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1

Mucosal Immunity: Immunoglobulin Distribution

___ is the predominant Ig in mucosal immunity

Systemic Immune system is primarily ___

 

Mucosal Immunity: Immunoglobulin Distribution

IgA is the predominant Ig in mucosal immunity

Systemic Immune system is primarily IgG

 

2

Unique Features of IgA Immunity

- In humans, IgA is found in both ___ and ___ forms.

- Monomeric IgA is produced mostly in __ __ and found mainly in ___.  ___ system

- Dimeric IgA is produced mostly in___ ___ of ___ tissues and found mainly in external ____.  ____ System

- Dimeric IgA is ___ transported into external secretions via the ___ ___ ___ (pIg-R).

 

Unique Features of IgA Immunity

- In humans, IgA is found in both monomeric and dimeric forms.

- Monomeric IgA is produced mostly in bone marrow and found mainly in blood.  Systemic system

- Dimeric IgA is produced mostly in lamina propria of mucosal tissues and found mainly in external secretions.  Mucosal System

- Dimeric IgA is actively transported into external secretions via the polymeric immunoglobulin receptor (pIg-R).

 

3

Secretory IgA

  • ___ g of sIgA per day
  • Isotypes (__ and___ are ___-specific
    • A1- predominant IgA subclass found in ___
      • 13 additional ___ ___ in ___ region offer greater ____
    • A2- ___ __ __
      • Greater ___ to bacterial IgA ____
  • Structure of sIgA
    • Resistant to common ____
  • ___-chain
  • ____ component

Secretory IgA

>3 g of sIgA per day

Isotypes (A1 and A2) are tissue-specificA1- predominant IgA subclass found in serum

13 additional amino acids in hinge region offer greater flexibility

A2- mucosal plasma cells

Greater resistance to bacterial IgA proteases

Structure of sIgA

Resistant to common proteases

J (Joining)-chain

Secretory component

 

4

J (Joining) Chain

  • 15,600 Da
  • Associated with ____ __
  • Synthesized by ___ __
  • ___ J chain per polymer regardless of ___
  • J chain ____ the multimers and allow polymeric Igs to complex with the ___ ___
    • Is probably associated with ____ of polymerization
    • Induces confirmation that ___ ____ to SC
  • ______ synthesized by plasma cell to ___ single IgA to another to form the ___

J (Joining) Chain

15,600 Da

Associated with polymeric Ig

Synthesized by Plasma cell

One J chain per polymer regardless of size

J chain stabilizes the multimers and allow polymeric Igs to complex with the secretory component

Is probably associated with initiation of polymerization

Induces confirmation that optimizes binding to SC

Polypeptide synthesized by plasma cell to join single IgA to another to form the polymer

5

Dimeric IgA

Dimeric IgA consists of ___ IgA monomers bound by _ chain.  Individual B cells are ___ to secretion of either ___ or ___ IgA.

 

Dimeric IgA

Dimeric IgA consists of two IgA monomers bound by J chain.  Individual B cells are committed to secretion of either monomeric or dimeric IgA.

 

6

Secretory Component

MW 80,000 Da

Synthesized by _____ cells of ___ ____

IgA dimer binding sites per epithelial cell is approximately ___ ____

Originates from the ________ (pIgR; 130 kD) that is responsible for the _______e and transcellular ___ of ____ (but not ____) IgA across the epithelial cells and into ____

Involved in transporting it from host ____  to the____ of the gut.

 

Secretory Component

MW 80,000 Da

Synthesized by epithelial cells of mucous membranes

IgA dimer binding sites per epithelial cell is approximately 260-7,000

Originates from the poly-Ig receptor (pIgR; 130 kD) that is responsible for the uptake and transcellular transport of oligomeric (but not monomeric) IgA across the epithelial cells and into secretions

Involved in transporting it from host interior to the lumen of the gut.

 

7

Transport of IgA thru epithelium

The poly-Ig receptor is a special ___ ____ that binds ____ IgA

 The process of transporting IgA across the cell is known as ____

 The IgA released into the gut lumen remains associated with ___ of the _______(known as the ___ ___) and this provides protection against ___ by gut ____

____-->____

Transport of IgA thru epithelium

The poly-Ig receptor is a special Fc receptor that binds dimeric IgA

 The process of transporting IgA across the cell is known as transcytosis

 The IgA released into the gut lumen remains associated with part of the poly-Ig receptor (known as the secretory component) and this provides protection against proteolysis by gut proteases

BasolateralàApical 

8

 sIgA Functions

___ ___:

___ ____ Properties

_____ of Commensals

 sIgA Functions

Immune exclusion:

Anti-inflammatory Properties

Homeostasis of Commensals

9

Intraepithelial Lymphocytes 

  • Found in ____ layer
    • Compose _____%
  • Exist in ____ _____ state
  • Primarily____T cells
    • Both ____ and ____
    • Limited repertoire of TCR
    • Recognize a ___ ___ of antigens
  • Functions
    • ____ effects
    • ____ production
  •  

Intraepithelial Lymphocytes 

Found in epithelial layer

Compose 10-15%

Exist in Semi-activated state

Primarily CD8+ T cells

Both TCRαβ and TCRgd

Limited repertoire of TCR

Recognize a limited number of antigens

Functions

Cytotoxic effects

Cytokine production

 

10

Lamina Propria Lymphocytes 

  • B cells & Plasma cells
    • Secrete antibodies
      • 70-90% Ig_
      • 10-20% Ig_
      • 2% Ig_
  • T cells
    • ~_:_ ratio CD4+ to CD8+ (~70% CD4+:30%CD8+)
    • CD4 help the B cells ____ and ____ and produce Ab
    • Both ____  and ____
    • Cytokines-primarily to help____________
  • M____
  • D____
  • I______
    • Contribute to ____, lymphoid ____, intestinal ____, ____against infections, and__ ___

Lamina Propria Lymphocytes 

B cells & Plasma cellsSecrete antibodies

70-90% IgA

10-20% IgM

2% IgE

T cells

~3:1 ratio CD4+ to CD8+ (~70% CD4+:30%CD8+)

CD4 help the B cells differentiate and class switch and produce Ab

Both TCRαβ and TCRgd

Cytokines-primarily to help B cell antibody production

Macrophages

Dendritic cells

Innate lymphoid cells

Contribute to cytotoxicity, lymphoid organogenesis, intestinal homeostasis, immunity against infections, and wound healing

 

 

11

Original Helper T cell model (Mosmann & Coffman~1986)

Th1 cells that produced __ gamma--> ____ Pathogens

Th2 cells that produced ___--> ____ Pathogens

 

Helper T cell model (mid-2000’s)

We added two more classes:

 

Th_: Produce ____ and are important for ____ against bacteria, ____ and ____ ____

T__: for immune____ by secreting____ and ____

Original Helper T cell model (Mosmann & Coffman~1986)

Th1 cells that produced IFN gammaà Intracellular Pathogens

Th2 cells that produced IL4àExtracellular Pathogens

Helper T cell model (mid-2000’s)

We added two more classes:

 

Th17: Produce IL17 and are important for defense against bacteria, inflammation and neutrophil activation

 

Treg: for immune suppression by secreting IL10 and TGFBeta 

12

Helper T cell model (2014) Most updated model of Th cell development

Now there is :

___

___

Th17

Th1

Th2

____

Treg

 

Trying to further define subsets of immune cell components

Helper T cell model (2014) Most updated model of Th cell development

Now there is :

Th22

ThF

Th17

Th1

Th2

Th9

Treg

 

Trying to further define subsets of immune cell components

13

Complex interactions of___ ___ in mediating ____ biology in T cells

 

Interaction bw various subtypes

___ involved in ___ these other cell types

Complex interactions of transcription factors in mediating cytokine biology in T cells

 

Interaction bw various subtypes

Treg involved in inhibiting these other cell types

14

Multiple effects of IL-17

___ cells' primary product is IL-17

Has important roles in ____, helps with__ ___ ____ and ____. Helps with ____ of ____. Aids in ___ ___

Multiple effects of IL-17

Th17 cells primary product is IL-17

Has important roles in immunity, helps with B cell survival and differentiation. Helps with recruitment of neutrophils. Aids in barrier FCN

15

Clinical targeting of IL-17

IL17 has been studied as clinical target for various__ ____ and other diseases that have ___ ____.

Various components targeting the pathways involved in the ____ of Th17 cells such as AIN457 and LY2439821 which ___ IL-17 FCN

Clinical targeting of IL-17

IL17 has been studied as clinical target for various GI diseases and other diseases that have barrier dysFCN.

Various components targeting the pathways involved in the development of Th17 cells such as AIN457 and LY2439821 which inhibit IL-17 FCN

16

  • gd T cells

gd T cells differ from their aβ cousins in several ways:

  • Their TCR is encoded by different gene segments
  • Their TCR binds to:
    • Antigens that can be ___ ___ (just as____  do) as well as a variety of other types of ____ molecules (often containing ___ atoms)
    • Antigens that are___ "____" within class I or class II histocompatibility molecules
    • Antigens that are not presented by "____" ___ __ ___ like dendritic cells
  • Most of these T cells have ___ ____ or ___ on their surface
    • Do not ____ class I and class II histocompatibility molecules
  • gd T cells, like aβ T cells, develop in the ____
    • However, they migrate from there into ___ __, especially ____ (e.g., intestine, skin, lining of the vagina), and don't ___ between___and __ ___(they represent no more than _% of the T cells in the blood and are even____ in lymph nodes)
    • They encounter antigens on the ____ of the ___ ___ that surround them rather than relying on the ____ found in lymph nodes

 

Act as innate defense as they don’t interact with MHC complexes

Recognize some of the PAMPS that innate cells do

  •  

gd T cells

gd T cells differ from their aβ cousins in several ways:

Their TCR is encoded by different gene segments

Their TCR binds to:

Antigens that can be intact proteins (just as antibodies do) as well as a variety of other types of organic molecules (often containing phosphorus atoms)

Antigens that are not "presented" within class I or class II histocompatibility molecules

A ntigens that are not presented by "professional" antigen-presenting cells (APCs) like dendritic cells

Most of these T cells have neither CD8 nor CD4 on their surface

Do not recognize class I and class II histocompatibility molecules

gd T cells, like aβ T cells, develop in the thymus

However, they migrate from there into body tissues, especially epithelia (e.g., intestine, skin, lining of the vagina), and don't recirculate between blood and lymph nodes (they represent no more than 5% of the T cells in the blood and are even rarer in lymph nodes)

They encounter antigens on the surface of the epithelial cells that surround them rather than relying on the APCs found in lymph nodes

Act as innate defense as they don’t interact with MHC complexes

Recognize some of the PAMPS that innate cells do

 

17

gd T Cell Functions

They can promote ___ ___ ____cytokines

They can promote expression of ____ peptides

gd T Cell Functions

They can promote Th1, Th2, Th17 cytokines

They can promote expression of antimicrobial peptides

18

Innate lymphoid cells (ILC)

Discovered in the mid-2000’s

Do not express__ __ ___

CD___,___ , ____

Involved in ___ and __ ___ and___

Categorized by ___

 Group 1 ILC: more similar to Th_ type cells in FCN

Group 2 ILC: more similar to Th_

Group 3 ILC: more similar to Th_

Innate lymphoid cells (ILC)

Discovered in the mid-2000’s

Do not express T cell receptors

CD3-, CD4-, and CD8-

Involved in immunity and tissue development and remodeling

Categorized by function

 Group 1 ILC: more similar to Th1 type cells in FCN

Group 2 ILC: more similar to Th2

Group 3 ILC: more similar to Th17

19

Due to ___ ___, we need specialized ways for sampling Ag

Modes of Antigen Sampling

  • Stratified,__-keratinized or ___karatinized epithelia (__ __, pharynx, esophagus, urethra, vagina)
    • Antigen sampling depends on _____
      • ___ and ___antigen-presenting “___”
    • Dendritic cells may then transport antigen to ___ and ___ lymphoid ____
  • Simple epithelia (bronchiole, ___, ____)
    • Antigen sampling depends on ____ and______ transport
    • ___ ___s may also participate in antigen ____
  • M cells are a ___ ___ ___

  1. Due to barrier FCN, we need specialized ways for sampling Ag

Modes of Antigen Sampling

Stratified, non-keratinized or parakaratinized epithelia (oral cavity, pharynx, esophagus, urethra, vagina)Antigen sampling depends on Dendritic cells

Motile and phagocytic antigen-presenting “scouts”

Dendritic cells may then transport antigen to local and regional lymphoid follicles

Simple epithelia (bronchiole, intestine, bronchi)

Antigen sampling depends on M cells and transepithelial transport

Dendritic cells may also participate in antigen transport

M cells are a specialized epithelial cell

20

Antigen Sampling across Simple Epithelia

Mucosal surfaces generally ____ by a single layer of epithelial cells

Barrier sealed by ___ ___ that exclude ___ and ___

Uptake of antigen requires active ___ ___(___ or ____cells)

Sampling can be blocked by mechanisms such as ___ ___, ____, ____, etc.

 

Antigen Sampling across Simple Epithelia

Mucosal surfaces generally lined by a single layer of epithelial cells

Barrier sealed by tight junctions that exclude peptides and macromolecules

Uptake of antigen requires active transepithelial transport (M-cells or Dendritic cells)

Sampling can be blocked by mechanisms such as local secretions, sIgA, mucins, etc.

 

21

Mucosal Immunity: Pathways for Antigen Uptake/Sampling

 

With mucosal uptake you can ___ ___the epithelium. 

You can have __ ___ that reaches a __ ___ into the___ o sample

You can also have specialized epithelial cells called ___ ___

Mucosal Immunity: Pathways for Antigen Uptake/Sampling

 

With mucosal uptake you can diffuse thru the epithelium. 

You can have dendritic cell that reaches a lamina podia into the lumen to sample

You can also have specialized epithelial cells called M cells

22

Dendritic cells

  • Derived from ___ __ ___  _____ cells
  • Capture____ in ___
  • Transport them to ___ ____ organs
  • _____ _ _ _
  • ___and ___ Ag to B and T cells
  • They activate B and T cells
  • An essential ___Between ___ and ___ immunity
  •  

Dendritic cells

Derived from hematopoietic bone marrow progenitor cells

Capture antigen in tissues

Transport them to secondary lymphoid organs

Professional APC

Process and present Ag to B and T cells

They activate B and T cells

An essential link between innate and adaptive immunity

 

23

Context is key: Microenvironment affects ___ _____ and resulting immune response

Like T cells, Dendritic cells can be ___ or ____

Immature DC exposed to proinflammatory signals  will differentiate into____DC, secrete proinflammatory cytokines and promote inflammation.

 

Immature DC exposed to ____ signals (IL10, TGFB) will differentiate into ____ DC, promote ____ T cell ____ and anti-inflammatory effects.

 

Activated DCs induce inflammatory or tolerogenic T cell responses

 

 

Context is key: Microenvironment affects DC maturation and resulting immune response

Like T cells, Dendritic cells can be proinflammatory or anti-inflammatory

Immature DC exposed to proinflammatory signals  will differentiate into stimulatory DC, secrete proinflammatory cytokines and promote inflammation.

 

Immature DC exposed to tolerogenic signals (IL10, TGFB) will differentiate into regulatory DC, promote regulatory T cell development and anti-inflammatory effects.

 

Activated DCs induce inflammatory or tolerogenic T cell responses

 

 

24

M (Microfold) Cells

  • Specialized epithelial cells in the____ ____ ____ that overlie ___ ___ and ___ ___.
  • Differ from normal ____
    • lack ____ on their ___ surface
    • possess ____ microfolds
  • Take up antigenic macromolecules from the ____ and ____ it via ___ ___ to an _____pocket on the _____side
  • M cells do NOT ____ the antigen
    • They simply ___ it from ____ to ____ side
    • Once antigen is passed to bl side it is transported to an ___(macrophage or dendritic cell)
  • Transport the antigen to antigen presenting cells and ____
    • Express distinct ____ surface proteins to attract_____
      • ____-____ that attracts B cells
      • ____- ____ to attract T and B cells
  • Called M cells because they have specialized microfolds
  •  

M (Microfold) Cells

Specialized epithelial cells in the follicle associated epithelium (FAE) that overlie lymphoid follicles and Peyer’s patches

Differ from normal enterocytes

lack microvilli on their apical surface

possess broader microfolds

Take up antigenic macromolecules from the lumen and transfer it via endocytic vesicles to an intraepithelial pocket on the basolateral sideM cells do NOT process the antigen

They simply transfer it from lumen to bl side

Once antigen is passed to bl side it is transported to an APC (macrophage or dendritic cell)

Transport the antigen to antigen presenting cells and lymphocytesExpress distinct basolateral surface proteins to attract lymphocytes

CD137-integrin that attracts B cells

CXCL16-chemokine to attract T and B cells

Called M cells because they have specialized microfolds

 

25

Antigen adherence to M cells

  • Adherence favors ____ and ____
    • M cell favors endocytosis and transcytosis when various macromolecules adhere to it
  • Adherent materials tend to evoke ____ immune responses
  • ____ variety of pathogens ____ to M-cells
  • Mechanism of adherence is ___
    • Display cell-specific ____molecules on ___ surface to attract ____
  • The glycocalyx layer, an extracellular ____ layer found throughout the ____ attached to ____,  is much ____ or ____on M cells (to aid in the FCN of Ag uptake and anherance)
  • Many _________ microorganisms ___ ___ to M-cells
  •  
  •  

Antigen adherence to M cells

Adherence favors endocytosis and transcytosis

M cell favors endocytosis and transcytosis when various macromolecules adhere to it

Adherent materials tend to evoke strong immune responses

Wide variety of pathogens adhere to M-cells

Mechanism of adherence is unclear

Display cell-specific surface molecules on apical surface to attract antigen

The glycocalyx layer, an extracellular polysaccharide layer found throughout the intestine attached to enterocytes, is much thinner or absent on M cells (to aid in the FCN of Ag uptake and anherance)

Many commensal microorganisms avoid adherence to M-cells

 

 

26

M cells and antigen uptake

M cells facilitate ___ ___  THEY ARE NOT ___

M cell “hands” off ___ antigen to ___ or___ cell

Enteric pathogens know how to ____ M cells

Macromolecule taken up by M cell, transported across and presented by a dendritic cell.

 

M cells and antigen uptake

M cells facilitate antigen entry.  THEY ARE NOT APC!

M cell “hands” off intact antigen to lymphocyte or dendritic cell

Enteric pathogens know how to exploit M cells

 

Macromolecule taken up by M cell, transported across and presented by a dendritic cell.

 

27

M cells may serve as ___ sites for pathogenic microorganisms

  • ____
    • Vibrio cholerae
    • Escherichia coli
    • Salmonella typhi: food poisoning
    • Salmonella typhimurium
    • Shigella flexneri: dysentery
    • Yersinia enterocolitica: plague
    • Yersinia pseudotuberculosis:  plagu
    • Campylobacter jejuni
  • ___
    • Reovirus
    • Poliovirus
    • HIV

M cells may serve as entry sites for pathogenic microorganisms

Bacteria

Vibrio cholerae

Escherichia coli

Salmonella typhi: food poisoning

Salmonella typhimurium

Shigella flexneri: dysentery

Yersinia enterocolitica: plague

Yersinia pseudotuberculosis:  plague

 

Campylobacter jejuni

Viruses

Reovirus

Poliovirus

HIV

 

 

28

Salmonella & Shigella spp___ M cells to___entry

 

Salmonella & Shigella spp. exploit M cells to gain entry

 

29

Mucosal immune responses

  • Differs from ___ immune responses
  • Major antibody isotype in mucosal secretions is ____ ____ ____ 
  • Most of the antibody-secreting cells and effector T cells exist within ____
  • There are separate ____ and ____ lymphoid sites
  •  

Mucosal immune responses

Differs from systemic immune responses

Major antibody isotype in mucosal secretions is secretory, dimeric IgA (sIgA)

Most of the antibody-secreting cells and effector T cells exist within MALT

There are separate inductive and effector lymphoid sites

 

30

Inductive versus effector sites

  • Inductive sites
    • Specialized areas where antigen ____ and ____ occurs
    • Best characterized in ___ tract (associated with ___ ___)
    • Also likely present in the ___
    • Contain _ cells, _ cells, and ____ (dendritic cells, Langerhans cells, macrophages)
    • Where ___ cells and ___ cells are.
    • Ag are ___ ___, ____ and ____to B and T cells for activation
  • Effector sites
    • Areas where effector ___ ____occur
    • Consist of both ___ and ____ responses
    • Contain:
      • ____
      • ___
        • ____ T cells often referred to as ____ _____
        • ___ ____ T cells
      • ____ (dendritic cells, Langerhans cells, macrophages)
    • Where activated B and T cells traverse to and ___the immune response
    • B cells go to __ __and excrete their Ab into the ___
    •  

Inductive versus effector sites

Inductive sites

Specialized areas where antigen uptake and processing occurs

Best characterized in GI tract (associated with Peyer’s patches)

Also likely present in the NALT

Contain B cells, T cells, and APCs (dendritic cells, Langerhans cells, macrophages)

Where M cells and dendritic cells are.

Ag are taken up, processed and presented to B and T cells for activation

Effector sites

Areas where effector immune responses occur

Consist of both humoral and cellular responses

Contain:

B cells

T cells

Epithelial T cells often referred to as intraepithelial lymphocytes (IELs)

Lamina propria T cells

APCs (dendritic cells, Langerhans cells, macrophages)

Where activated B and T cells traverse to and affect the immune response

B cells go to lamina propia and excrete their Ab into the lumen