Immuno 13 Mucosal Immunity

Front 1

MALT

Back 1

-mucosa-assoc lymphoid tissue
-highly specialized immune sys which protects mucosal surfaces
-lymphoid elements share organizational & functional similarities
-largest mammalian lymphoid organ sys and in an adult it comprises approx 80% of all lymphocytes

Front 2

Type I mucosal surface
-epithelia
-MALT
-pIgR
-Ig isotype
-Goblet cells

Back 2

-simple epith
-MALT present
-pIgR present
-IgA
-goblet cells present

Front 3

Type II mucosal surface
-epithelia
-MALT
-pIgR
-Ig isotype
-Goblet cells

Back 3

-stratified epith
-no MALT
-no pIgR
-IgG
-no goblet cells

Front 4

challenges regarding mucosal immunity

Back 4

1. most freq portal of entry for harmful substances-->malt has to mount effective response against a vast number of potential pathogens

2. mucosal membranes of dig tract must allow for nutrient absorption-->malt must remain hyporesponsive to an entire array of harmless substances

Front 5

Role of B Cells

Back 5

-humoral responses are central to effective mucosal immunity
-main humoral mediators of specific mucosal immunity are secretory IgA and sec IgM
-normal intestinal mucosa contains at least 20x's more IgA+ than IgG+ lymphocytes

Front 6

critical features of secretory IgA

Back 6

-resistance against common intestinal proteases
-inability to interact with complement or cells in a way to cause inflammation

Front 7

mech of protection by SIgA at Mucosal surfaces

Back 7

-inhibition of adherence
-virus neutralization
-neutralization of enzymes and toxins
-immune exclusion and inhibition of Ag absorption

Front 8

factors controlling IgA isotype switching

Back 8

1. CD40-CD40L
2. Cytokines-in order of appearance:
a.TGF-B
b. IL-2/IL-4
c. IL-5
d. IL10
e. IL-6

Front 9

factors controlling secretion of IgA: J Chain

Back 9

1. J chain disulfide-bonded to tail of both IgM and IgA
2. IgA secreting B cells in bone marrow do not express J Chain and thus secrete IgA monomers
3. majority of IgA prod B Cells in mucosa express J chain-->dimeric IgA
4. J chain stabilizes multimers, determines polymeric structure which allows Igs to complex with secretory component

Front 10

lamina propria lymphocytes

Back 10

-lymphocytes that are scattered diffusely throughout the lam pro of intestine (nice def!)
-largest single T cell site in humans!
-most T cells w/in LP are CD4+

Front 11

Intraepithelial Lymphocytes

Back 11

IELs
-lymphocytes which are interspersed between the columnar epithelial cells of villi in small & large intestine
-most CD*+
-~10% delta-gamma cells
-both d-g and a-b TCR+ IELs show limited diversity of TCR

Front 12

Th1, Th2 or Th17?

Back 12

-naive T cell precursor
-IL-4-->Th2-->IL-4-->worms, allergies
-IL-12-->Th1-->IFN-g-->intracell path
-TGF-b-->Th17-->IL-17-->extracell bact, cancer, autoimmunity

**Th17 critical to fight extracellular bacteria in GI tract

Front 13

functional properties of IELs

Back 13

-first immune cell line of defense in intestine
-display cytotoxic activity
-secrete large amounts of cytokines especially IFN-g and TNF-a
-modulate kinetics of epith cell renewal

Front 14

CD4+ Regulatory T cells

Back 14

-TH3 cells: produce TGF-b
-TR1:produce IL-10
-CD4+CD25+ Tregs: can prevent autoreactivity in vivo

Front 15

CD8+ T regs

Back 15

-CD8+ Suppressor T cells: involved in oral tolerance
-gamma-delta Tcells: studies in mice indicate important role in oral tolerance

Front 16

Oral tolerance

Back 16

-oral admin of a protein Ag may lead to suppression of systemic humoral and cell-mediated immune responses to immunization with the same Ag
-possible mech:
1. inducation of anergy of Ag-spec T cells
2. clonal deletion of Ag-spec TCs
3.Selective expansion of cells producing immunosupp cytokines (IL-4, IL-10, TGF-b)

Front 17

M Cells-characteristics

Back 17

-"Membrane-like" specialized epith cells
-overlie lymphoid follicle domes along length of small&large intestine

Front 18

M Cells-Structural Features

Back 18

-few short irreg microvilli
-abundant endocytic vesicles
-low lysosomal content
-distinctive glycocalyx
-binding sites for secretory IgA but no SC
-pockets in B/L surface

Front 19

M Cells-Functions

Back 19

-Ag sampling (from lumen)
-portal of entry for selected pathogens (e.g. shigella, salmonella)

Front 20

DCs and Mucosal Immunity

Back 20

-dendritic cell-mediated transport of commensal bacteria in gut
-DCs can sample
Antigen indirectly via M-cell
transcytosis or
directly via processes that
extend across the epithelial
barrier
-DCs present
antigen to B- and T-cells,
either directly within the
lamina propia or following
trafficking to the regional
lymph nodes
-CX3CR1 involved in luminal sampling by gut DCs

Front 21

Peyers Patches

Back 21

-ORGANIZED MUCOSAL
LYMPHOID FOLLICLES WHICH
LACK AFFERENT LYMPHATICS
-FOUND IN SMALL INTESTINE
-FOLLICLES SIMILAR TO
PEYER’S PATCHES ARE FOUND
IN THE APPENDIX, IN THE
REST OF THE GI TRACT AND
IN THE RESPIRATORY TRACT

Front 22

Cellular Traffic in organized Mucosal Lymphoid Tissues

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Follicle-Assoc Epith-->draining LN-->Thoracic Duct-->periph blood-->local and distal Lamina Propria (effector sites)

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IgA deficiency

Back 23

-most common primary immunodef.
-usually defined by serum IgA conc less than 50ug/ml
-IgA def indiv often appear perfectly healthy, only identified when:
1. become blood donors
2. undergo anaphylactic shock when receiving blood transfusion (IgE against IgA in donor blood)

Front 24

Clinical manifestations of IgA def

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-Increased incidence of infections (URI, LRI, GI)
-higher inc of:
autoimmune disease, allergic diseases, celiac disease

Front 25

Celiac disease

Back 25

-T-cell mediated immune disease of small intestine
-triggered by gluten
-Major features:
1. villous atrophy w/ lymphocytic infiltrate
2. increased epith. prolif w/ crypt hyperplasia
3. malabsorption

Front 26

celiac disease: immunologic features

Back 26

1. Ag: gluten (gliadin and glutenins)
2. assoc with HLA-DQ2 or HLA-DQ8 restricted lam propria CD4+ TCs that recognize gluten and secrete IFN-g
3. gliadin a substrate of tissue transglutaminase
4. Increased B cell activity
-anti-gliadin Abs (IgA-AGA)
-endomysial Abs (IgA-EMA)
-Tissue transglutaminase (Iga-tTG)

Front 27

Inflammatory Bowel Disease

Back 27

IBD
-chronic, relapsing/remitting inflammatory condition
-2 overlapping phenotypes:
1. Crohn's Disease (CD): affects distal small intestine and colon in transmural manner
2. Ulcerative Colitis (UC): predom affects colon in superficial manner

Front 28

IBD: immunologic features

Back 28

1. cell-mediated immunity (active CD):
-more IFN-g secretion from Th1
-increased production of cytokines that activate Th1 cells (IL-12 and IL-18)
-defects in Tregs

2. Humoral Immunity: massive increase in number of plasma cells and in IgG prod

**Imbalance of pro-inflamm (TNF-a, IL-1, IL-8, !L-12) and anti-inflamm (IL-10, IL-4, IL-13

Front 29

IBD and Nod2

Back 29

-IBD pathogenesis
-NOD2-cytosolic rec for pathogenic bacterial signals
-mutations in NOD2 increase the risk of CD by factor of 2-40

Front 30

IBD: emerging therapies

Back 30

1. Inhibitors of Pro-Inflamm Cytokines
*anti-TNF (infliximab)
2. Anti-Inflamm Cytokines
*IL-10, IL-11
3. Anti-Leukocyte adhesion therapy
*anti-alpha 4 integrin: Natalizumab
4. Inhib of Th1/Th17 polarization
*anti-IL-12/Il-23
*Anti-IL-18
*Anti-IFN-g

Front 31

Mucosal Vaccines

Back 31

-must stimulate the MALT in order to be effective
-b/c of subcompartmentalization w/in MALT, vaccines must be administered by appropriate route
-nonreplicating Ags often relatively ineffective in yielding strong/long-lasting mucocal Ab response

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Mucosal Vaccines: New strategies for Ag delivery

Back 32

1.live attenuated recombinact bateria and viruses with known mucosal tropism
2. protective vehicles (e.g. liposomes and biodegradable microspheres)
3. mucosal lectin-like molecules endowed w/ immunostim properties (e.g. cholera toxin)

Front 33

Mucosal Immunotherapy

Back 33

-strategy to attempt to treat illnesses resulting from immune reactions against autoantigens encountered in nonmucosal tissues
-human trials have been conducted in MS, RA, uveoretinitis and DM1

Front 34

Mucosal Immunotherapy-potential problems

Back 34

-limited success in suppressing the expression of an already established immune response
-massive amounts of tolerogens are required
-immunosupp effect is short duration