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Immunology Exam 2 Avery Rocks
Immunology Exam 2
124
Immunology
Graduate
10/16/2011

Additional Immunology Flashcards

 


 

Cards

Term
Process of CD8 T Cell Activation
Definition

1) CD8 TCR binds to peptide antigen presented on dendritic cell class I MHC. (direct infection or cross presentation)

2) CD8 TCR sends signal that causes NF-AT to translocate to the nucleus, upregulating expression of the IL-2 recepter alpha chain (CD25), and making a limited amount of IL-2.

3) CD4 TCR binds to peptide antigen on same DC presented by class II MHC.

4) CD4 T cell makes high amounts of IL-2, which bind to neighboring CD8 T cell.

5) Both cell types divide, expanding the population of antigen-specific T cells.

Term
Only APC that will activate naive T cells.
Definition

Dendritic Cells

 

 

Term
Dendritic Cell activation of CD 8 T Cells
Definition

Present ag via MHC Class I, through direct infection or cross presentation.

 

B7/CD80 co-stimulatory molecule binds to CD28 on naive T cell.

 

Activated T cell makes IL-2, driving its own proliferation and differentiation.

 

APC activates CD4 T cell to make IL-2 and naive CD8 T cell to express IL-2 receptor.

 

IL-2 secreted by CD4 T cell is bound by CD8 T cell.

 

 

 

 

 

Term
Cross Presentation
Definition

Process by which DCs shuttle endosomal antigen to the cytosol for presentation by class I MHC.

 

DCs phagocytose (or macropinocytose) viral nucleic acids released into endosomes.

 

This antigen can then be shuttled to surface on MHC I.

 

Meanwhicle, endosomal TLR recognizes virus, causing NFKB to transolocate and CD80 to be upregulated.

 

 

Term
Role of IL-2
Definition

Growth factor for T cells.

 

Production of the cytokine is much higher in CD4 T cells but does occur in CD8 T cells.

 

Alpha chain of its receptor is induced by NF-AT translocation to the nucleus. 

 

Alpha chain expression is equally strong among both CD4 and CD8 T cells.

 

The cytokine, which can be secreted in both an autocrine and paracrine fashion, drives T cell proliferation.

Term
CD8 T Cell effector function
Definition

Get out into periphery and kill infected cells to stop the proliferation of the virus.

 

Target host cells express adhesion molecules that cuase collision with CD8 T cell.

 

Recognition of host MHC Class I:antigen causes T cell to align its granules for targted contact with host cell.

 

Unload contents of cytotoxic granules: perforin and granzyme.

 

CD8 T cell moves on to destroy many more infected cells.

Term
Sequence of events in CD8 T cell effector function, once activated.
Definition

Start packaging granzyme and perfroin into granules (in the cytosol) upon activation in the Lymph Nodes.

 

CD8s exit LN and home to epithelial and other sites.

 

Undergo brief interactions with potential target cells.

 

TCR recognizes virus presented by class I MHC on target cell.

 

Granules line up and release contents into target cell.

 

 

 

 

Term
Johne's Disease
Definition

Mycobacterium paratuberculosis: Intracellular bacteria that lives in endosomes of macrophages, preventing phagosome-lysosome fusion

 

Infects macrophages in the small intestine of most ruminants

 

Very slow progression of clinical signs:

Stage I = no disease

 

Stage II = infection, perhaps subclinical disease, manifested in decreased milk production

 

Stage III = clinical signs such as submandiublar edema, diarrhea, weight loss, decreased milk production

Term
Testing for Johne's Disease
Definition

In clinical cases: mucosal biopsy or necropsy, which will find thickened ileum and granulomas in submucosa caused by decreased abosprotion of nutrients.

 

In subclinical cases: pooled fecal culture

 

(ab testing not conclusive bc infected animals don't make abs for months after infection; individual fecal cultures not sensitive enough; T cell responses not specific enough)

Term
Granulomas
Definition

Central collection of infected macrophages surrounded by ring of CD4 (Th1) and CD8 T cells.

 

Serve to wall off the organizm with the macrophage to contain the infection.

Term
Point of entry into gut for Johne's mycobacteria
Definition
M cells
Term
M Cells
Definition

Line epithelial side of Peyer's Patches (secondary lymphoid structures underlying intestinal epithelium)

 

Take up antigen via endo or phagocytosis and transport it from lumen of intestine to Peyer's Patch, where it is bound to dendritic cells, which in turn present to and activate T cells.

 

Induce tolerance to injested bacteria.

 

 

Term
Infection of macrophage or DC by M paratb.
Definition

M cell transports bacteria into Peyer's Patch, where it is taken up by macrophages and dendritic cells.

 

DCs can phagocytose and/or be directly infected by MTb.

 

TLRs (but not RIG-like receptors) on the DC can recognize the pahtogen, signalling NFKB to translocate, cytokines to be produced, and co-stimulatory and adhesion molecules to be upregulated.

 

MTB lives in the endosome, preventing it from fusing with a lysosome, preventing expression of its antigen in MHC Class II (though partial expression can occur)

Term
T cell role in fighting intracellular bacteria like MTb
Definition
Activation of macrophages by CD4 T cells increases the MO's phagolysosome fusion.
Term
Th0 T cell
Definition

initial CD4 T cell activated by dendritic cell in the lymph node

 

can make IL-2, emitting via autocrine and paracrine pathways

 

after several rounds of divison, develop into Th1, Th2, or Th17 T cells, depending on which cytokines are nearby

Term
Th1 cell products
Definition

 

activated when IL-12R is dominant cytokine

 

produces: INF-gamma

IL-2

TNF-alpha

 

 

Term
Th1 cell targets
Definition

 

activates macrophages and dendritic cells, improving their ability to kill infectious agents;

 

 

 

Term
Th1 infectious agents
Definition

 

intracellular bacteria

fungi

viurses

intracellular protozoa

Term
Th17 cell products
Definition

IL-17: binds to epithelial cells, which in turn produce defensins

 

IL-21

 

IL-22

 

 

 

Term
Th17 cell target
Definition
recruits neutrophils
Term
Th17 infectious agents
Definition

Extracellular bacteria

 

Fungi

 

Small role in granuloma formation

Term
Th2 cell products
Definition

IL-4

 

IL-13

 

IL-5

Term
Th2 cell target
Definition
recruits and increases production of eosinophils and basophils
Term
Th2 infectious agents
Definition

parasites

 

allergens

Term
CD4 T cells differentiation
Definition

After initial ativation, CD4 T cells are considered Th0 cells.  They produce IL-2 and undergo a few rounds of replication.

 

Depending on the cytokines produced by DCs and in the environment at thet ime of activation, the CD4 T cells develop into one of three main helper lineages:

 

Th1, Th2, Th17

Term
Differentiation Pathway for Th17 T cells
Definition

Cytokines required for differentiation:

TGF-beta and IL-6

 

 

Transcription factors induced to translocate:

RORgt

 

Cytokines produced by the Th cell:

IL-17

Term
Differentiation pathway for Treg T cells
Definition

Cytokines required for differentiation:

TGF-beta

 

Transcription factor induced to translocate:

FoxP3

 

Cytokines produced by the Th cell:

TGF-beta, IL-10

Term
Th1 differentiation pathway
Definition

Cytokines required for differentiation:

IL-12

 

Transcription factor induced to translocate:

T-bet

 

Cytokines produced by Th cell:

IL-2

IFN-gamma

TNF-alhpa

Term
Th2 differentiation pathway
Definition

Cytokines required for differentiation:

IL-4

 

Transcription factor induced to translocate:

GATA-3

 

Cytokines produced by Th cell:

IL-4

IL-5

IL-13

Term
Th1 T cells development
Definition

TLR binding of pathogen-derived molecules by DCs induces DC to make IL-12

 

IL-12 induces the transcription factor Tbet, which in turn induces T cells to differentiate.

Term
Th1 T cells function
Definition

Interact with MOs presenting ag on Class II MHC and with CD40 on the MO, resulting in its activation.

 

Produce IFN-gamma, which also assists with MO activation and efficient killing of organisms infected with intracellular pathogens by increasing: phagolysosome fusion, class II MHC expression, reactive oxygen intermediate production, and MO production of TNF-alpha

 

Produce IL-2, which aids in CD4 and CD8 proliferation.

 

Produce TNF-alpha to activate endothelium, recruiting additional cells to site of infection

 

Induce MOs to produce chemokines that attract more MOs

 

Produce IL-3 and GM-CSF, which induce MO differentiation in the bone marrow.

Term
 IFN-gamma/CD40 ligand mediated function of Th1 cell
Definition

Activates macrophages to destroy engulfed bacteria

 

Term

IL-2 mediated function of Th1 cell

 

Definition
Induces T cell proliferation, increasing the number of effector T cells
Term

IL-3 and GM-CSF mediated function of Th1 cell

 

Definition

 

Induces macrophage differentiation in the bone marrow

 

Term

 TNF-alpha and LT mediated function of Th1 cell

 

Definition

 

Activates endothelium to induce macrophage adhesion and exit from blood vessel at site of infection

 

Term

CXCL2 mediated function of Th1 cell

Definition
Causes macrophages to accumulate at site of infection
Term

 

Sequence of events in mTB infection:

 

Definition

1)      Pathogen crosses intestinal epithelium via M cells and is released into Peyer’s Patches in the submucosa.

2)      Pathogen binds to MOs and DCs through lectin receptors (which recognize sugars) and are phagocytized.

3)      Pathogen can bind to TLRs on surface of MOs and DCs.  This binding can induce low-level pro-inflammatory response through release of TNF-alpha, IL-1, IL-6, IL-12)

4)      DCs present antigen on MHC Class II.

5)      DCs have been activated by TLR binding, and can upregulate ICAMs, CD80, and MHC Class II, and produce IL-12.

6)      Naïve T cells that recognize the antigen are activated, proliferate, and differentiate into Th1 T cells under the influence of IL-12.

7)      Th1 T cells recognize antigen on MHC Class II presented by infected APC and they:

a.       Produce IFN-gamma, inducing MOs to kill.

b.      Send signal to MO via CD40, enhancing activation.

c.       Produce IL-2 to help additional T cells divide.

d.      Produce chemokines to attract MOs to the site of infection.

8)      The accumulation of T cells and MOs result in a granuloma.

 

Term

 

Th1 T cells’ relationship with CD8 T cells

 

Definition

 

Can activate CD8 T cells by releasing lots of Il-2 to help CD8 T cells to proliferate.

 

Term

 

How do T cells travel to the intestinal epithelium to attack pathogens?

 

Definition

1)      Pathogen crosses intestinal epithelium via M cells and is released into Peyer’s Patches in the submucosa, where DCs and MOs take it up.

2)      Naïve T cells that recognize the antigen presented on MHC Class II by DCs are activated, proliferate, and differentiate.

3)      The T cells exit the Peyer’s Patch and travel via the lymphatics to lymph node, then thoracic duct, emptying into the bloodstream to circulate.

4)      Alpha 4 beta 7 expressed by T cells activated in the intestinal lymphoid tissue bind to MadCAM, which is found only on the intestinal endothelium.

5)      This binding allows the T cells to enter the lamina propria.

6)      In the lamina propria, gut-homing T cells bind to chemokines expressed by the intestinal epithelium.

 

Term

 

T cell migration in Parvovirus Infection

 

Definition

1)      Virus infects rapidly dividing epithelial cells and activates interferon production.

2)      Interferon activates NK cells and activates the production of chemokines by the epithelium.

3)      Viral antigen is phagocytized by DCs which then travel to Peyer’s Patches and nearby LNs. These DCs present the antigen via MHC Class II and cross presentation on MHC Class I.

4)      DCs are activated by TLR ligands on the virus.

5)      CD4 and CD8 T cells are activated. Th0 and Th1 CD4 T cells make IL-2 and support proliferation of CD8 T cells.

6)      CD4 and CD8 T cells exit the LNs via the efferent lymphatics, return to the blood, and circulate to intestine where alpha4 beta7/MadCAM interaction causes T cells to exit.

7)      CD8 T cells are attracted to the infected epithelium by chemokines.

8)      CD8 T cells kill virally infected cells through recognition of peptide on MHC Class I.

 

Term

 

Th17 T cells Development

 

Definition

 

1)      TLR binding of extracellular bacteria-derived molecules by DCs induces DCs to make IL-6.

 

2)      IL-6 and TGF-beta induce differentiation of the T cells.

 

Term

 

What determines whether Th17 or Th1 T cells are produced?

 

Definition

 

Different TLRs induce qualitatively different responses by DCs.

 

Term

 

Th17 T Cell Function

 

Definition

1)      Th17 T cells migrate to the site of infection and produce IL-17 and other cytokines.

2)      IL-17 induces the production of defensins by epithelial cells.

a.       Defensins poke holes in fungi and extracellular bacteria.

3)      IL-17 induces epithelial cells to make chemokines that attract neutrophils.

 

Term

 

Job’s Syndrome

 

Definition

 

 

 

Absence of Th17 T cell subset.

 

Results in severe, recurrent extracellular bacterial and fungal infections.

 

Term
Haemonchus contortus
Definition

Intestinal, macroscopic, blood-sucking parasitic worm.

 

Found in sheep and goat abomasum. Most prevalent in Southeast and high concentration grazing areas.

 

Uses blood for nutrition.

 

Low level parasitism results in weight loss and decreased production.

 

High level acute parasitism can lead to hemorrhage and death.

 

Term
Life cylce of haemonchus contortus
Definition

1) Goat eats plant infested with the worms.

2) There are macroscopic adult worms that live in the gut, which lay eggs that exit in the feces.

3) Larvae live in the tissues.

Term
Goals of immunity to intestinal nematodes
Definition

Immune response to larvae

  • prevent migration
  • wall off migrating larvae

Immune response to adult worms

  • expel the adults from the GI tract
  • increase motility
  • increase mucous production
  • wall off adult worms trying to infect

 

Term
Can lymphocytes survive in the gut?
Definition

No

 

Term
Heartworm symptoms
Definition
  • Cough
  • Eosinophilia
  • Weight loss
  • Poor hair coat
  • Heart murmur
  • Increased brochovesicular sounds in lungs

Later stages:

  • right heart failure due to chronic inflammation
  • glomerular disease
Term
Heartworm diagnostic tests
Definition

CBC/Chem (hypoalbuminemia, neutrophilia, eosinophilia, basophilia, presence of microfilaria)

 

urinalysis (increased protein)

 

Chest X-rays (worms)

 

snap test (heartworm ag shed by adult worms)

Term
microfilaria
Definition

live young of blood/lymph dwelling worms (not larvae)

 

live in blood

 

indicate presence of live adult heartworms in patient's heart

 

ingested by mosiqutoes; develop into infective larvae within the mosquito and escape into dogs bitten by the mosquito

Term
Dirofilaria immitis
Definition

Heartworm

  • Nematode that lives in blood/lymph
  • Complex life cycle, transmitted by mosquitoes
  • Upon infection, larvae develop within tissues and begin migration to heart.
  • Adults live in the right heart and can persist for several years.
  • Life most nematodes, early life cycle stages are completely susceptible to ivermectin and its derivatives

 

Term

Goals of immunity to intravascular and intralymphatic nematodes

 

Definition

 

Immune responses to larvae:

  • Prevent migration
  • Wall of migrating larvae

Immune response to adult worms:

  • Try to kill adult worms
  • Generally unsuccessful

 

 

Term
Helminths
Definition

Nematodes most important subset

 

Pose trouble for immune system because of:

  • their size
  • where they live
    • lumens
      • inside blood vessels
      • inside lymphatics
      • inside air spaces in the lungs
      • inside the gut lument
    • subcutaneous tissues
Term
Type of immune response helminths induce
Definition

Th2

 

Characterized by:

  • IgE production
  • Eosinophil and Basophil expansion
  • Mast cell activation and proliveration

Success defined not by whether the animals are completely immune, but by how effectively the Th2 response contains the maginitude of the infestation.

 

Term
Immune response to large, multicellular parasitic organisms (nematodes)
Definition

Goals of immunity to these parasites are:

(1) explusion of GI parasites in the case of intestinal infections

(2) killing of intravascular parasites, in the case of heartwroms or similar parasites

 

Immune responses are dominated by eosinophils, basophils, and IgE

 

Th2 CD4 T cells make the cytokines IL-4, 5, and 13, which induce growth of eosniophils and basophils and induce B cells to isotype switch to IgE

Term
Th2 T cell differentiation
Definition

Characterized by lack of TLR-ligation (which occurs in both Th1 and Th17 differentiation)

 

IL-4 is cytokine that induces Th0 to become Th2

 

IL-4 is not produced by DCs, but not known where it comes from, just that it is in the vicinity of Th0 and DC and is produced (1) upon recognition of pathogen-derived molecules or (2) in response to damage to endothelium or epithelium.

 

IL-4 receptors on Th0 cell which recognize the IL-4 released as it meets up with DC.

 

 

Term
What inhibits differentiation of Th2 T cells?
Definition
IFN-gamma, a Th1 cytokine
Term
Pathogen-derived molecules for nematodes
Definition

NOT TLR ligands

 

Mostly, we don't know what they are.

 

Cysteine proteases -- enzymes that degrade proteins -- produced by some parasites are somehow involved.

 

Cysteine proteases are also the main component of some allergens

Term
Effector function of Th2 T cells
Definition

IL-4, IL-5, IL-13

  • Induce growth of eosinophils and basophils
  • Induce growth of mast cells
  • Bind to epithelial cells to induce anti-parasite responses
  • Binds to smooth muscle to increase contractility (expulsion of adult worms from intestine, induce cough to expel lung worms, etc.)
  • Causes B cells to switch to IgE production
  • Cause B cell proliferation

 

Term
Eosinophil and Basophil role in Th2 response
Definition

Eosinophils degranulate, releasing toxic molecules that can help kill intravascular, pulmonary, intralymphatic, and cutaneous parasites.

 

 

May be effective against larvae migrating through the skin.

 

Basophils produce more IL-4, and may help perpetuate the Th2 response.  Basophils can migrate.

Term
Toxic proteins released by eosinophils
Definition

Major basic proteins: bind to and damage cells of parasite

 

Reactive oxygen species: in environment around worm, can damage it (and the host cell)

 

Term
Epithelial cell involvement in Th2 response
Definition

Upon binding with IL-4, IL-5, IL-13, induce anti-parasite responses:

 

  • Bind goblet cells, causing them to make mucous and proliferate.
  • Produce anti-nematode molecules, such as RELM (anti-nematode resistance molecule)

 

Term
IgE role in Th2 response
Definition

Type 2 (Th2) cytokins cause B cells to switch to IgE production

 

IgE circulates and binds to high affinity Fc receptors on mast cells and eosinophils

 

Upon second encounter with antigen, IgE is cross linked, causing causing mast cells and eosinophils to degranulate

 

IgE binding to mast cells and eosinophils can be long-lasting.

 

IgEs can be specific for different epitopes of antigen on the same parasite.

 

Term
Th2 effector functions
Definition

GI/Lung parasites:

  • Mast cell degranulation causes smooth muscle contraction
  • Epithelial cells produce defensin-like anti-nematode proteins
  • goblet cells produce more mucous

Intravascular parasites

  • Eosinophil degranulation releases toxic products that bind to and attack the parasite
  • Not very effective.

 

 

Term
Sequence of events in response to nematode infection such as Dirofilaria immitis
Definition

1) Adult worms shed ag into the circulation.

2) DCs in the spleen take up ag and present it to T cells.

3) Endothelium and epithelium produce TSLP and IL33, and basophils produce IL-4.

4) DCs present ag on class II MHC to T cells, which are stimulated to become Th2 cells by IL-33/TSLP and IL-4.

5) Th2 T cells produce IL-4, 5, and 13, causing B cells to switch to IgE production, and the growth of eosinophils and basophils.

6) Circulating IgE binds to Fc receptors on Eosinophils and Mast cells.

7) Ag shed from the organism into the blood cross-link Fc receptors, causing eosinophils to degranulate.

 

 

Term
Events in Haemonchus contortus infection
Definition

1) Adult worms live in GI tract.

2) DCs in submucosa take up ag and present it to T cells in LN, with IL-4 in the vicinity.

3) Th2 T cells produce IL-4, IL-5, and IL-13, causing B cells to switch to IgE, and activating eosinophils and basophils.

4) Circulating IgE binds to Fc receptors on EOS and Mast Cells

5) Ag shed from parasite circulate in blood and crosslinks Fc receptors, causing mast cells to degranuatle.

 

Term
Transcription factors for the different T cell subsets
Definition

IL-12 induces the translocation of Tbet into the nucleus of T cells, causing them to differentiate into Th1 cells.  Tbet mediates the transcription of IFN-gamma, TNF-alpha, and IL-2 cytokines.

 

IL-6 and TGFb induce the translocation of RORg into the nucleus of T cells, causing them to differentiate into Th17 cells.  RORg mediates the transcription of IL-17, IL-21, and IL-22.

 

IL-4 and TSLP or IL-33 induce the translocation of GATA2 into the nucleus of T cells, causing them to differentiate into Th2 cells.  GATA3 mediates the transcription of IL-4, IL-5, and IL-13.

Term
T reg development
Definition

Develop when only TGFb is present (without IL-6)

 

Produce TGF-beta and IL-10, which are the only two immuno-suppressive cytokines

Term
T regs
Definition

CD4 T cell subset

 

Produce the universally immunosuppresive cytokines TGFb and IL-10

 

Actively suppress autoreactive T cells -- circulating T cells that would otherwsie recognize self antigen

 

 

Term
Function of TGFb and IL-10
Definition

Suppress proliferation of other T cells

 

Inhibit macrophage activation

 

Antagonize the actions of the three other T helper subsets

Term
MALT
Definition

Mucosa associated lymphoid tissue

 

lymph nodes that directly drain mucosal sites in gut, lungs, eye, and reproductive tract

 

Peyer's patches, which are directly adjacent to epithelium in the small intestine, are one form of MALT

 

Lamina propria is packed with lymphocytes, even in healthy intestine.

 

Lymphatics drain submucosal tissue, Peyer's patches, etc. to mesenteric LN

 

 

Term
Properties unique to B and T cells that are activated in the MALT
Definition

They home to the lamina propria after they are activated

 

The B cells produce IgA almost exclusively

 

The CD4 T cells are often immunosuppressive (Tregs)

Term
Which cell mediates antigen presentation in mucosal tissue?
Definition

Dendritic cells in lymphoid follicle:

1) M cells take up ag by endocytosis and phagocytosis.

2) Ag is transported across the M cells in vesicles and released at the basal surface.

3) Ag is bound by DCs, which activate T cells.

 

OR

 

Dendritic cells in the lamina propria:

DCs can extend their processes across the epithelial layer to capture ag from the lumen of the gut

Term
Pathway for T and B cells activated in the MALT
Definition

1) lymphocytes activated in the MALT upregulate alpha4-beta7.

2) they move through the mesenteric LN and lymphatics until they end up in the bloodstream.

3) alpha4-beta7 binds to MadCAM in the endothelium lining submucosal tissue near the site of infection.

4) effector T cells enter the lamina propria, where they bind to chemokines expressed by the intestinal epithelium.

Term

Immune system activity in healthy gut

 

Definition
  • DCs continually sample the intestinal lumen.
  • B and T cells specific for GI tract ag are generated, and recirculate to the lamina propria.
  • IgA helps to prevent lumenal bacteria from invading past the epithelial layer.
  • In the case of a breach of the epithelial layer, these celss are poised to defend against pathogens.

 

Term
What Ab do MALT-associated B cells preferentially produce?
Definition

IgA

 

MALT has high levels of TGFb, which promotes isotype switching to IgA

 

IgA can be either monomeric or dimeric

 

Dimeric IgA is transported across epithelial surfaces through a special transport system.

 

A human produces 5 grams of IgA/day.

Term
Process by which IgA and IgM are transported across epithelial surfaces
Definition

Receptor-mediated endocytosis

 

  A poly-Ig receptor on basolateral face of epithelial cell binds to the multiple Fc regions around the J chain.

 

Shuttles the IgA (or IgM) across the epithelial surface via endocytosis.

 

Receptor is cleaved and IgA is bound to mucous.

Term
Role of IgA in intestine
Definition

1) binds to and neutralizes antigens internalized in endosomes or on gut surface

 

2) opsonizes pathogen

 

3) enhances antigen uptake and trnasport into underlying secondary lymphoid follicles

 

Term
Where is IgA secreted?
Definition

On all mucosal surfaces and through secretions.

 

  • Gut, lungs, urinary tract, saliva, tears, milk
  • IgA induced in B cells at any mucosal surface can home to breast tissue, where it can be secreted in milk.
  • Thus, milk contains a sample of IgA specific for all the pathogens recognized by the mother during pregnancy.

 

 

Term
MALT-associated CD8 T cells
Definition

Return to the lamina prpria to kill virally-infected cells

 

Can be found in the lamina propria or between epithelial cells, in which case they are referred to as intraepithelial lymphocytes.

 

Intraepithelial lymphocytes can give rise to feline GI lympoma

Term
MALT-associated CD4 T cells
Definition

Return to the lamina propria to carry out Th1, Th2, and Th17 functions

  • Th1 T cells activate MOs that have ingested a pathogen and present ag on Class II MHC
    • Th1 cells produce IFN-gamma, and ligate CD40
    • Increased klling of intracellular pathogens
  • Th17 T cells are activated by MOs and DCs in the lamina propria which have phagocytized extracellular bacteria
    • Recruit neutrophils, activate epithelial cells
  • Th2 T cells are activated by MOs and DCs that present parasite ag.
    • Th2 cytokines activate epithelium
    • Cause mast cell proliferation
    • Cause smooth muscle contraction
Term
Summary of Mucosal Immunity
Definition

1) MALT induces B and T cells specific for ag seen in the lumen of the GI tract

2) Lymphocytes activated in MALT return to mucosal lymphoid tissue

3) Wait there for infection (breach of epithelial defensins)

4) B cells preferentially produce IgA

5) CD4 T cells can be any subset, and produce relevant cytokines when re-activated by APCs in lamina propria

6) CD8 T cells reside in lamina propria or as intraepithelial lymphoctyes

 

Term
Immunologic Memory
Definition
After an infection has been cleared, the host has a population of long-lived memory B and T cells, and long-lived antibody in circulation.
Term
Timeline of primary vs memory immune responses
Definition

Primary:

  • ~1 week after infection before the initial adaptive immune response can be detected, at which point it will be primarily IgM. 
  • By week 2, IgG is usually the predominant antibody.
  • Within 1 month, IgM has disappeared, so its presence indicates that an individual is fighting a pathogen for the first time.

Secondary (memory):

  • about 1 day to detect adaptive immune response to subsequent infections.
  • antibodies present will be IgG, IgA, IgE
Term
How memory B and T cells can prevent re-infection
Definition
  • IgA at mucosal surfaces can bind to a virus (such as parvo), and prevent attachment to epithelial cells.
  • IgG in the blood and tissues can bind to pathogens invading skin epithelium or blood and opsonize or activate complement for bacterial killing.
  • T cells at the site of infection may kill virally-infected cells.
Term
Why are memory responses more effective than primary responses?
Definition
  • There are more lymphocytes specific for the pathogen
  • There is already circulating antibody
  • The B cells have already undergone somatic hypermutation and isotype switching and are therefore higher affinity.
  • Ag specific T cells can be found at the site of re-infection rather than waiting in the LN to be activated and begin circulation.
  • No requirement for B7 (CD80) co-stimulation for memory T cells.
  • Ag specific B cells that haven't differentiated into plasma celss reside at the T cell edge of the follicle and can rapidly receive T cell help for further differentiation.
Term
What type of lymphocytes does every immune response generate?
Definition

A population of effector cells

 

A population of memory cells

 

  • Memory B cells can be plasma cells, which actively secrete ab, or resting B cells.
Term
Secondary immune response to parvovirus infection
Definition

1) Long-lived IgA producing plasma cells in the intestine provide IgA to prevent virus attachment to epithelium.

2) If virus infects the epithelial cell, IgG ab present in the serum and intracellular spaces can prevent spread from one epithelial cell to the next.

3) CD8 T cells in the lamina propria can recognize and kill virally-infected epithelial cells.

4) Virus can be carried to draining mesenteric LN or Peyer's patch by DC or via lymph.  LN is enriched for ag specific T and B cells, which are rapidly activated to produce more ab and further divide.

5) Activated B & T cells recirculate to the infection site.

Term
Secondary immune responses to strangles infection
Definition

1) Plasma cells producing IgA live in submucosa and coat nasal mucosa with IgA.  IgA can bind to receptors that Strep equi uses to cling to mucosal epithelium.

2) If organism colonizes the mucosa and reaches submucosa, IgG present in the tissues coat the bacteria, opsonizing and activating complement.

3) Memory Th17 T cells can be activated by pathogen-derived peptides on class II MHC of DCs and MOs in the submucosa, to enhance defensin production by epithelial cells and neutrophil recruitment.

4) Ag travels to LNs, where it activates memory B and T cells to further enhance the immune response.

Term
Clinical characteristics of lymphocyte tumors
Definition

Acute leukemias (leukemias of stem cells) have a terrible prognosis.

 

In B cells, acute leukemias involve B cells infected before they could make it out of phase 1 (no surface IgM).

 

B cell and T cell leukemias and lymphomas have good prognoses.

 

 

Term
Phases in B cell development
Definition

1) Repertoire assembly

2) Negative selection

3) Positive selection

4) Searching for infection

5) Finding infection

6) Attacking infection

Term
Phase 1 of B cell devo
Definition

Goal: B cell produces a functional immunoglobulin gene and protein

Location: bone marrow

Progression: starts as common, CD34+ lymphoid progenitor; ends as immature CD34- immature B cell

 

VDJ rearrangement: First Hc gene rearranges D-J, then V-DJ. Attempt with second Hc gene if necessary, and signalled to die if nonfunctional at that point.  Functionality tested with surrogate light chain.

 

Light chain then rearranges and, if functional, result is immature B cell with IgM on surface (otherwise, death).

Term
Phase 2 of B Cell devo
Definition

Goal: kill all B cells that are self-reactive (negative selection)

Location: Bone marrow

Progression: begins as immature B cell expressing IgM on surface; ends as immature B cell in blood

 

Negative selection: IgM is exposed to self antigen. If it doesn't recognize the self ag, it leaves the bone marrow.  If it does recognize self ag, its light chain is rearranged via receptor editing.  If it still recognizes self, it dies.

Term
Phases 3 and 4 of B cell devo
Definition

Goal: populate lympohid organs (LNs, spleen, MALT) with mature, naive B cells

Location: Move from blood to LNs

Progression:From naive, immature B cell to mature B cell

 

Enter LNs via high endothelial venules (HEV), attracted by chemokines.  Enter primary lymphoid follicles, where they undergo a final maturation (interaction with stromal elements in LN). If it doesn't encounter its ag, it exits via efferent lymphatics and recirculates

Term
Phases 5 and 6 of B cell devo
Definition

Goal: expand population of ag-specific B cells with help from T cells.

Location: LNs, tissues, bone marrow depending on final fate

Progression: from mature B cells to high affinity ab-producing plasma cells and memory B cells.

 

3 fates for B cells activated in LN:

1) differentiate immediately into short-lived IgM plasma cells

2) with T cell help: istoype switching/somatic hypermuation in germinal centers, then proliferation

3) differentiate into memory B cells

Term
B cell neoplasms
Definition

Reflect the stage at whicy they become neoplastic

 

Acute lymphoblastic leukemia (ALL) and Pre-B-cell leukemia are CD34 positive (unmutated Ig V genes; location is bone marrow and blood)

 

Diffuse large B cell (DLBC) lymphoma  most common in dogs/people (mature B cell in periphery with mutated Ig V gene)

 

Hodgkin's lymphoma and Waldenstrom's macroglubulinemia have been identified in cats but not dogs (mature B cells with mutated Ig V genes)

Term
T cell development overview
Definition

1) Common CD34+ lymphoid progenitors leave bone marrow and enter thymus via HEV

2) Commit to the T cell lineage once they have entered the thymus.

3) TCR genes rearrange sequentially, similarly to Ig genes (TCR beta chain first, then TCR alpha chain)

4) When T cells express TCR, they undergo negative and then positive selection to ensure only T cells that recognize MHC but are not self-reactive exit to periphery.

Term
thymus
Definition

primary lymphoid organ (like bone marrow)

 

where T cells develop

 

located between central sternum and pericardium

 

consists of cortex and medulla

 

3 main cell types: epithelial cells, lymphocytes, DCs

 

atrophies with age, as most T cell development happens in utero and early in life

Term
Phases of T cell development
Definition

Phase 1: commitment to T cell lineage

 

Phase 2: TCR gene rearrangement

 

Phase 3: Positive selection

 

Phase 4: negative selection

 

Phase 5: populate peripheral lymphoid tissue

 

Phase 6: activation and differentiation

Term
Phase 1 of T cell devo
Definition

Goal: recruit lymphoid progenitors to the thymus and commit them to T cell lineage

Location: start in bone marrow and end up in thymic medulla.

Progression: begin as CD34+ precursors in bone marrow, end as Double Negative thymocytes in thymus

 

1) CD34+ lymphoid precursors express Notch. 

2) Precursor enters thymus via HEV.

3) Upon entering the thymus, notch ligand on thymic epithelium binds to Notch. 

4) Notch becomes a transcription factor and commits the cell to T cell lineage.

5) Proliferation of the Double Negative T cell is supported by IL-7.

Term
Phase 2 of T cell devo
Definition

Goal: T cell expresses a functional TCR on its surface.

Location: thymic cortex

Porgression: begins as Double Negative thymocyte, ends as Double Positive thymocyte

 

VDJ rearrangement of Gamma chain.  If successful, thymocyte becomes committed gamma/delta T cell, but that is uncommon.

 

When Gamma chain fails, VDJ rearrangement begins of Beta chain, which is tested with surrogate alpha chain to test functionality of pre-TCR.  If functional, alpha chain rearrangement proceeds.  If alpha chain rearrangment is succesful, result is Double Positive thymocyte expressing TCR, CD4, and CD8

 

Term
Phase 3 of T cell devo
Definition

Goal: select for cells whose TCRs can recognize peptide plus MHC (positive selection).

Location: thymic cortex

Progression: from Double Positive thymocyte to single positive thymocyte

 

Positive selection: TCR binds self peptide plus MHC (I or II) presented by cortical epithelial cells in thymus, sending positive signal to the T cell to live. If no binding or weak binding, alpha chain can undergo receptor editing, but cell is destroyed if that's unsuccessful.  Most T cells are NOT positively selected, and die at this stage.  Those that survive become either CD4 or CD8 thymocytes depending on which MHC:peptide complex they recognized and bound to, and move on to medulla.

Term
Phase 4 of T cell devo
Definition

Goal: prevent T cells that bind STRONGLY to self antigen from leaving the thymus (negative selection).

Location: thymic medulla

Progression: Single positive thymocyte

 

Negative selection: single positive thymocytes encounter self antigen presented on thymic DCs.  CD8 thymocytes that bind self ag too strongly are killed.  CD4 thymocytes that bind self ag too strongly either (1) die by apoptosis or (2) become T regs and exit the periphery to prevent autoreactivity.  If either cell type binds self af weakly, the cell exits to the periphery.

Term
Central tolerance
Definition
refers to the elimination of self-reactive T cells in the thymus via negative selection
Term
AIRE gene
Definition

Gene that is expressed in thymic epithelium and DCs.  It allows for promiscous expression of genes not normally expressed in the thymus, so that T cells reactive to peripheral ag can be negatively selected.

 

Term
APECED
Definition

autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy

 

disease in which autoimmune responses develop against multiple organs, including endocrine orgnas

 

thryoid, parthyroid, pancreas (diabetes), ovaries, liver

Term
Phases 5 and 6 in T cell devo
Definition

Goal: to populate peripheral lymphoid organs with naive T cells that express either CD4 or CD8.

Location: peripheral lymphoid tissue

Progression: from naive CD4 or CD8 T cells to effector and memory T cells

 

Naive CD4 and CD8 T cells exit the thymus and populate LNs, spleen, and MALT.  They then undergo activation by DCs, and differentiate into effector and memory cells.

Term
Primary immune deficiencies
Definition

genetically determined failures of host defense systems (animal is born with the problem)

 

Defect may involve:

a) complement system

b) phagocytic cells

c) T lymphocytes and/or B lymphocytes

Term
Common clinical signs of primary immune deficiency
Definition

1) failure to thrive

2) repeated episodes of infection

3) increased susceptibility to infection with opportunistic agents

4) poor response to standard therapy

5) poor protection following immunization

6) infection following immunization with modified live vaccines

Term
3 most important words for clinicians confronted with animal displaying signs like failure to thrive
Definition
I wonder if (primary immune decificiency is responsible)
Term
thymic aplasia
Definition

no thymus = no functional T cells

 

Nude mice, Birman kittens

 

afflicted with intracellular infections, protozoal infections, and are often hairless

Term
SCID
Definition

severe combined immunodeficiency

 

Inherited disorder in which individuals can't produce any adaptive, antigen-specific immune responses

 

affects human children, mice, Arabian foals, and dogs

 

uniformly fatal in horses, with foals developing infections at about 2 months of age and typically dying by 5 months

 

human children with SCID can be isolated until bone marrow transplant is performed from histocompatible full sibling

 

Term

Agammaglobulinemia

 

Definition

failure to synthesize Ig due to absence of mature B cells

 

affects boys, male Thoroughbred and Standard bred horses (X-linked disorder)

 

prone to extracellular bacterial infections and some viruses

Term

best way to diagnose immune deficiencies

 

Definition

systematic protocol that allows you to evaluate the general function of each host defense system:

1) CBC (are total differential leukocyte counts within normal levels? conduct more tests on any that are abnormally high or low).

2) phagocytosis assays and killing assys (test for Fc receptors if neutrophils or MOs are suspected).

3) hemolytic complement assay

4) single radial immunodiffusion to measure serum Ig

5) Determine if specific Abs are present in previously immunized animal

6) measure B cells, CD3+ T cells, CD4+ T cells, and CD8+ T cells using flow cytometry

7) assess ability to produce specific ab following immunization with known ag

8) GOLD STANDARD: assess the genotype of affected animal if you suspect it has a disorder for which gene tests are commercially available

 

Term
diagnosis of SCID in Arabian foals
Definition

1) profound lymphopenia (<1000 lymphocytes/ul of blood)

2) absence of IgM in serum

3) Hypoplasia of lymphoid tissues (spleen and thymus), which can be confirmed during necropsy

Term
What is the best way to manage a non-treatable, genetically-based disorder?
Definition

prevent production of affected offspring

 

genetic testing of parents (e.g. screen for defect in DNA-PK in Arabians to prevent SCID births)

Term

categories of immune response

 

Definition

1) helpful to the host

2) neutral to the host (most common)

3) harmful to the host

Term
maternal Ig passed on to (1) humans, (2) dogs/cats, (3) horse
Definition

(1) major amount of IgG transferred across placenta; minor amount of IgG and IgA transfer via colostrum

 

(2) minor amount (5-10%) of IgG crosses placenta; major (90-95%) amoung if IgG and IgA transferred via colostrum

 

(3) no transfer of Ab across placenta; all maternal Ab transferred via colostrum (IgG>>IgM>IgA>IgE)

Term
colostrum
Definition

produced once

 

most colostral IG transferred from serum

 

derived separately from milk Ig (which are produced locally in the mammary gland)

 

much higher concentration of Ig than found in normal milk

 

IgG dominant Ig in colostrum (IgA in dogs and in milk)

Term
absorption of colostrum
Definition

time dependent: highly efficient in first 6 hours, declines sharply beginning at 8 hours and negligible by 24 hours

 

receptor dependent: colostral Igs bind to a specialized MHC-like Fc rectper (FcRN) on intestinal epithelial cells of newboran animals.

 

Once bound to the FcRN receptor, Igs enter intestinal epithelial cells by pinocytosis and ultimately reach systemic circulation

 

under normal conditions about 25% to 35% of ingested colostral Ig reach the systemic circulation

Term
half-lives of maternal Ig in the circulation of newborns
Definition

IgG: 21 days

 

IgM - 4 days

 

IgA - 3 days

Term

Desired concentration of Ig in foals:

(1) at birth

(2) at 24 hours of age

(3) in cases of failure of passive transfer

(4) in cases of partial failure of passive transfer

Definition

(1) at birth, 10-20 mg/dl

(2) at 24 hours, >400 mg/dl

(3) <200 mg/dl

(4) 200-400 mg/dl

Term
How long does it take for foals to make their own Ig?
Definition

8 weeks.

 

dependent on maternal immunity until then

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