Mucosal Immunity 2 Flashcards
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
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).
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 ____
- A1- predominant IgA subclass found in ___
- 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
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
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.
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.
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
sIgA Functions
___ ___:
___ ____ Properties
_____ of Commensals
sIgA Functions
Immune exclusion:
Anti-inflammatory Properties
Homeostasis of Commensals
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
Lamina Propria Lymphocytes
- B cells & Plasma cells
- Secrete antibodies
- 70-90% Ig_
- 10-20% Ig_
- 2% Ig_
- Secrete antibodies
- 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
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
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
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
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
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
- 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
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
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
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 ____
- Antigen sampling depends on _____
- Simple epithelia (bronchiole, ___, ____)
- Antigen sampling depends on ____ and______ transport
- ___ ___s may also participate in antigen ____
- M cells are a ___ ___ ___
- 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
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.
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
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
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
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
- Express distinct ____ surface proteins to attract_____
- 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
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
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.
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
Salmonella & Shigella spp___ M cells to___entry
Salmonella & Shigella spp. exploit M cells to gain entry
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
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
The intestinal immune system
Inductive Site
M cell. If Ag comes across, the___ goes down to the ___ ___, ____ it to B cells and ___ T cells to activate them. Those activated B and T cells exit the follicle via the ___, traverse the ____ ___ and exit at an ___ site where they can then exert their ___ ___
The intestinal immune system
Inductive Site
M cell. If Ag comes across, the APC goes down to the lymphoid follicle, presents it to B cells and CD4 T cells to activate them. Those activated B and T cells exit the follicle via the lymph, traverse the peripheral blood and exit at an effector site where they can then exert their immune FCN
Effector sites: Epithelium and lamina propria
Generally cells have characteristics of ____ cells
Lamina propria contains the ___ ___ of immune cells
Epithelium contains ___ T cells
Lamina Propia: that’s where __ cells will be to ___ ___
Epithelium has ____ ____, the ______
Effector sites: Epithelium and lamina propria
Generally cells have characteristics of activated cells
Lamina propria contains the whole range of immune cells
Epithelium contains CD8 T cells
Lamina Propia: that’s where B cells will be to secrete Ab.
Epithelium has interepithelial lymphocytes, the CD8 cytotoxic T cells
T cell homing to intestinal tissue
B cells and T cells are activated in inductive sites (___ ___) and traffic to specific effector sites (___ ___ ___)
There is specialized____ in terms of your immune cells and the mucosa
When they become activated, they start expressing specific cell _____molecules that allow them to ___ back to the ___ and the ___ ___
T cell homing to intestinal tissue
B cells and T cells are activated in inductive sites (PP) and traffic to specific effector sites (intestinal lamina propria)
There is specialized homing in terms of your immune cells and the mucosa
When they become activated, they start expressing specific cell adhesion molecules that allow them to home back to the mucosa and the effector sites.
____ and ___ ___ molecules direct homing
_____ (Alpha4Beta7):Addressin (MadCAM) Interactions
Chemokine Receptor(CCR9/10): Chemokine (CCL25/28) Interactions
Areas of mucosa express the cell adhesion molecule ______while the lymphocytes express the ______ and that helps the T cell or B cell home to those mucosal sites
Chemokines and cell adhesion molecules direct homing
Integrin (Alpha4Beta7):Addressin (MadCAM) Interactions
Chemokine Receptor(CCR9/10): Chemokine (CCL25/28) Interactions
Areas of mucosa express the cell adhesion molecule MadCAM while the lymphocytes express the alpha4beta7 and that helps the T cell or B cell home to those mucosal sites
A common mucosal immune system
Common means that dependent upon the site of ____ of a mucosal immune response, ____ will be conferred to ___ mucosal sites.
Mucosal system is a common system such that if the induction or site of Ag first recognition is in, say the tonsils, the effector site will be distributed thruout the mucosal system. It wont be limited to just the nasal cavity
A common mucosal immune system
Common means that dependent upon the site of induction of a mucosal immune response, immunity will be conferred to other mucosal sites.
Mucosal system is a common system such that if the induction or site of Ag first recognition is in, say the tonsils, the effector site will be distributed thruout the mucosal system. It wont be limited to just the nasal cavity
