Mucosal Immunity by alicejenny

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									Immunology 23 - Mucosal Immunity
A Pernis
Transcribed by Mia Woodward (maw149)


The mucosal surfaces are the entry point of many pathogens. Mucosal pathogens are the highest killer of children
under the age of 5 years old.

The Challenges Faced by the Mucosal Immune System: (Slide #10)
The MALT has two challenges:
    - the most frequent portal of entry for harmful substances. The MALT must recognize the harmful
         substances and surmount an effective response.
    - The mucosal membranes, especially of the digestive tract, must allow nutrient absorption. So the MALT
         must ignore a lot of harmless substances.
A very complex decision to make: to differentiate between harmful antigens and harmless antigens. The cells are
specialized to face these two challenges simultaneously.

Specialization of Cells (Slide #11)
B cells mediate the mucosal immune response by secreting IgA at least 20X more than IgG+ and by secreting IgM

Critical Features of Secretory IgA: (Slide #12)
     1. resistant against common intestinal proteases
             - the mucosal immune system makes special secretory IgA resistant to this proteolytic environment
             which would normally cleave protein IgA
     2. does not interact with complement or cells in a way to cause inflammation.
             - keeps harmful Ags in the lumen

So how does secretory IgA protect? (Slide #13)
    1. inhibits the adherence of different pathogens to mucosal surfaces
            - dimeric IgA creates a negatively-charged hydrophilic shell around pathogens and thereby prevents
            their adherence to the mucosal surfaces: pathogens retained in the lumen
    2. neutralizes viruses
            - blocks viral ability to interact with cellular receptors used for viral endocytosis
    3. neutralizes a variety of enzymes and toxins
            ex. Cholera toxins
    4. immune exclusion: pathogens remains in the lumen
            a. IgA inhibits antigen absorption
            b. minimizes the inflammatory responses because the antigen is never presented
            c. minimizes the chance of pathogen replication or pathogenic cause of infections

Factors Controlling IgA Isotype Switching (Slide #14)
Review of the Diagram:
An APC picks up the antigen, processes it, and presents it in the context of class II MHC to T cells. This occurs in
the presence of co-stimulatory signals (B7:CD28). The APC presents antigen to the T cell, and the T cells in turn
gets activated. Now the T cell can provide help to B cells. T cell help comes in two forms: (1) contact dependent
interaction (eg. CD40:CD40L) and (2) production of cytokines. TGF-β is the key cytokine implicated as the switch
factor for IgA. TGF- β is key in this primary event. These two events drive B cells from IgM+ to IgA+.
Other cytokines important (after the B cell has switched to IgA) to help in the terminal differentiation of B cells into
plasma cells include IL-2, IL-4, IL-5, IL-6, IL-10. These are called TH2 type cytokines. (more later)
Finally, the plasma cell starts secreting a large amount of IgA.

In addition to IgA production, you need a J chain (Slide #15)
The J chain:
    - a small polypeptide
    -    binds to the tail of both IgM and IgA creating pentamers and dimers, respectively
    -    production found in plasma cells at mucosal surfaces… where you need secretory IgA
              o not in the bone marrow: there you secrete monomeric IgA
    -    stabilizes the dimers: the homomeric form of IgA
    -    interacts with the secretory component (the polymeric IgA receptor)
              o secretory component allows IgA to travel from the mucosal surface into the gut

The Secretory Component/Polymeric Ig Receptor (Slide #16)
IgA gets from the lamina propria to the lumen of any mucosal surface by attachment of the secretory component to J
chain portion of dimeric IgA
The Secretory Component:
     - a receptor in the basolateral membrane of a mucosal epithelial cell
     - binds IgA:J chain,
     - the complex is internalized, endocytosed, transported to the other side of the epithelial cells, and cleaved
          off into the lumen: the intra-cytoplasmic and transmembrane portions of S.C./receptor stays within the cell.
          The rest gets released into the lumen with the IgA.
This new complex in the lumen consists of: two IgA molecules, the J chain, and a piece of the receptor. The
receptor piece protects IgA from proteolytic cleavages, so IgA can mount an effective immune response in the
face of a proteolytic environment.


Cytokine Production in Mucosal Surfaces: (slide #18)
TH1 cytokines are mostly IFNγ and IL2: proinflammatory
TH2 cytokines are IL-4,5,6,10,13: not as inflammatory

at Inductive sites (where pathogen enters):
                            - a balance of TH1 and TH2 cytokines: see both pro- and anti-inflammatory
                            - mostly CD4+
at Effector sites
1. Lamina propria           - lamina propria lymphocytes (see below)
                            - CD3 T cells
                            - mainly αβ conventional T cells
                            - CD4+ cells
                            - shift in balance of cytokines to TH2 cells: shift toward anti-inflammatory and produce
                            terminal differentiation of sIgA+ B Cells to IgA secreting plasma cells

2. Intraepithelium         - intraepithelial lymphocytes (see below)
                           - CD8+ cells
                           - balance of TH1 and TH2 cytokines

Lamina Propria Lymphocyte: T cells (Slide #7)
Mucosal T cells have specialized subsets of cells: lamina propria lymphocytes & interepithelial cells (see below)
   - LPLs scattered diffusely throughout the small intestine in the lamina propria
   - The lamina propria is the single largest T cell site in humans
            o most are CD4+ cells

The Intraepithelial Lymphocytes (IELs): (slide #19)
The second specialized subset of mucosal T cells
    - between columnar epithelial cells in the small & large intestine
    - mostly CD8+ cells
    - approximately 10% are γ/δ cells
    - IEL T cell receptor shows limited diversity:
             o IELs likely to recognize common pathogens
    - IELs express a novel integrin HML-1 so IELs can migrate to its correct location between epithelial cells
             o Note: many mucosal T cells express integrins or addressins to get to a specific location
Functional Properties of IELs (speculative) (slide #20)
    - first immune cell line of defense in the intestine
    - lymphocytes against many common pathogens by:
                         (1) killer, cytotoxic activity (CD8+)
                         (2) secretion of large amounts of cytokines incl. IFNγ and TNFα
    - monitor the epithelial cell layer
                         (1) if a cell infected, IELs kill the cell, then secrete growth factors to promote epithelial
                             cell renewal -- the barrier stays intact
                         (2) play a regulatory role in tolerance of dietary antigens

M Cells: specialized epithelial cells (slide #22)
    - look like membranes in the gut
    - over the lymphoid follicle domes along small and large intestine
    - very thin
Features important for M cell functions:
    1. Short irregular microvilli: M cells sample antigen, not for GI absorption through microvilli
    2. Abundant endocytic vesicles: bring in antigen from the lumen to the lamina propria
    3. Pockets in the basolateral surface: for APCs (B cells, macrophages, or other professional APCs) which take
         antigen from the M cells: antigen sampling
    4. Low lysosomal content: M cells are involved in transport, not Ag presentation or processing
    5. Distinctive glycocalx: portal of pathogen entry using M cell receptors
                  - ex. Shigella
    6. Binding sites for secretory IgA, but not for secretory component
              a. IgA:Ag binds M cells and moves from the lumen into the lamina propria
              b. M cells do not transport IgA in the opposite direction

Peyer’s Patches (slide #6)
    - the “afferent limb” of the immune response
    - organized mucosal lymphoid follicles lacking afferent lymphatics (so only bring antigen from lumen)
    - found in the small intestine
    - similar follicles in other mucosal sites found in the appendix, in the rest of the GI tract, and in the
         respiratory tract
Diagram of a Peyer’s patch (slide #25)
    1. antigens get brought in through the M cells: endocytosis into the vesicles, transportation to the APCs
    2. APC processes and presents Ag to T cell
    3. if a T cell recognizes the Ag, it gets activated
    4. form a lymphoid follicle (under these M cells) = the Peyer’s Patch
    5. T cells secrete factors like TGFβ
             a. So B cells switch to surface IgA (switched from IgM)
    6. Surface IgA+ B cells and activated T cells migrate to the mesenteric lymph nodes, through the thoracic
         duct, and into the peripheral blood
    7. Go to effector sites (slide #26) in the lamina propria and intraepithelium
Sum so Far: The antigen is seen in a few Peyer’s Patches. The B cells and T cells which recognize the antigen
migrate into many different sites. (So more places in the mucosa can mount a response to the specific antigen.)

     8. surface IgA+ B cell (specific for this antigen) starts last step in differentiation: becomes a plasma cell
     9. plasma cell secretes J chain with IgA (which dimerizes)
     10. dimeric IgA + J chain bind to the secretory component:
               a. transcytosis into the lumen
               b. complex is secreted
     11. Note: lamina propria lymphocytes provide a TH2 cytokine environment: IL-4, 5, 6, 10
               a. B cells need TH2 help to complete their differentiation
     12. IELs protect you against common pathogens
Note: This is very compartmentalized process. The B cells recognize antigens in the Peyer’s patches do not go to
the bronchial tissue to mount a response there. They go back to the gut. B cells have a variety of receptors for B
cell localization . The differences between receptors clearly bear clinical importance
IgA Deficiency: When Things Go Wrong (Slide #30)
    - the most common primary immunodeficiency: occurs in about 1:600 people
    - deficiency = a concentration less than 50 μg/mL of IgA
    - although IgA is essential for an immune response, patients are fairly healthy
            o the immune system has backups: more secretory IgM and more IgG
    - recognize patients because undergo anaphylactic shock when receive blood transfusions
            o IgA is a foreign antigen and patients may have ABs against IgA
Clinical manifestations (Slide #31)
    - increased incidence of the infections in mucosal surfaces: secretory IgM not as good as secretory IgA
            o in the upper and lower respiratory tract
            o in the GI tract
    - higher incidences of autoimmune diseases and allergic diseases
            o IgG has more inflammatory nature: more potential for developing autoimmune diseases
            o secretory IgA diminishes/minimizes the antigenic load
            o With more antigens, you increase the chance of a de-regulated response (leading to disease states)


Inflammatory Bowel Disease (IBD): Problem of T cell Compartment (Slide #32)
     - a chronic, relapsing inflammatory condition
     - Two overlapping phenotypes:
             1. Ulcerative Colitis: predominantly affects the colon in a superficial manner
             2. Crohn’s Disease: affects the distal small intestine and colon in a transmural manner
     - a dysregulated mucosal immune response to unknown Ags possibly ones present in the normal, indigenous
        bacterial flora? -- unknown etiology
     -
Immunologic Features (slide #33)
     1. cell-mediated immunity
             - increased number of activated mucosal TH1 cells that secrete IFNγ – proinflammatory
             - increased production of cytokines to activate TH1 cells (IL-12, IL-18): feedback loop
             - defects in regulatory T cells (IL-10 producing) result in shift to inflammatory state
     2. humoral immunity
             - IFNγ increase lead to increased plasma cells and increased IgG production
                         - IgG isotype, in contrast to IgA, can fix complement and create an inflammatory response
     3. imbalance in proinflammatory (TNFα and IL-1, 8, 12) vs. anti-inflammatory cytokines (IL-4, 10, 13)
             - clinical perspective: TNFα is the recent target of a drug / anti-TNF antibody and try to down-
                  regulate the inflammatory response




Mucosal Immunization:
We attempt to use knowledge of mucosal immune response to protect against pathogens (mucosal vaccines) and to
help our knowledge of other diseases (via knowledge of oral tolerance).

Mucosal Vaccines (slide #29)
Features:
    1. attempt to stimulate the MALT
    2. Because of MALT subcompartimentalization, vaccines must be administered by the appropriate route
    3. Nonreplicating antigens are relatively inefficient in yielding strong and long-lasting mucosal antibody
         responses

Strategies for Antigen Delivery in Mucosal Vaccinations (slide #34)
Goal: target your vaccine to mucosal surfaces in such a way that the immune system will see it
Various Methods:
    1. use live attenuated recombinant bacteria or viruses with known mucosal tropism
             a.  genetically engineer a bacteria so it is not an infection and that which contains your “target”
                 antigen
              b. not as clear-cut or as effective as hoped: the cells are making an immune response to the vector,
                 but not to the attached, “target” Ag
    2.   liposomes and biodegradable microspheres used: put vaccine in protective vehicles (an oral vaccine, can by
         proteasome)
    3.   Antigens with lectin-like molecules with immunostimulatory properties (eg. Cholera toxin)
              a. Great idea, not as successful as hoped


Oral Tolerance (slide #27)
Oral tolerance – when given a potent antigen orally, the next time you re-challenge the individual with this antigen
systemically you will not get any immune response, either humoral or cell-mediated, to this same antigen. In other
words, if given the antigen orally, and Ag tries to come back, the individual has been tolerized to that antigen.
-- This method can be used to decrease some other diseases, such as autoimmune diseases.
-- Oral tolerance has been recognized known for a long time, but the mechanism is still not well-understood

Possible mechanisms:
    1. anergy of antigen-specific T cells
            a. Anergy - making antigen-specific T cells non-responsive
            b. The 2nd time T cells see an antigen, they will not respond to Ag, not produce cytokines and not
                 become activated
    2. Clonal deletion of these antigen specific T cells
    3. Selective expansion of regulatory cells producing immunosuppressive cytokines: IL4, IL-10, TGFβ
            b. called the TH3 cells

Multiple Factors Influence the Regulation of Oral Tolerance (slide #35)
    1. dose of an antigen: low dose, v. low, or even v. high dose can induce oral tolerance
    2. form/nature of Ag: soluble form or particulate form
    3. type of APCs present
    4. Cytokine Mileu: immunosuppressive cytokines present? inflammatory cytokines present?
    5. Adjuvants - substances that can enhance the immune response to a potent Ag when that Ag is administered
             a. Wide variety of adjuvants: can mount TH1 or TH2 responses
             b. depending on which Ag with the adjuvant, you can either tolerize or immunize 1
    6. luminal factors
    7. age
Note: These factors contributing to regulation of oral tolerance are interrelated and occur simultaneously. This
environment is difficult to reproduce in the laboratory in a systematic, clinically-relevant way.

Mucosal Immunotherapy (slide #36)
If you give an antigen orally, hopefully would induce oral tolerance so the individual wouldn’t respond to that
antigen again, even in a different form. Use this theory in an attempt to treat for autoantigens found in nonmucosal
tissues.
Trials for these autoimmune diseases: MS, rheumatoid arthritis, uveotetinitis, and type I diabetes haven’t been as
successful as hoped.
Three key problems:
     1. limited success in suppressing an already established immune response. The patient has already seen these
          autoantigens. So you are attempting to block an ongoing immune response.
     2. massive amounts of tolerogens (administered antigens) are required
     3. Immunosuppressive effect is of short duration.




1
 Dr. Pernis… Im not sure what it means that you can either tolerize or immunize depending on the Ag could you
explain further? Thanks

								
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