1 - Opsonization of pathogens

2 - Killing of pathogens

3 - Recruitment of inflammatory cells

4 - Disposition of immune complexes

IL-1, IL-6, IL-12 and TNFa

Also activates CXCL8 transcription

Receptors that mediate attachment between cell and the tissues surrounding it

Bind to Ig family of proteins, or extracellular matrix proteins

Strong interactions (CHO binding)

- Interference with viral replication

- Interference with viral protein synthesis

- Production of more interferons

- Activation of NK cells

Inhibiting ligands - MHC

Activating ligands - MIC

Somatic Recombination

Junctional diversity through N-linked addition of nucleotides

Somatic Hypermutation

Class 1, 8 - 10 amino acids longs

Class2, up to 20 amino acids

Pick up and carry antigen to lymphnode

Present antigen to T cells in lymphnode

• Ingestion of anything in the immediate vicinity

• Increased expression of Class II MHC
• Increased expression of ICAM
• Increased expression of CCR7 
• Production of various cytokines which affect T cell differentiation

Cytokine: IL4, TSLP, IL33

Transcription Factor: Gata-3

Cytokine: IL-12 and/or IFNy

Transcription Factor: T-bet

Cytokine: TGFb

Transcription Factor: FoxP3

Cytokines: TGFb & IL-6

Transcription Factor: RORgt

It gets signaled to undergo further light chain rearragement - receptor editing.

Only happens 2 - 3 times

1. Differentiate immediately into plasma cells producing IgM

2. Undergo isotype switching, somatic hypermutation and proliferation with the help of T cells and T cell cytokines

3. Differentiate into memory b cells (remain in lymphnode) or antibody producing plasma cells (exit node and go to tisses or bone marrow)

CD4- and CD8-

IL7 supports its proliferation

Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy 

disease which autoimmune responses develop against multiple organs

Direct destruction of peripheral blood elements by antibody

Direct destruction of skin by antibody

Direct destruction of tissue by T cells

Deletion or anergy during development if receptor recognizes self antigen

Lack of T cell help in the lymph nodes and spleen if there are no self reactive T cells

Never encounter self antigen - no AIRE gene in bone marrow

Weakly reactive B cells are not negatively selected - may be stimulated by foreign antigen to divide and undergo somatic hypermutation with T cell help which will make it bind to self antigen more readily

Would be anergized. Can onl be actived if a dendritic cell is expressing B7 molecule.

Needs cd28/cd80 interaction with dendritic cell

Causes neovascularization in the cornea mediated by inflammatory cytokines, antigen goes to draining lymph. 

Self reactive T cells in the Lymph become activated

Massive cytokine production, systemic response

TLR binding induces sepsis

Stimulation of t CELLS by superantigen

Mast cells. 

Eosinophils play a role in the long term inflammation following Type 1 hypersensitivity

Steroids - stabilize mast cells, down regulate FC receptors

Anti histamines

Antigen specific approaches - hyposensitization, stimulating IgG rather than IgE antibodies

1 - ab against hapten or drug modified self antigen 

2 - ab against blood group

3 - ab against self

4 - ab against pathogen (infection of erythrocyte wth pathogen)

Penicillin covalently binds to RBC surface proteins by opening the b lactam ring

Macrophages/DC take up coated RBC through C' receptor and lyse it, like a bitch.

Transfusion of RBC from one patient to another

Antibodies to environmental antigens develop over time - antigens found on bacteria cross react with carbohydrate groups on RBCs

First pregnancy by an A negative dam to an A+ sire is safe

2nd pregnancy to A+ is safe until foal nurses - maternal antibody against paternal A blood group antigen is absorbed across the gut. Antibody bind to foal RBC and cause lysis

- Erythrocytes - anemia, fever, hypotension, hyperbilirubinemia, hypercoagualability, spherocytosis

- platelets - thrombocytopenia, hemorrhage

- neutrophils - neutropenia, fever, 2ndary infection

Direct lysis by IgG and/or IgM antibody mediated complement fixaction

release of free hemoglobin

Opsonization by IgG and/or IgM antibodies and complement

Intracellular digestion of erythrocytes

- Antibody plus complement leading to lysis

- Opsonization leading to phagocytosis

- Mechanisms for metabolizing hemoglobin are overwhelmed

- Increased Bilirubin (Bilirubin (formerly referred to as hematoidin) is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin)

- Activation of the complement cascade leading to release of anaphylotoxins

- Mast cell defranulation and histamine release

TH1 Responses

- caused by intracellular pathogen, indigestable material

- Granuloma formation

Epidermal Destruction

- Poison oak/ivy

- Toxic epidermal necrolysis(characterized by the detachment of the top layer of skin (the epidermis) from the lower layers of the skin (the dermis) all over the body.)

- Allograft destruction

- Organ specific autoimmune disease

Hypotension

Fever

Vascular leakage

Activation of the clotting system

Organ failure

TLR ligands bind to TLR

Superantigen binf to TCR Vb

Complement binds to Immune complex

Complement/immune complex binds to RBC or platelet CR1 receptor

In Liver/Spleen Factor 1 cleaves CR1/Complement/Immune complex

Uptake and digestion by tissue macrophage in liver and spleen

1. Lack of CR1 receptor on RBC/platelet

2. Deficiency of complement

Immune complexes actvate Fc receptor on Macrophages and neutrophils, and initiate cytokine response and release tissue destructive enzymes

Complement activation leads to the production of C5a(mast cell degranulation)

C3a attracts neutrophils which produce destructive enzymes

Chronic infection

Introduction of high doses of antigen

Complement deficiency

Azotemia (High BUN, Creatine)

Hypoalbuminemia (a medical condition where levels of albumin in blood serum are abnormally low.)

Proteinuria ( excess of serum proteinsin the urine. )

Killed Vaccines 

Toxoids - vaccination against secreted products

Recombinant proteins, subunit vaccines - Protective antigen cloned into bacteria which produce large quantities of the protein

Modified live vaccines - non virulent bacteria or virus

Recombinant organisms - protective antigen introduced into harmless infectious agent

These vaccines replicate in host

Part of a complex of proteins called the inflammasome

In the cytosol

Recognize crystalline substances - Like Alum

- Formation of the membrane attack complex

- Degranulation of mast cells because of the formation of C3a and C5a

1. Antibody on the surface of the B cell binds antigen

2. Peptides appear on the surface of the B cell bound to class II MHC

3. Somatic Hypermutation

4. B cell matures to plasma cell where it secretes IgG

The antibody is low affinity

The antibody is more likely to be IgM than IgG

NK cells are not antigen specific - CD8 are

NK cells can recognize and kill cells infected with a variety of pathogens - CD8 only recognize cells that display Class I MHC that binds to TCR

The T cell needs to receive a signal from the dendritic cell through CD80/CD28 interaction

NF AT must translocate to the nucleus to initiate IL-2 gene transcription

A number of human derived recombinant proteins are used in veterinary medicine.  Human erythropoietin is used to treat anemic cats, and is usually given as a subcutaneous injection using a small gauge needle.  Feline erythropoietin usually does not generate an immune response.  Sometimes, however, it does. 

What circumstances would likely result in generating an immune response to erythropoietin? 

The erythropoietin preparation was produced in bacteria, and is contaminated with bacterial molecules such as LPS (lipopolysaccharide)

The erythropoietin was given in an area of skin that is infected with the extracellular bacteria Staph intermdius

10V x 5D x 2J x 5V x 5J

2500

You are presented with an 8 month old dog who has had a lifelong history of bacterial infections – pneumonia, skin infections, and urinary tract infections.  A variety of extracellular bacteria have been identified.  At presentation, the dog has several infected skin lesions, and a cough.  You suspect the dog has an immunodeficiency, most likely a genetic one.

You take a swab of what looks like pus from one of the skin lesions and look at it under the microscope – almost all the cells are neutrophils, and many of them have bacteria inside the cells.  Without doing any other diagnostics, what can you conclude about this dog? 

Increase phagolysosome fusion, upregulation of MHC, secretion of cytokines, secretion of chemokines

Increase production of ROS

Antibodies can be secreted across mucosal surfaces where they can bind to pathogens to prevent their adhesion to mucosal epithelium

Antibodies can opsonize bacteria for uptake by neutrophils and macrophages through Fc receptors.

Producing IL-2 which is needed by CD8 T cells to divide.

 Inducing isotype switch and somatic hypermutation by B cells to produce a higher affinity antibody, which can then neutralize virus before it infects the next cell.

Killed parvoviral vaccines cannot infect epithelial cells of the small intestine.  These vaccines elicit immune responses in the peripheral node that drains the site of subcutaneous administration of the vaccine. 

What would NOT be efficiently induced by a killed vaccine? 

Parvovirus specific CD8 T cells in the lamina propria

            Parvovirus specific B cells in the lamina propria

            Parvovirus specific CD4 T cells in the lamina propria

Th2 cytokines acting on epithelial cells

            Mast cell degranulation and histamine release

Eosinophil degranulation

1  Common lymphoid precursor

2  Heavy chain VDJ rearrangement

3  Light chain V-J rearrangement

4  Expression of IgM on the surface of B cells

5  Encounter with self antigen to test for self reactivity 

1  Common lymphoid progenitor

2  Commitment to the T cell lineage through Notch expression

3  Rearrangement of the beta chain

4  Signal to survive after T cell receptor interacts successfully with self MHC+peptide

5  Down-regulation of either CD4 or CD8 depending on which MHC+ peptide is recognized

6  Signal to die after T cell receptor interacts strongly with self MHC plus peptide

It was once activated by antigen 

            It expressed CD40

            It processed and presented antigen to CD4 T cells

It could have been in a lymph node or spleen

The drugs enhance complement deposition on the surface of red blood cells.

The drugs bind covalently to molecules on the surface of the red blood cells, creating a new, foreign antigen.

A mutation that results in permanent activation of the IL-4 receptor

Deficiency in interferon gamma

The individual has a genetic mutation in the AIRE gene, so it is not expressed.

The AIRE gene is functional, but does not initiate transcription of proteins from that particular peripheral tissue in the thymus.

The foal did not nurse well when he was first born

The mare had been leaking colostrum during the previous few days

CD4 T cells with high specificity for the virus will be deleted during the negative selection stage thymic development, and the animal will have no helper T cells that recognize the virus.

CD8 T cells with high specificity for the virus will be deleted during the negative selection stage thymic development, and the animal will have no cytotoxic that efficiently recognize the virus.

Antibody responses to the virus will be weak or undetectable, because of the lack of T helper cells specific for the virus.

The cell would be found in the bone marrow

RELM - anti nematode

Chemokines - Attract neutrophils

Defensins - Anti bacterial

A peptide consisting entirely of non-polar amino acids would not bind well to the peptide binding groove

True/False

Class I and Class II MHC molecules cannot distinguish between self peptides and peptides derived from pathogens. They will bind either.

True/False

MHC molecules on dendritic cells undergo mutation in their peptide binding site creating multiple different peptide binding sequences on a single cell

True/False

The MHC peptide binding groove contacts peptides at only two sites

True/False

Be unable to bind to IL-2 with high affinity, and therefore will be inhibited in their ability to divide and expand in response to antigen

Eosinophils

The patient's CD4 T cells are not functional (such as in an AIDS patient)

The patient has never been exposed to tuberculosis

NLRs are in the cytoplasm, whereas TLRs are on the surface of cells or in endosomes

True/False

NLRs recognize crystalline structures which are not directly pathogen derived, whereas TLRs recognize pathogen derived molecules

True/False

Under normal circumstances, mechanisms which prevent animals from making IgG that recognizes their own red blood cells include:    

- B cells are deleted in the bone marrow during development if they recognize self antigen.

- T cells recognizing red cell antigens peptides in the thymus are deleted (assume that red cell peptides are presented in the thymus), so cannot provide help for B cells.

The AIRE gene is a transcription factor which transcribes genes normally only expressed in peripheral tissue, resulting in deletion of T cells reactive with antigens expressed on peripheral tissues. 

Which of the following therapies might be able to inhibit the activation of autoimmune CD4 T cells (assuming you could predict when such a response would begin).

a.Give the patient an antibody to class I MHC, which inhibits the ability of the T cell receptor to recognize peptide presented by class I. 

            b. Give the patient a drug that inhibits IL-2 production, such as cyclosporine.

            c.Give the patient a drug that inhibits IL-10 production.

           d. Give the patient a drug that inhibits the expression of B7/CD80

- Give the patient a drug that inhibits IL-2 production, such as cyclosporine.

- Give the patient a drug that inhibits the expression of B7/CD80

A cow carries the class II MHC alleles BoLA A1, B2 and C3 on one chromosome and A1, B2 and C4 on the other chromosome.  She is bred to a bull with exactly the same MHC alleles (they are full siblings, and she is a particularly valuable cow.  What is the maximum and minimum number of different class II proteins a calf from this mating could express? 

Maximum - 4

A1 B2 C3/A1 B2 C3

A1 B2 C3/A1 B2 C4

A1 B2 C4/A1 B2 C3

A1 B2 C3/A1 B2 C3

Minimum - 3

- vasodilation

- Itching

- Increased ICAM expression on vascular endothelium

What T helper subset inhibits the development of type I hypersensitivity responses? 

The reason(s) that the acute clinical signs (i.e. the ones you see within seconds to minutes after the the antigen is injected/inhaled/ingested) associated with an allergy are not seen until the second exposure is/are:

It takes days to weeks to make enough IgE to cause clinical signs.    

Type II hypersensitivity refers to the destruction of tissue (primarily peripheral blood elements) by antibodies.  There are multiple ways that antibodies to red blood cells can be generated, but in the end, the mechanisms of destruction are the same.  List two ways that antibodies mediate the destruction or removal of red blood cells.

Intravascular Hemolysis - Ab bind to RBC and activate complement, causing lysis

Extravascular Hemolysis - Ab opsonize RBC for uptake in the liver or spleen

“Transfusion reaction” is the name given to the clinical signs seen in patients who are being transfused with red blood cells, and the clinician suspects they already have antibody to those red blood cells.  The clinical signs include hypotension, which is treated with anti-histamines.   The cause of the histamine release in this case is:    

The complement cascade is activated when antibodies bind to the transfused red blood cells, and C3a and C5a are produced which cause mast cell degranulation.

You are called to a farm to examine an Arabian foal who is ill.  He was born the previous week although the owners were not sure exactly how old he was when they first found him (he was born in the pasture).  They reported that he appeared healthy and vigorous the first day and was nursing when they finally found him, but after two or three days became lethargic and developed a fever.  The mare is healthy but the owners know nothing about her past history.  You’re limited in your ability to do laboratory work in the field, so you can’t determine if the foal is anemic, or if he has evidence of an infectious disease on his CBC.  He is, however, icteric (yellow mucus membranes).  When you draw blood to bring back to the clinic, you note that the foal’s cells agglutinate in the tube, indicating he has antibodies in his serum to his own red blood cells.  In addition, when you add the mare’s serum to these cells, the agglutination is even more pronounced, suggesting that she also has antibodies to the foal’s red blood cells.  What can you conclude?    

- The foal probably has Hemolytic disease of newborns

- The foal nursed within 8 hours

- The mare has bred previously

First, immune complexes bind to ______ via CR1.  These cells carry the immune complex to the liver and spleen where an enzyme called ________ cleaves the complex from the red blood cell.  The complex is then phagocytized by macrophages.

Red Blood Cells

Factor 1

Which of the following situations would predispose a patient to type III hypersensitivity response?

a. Treatment of a dog with 11 grams (note: 11 grams is a lot) of equine antibody to rattlesnake venom, intravenously.

            b. Feline infectious peritonitis, a chronic viral disease in which very high levels of virus is found in the blood.

            c. A third vaccine in a dog who had facial swelling after the second vaccine.

            d. A healthy foal who was given oral colostrum by mistake, even though he had nursed successfully and had >800 mg/dl of IgG in his serum.

            e. A patient genetically deficient in complement. 

A - Treatment of a dog with 11 grams (note: 11 grams is a lot) of equine antibody to rattlesnake venom, intravenously.

B - Feline infectious peritonitis, a chronic viral disease in which very high levels of virus is found in the blood.

E - A patient genetically deficient in complement.

Although live vaccines are generally considered more efficacious than their killed or inactivated counterparts, there are certain situations where you would choose a killed vaccine.  In which of the choices below would a killed vaccine be preferrable?

            a. A pregnant heifer 

b. A healthy 8 week old puppy

            c. A cat who is immunodeficient because she has FIV infection (feline immunodeficiency virus)

            d. An adult breeding stallion

            e. A trip to Botswana to vaccinate African Wild Dogs, which will involve 300 miles of driving in a non-air conditioned vehicle, and no means of refrigeration

a. A pregnant heifer

c. A cat who is immunodeficient because she has FIV infection (feline immunodeficiency virus)

e. A trip to Botswana to vaccinate African Wild Dogs, which will involve 300 miles of driving in a non-air conditioned vehicle, and no means of refrigeration 

What kind of vaccine would allow the rabies glycoprotein to be efficiently presented by class I MHC, and therefore stimulate a better CD8 T cell response?

Must be a Live Vaccine that can replicate

- A rabies virus grown in tissue culture and passaged to make it non-virulent (modified live viral vaccine)

- A benign, live vaccinia virus which has incorporated the rabies glycoprotein (recombinant vaccine)

Name the most common adjuvant in veterinary vaccines _______.  

The adjuvant is recognized by a receptor in the cytosol called_______.   

Activation of this receptor results in the production of what cytokine? 

- Alum

- NLR, Nod Like Receptor

- IL-1 & IL-33

If you suspect an animal is exhibiting a Type IV hypersensitivity response after an SQ vaccination (lump formation after several days), what two cell types would you expect to find if the lump were biopsied? 

I wrote this question and I feel like a boss.

- Macrophages

- Leukocytes (Probably T cells)

The patient - age, health, risk of disease

The Vaccine - manufacturer, active vs inactive, delivery method

The disease - Is patient at risk? Is disease seasonal?

- Prevents disease surveillance by serology

- Local irritation

- Local and systemic allergic response

- Live virus in pregnant or immune compromised people

- Contamination of vaccine

- Tumors (its nawt a tumah)

ELISA

Western Blot

Immunofluorescence on cell cultures

Agar gel Immunodiffusion

Rarely, so basically fucking No

Detection of antibody to FIV in cats serum means that the animal is infected

- Cat not infected

- Cat is infected, but too early to detect FIV antibody

- Determine the amount of antibody present

- Compare amounts of antibody on two seperate occasions

- Can quantify IgM to determine if the animal has been recently infected

True / False

Killed Vaccines require Boosters

disease: AIHA

Papers: 1

TH17 Cytokine: TGFb & IL-6

Transcription Factor: RORgt

Cytokines Produced: IL-17, IL-21, IL-22

Treg Cytokine: TGFb

Transcription Factor: Foxp3

Cytokines Produced: IL-17, IL-21, IL-22 

TH1 Cytokine: IL-12 and/or IFNy