Final Exam Flashcards
Where do naive lymphocytes in the blood migrate to?
Secondary lymphoid tissues
Where do effector and memory T cells in the blood migrate to?
Site of infection
What are HEVs and what is their function?
High endothelial venules - specialized blood vessels which facilitate extravasation of lymphocytes into the lymph node
What are distinctive characteristics of HEVs (as compared to regular venules)?
Tall endothelial cells
Thick basal lamina
Concentrically arranged reticular fibroblasts making up a perivascular sheath
Increased expression of molecules associated with cell migration into lymphoid tissues
What are the four primary stages of lymphocyte trafficking from blood vessel to tissue, and which molecules facilitate them?
Rolling - Selectins
Activation - Chemokines
Adhesion - Integrins
Diapedesis - Chemokines
What are the three classes of molecules grouped as “adhesion molecules”?
Selectins, chemokines, integrins
What are chemokines and what is their function?
Small soluble (secreted) proteins. Chemoattractants for immune cells
What are selectins?
Cell surface proteins, allow for extravasation of immune cells
What are integrins?
Cell surface proteins, allow immune cells to migrate to specific tissues
What is monocyte-chemoattractant protein 1?
Mucosal homing receptor - Regulates migration and infiltration of monocytes/macrophages
What are the primary lymphoid organs?
Thymus, bone marrow/bursa fabricius, Ileal Peyer’s patch, lymphoglandular complexes
What are the (groupings of) secondary lymphoid organs?
Lymph nodes, spleen, tonsils, Peyer’s patches
Which part of the thymus is most densely packed with lymphocytes?
Cortex (outer part)
What is Hassal’s corpuscule?
Structure in the thymic medulla containing a blood vessel with very thick walls preventing antigen from entering the thymus.
What is the bursa fabricius and where is it located?
Primary lymphoid organ (source of B cells AND traps antigen) in birds. Round sac with a connecting duct to the cloaca
What are the two types of Peyer’s patches and what is the difference between them?
Ileal patch - site of lymphocyte (B cell) development
Jejunal patches - secondary lymphoid organ
What is the mammalian equivalent to the bursa fabricius?
Ileal peyer’s patch
Which animals do not have lymph nodes?
Birds
What are the residential cells of lymph nodes?
(Follicular) dendritic cells, follicular T helper cells
Which cells are located in the cortex vs. paracortex of the lymph nodes?
T cells in paracortex
B cells in cortex (follicles)
Where is the germinal center visible in the lymph node?
Round structure near the junction of cortex and paraxortex
Which B cell-related processes occur in the dark zone vs. light zone of the germinal center?
Dark zone - Somatic hypermutation
Light zone - Testing of antibody affinity
What is the primary cell type found in the subcapsular sinus of lymph nodes?
Macrophages
What are the three immune-related structures in tonsils/Peyer’s patches and which cell types are they associated with?
Dome region - macrophages and DCs
Follicles - B cells, follicular DCs/Th cells
Interfollicular region - T cells
What are the specialized cells associated with antigen uptake at mucosal surfaces (tonsils/Peyer’s patches)?
M cells
Which cells are highly prevalent in the marginal zone in the spleen?
APCs
Where are B and T cells located in the spleen?
B cells in follicles
T cells surrounding incoming arterioles
What is the largest immune compartment in the body?
Mucosal surfaces
What is the difference between inducive and effector sites in mucosal immunity?
Inducive sites are lymphoid tissues - where immune response is being induced (site of antigen uptake)
Effector sites are were we find mature lymphocytes that have been exposed to their specific antigen (e.g. lamina propria)
What are the specialized characteristics of M cells which allow them to transfer antigen to lymphocytes/APCs?
Shorter glycocalyx on apical side to create a physical trap for antigens/pathogens
Pockets on basal side where immune cells can access antigen
Other than M cells, what is another system by which immune cells can access antigen across mucosal surfaces?
DCs can extend their dendrites between epithelial cells to “fish” for antigen
In what tissue(s) are M cells located?
Epithelium of small intestine, colon, rectum, tonsils, and adenoids
What are the primary (immune) cell types found in the lamina propria of mucosal tissues?
B cells (mostly IgA, some IgG/IgE) and T helper cells (to provide a suitable microenvironment)
What are the primary (immune) cell types found in the intraepithelial tissue of mucosae?
Cytotoxic T cells
What is the mechanism by which IgA dimers cross mucosal surfaces to enter the epithelium?
Endocytosis/exocytosis by epithelial cells - facilitated by polyimmunoglobulin receptor (pIgR)
In what tissues do oral mucosal vaccines induce an effective immune response?
Small intestine, ascending colon, mammary and salivary glands
In what tissues do rectal mucosal vaccines induce an effective immune response?
Rectum only
In what tissues do nasal/tonsilar mucosal vaccines induce an effective immune response?
Upper airways, regional secretions, genital mucosa
In what tissues do vaginal mucosal vaccines induce an effective immune response?
Genital mucosa only
In what tissues do skin vaccines induce an effective immune response?
Possibly the gut. Ineffective in most mucosal surfaces
How is exclusion immunity induced?
If antigen is detected along with a danger signal either via M cells or DCs across the mucosa, an immune response will be induced and secretory antibodies will be produced
How is oral tolerance induced?
Non-adherent food antigens induce activation of Treg cells and suppression of Th1/Th2/Th17 inflammatory response
What are examples of cytokines produced by Treg cells in the case of oral tolerance of food antigens?
IL-10, TGF-b
What can cause oral tolerance of food antigens to fail?
When there is a large influx of food antigens past the GI mucosa due to increased permeability/damage to the epithelium
In terms of the immune system, what is the difference between commensal and pathogenic bacteria?
Location (if they cross/damage the epithelium, they are treated as pathogenic)
What are the six placental layers (in order) acting as the barrier between maternal and fetal blood? - assume epithelochorial placentation
Maternal endothelium
Endometrial CT
Uerine epithelium
Chorion epithelium
Fetal placental mesenchyme
Fetal endothelium
What are the three types of placentation (as it relates to proximity between maternal and fetal blood)?
Epitheliochorial (most layers)
Endotheliochorial
Hemochorial (fewest layers)
Which species have epitheliochorial placentation type?
Cows, pigs, horses
Which species have endotheliochorial placentation type?
Dogs and cats
Which species have hemochorial placentation type?
Humans and rodents
What is the importance of the thickness of the barrier between maternal and fetal blood?
Determines the extent to which maternal antibodies are able to enter the fetal bloodstream (thus determining the degree of reliance on colostrum for immunity)
Describe epitheliochorial placentation
Maternal side has both uterine epithelium and BV endothelium
No transfer of maternal antibodies
Describe endotheliochorial placentation?
Maternal side only has BV endothelium
Limited transfer of maternal antibodies
Describe hemochorial placentation?
Maternal side has neither uterine epithelium OR BV endothelium
Good transfer of maternal antibodies
Which type of immune response is suppressed during pregnancy?
Th1
What is the avian equivalent of IgG?
IgY
How is antibody transfer achieved in birds?
IgY is concentrated in the egg
IgM and IgA enter the albumin in the oviduct and are swallowed by the chick
From which point in gestation is the fetus able to mount an active immune response?
Second trimester
Which vaccine is routinely administered during fetal development and in which species?
Marek’s disease - chickens
What are the two primary reasons why a neonate is unable to mount an effective immune response against a pathogen?
Immune system is IMMATURE and IMPAIRED
What are the characteristics of the “neonate immune environment”
- Th2 (mother) / Treg (neonate)-biased immune system
- High levels of IL-10/Treg
- High levels of corticosteroids after birth
- Inability to mount effective IFN-g response
- Passively transferred immunity
- Developing mucosal immune system
Which hormone(s) are involved in immune suppression in neonates?
Corticosteroids
Which factor is primarily responsible for driving the maturation of the neonatal immune system?
Intestinal microbiota
What is the difference between passive and active neonatal immunity?
Passive = antibodies transferred from mother to offspring
Active = immune response of neonate to vaccination or infection
What is colostrum?
The first milk - essentially concentrated maternal serum, rich in maternal antibodies
What is the approximate time frame in which immunoglobulins from colostrum can be absorbed into the fetal circulation?
6-24hrs
What is a disadvantage to giving a neonate pre-purchased colostrum?
Colostrum from the mother contains antibodies (IgG) that are specific to the environment in which the mother (and therefore offspring) is living. Pre-purchased colostrum is not “personalized”
What is the contribution of milk to the immune system of offspring?
Contains antibodies from pathogens encountered in the maternal gut, thereby protecting the fetal gut
Other than immunoglobulins and immune cells, what are other crucial protein contents of colostrum?
Lactoferrin, lactoperoxidase, and lysozyme (nonspecific lysis/effects on growth of pathogens)
Insulin-like growth factor, epidermal growth factor, alpha lactalbumin, TGFb, IL1, CSF, IL6 (stimulates growth, cell division, protein synthesis, etc.)
Which immunoglobulin classes are more common in (non-ruminant) colostrum vs. milk?
Colostrum: IgG
Milk: IgA
How are the immunoglobulins secreted in milk produced?
Plasma cells migrate from the intestine to the mammary tissue via CCL28
Which problem is created by maternal antibodies in the neonate?
Immune interference - they can bind to and neutralize vaccines before the neonate can respond
What do IFNa and IFNb do?
Establish an anti-viral state (resistance to replication, increase ligands for NK receptors, activate NK cells)
What does IFNg do in the context of a Th1 response?
Activates (M1) macrophages, enhances CD8 T cell killing
What antibody class is produced during a Th1 response and what is its primary function?
IgG; primarily for virus neutralization and opsonization, as well as antigen-dependent cell-mediated cytotoxicity by NK cells
Which cells are targeted by HIV?
CD4+ T cells
What causes pigs infected with high-path strains of PRRSV to die?
Cytokine storm
How do bacteria interact with the complement system?
Motifs on bacterial cell surface can activate complement via alternative pathway. C3b can opsonize, C3a and C5a are anaphylatoxins, MAC forms
What are the roles of antibodies during bacterial infection/Th2 response?
Neutralizing toxins/bacterial attachment, opsonization, activating complement (classical)
What class of immune response is initiated by protozoa infection?
Th1/Th2
What class of immune response is initiated by helminth infection?
Th2
What class of immune response is initiated by arthropod parasites?
Th1/Th2
What type of life cycle does toxoplasma have?
Extracellular pathogen with intracellular reproduction (Th1 response primarily)
How have African trypanosomes evolved to evade the immune system?
Switching/shuffling of cell surface glycoprotein expression (evades antibodies)
How do helminths evade the immune system?
Thick extracellular cuticle to prevent attachment of MAC, too big to phagocytose
What is the body’s main response to helminth infection?
IgE antibodies (against salivary antigens) initiating mast cell and eosinophil degranulation, resulting in the worm detaching from the intestinal wall
Against what arthropod proteins do our bodies primarily generate antibodies?
Salivary proteins
How do arthropods evade our immune system?
Saliva has immune modulatory effect, suppressing inflammation
What is the name for the immune response generated during the body’s second exposure to a pathogen?
Anamnestic response
What is a DIVA vaccine?
One which allows us to Differentiate Infected from Vaccinated Animals
What are some possible components of a vaccine (other than antigen/adjuvant)
Diluents, stabilizers, preservatives, etc.
What is a multivalent vaccine?
One which contains multiple antigens
What are the three main approaches to constructing a vaccine?
Whole (attenuated) pathogen, parts, or genetic material
Describe the endogenous vs. exogenous pathways for antigen presentation
Endogenous: Intracellular pathogen breakdown, expression on MHCI
Exogenous: Extracellular pathogen phagocytosis and expression on MHCII
What is cross-presentation of an antigen?
Exogenous antigen being processed via the endogenous pathway and expressed on MHCI
What are the main advantages to using a live attenuated viral vaccine?
Very effective for intracellular pathogens, long-lasting rapid-onset immunity, strong antibody and T cell response (overall best response)
What are the main disadvantages to using a live attenuated viral vaccine?
Shedding of vaccine virus into the environment, possible to revert to full virulence, not recommended if animal pregnant or immune compromised
Which pathway(s) are activated by a live attenuated viral vaccine?
Endogenous and exogenous
Which pathway(s) are activated by an inactivated viral or subunit vaccine?
Exogenous only
What are the main disadvantages to using an inactivated viral vaccine?
Immune response not as strong, more short lived compared to live attenuated. Weak T cell response. Requires adjuvants
What are the main advantages to using an inactivated viral vaccine?
Very safe (no reversion to virulence), no virus shedding
What are the two types of subunit vaccines?
Split - purified from disrupted pathogen
Recombinant - expressed in other cells/virus then purified
What are the main advantages to using a subunit vaccine?
Very safe, no shedding into the environment, very cost effective, strong antibody response
What are the main disadvantages to using a subunit vaccine?
Immune response relatively weak and short-lived, weak T cell response, requires an adjuvant
What is a vectored vaccine?
Desired target antigen is expressed on the surface of a non-pathogenic virus
What are the main advantages to using a vectored vaccine?
Long-lasting and rapid immune response, strong antibody and T cell response, cannot revert to full virulence
What are the main disadvantages to using a vectored vaccine?
Viral shedding into the environment, immunity against the vector can reduce efficacy of booster vaccines
What are the main advantages to using a DNA/RNA vaccine?
Long-lasting and rapid-onset, good antibody and T cell response, no live pathogen involved
What are the main disadvantages to using a DNA/RNA vaccine?
Delivery is complicated (requires a carrier or nanoparticles)
What are replicons?
Self-amplifying RNA. Could potentially be utilized in vaccines
What are common vaccine adjuvants (in inactivated or subunit vaccines)?
Aluminum, oil-in-water (squalene), etc.
What are the three main functions of adjuvants?
Delivery of vaccine (depot effect, slow-release, localization)
Targeting of specific cells (APCs, specific tissues, etc.)
Stimulation of innate/acquired immune systems (danger signal)
By what mechanism(s) can we create DIVA vaccines?
Typically involves removal of a marker protein from the vaccine. Animals which do not have antibodies against the marker have not been infected
What is the main Canadian organization responsible for regulatory approval of vaccines?
CFIA Canadian Centre for Veterinary Biologics
What are the primary players in a type I hypersensitivity response?
IgE, mast cells, basophils, and eosinophils
What is the difference between an allergic reaction and anaphylaxis?
Allergy is local and not immediately life-threatening. Anaphylaxis is systemic and severe
By what mechanism are tissues damaged during an allergic reaction?
Mast cell and basophil degranulation in response to antibody-bound IgE (contents cause vasodilation, pruritus, bronchoconstriction)
At which sites is IgE mainly produced?
Body surfaces (skin, lung, intestine)
What is the difference between “allergy” and “atopy”?
Allergy: Production of IgE in response to an antigen
Atopy: Production of IgE at abnormally high levels in response to many antigens
What is FcERI and on which cell type(s) is it found?
Receptor with very high IgE binding affinity
Found primarily on mast cells and basophils, eosinophils to a lesser extent, and on DCs/monocytes of atopic patients
What is FcERII and on which cell type(s) is it found?
Receptor with relatively weak IgE affinity
Found on NK cells, macrophages, DCs, eosinophils, platelets, and some B cells
What is the function of histamine (released by mast cell degranulation)?
Smooth muscle contraction (bronchoconstriction), exocrine secretion of mucus, tears, saliva
What is the function of serotonin (released by mast cell degranulation)?
Vasodilation/edema
What is the function of arachidonic acid (released by mast cells)?
Precursor for eicosanoids, which in turn have effects on vessel tone and permeability
What are the contents released during mast cell degranulation?
Histamine, serotonin, tryptase, Kallikreins, proteases, proteoglycans
What cytokines are secreted by mast cells?
IL-4, IL-5, IL6, IL-13, TNF-a, MIP-1a
Which cytokine activates eosinophils?
IL-5 causes mobilization and degranulation
Which antibody receptor triggers eosinophil degranulation?
FcERII
What are the two phases of a type I hypersensitivity reaction?
Sensitization: Phase of exposure which generates an IgE response
Re-exposure: Results in cross-linking of IgE on mast cells, triggering degranulation
What are the primary clinical signs of anaphylaxis in sheep and cattle?
Dyspnea due to bronchoconstriction and pulmonary edema
What are the primary clinical signs of anaphylaxis in horses?
Coughing, dyspnea, diarrhea
What are the primary clinical signs of anaphylaxis in dogs?
Weakness and collapse
What are the primary clinical signs of anaphylaxis in pigs?
Dyspnea
What are the primary clinical signs of anaphylaxis in cats?
Dyspnea, scratching
Where in the body do clinical signs of allergies typically manifest in dogs?
Skin (regardless of route of entry)
What is urticaria?
Hives - acute local allergic response manifesting as wheals (lesions confined to the dermis)
What is angioedema?
Generalized dermal edema which may progress to involve subcutaneous tissue
Which cytokine plays a key role in atopic dermatitis and what does it do?
IL-31: Itch mediator and causes respiratory symptoms
What is an a possible immune-related cause of food allergies?
IgA deficiency (failure of immune exclusion)
How is hyposensitization accomplished in allergic patients?
Repeated subcutaneous injection of the allergen at increasing doses, promotes switching to a Th1 response (may require lifelong therapy)
What is the basis of type II hypersensitivity?
Destruction of cells due to the binding of antibodies (IgG/IgM) to the cell surface - associated with NK cells, complement, and phagocytes
What are the two primary means of RBC destruction in IMHA?
Phagocytosis in the spleen
Complement-mediated lysis in the bloodstream
What are the five types of targets of antigen targets that could be associated with intra-vascular hemolysis?
- Self RBC antigens
- Alloantigens (blood transfusion)
- Foreign antigens adsorbed to cell surface
- Altered self antigen
- Exposed cryptic antigen
What is a major cross-match?
Mix recipient serum with donor cells
What is a minor cross-match?
Mix donor serum with recipient cells
What is HDN?
Hemolytic disease of the newborn - placental tears allow fetal blood to enter maternal circulation, mother mounts an immune response, antibodies concentrate in the colostrum, colostral antibodies cause hemolysis in the newborn
What is the Direct Coombs Test for IMHA?
Can demonstrate antibodies bound to RBCs
What is Evans Syndrome?
IMHA combined with immune mediated thrombocytopenia
What is pemphigoid disease?
Type II hypersensitivity reaction - antibodies/complement targeting antigens in the epithelium. Lesions can be superficial to deep
What is a potential cause of Addison’s disease?
Antibody-mediated targeting and killing of adrenal cortex cells
What is a potential cause of diabetes mellitus?
Antibody-mediated targeting and killing of pancreatic beta cells
What is myasthenia gravis?
Disease characterized by muscle weakness. Antibodies targeting Ach receptor, damaging the post-synaptic membrane
What is the basis of type III hypersensitivity reactions?
Antigen-antibody complexes formed between soluble antigen in the serum or tissues
What is the mechanism behind “immune complex disease”?
Type III hypersensitivity reaction occurs, forming immune complexes. Antibodies activate complement, including C3a and C5a, causing neutrophil and mast cell degranulation which damage tissues
When are type III hypersensitivity reactions dangerous?
They are normal in small levels, but become dangerous when there is high levels of antigen and/or persistence of the antigen
What is an “arthus reaction”?
Antigen injected subcutaneously into an animal with high levels of antibodies, resulting in neutrophil infiltration and inflammation within a few hours
What is hypersensitivity pneumonitis?
Inhalation of antigen results in immune complex formation in alveolar walls (coughing/dyspnea)
What is COPD?
Chronic obstructive pulmonary disease. Combination of type I and type III hypersensitivity reactions which occur in horses repeatedly fed mouldy hay
How are serum immune complexes removed in generalized (intravascular) type III hypersensitivity reactions?
By binding to either RBCs or platelets which are removed by phagocytes
What is the primary danger associated with generalized type III hypersensitivity reactions?
Large, insoluble immune complexes OR very large numbers of small soluble complexes can deposit in and block small blood vessels
What is lupus erythematosus?
Antibodies to self antigens forming complexes in the basement membrane of the skin, kidney glomerulus, and small vessels
How does rheumatoid arthritis occur?
Type III hypersensitivity reaction resulting in immune complex deposition in the synovial membrane
What is the primary mechanism behind type IV hypersensitivity reactions?
Tissue damage due to activated macrophages and cytotoxic T cells. (Th1 response from antigen presented on APCs)
What is the cause of a positive DTH test?
Inflammation occurs due to a population of memory Th1 cells in a previously exposed animal
By what type of hypersensitivity reaction are granulomas formed?
Type IV - when antigen cannot be cleared. Remember that granulomas can contain multi-nucleate giant cells
What is a potential pathological consequence to a persistent type IV hypersensitivity reaction?
Malabsorption syndrome due to granuloma formation in the gut
What is leishmaniasis?
Granuloma formation resulting in granulomatous dermatitis caused by protozoa
What is a cause of contact hypersensitivity?
Type IV hypersensitivity in response to prolonged exposure to small reactive molecules (latex, etc.)
Describe the sensitization phase of contact hypersensitivity?
A molecule too small to be an antigen itself is absorbed into the skin and becomes associated with a “carrier” self-antigen, provoking an immune response
What are the four types of grafts?
Autograft: within an individual
Isograft: between genetically identical individuals
Allograft: within a species
Xenograft: between species
What is the main cause of allograft rejection?
Type IV hypersensitivity reaction to donor MHC or blood group antigens
What is “graft versus host disease”?
Donor “passenger” lymphocytes reacting to (immunosuppresed) recipient tissue
What is the “rheumatoid factor”?
Auto-antibodies to the Fc portion of IgG immune complexes (happen when antigen binding causes changes to Fc)
What are cross-reactive antigens?
Pathogenic antigens which resemble self antigens (combines the common epitope with a danger signal)
What is the cause of rheumatic fever?
Streptococcal cell walls causes cross-reactivity with host heart valve antigen
What are the main differences between organ-specific and systemic autoimmune diseases?
Location, and organ-specific is more Th2, systemic is Th1 and Th2
Which gene may be related to the development of systemic autoimmune diseases?
Deficiency in “aire”, an autoimmune regulatory gene which promotes self-antigen expression in the thymus
What is combined immunodeficiency?
Failed development of lymphoid precursors
What is thymic aplasia?
Failed development of T cells
What is agammaglobulinemia?
Failed B cell development
Where else can B cells fail?
Deficiencies in specific antibody classes
What is the main immune deficiency seen in the innate immune system?
Neutrophil defects
What is leukocyte adhesion deficiency?
Defect in adhesion proteins (CD18) which would allow neutrophils/T cells to leave the blood. Seen in Holstein cattle. Recurrent infection, fever, stunted growth, neutrophilia
How long do SCID/agammaglobulinemia individuals typically survive?
As long as colostral Ig lasts (up to a few weeks)
Which animals are known to have thymic aplasia?
Nude mice. No thymus
What is the primary consequence of infectious bursal disease virus?
Damage to bursa fabricius leading to impaired B cell development. More severe in young birds
What is the main difference between FIV and HIV?
HIV targets CD4 T cells specifically. FIV targets all T cell types
How does canine distemper affect the immune system?
Infects and destroys secondary lymphoid tissues, depresses lymphocyte and macrophage activity
How do viruses like feline panleukopenia, canine parvovirus, and african swine fever affect the immune system?
Destroy all rapidly dividing cells, including those in germinal centers
What is the main gene involved in tumor suppression that, when mutated, causes cancer?
p53
What are the two phases of tumor growth?
Avascular phase (tumor is dormant)
Vascular phase (rapid growth and angiogenic switch)
Which cytokines promote an immune suppressed state in tumors?
IL-10 and TGFb
Which cell surface protein on tumors inhibits Teff cells?
PDL1
What are the three types of cell surface antigens that are abnormal in tumors?
Reactivated gene products (developmental genes), viral antigens, and mutated gene products
What are MICA and MICB?
Stress molecules recognized by NK cells
What are the two main mechanisms by which we can use immunotherapy to induce an effector state against tumors?
- Overcoming the suppression in the tumor microenvironment
- Immunizing against a specific antigen
What are dendritic cell vaccines?
Patient DCs are isolated and exposed to the antigen of interest in vitro, then inject them back into the patient to induce a cell-mediated response
How can monoclonal antibodies be used in cancer therapy?
- Complement cytotoxicity
- Antibody coupling to a toxin, cytokine, radioisotope
- Targeted chemo (antibody coupled to an enzyme which activates a cytotoxic drug)
- Antibody-induced apoptosis
How are cytokines used in cancer therapy?
Dangerous to administer systemically (capillary leak syndrome, rash, fever, chills, nausea, depression) but can be injected directly into a tumor
