high amounts, that is actually abnormal and
your mucosal immune system needs to figure out how to get it back into the normal proportion.
b. We now know that most of the bacteria in the oral cavity or GI tract is not culturable.
c. If you just swabbed the mouth, you would get a large number of bacteria, but there are also other bacteria out
there that we don’t know how to culture and if we do DNA-based techniques, we can find a lot of those
organisms.
d. We are now just trying to figure out what their effects are on the mucosal immune system.
VII. Factors Controlling the Intestinal Microflora [S7]
a. A number of factors control the types of bacterial that are in the oral mucosa and intestinal tract.
b. Your saliva, your stomach acid, the different microbial peptides that are made in your intestine, the IgA
content, your mucous content, and all of these actually shape the types of bacteria that are there and, we
believe, shape the mucosal immune response that occurs.
c. There is a lot of study looking at how these essentially shape the immune response.
d. The mucosal immune system is essentially considered to encompass not only the immune cells but also the
epithelial layer that can make these mucous and antimicrobial products and the bacteria that are there also.
i. All of those play a role in the immune response that eventually occurs.
e. Particularly important is the presence of acid in the stomach, innate immune factors (e.g., antimicrobial
peptides and mediators).
VIII. Picture [S8]
IX. Physiologic Functions of Intestinal Microflora [S9]
a. Remember that we do not need bacteria in order to survive.
b. Germ-free animals have no bacterial component.
i. They are derived to be sterile and are never exposed to any microbiota.
ii. Those animals are perfectly healthy as long as you give them the appropriate amino acids that you
normally need to get.
iii. They reproduce normally.
iv. They do not have a normal mucosal immune response because you need that bacteria in order to stimulate
mucosa and the production of IgA and various other things.
v. But those animals do live and they have no problem as long as they are in their bubble and not exposed to
other types of infectious organisms.
c. Intestinal microbiota is important for colonization resistance.
d. Microbiota influences a lot of metabolic functions, as far as absorption of food products, and the mucosal
immune response.
X. Our Mucosal Flora Helps Prevent Colonisation by Pathogens [S10]
a. Colonization resistance is a term used to explain the fact that the microbiota that is normally in your GI tract
actually helps protect you from infection from various other organisms because it keeps those organisms from
finding a nitch in your GI tract.
b. Normally, you’re colonized by a number of different bacteria in your GI tract
c. If you come into the hospital because something is wrong, they will give you broad spectrum antibiotics.
i. These are very good in this day and age and can wipe out almost every microbiota in your GI tract.
ii. That will be good if it is getting rid of whatever is causing your disease.
FUNDAMENTALS HOUR 2
Scribe: FARAH BUTT
SEPTEMBER 30, 2010
Proof: CALVIN SIMS
LORENZ
MUCOSAL IMMUNOLOGY
Page 3 of 9
iii. The other thing it does is that it leaves you with almost no microbiota in your GI tract.
iv. What happens is there are organisms, and the best known example of this is C. difficile, which decides to
come in because nothing else is living there.
v. It produces a toxin and causes very severe diarrhea. It can only do this when a person’s microbiota is
compromised.
vi. In patients getting these broad spectrum antibiotics, we give them yogurt with live bacterial cultures in it in
order to try to prevent this from happening.
vii. This is where probiotics are well-known to have a beneficial effect. We try to prevent these other organisms
from coming in and finding a nitch in the GI tract.
d. That’s colonization resistance. It protects you from other organisms coming in and colonizing.
e. Microbiota are one component of the mucosal immune system.
XI. Organization of the Mucosal Immune system [S11]
a. If you think of typical components of immunology, which would be your B cells and T cells, this is how the
mucosal system is organized.
b. The first large category is known as MALT (organized mucosal lymphoid tissue).
i. That is a whole series of structures that are very similar to what you think of in the systemic immune
system as your lymph nodes.
ii. They do very similar functions as a lymph node, but there are differences that will be pointed out.
c. Peyer’s patches are in the intestine
d. Isolated lymphoid follicles are also in the intestine and appendix
e. Those are all organized mucosal lymphoid tissues.
XII. Three major lymphoid populations in the intestinal tract [S12]
a. There are three major lymphoid populations in the intestinal tract that can be distinguished based on their
organization and location.
b. Peyer’s patches are large organized collections of lymphoid tissue present in the small intestine.
c. There are also small lymphoid follicles scattered in the colon (not shown).
d. Intraepithelial lymphocytes are mainly CD8+ T cells located between intestinal epithelial cells.
e. Lamina propria lymphocytes are the scattered lymphocytes within the loose connective tissue under the
epithelium (area termed the lamina propria).
f. Shows where in the GI tract these are found.
g. They are found in similar locations in the oral cavity also.
h. The Peyer’s patch is very similar to a lymph node.
i. It’s found right underneath the epithelial surface. The same is true for tonsils, etc.
i. The second one, the intraepithelial lymphocytes (are called essentially where they are), are found in the
epithelium of the GI tract.
i. It is above the basement membrane, so they have something to do with keeping this epithelial barrier
intact in some of the first line of defenses against various infections.
j. In the potential space underneath the epithelium is the lamina propria.
XIII. Peyer’s patch Structure [S13]
a. Intestinal villi role is to absorb various food products.
i. They produce mucous which helps move products along.
b. The Peyer’s patch on right is similar to a lymph node in that there is a B cell area, germinal centers, and T
cell areas where they can provide help for B cell switch.
c. One interesting about the mucosal immune system and the Peyer’s patch in general is that almost always
they will have a germinal center.
i. If you look at lymph nodes in the body in a patient that does not have any kind of disease, they usually will
NOT have the germinal center.
ii. Germinal center is evidence that there is ongoing immune response.
iii. This is one of the ways we know that the mucosal immune system is constantly being exposed to various
antigens, either from the food or bacteria that are there, because it almost always has these germinal
centers at the Peyer’s patches.
iv. That is one evidence that there is activation continuously going on in mucosa.
XIV.
Peyer’s patches [S14]
a. They are very close to external surface and are only separated by one single layer of epithelium.
i. They are very close to the antigen exposure.
FUNDAMENTALS HOUR 2
Scribe: FARAH BUTT
SEPTEMBER 30, 2010
Proof: CALVIN SIMS
LORENZ
MUCOSAL IMMUNOLOGY
Page 4 of 9
b. They don’t have afferent lymphatics.
c. They don’t have a way for your body to bring in antigen.
d. If you think about draining lymph nodes in your foot, there is an afferent lymphatic that brings that antigen up
from when you stepped on the rusty nail into the lymph node to stimulate the immune response.
e. This doesn’t happen in the mucosa.
i. There are some specialized cells called M cells that are thought to transport antigens across, but there are
no afferent lymphatics.
f. The efferent lymphatics are what bring the cells out of the Peyer’s patch, just like other lymph nodes, and
those then drain into the mesenteric lymph node if you’re talking about the mucosa.
g. The key thing about these organized lymphoid structures is the antibodies switched to IgA.
h. That’s the mucosal immunoglobulin and there are the cytokines that are produced by T cells in these
structures.
XV. Peyer’s patches [S15]
a. B and T cells are compartmentalized within the Peyer’s patch with B cells being in central follicles and T cell
comprising the interfollicular zone.
b. Scattered M cells are depicted in the epithelial layer covering the luminal side of the patch.
c. PP differ from lymph nodes in other parts of the body because they lack afferent lymphatics
d. Peyer’s patch gets antigens primarily through two ways.
i. One is shown on this slide.
ii. These are known as M cells (microfold cells), based on what they look like.
iii. They have been shown to transport antigen from lumenal side of GI tract into these Peyer’s patch
structures in order that they can then be taken up by dendritic cells and initiate the immune response.
e. There are also dendritic cells that live under this layer and stick their processes through the epithelium, and
they can also get antigen that way.
XVI.
Initiation of Gut Responses [S16]
a. Epithelial cells have villi structures that are absorptive, known as microvilli.
b. M cells don’t have that structure, so they look different on EM.
c. Antigen comes in, can be transported across to the dendritic cells and other cells found underneath the M cell
and initiate the immune response.
XVII.
Diagram- Inductive sites/Effector sites [S17]
a. The mucosal immune response is not only initiated, but is continued.
b. One concept useful to think about: antigen coming in, gets taken up by antigen-presenting cell such as the
dendritic cell, presents to T cell, activates B cells, etc.
c. These cells will come out of Peyer’s patch and into the draining lymph node (if it’s the GI tract, that is a
mesenteric lymph node), go out into the thoracic duct from that lymph node back through the blood and will
circulate back via the homing receptors into the mucosa.
i. This is known as the common mucosal immune system.
ii. This is the primary unifying concept behind the fact that we believe that for good mucosal vaccines, you
have to immunize the mucosal site.
d. That way, the cells will home back into the same place you want them to work. This is the process that occurs
in order to get the cells back into the mucosa.
XVIII.
Diagrams of Mouse Isolated Lymphoid Follicle [S18]
a. Picture of Peyer’s patch-like structure
i. It is known as an isolated lymphoid follicle.
b. In nasal mucosa (this is in a newborn mouse, but the same thing occurs in humans), there isn’t any lymphoid
structure.
c. But as you go to adulthood, there is whole collection of lymphocytes which helps initiate immune response in
nasal mucosa.
d. The nose is a little bit delayed from the GI tract.
i. Whether or not that’s because there is a delay in how many antigens and bacteria are there to initiate the
influx of these cells, she hasn’t seen any data on it.
e. The Peyer’s patch is started before birth and is expanded dramatically right after birth.
f. The nasal isolated lymphoid follicles take a little bit longer, but they work in a very similar fashion.
XIX.
Diagram from Humans [S19]
FUNDAMENTALS HOUR 2
SEPTEMBER 30, 2010
LORENZ
MUCOSAL IMMUNOLOGY
a. Diagram from the human so you can get a feel for how these structures occur.
b. In nasal mucosa, instead of being called MALT, it is called NALT.
c. This Waldeyer’s ring is essentially lymphoid tissues
i. They have the M cells that overlay those tissues, and they can take up antigen.
d. Adenoids and tonsils are structures which can initiate immune response.
Scribe: FARAH BUTT
Proof: CALVIN SIMS
Page 5 of 9
XX. Diagram- Draining of Nasal Mucosa [S20]
a. This is what happens in the draining of the nasal mucosa.
i. You have M cell overlying lymphoid structure.
ii. It transports antigen into the lymphoid structure, causing antigen-presenting cells to present antigen to T
cells, help B cells, and these would drain in the case of oral and nasal mucosa into the cervical lymph
nodes, and then those would go back out into the circulation and again come back into the mucosal
lymphoid tissues.
b. That is the organized lymphoid structures.
i. Although they all look a little different depending on where they are, they have very similar functions.
XXI.
Small Intestinal Villous [S21]
a. The other two areas of lymphoid structure are intraepithelial lymphocytes and the lamina propria.
b. This is a larger diagram to show that these IEL are in the epithelial layer, and those are almost entirely T
cells.
c. The lamina propria are all cells that are essentially in the potential space beneath the epithelium are every
type of immune cell you can think about (B cells, T cells, dendritic cells, macrophages, etc.).
d. This is where a lot of the plasma cells are to make the IgA.
e. This slide shows a small intestinal villus with surface epithelium and intraepithelial lymphocytes located
between intestinal epithelial cells.
XXII.
Intraepithelial Lymphocytes (IEL) Reside in the Paracellular Space Between Epithelial Cells [S22]
a. How does a lymphocyte keep itself within that epithelium?
i. Epithelia that line the intestinal and oral mucosa are very rapidly turning over.
ii. So a lifespan of an epithelial cell of the intestinal mucosa is about 3 days.
iii. That lymphocyte has to somehow keep itself there while these epithelial cells are going on past it.
iv. It does this through a unique way of attaching itself to epithelial cells.
v. This is via what is known as CD103, which is an integrin known as E7 (easy to remember because has
an “E” for “epithelial” in it).
vi. E7 binds to E cadherin on the epithelial cells. That’s how IELs hold themselves in the epithelial layer.
b. IEL are mostly CD8 T cells.
c. IEL are retained in the epithelium by an interaction between the CD103 integrin on their surface ( E 7) and
E cadherin on the surface of the epithelial cell.
XXIII.
Intraepithelial lymphocytes (IEL) [S23]
a. Found throughout the epithelial layer in the mucosa
b. The majority of these are T cells.
c. Most T cells are what are known as  T cells and has two chains.
d. There is a second type of T cell receptor (TCR) known as  TCR, so it also has two chains.
e. T cells that have the  TCR like to be at mucosal surfaces.
f. A significant percentage of IELs express this TCR.
g. Almost all IELs within the GI tract (where they have been studied most extensively) are CD 8+.
h. CD 8+ T cells in the systemic circulation have two chains- a heterodimer of an alpha and beta chain. So it’s
CD 8 and CD 8.
i. That’s not to be confused with the TCR  and .
ii. They are two completely separate things.
i. The CD 8 molecule on the IELs is a homodimer of the  chain. So it’s a CD 8.
j. The unique cell type in the IELs is the CD 8 TCR  cell.
k. These cells are very specialized to binding various receptors that are on epithelial cells or antigens they are
being exposed to in the mucosa in order to mount a very rapid immune response.
l. The concept is the  T cells are actually more of an innate type of T cell.
i. Although they do rearrange their TCRs, they almost always just have germline configurations.
FUNDAMENTALS HOUR 2
Scribe: FARAH BUTT
SEPTEMBER 30, 2010
Proof: CALVIN SIMS
LORENZ
MUCOSAL IMMUNOLOGY
Page 6 of 9
ii. So they aren’t the same type of T cell that keeps rearranging to get the most avid reaction and can mount
an immune response against a lot of different antigens.
m.  T cells are fairly restricted in what antigens they can respond to.
n. Question from student (inaudible)
Answer: Specialized to bind two epithelial cells with CD 103E7
o. IELs can produce cytokines just like other T cells.
i. Because they’re CD 8, they can also by cytolytic and try to get rid of infected or damaged epithelial cells.
ii. That’s part of their function in the immune response.
XXIV.
Small Intestinal Villous [S24]
XXV.
Lamina propria lymphocytes (LPL) [S25]
a. The T cells here are almost all your normal, everyday systemic T cells.
b. They’re almost all  TCR, they have normal CD 8, and the ones that are CD 8 are CD 8 , but they are
primarily CD 4 T cells.
c. You have this dichotomy between the type of T cells in the lamina propria and the type of T cells in the IEL
compartment.
d. There are a lot of plasma cells in the lamina propria, and almost all of them produce IgA.
XXVI. CD8 T Cells Predominate in the Intraepithelial Region and CD4 T Cells Predominate in the Lamina Propria
[S26]
a. Sections of small intestinal villi
b. The green fluorescence on the left shows CD8 T cells mainly in the intraepithelial region with some also in the
lamina propria.
c. As shown on the right, few CD4T cells are present in the intraepithelial region, but many are present in the
lamina propria.
d. Almost all of the CD 8+ cells are in the epithelium, which is the IEL compartment.
e. Almost all CD 4T cells are in the lamina propria.
f. Left- you have immunofluorescent stain in green. On right you have stain for CD4.
XXVII. Immunofluorescent stain showing IgA B Cells (yellow) in the Lamina Propria of Small Intestine [S27]
a. There are a lot of IgA-producing plasma cells in lamina propria.
XXVIII. Lymphoid Migration and Homing in the Intestinal Tract [S28]
XXIX. Lymphocytes Traffic from Peyer’s Patches to Other Mucosal Sites: The “Common Mucosal Immune
System” [S29]
a. How are cells getting into the mucosa once they’ve been stimulated in the Peyer’s patch and want to home
back?
b. Once cells are stimulated in the mucosa, they will traffic back to all the different mucosal surfaces.
c. They preferentially traffic back to where they were stimulated, but they will go to all of the mucosal surfaces.
d. Antigen crosses into the Peyer’s patches across M cells and primes T and B cells in Peyer’s patches.
e. The primed cells then migrate to mesenteric lymph nodes, into the thoracic duct lymph, and thence into the
circulation where they either traffic to the lamina propria of the intestine or to other mucosal sites such as the
salivary glands or female genital tract.
f. Some cells may also go the lungs.
g. Cells migrate to the mammary gland mainly during lactation.
i. This explains why antibodies in breast milk are often directed to gut antigens.
XXX. LYMPHOCYTE MIGRATION INTO MUCOSAL SITES INVOLVES AN INTERACTION BETWEEN THE
LYMPHOCYTE INTEGRIN a4b7 AND A MUCOSAL VASCULAR ADDRESSIN, MadCAM-1 [S30]
a. The primary way we know that lymphocytes migrate back into the mucosa is via the addressin, MadCAM-1.
b. MadCAM-1 is found on the endothelial cells of the mucosa.
c. As the lymphocytes come in through the blood vessel, it sees MadCAM-1 on these endothelial cells and
stops.
d. The integrin that’s on the lymphocyte that binds to the MadCAM-1 is known as 47 integrin.
i. The beta subunit is the same as the CD103 on the IELs but the alpha subunit is different.
ii. This is 4 as the one before was E.
FUNDAMENTALS HOUR 2
Scribe: FARAH BUTT
SEPTEMBER 30, 2010
Proof: CALVIN SIMS
LORENZ
MUCOSAL IMMUNOLOGY
Page 7 of 9
e. When the integrin bindsto the MadCAM-1, it stops the lymphocyte, and then it crawls through and comes into
the mucosa.
f. The 47 integrin is a marker of mucosal “homing” and mucosal-derived lymphocytes.
i. For example, if you find a lymphocyte in the peripheral circulation with 47 it is likely that it is in the
process of coming from or going to a mucosal site.
ii. This integrin interacts with mucosal vascular addressin 1 (MadCAM-1) expressed on the vasculature in
mucosal sites.
g. In several inflammatory diseases of the mucosa inflammatory bowel disease, Crohn’s disease, ulcerative
colitis), in phase 2 trials there are now antibodies against 47 to keep these lymphocytes from getting into
the mucosa and causing the inflammation.
XXXI.
Two special features of the intestinal immune system [S31]
a. It is predominantly secretory IgA that is produced
b. The baseline response of the mucosa is tolerance – not an immune response to get rid of organisms or get
rid of antigens.
XXXII. Synthesis of IgA exceeds that of all other immunoglobulins in the body [S32]
a. We don’t really think of IgA being a major player in systemic immune system, and that is because it isn’t.
b. IgA is one of the lowest immunoglobulins in the serum.
c. IgG is the highest, then IgM.
d. You usually have no IgD in the serum.
e. Only if you are allergic do you have IgE.
f. IgA is third most prominent in serum.
i. But if you look at how much immunoglobulin is produced by plasma cells in the total body, it turns out that
IgA is by far the immunoglobulin made in highest concentrations.
ii. The reason you don’t see it in serum is because it is made at mucosal surfaces and it is secreted out into
the lumen.
iii. It’s secreted into the saliva, mucous in GI tract, breast milk, etc.
iv. It’s primarily a secreted immunoglobulin.
XXXIII. Development of IgA Producing Cells in Human Small Intestine [S33]
a. The secretory IgA system in the intestine is not fully developed at birth and becomes fully developed by 5 to 6
months of age.
b. Its production is stimulated by exposure to antigens in the GI tract and the oral mucosa.
c. When a baby is born, it is born with sterile mucosa.
i. As it passes through the vaginal tract or handled by mother, that baby is exposed to lots of microbrial
antigens.
ii. It is that exposure that very soon triggers the production of IgA in the mucosal immune system.
d. Germ-free animals make minimal IgA because they don’t have exposure to bacterial antigens.
e. The baby has close to normal IgA by the time it is about 6 months old.
f. One reason people argue that breastfeeding is good for a newborn is that there is a lot of IgA in mother’s
milk.
i. It can help protect the baby from various potential infections when it’s young.
XXXIV. Schematic of sIgA Molecule [S34]
a. Secretory IgA (sIgA) is a dimer that consists of two IgA monomer units (each monomer has two heavy chains
and two light chains).
b. In addition, there is a J chain that is important for immunoglobulin polymerization and binding of
immunogloublin polymers to the polyimmunoglobulin receptor.
c. That J chain is just like what holds IgM together. They both are known as polymeric immunoglobulin.
d. Secretory IgA also contains a molecule known as secretory component (SC) which helps stabilize the sIgA
molecule in the proteolytic enzyme rich lumen of the intestine. (SC is the cleaved polyimmunoglobulin
receptor-see also slide 34).
e. It doesn’t get SC from the B cell where it is made.
f. This is the only antibody that is made up of components that come both from the B cell or plasma cell that is
making the antibody and the epithelial cell it had to cross to get into the secretions.
XXXV. Structure of secretory IgA (sIgA) [S35]
a. Heavy and light chains are synthesized by B cell.
FUNDAMENTALS HOUR 2
Scribe: FARAH BUTT
SEPTEMBER 30, 2010
Proof: CALVIN SIMS
LORENZ
MUCOSAL IMMUNOLOGY
Page 8 of 9
b. The IgA molecule with the J chain will bind on the epithelial cell something known as a polymeric IgA
receptor.
c. Based on its name, you can assume the polymeric IgA receptor binds dimeric IgA, and it binds pentameric
IgM.
i. Those are the two antibodies it will bind because those are both polymeric immunoglobulin.
d. That polymeric IgA receptor is on the basal side of epithelial cell.
e. After IgA binds to that polymeric IgA receptor on the basolateral side of the epithelial cell, that triggers the
polymeric IgA receptor to be internalized in the epithelial cell and go from the basolateral surface out to the
luminal surface.
f. It transports itself all the way across the epithelial cell and then when it gets to the other side, it releases the
IgA.
g. When it releases the IgA, it leaves a part of the polymeric IgA receptor with the IgA and that part is the
secretory component.
h. So the secretory component is a little piece of the polymeric IgA receptor that stays with the antibody when it
gets released on the luminal side of the epithelial cell.
XXXVI.
IgA transport into the intestinal lumen [S36]
a. Dimeric IgA containing a J chain is produced by the IgA plasma cells.
b. This molecule then binds via the J chain to the polyimmunoglobulin receptor (pIgR) on the basolateral surface
of intestinal epithelial cells after which IgA bound to the pIgR is transported across the intestinal epithelial
cell.
c. The membrane bound tail of the pIgR is cleaved, and the pIgR bound to dimeric IgA containing the J chain is
secreted into the intestinal lumen as sIgA.
d. Note that this cleaved pIgR molecule bound to IgA is now termed secretory component.
e. The secretory component tends to protect the IgA from proteases in the GI tract, so it makes it stick around
longer.
i. If you don’t have secretory component on your IgA, it gets degraded much faster.
XXXVII. There are 2 subclasses of Human IgA and differences in the Relative amounts of each present in serum
and secretions [S37]
a. The IgA in the mucosa is a slightly different class of IgA that is in the serum.
b. In humans (this isn’t true for mice), there are two types of IgA, IgA 1 and IgA 2.
c. In serum, you have almost all IgA 1 and almost all IgA monomer.
d. In mucosa, the plasma cells that make IgA make about half and half IgA 1 and IgA 2.
i. Almost all of it is dimer.
e. So there is a slight difference in how the B cells are stimulated to switch to make the different types of IgA.
f. IgA1 and IgA2 are coded for by separate genes in the immunoglobulin locus.
i. IgA2 is most prevalent in secretions in the distal small intestine and colon and is more resistant than IgA1
to breakdown by bacteria.
g. The most common immunodeficiencies is IgA deficiency.
i. Most people don’t have many problems from IgA deficiency because it turns out that IgM can essentially
take its place primarily in the mucosa and protect the mucosa from various types of infections.
ii. The only problem in a patient that is IgA deficient is if they need blood products because most blood
products have a little bit of serum in it, and that serum has little bit of IgA.
iii. The first time that patient gets blood there is no problem.
iv. The second time that patient gets blood, their immune system has reacted against the IgA that is and then
they have a transfusion reaction which can be fairly severe.
XXXVIII.
Physiologic functions of secretory IgA [S38]
a. Why do we need all this IgA?
i. IgA in the mucosa or secretions can bind a lot of different antigens (bacteria, viruses, etc.) and keeps them
from interacting with epithelial cells.
ii. It prevents those bacteria or viruses from coming up to the epithelial cells and trying to infect it.
b. IgA is relatively non-inflammatory immunoglobulin.
i. That is sort of the function of the mucosal immune system – tolerance or not inflammation.
ii. That’s because it doesn’t activate any of the classical complement pathways, so it can’t really activate the
immune system in that fashion.
c. Patients with inflammatory bowel disease- they have a switch where they now primarily make IgG instead of
IgA.
FUNDAMENTALS HOUR 2
Scribe: FARAH BUTT
SEPTEMBER 30, 2010
Proof: CALVIN SIMS
LORENZ
MUCOSAL IMMUNOLOGY
Page 9 of 9
i. We think that’s part of the inflammatory process.
XXXIX. Figure [S39]
a. Overview
b. Microbiota important for development of mucosal response.
c. Peyer’s patch where antigens are coming across being presented by dendritic cells, macrophages, are being
taken up by those cells, antigens are presented to T cells, they help B cells switch to IgA producing cells,
those cells can migrate out into the circulation and can home back into the intestine, where you have both the
lamina propria with effector cells and your IEL.
XL. Ocular Immune Privilege [S40]
a. Did not write any question on this. Just take it as information.
b. There is an immune system that is part of the ocular complex.
c. Ocular immune privilege means that it is an immune privileged site.
d. Immune privilege means that antigens that are placed in this site really do not induce immune response.
e. Mucosal immune system is there to dampen the immune response or be tolerant of antigens that it is
exposed to.
f. Ocular immune privilege has a very specific term associated with it, which is known as Anterior Chamber
Associated Immune Deviation (ACAID).
g. We are now discovering that this mechanism is true for also the intestinal and oral mucosa.
h. If the antigen is exposed in the eye and aqueous humor, these dendritic cells and macrophages will take the
antigen, process it, and then they migrate across the trabecular meshwork into the blood, then to the spleen.
i. That is how antigens come in that type of surface.
XLI.
ACAID [S41]
XLII.
Table 3: Soluble Factors in Aqueous Humor [S42]
a. There are various aqueous factor or cytokines that promote this type of tolerance response. Remember the
first one – TGF -2, which is known to be immunosuppressor cytokine.
b. We now find that it is involved in a lot of these types of mucosal responses where you get this tolerance
phenotype instead of inducing a full-blown normal immunal resonse.
XLIII.
Table 1: Body Sites and Tissues that are Immune Privileged [S43]
a. There are a number of sites that are primarily immune privileged.
b. They have very similar responses to antigens in that there is a type of tolerance response, including the brain.
c. What happens is that when you get infected with something, they have various other ways of triggering the
immune response to get around this tolerance.
XLIV.
Background Reading [S44]
[End 48:09 mins]