Immunology: 3

Question 1

Which cell is this?

Answer 1

Macrophage

Question 2

Explain innate immunity with the most important cells and receptors involved.

Answer 2

rapid, non specific, no memory

PAMPs and DAMPs –> pattern recognition receptors of macrophages, dendritic cells and mast cells

most important pathway: –> CD14/TLR on macrophages –> NFkB –> proinflammlatory cytokins:

• Il 1
• Il-6: increased production of acute phase proteins by hepatcytes, SAA, C-reactive Protein, complement proteins,…
• TNF-Alpha
• PDGF

OR/AND generation of type I interferons in case of viral infections

Question 3

What are opsonins?

Answer 3

antibodies or other substances binding to foreign microorganisms or cells makin gthem more susceptible to phagocytosis

Question 4

Main products of mastcells?

Answer 4

histamine

leucotrines

prostaglandin

Question 5

Where are leucocytes produced? Guyton 455

Answer 5

bone marrow: granulocytes and monocytes

lymph tissue: lymphocytes and plasma cells

Question 6

Name the 6 types of leucocytes. Guyton 455

Answer 6

neutrophils (62%)

eosinophils (2.3)

basophils (0.4)

monocytes (5.3)

lymphocytes (30)

plasma cells

Question 7

What are granulocytes?

What is their lifespan?

Answer 7

polymorphnuclear cells (neutros, eos, basos)

bone marrow –> 4-8hrs circulating in the blood –> 4-5 days in tissues –> death

Question 8

Which two major lineages of WBC are formed?

Answer 8

myelocytic (myeloblast) –> granulocytes, monocytes, (megacaryocytes)

lymphocytic (lymphoblast) –> lymphocytes

Question 9

What is the reticuloendothelial system?

Answer 9

monocyte-macrophage system

Question 10

microbiome in the stomach and duodenum?

Answer 10

stomach: A dense population of gram-positive bacterial rods, primarily composed of Lactobacillus spp., colonizes the nonsquamous portion of the equine stomach.
duodenum: large population of proteolytic bacteria, and this colonization increases bytenfold in the ileum.

Question 11

Physiologic skin inhabitants

Answer 11

Normal inhabitants include mixed populations of bacteria of species of Acinetobacter, Aerococcus, Aeromonas, Bacillus, Corynebacterium, Flavobacterium,

Micrococcus, Nocardia, coagulase-negative Staphylococcus, Staphylococcus aureus, Streptomyces, and nonhemolytic Streptococcus generae.

30 species of fungi can inhabit the skin and Alternaria, Aspergillus, Candida, Fusarium, Rhizopus, and Trichophyton spp., Malassezia are commonly present.

Question 12

Bacterial flora in the large intestine

Answer 12

the predominant flora are the low guanine-cytosine (GC)-content bacteria, which include Cytophaga-Flexibacter-Bacteroides and Clostridium bacteria;

Standard microbiologic techniques specifically demonstrate Enterobacteriaceae,

Butyrivibrio spp., Streptococcus spp., Bacteroides spp., Lactobacillus spp., Selenomonas spp., Eubacterium spp., Propionibacterium spp., and Staphylococcus spp. in residence.

Question 13

Rapid change from a roughage diet to concentrate results in ?

Answer 13

Rapid change from a roughage diet to concentrate results in

• increased anaerobes,
• decreased cellulolytic bacteria,
• decreased cecal protozoa diversity, and
• decreased pH in the equine cecum.

Question 14

Which are the most frequent and prolific colonizers of the trachea after prolonged head elevation?

Answer 14

Pasteurella,

Actinobacillus, and

Streptococcus spp.

are the most frequent and prolific colonizers of the trachea after prolonged head elevation.

Question 15

What are protein secretion systems?

Answer 15

Protein secretion systems (PSSs) are a structurally diverse complex of essential virulence factors for bacteria that allow specialized interactions among cells.

These main systems function to translocate various sized molecules and are important in the formation of adhesins on attachment to host cells.

Question 16

Which are the most important PSS subgroups?

Answer 16

Fibrillar adhesins (FAs) and

nonfibrillar adhesins (NFAs)

Question 17

What is the primary clinical significance of enveloped versus non-envelopped viruses?

Answer 17

The primary clinical significance of these features is that enveloped viruses, because of their fragile lipid membrane, are highly susceptible to inactivation by heat, desiccation, or detergents, and transmission typically requires direct exchange of body fluids, short distance aerosols, or arthropod vectors.

In contrast, nonenveloped viruses (e.g., equine rotavirus) are resistant to physical inactivation, and environmental contamination is more likely to be a significant factor in their transmission.

Question 18

Basic structure of a virus?

Answer 18

DNA or RNA genome enclosed by a coat of protein called the capsid

For viruses that are enveloped, the capsid is enclosed further by a host cell–derived lipid membrane into which viral proteins have been incorporated.

Question 19

What are retroviruses?

Answer 19

Retroviruses are a subset of single-stranded, positive-polarity RNA viruses that use their RNA genomes as templates to produce double-stranded DNA,
which in turn is used for the transcription of mRNA and new
viral genomes.

Question 20

ssRNA enveloped viruses?

Answer 20

Coronaviridae Paramyxoviridae Bunyaviridae Toroviridae

Orthomyxoviridae Arenaviridae Togaviridae Flaviridae

Retroviridae Rhabdoviridae

Filoviridae

Question 21

dsDNA enveloped viruses

Answer 21

Herpesviridae

Poxviridae, Chordopoxviridae

Hepadnaviridae

Question 22

dsDNA non-enveloped viruses?

Answer 22

Iridoviridae

Adenoviridae

Polyomaviridae

Question 23

What are viral inclusion bodies?

Answer 23

RNA viruses typically replicate, transcribe mRNA, and translate viral proteins in the cytoplasm. These sites of replication account, respectively, for the location of viral inclusion bodies that are diagnostically useful in histopathologic sections.

Question 24

Define virologic latency and give an example

Answer 24

Virologic latency is defined as the presence of a viral genome that is not producing infectious virus.

The genomes of latent viruses are transcriptionally suppressed and trans-
lationally silent so that no viral proteins are expressed that may identify the cell to the immune system as infected.

The classic latent infection is that of the herpesviruses. For the α-herpesviruses, such as EHV1 and EHV4, latent infections are established in the nuclei of
sensory neurons and can be maintained indefinitely, and infected animals serve as the reservoir of the virus. On reactivation viral nucleic acids are translocated across synapses to epithelial cells of the nasopharynx, which produce infectious virus. The stimuli that induce reactivation are poorly defined, but reactivation can be induced by immunosuppression (e.g., corticosteroids) and presumably by other stressors, such as pregnancy, transport, and social stress.

Question 25

Meachanism of spread of EHV1 in the body

Answer 25

EHV1 infection is rhinopneumo- nitis caused by a localized infection of the nasopharyngeal mucosa.

In almost all cases, a cell-associated viremia alsooccurs in lymphocytes, but in most infected horses this does not result in disease.

However, in some cases, viremia is associated with infection of endothelial cells, and in the pregnant mare vascular damage to the uterus and placenta may lead to
abortion.Similarly, infection of the vascular endothelium in the central nervous system results in neurologic disease.

Question 26

What is viral tropism?

Answer 26

ability of different viral strains to infect different cell typesand cause syncytia (fusion of an infected cell with neighboring cells leading to formation of multinucleate enlarged cells) formation

Question 27

Which parasites infect the lung?

Answer 27

Several nematode parasites infect the equine lung. These include migrating stages of Strongyloides westeri and Parascaris spp. en route to the small intestine.

Migrating stages of aberrant parasites, such as Habronema sp., Draschia megas-
toma, and Strongylus spp., which induce granulomatous foci in the lung parenchyma, and adults and larvae of the lungworm Dictyocalus arnfieldi, which inhabit the bronchi, also occur.

Question 28

Which parasites are stimulating intestinal smooth muscle hyperplasia?

Answer 28

A number of helminth parasites, including Parascaris
spp., stimulate intestinal smooth muscle hyperplasia.

Question 29

Nematodes, particularly Cyathostomes, induce which type of inflammation?

Answer 29

a type 2 T-helper cell cytokine response consisting of interleukins (ILs) IL-4, IL-5, IL-9, and IL-13. IL-4 and

IL-13 induction of the Stat6 pathway is cen-tral to most of the resulting responses. There is a consistent mastocytosis and eosinophil infiltration of the intestine.

Question 30

Which parasite is causing seasonal ventral midline dermatitis?

Answer 30

Onchocerca cervicalis infections (microfilariae in the skin)

vector: culicoides spp

Focal, alopecic, depigmented, pruritic lesions are often seen in infected horses

Lesion development is associated with immune-mediated killing of microfilariae in

the skin.

sensitive to macrocyclic lactone anthelmintics

[adults can be found in the nuchal ligament - normally asymptomatic - cannot be killed by Ivermectins]

Question 31

Which parasites is transferred via mare’s milk?

Answer 31

Strongyloides westeri:

Mares remain infected with arrested third-stage larvae, which subsequent to foaling are transmitted to the foals in milk starting at 4 days postpartum.

Question 32

What are PAMPs?

Which cells have them?

Which types are there?

Answer 32

The cell walls and membranes of bacteria contain various proteins and polysaccharides with characteristic, often repeating, molecular structures. These
pathogen-associated molecular patterns (PAMPs) include lipopolysaccharides (LPSs), peptidoglycans, lipoteichoic acid, and flagellins. Other PAMPs include viral nucleic acids and unmethylated bacterial cytosine-guanosine dinucleotides
(CpG).

PAMPs are recognized by pattern recognition receptors found on cells of the immune system, particularly those cells involved in the initial encounter with invading microbes. These “sentinel cells” include macrophages, dendritic cells, and mastcells, with macrophages being the most important for initiating
the inflammatory response.

• toll-like receptors (TLRs),
• retinoic acid–inducible gene–1 (RIG-1)–like receptors, and n
• ucleotide-binding oligomerization domain–like receptors.

Question 33

How do injured cells provoke inflammation?

Answer 33

Injured cells release products collectively termed damage-associated molecular patterns (DAMPs) that bind TLRs on macrophages and other cells leading to the
production of proinflammatory cytokines that augment the inflammatory process.

Question 34

Which are the cytokines initially release by the innate immune system?

Answer 34

Resident macrophages that encounter the invader initiate the inflammatory response through the production of proinflammatory cytokines such as interleukin- 1 (IL-1), IL-6, and tumor necrosis factor–alpha (TNF-α)

Question 35

Main function of Il-1?

Answer 35

Many of the effects of IL-1 are mediated through its capacity to increase the production of other cytokines, such as granulocyte colony-stimulating factor (G-CSF), TNF-α, IL-6, and platelet-derived growth factor (PDGF). IL-6 is responsible for the increased production of acute phase proteins by hepatocytes, including complement proteins, C-reactive protein, and serum amyloid A (SAA).

Activates T cells, Chemotactic for neutrophils, Activates neutrophils

Induces fever, Activates B cells,
Enhances NK cell killing
Fibroblast growth factor Stimulates collagen production
Stimulates PGE synthesis Stimulates keratinocyte growth
Stimulates bone resorption
Activates osteoclasts Induces IL-6 production

Question 36

Describe the immunologic pathway happening in the cell after a viral infection

Answer 36

During viral infections, intracellular pattern recognition receptors (such as RIG-1) bind to viral PAMPs and induce the production of type I interferons (IFNs), including IFN-α and IFN-β. These are produced in virus-infected cells within hours
and inhibit viral replication through various mechanisms. In addition, natural killer (NK) cells are capable of lysing virus infected cells via recognition of different types of receptors on the surface of infected cells, as well as recognizing cells expressing fewer major histocompatibility complex molecules, the expression of which can be downregulated by viral infection. Finally, NK cells have surface Fc receptors that can bind the Fc portion of antibodies bound to the surface of infected cells and subsequently kill the infected cell through the process of antibodydependent cellular cytotoxicity

Question 37

what is the complement system?

Answer 37

The complement system (part of innate response) consists of over 30 different plasma proteins that are produced primarily in the liver. This complex interacting series of proteases and their substrates results in the production of physiologically active intermediaries that can damage membranes, attract neutrophils and other cells, increase blood flow and vascular permeability, and opsonize bacteria and other particles for phagocytosis

Question 38

Describe the pathways initiating the complement system

Answer 38

lectin pathway is initiated when soluble carbohydrate-binding proteins bind to carbohydratestructures on microbial surfaces. Proteases associated with these carbohydrate binding lectins then initiate the cleavage of complement components and activate the pathway.

The classical pathway involves the binding of C1q to antibodies already bound to the surface of a microbe. Bound C1q is proteolytic and cleaves other complement components activating the pathway.

The activation of complement via the alternate pathway does not involve antibodies. Instead, certain microbial products stimulate the association of factor D, a proteolytic enzyme, with the complex of factor B and C3b leading to the
formation of C3 convertase and its deposition on the microbial surface.

All three pathways converge with the generation of C3 convertase and the cleavage of C3. Soluble C3a, producedby the cleavage of C3 by the C3 convertases, can bind to mast cells causing them to degranulate and is thus referred to as an anaphylatoxin, as is C4a. C3b serves as an opsonin for C3b receptor-bearing phagocytic cells. C3b is also required for the formation of the membrane attack complex by the terminal complement components, C5 through C9. In this process C5 is cleaved and C5a is generated, which, along with C3a, is a chemoattractive factor for neutrophils and monocytes. C5b forms a complex with C6, C7, and C8 on cell surfaces. This leads to the insertion and polymerization of C9 that forms a pore in the membrane leading to cell lysis.

Question 39

Lipid mediators of the immune system?

Where do they come from?

Answer 39

Prostanoids are lipid mediators that regulate the inflammatory response.The prostanoids include the prostaglandins (PGs), leukotrienes (LTs), and prostacyclin (PGI2), and they are the

product of cyclooxygenase cleavage of arachidonic acid followed by endoperoxidation.

The major sources of prostanoids in acute inflammation are the phagocytes, endothelial cells, and platelets.

Question 40

Prostanoid production depends on?

Answer 40

Prostanoid production depends on the activity of the two isoforms of the cyclooxygenase(COX) enzymes within cells:

• *COX-1,** which is present in most cells and its expression is generally constitutive, and
• *COX-2,** for which expression is low or undetectable in most cells but its expression increases dramatically on stimulation, particularly in cells of the immune system.

Question 41

Proinflammatory and anti-inflammatory effects of PGE2?

Answer 41

PGE2 is considered proinflammatory because it promotes

• vasodilation by activating receptors on vascular smooth muscle and
• increases vascular permeability indirectly by enhancing the release of histamine and other mediators from tissue leukocytes such as mast cells.
• responsible for fever production.

However, as inflammation progresses, PGE2 synthesis by macrophages is enhanced as a result of increased expression of COX-2 and PGE-synthase, and the resulting increased levels of PGE2

• inhibit leukocyte activation,
• inhibit mast cell degranulation, and
• relax smooth muscle contractions
• In the lung, PGE2 promotes bronchodilation.

Thus in these situations PGE2 may be considered antiinflammatory.

Question 42

what are chemokines?

Which one plays a central role?

Answer 42

Chemokines are chemotactic cytokines. These are soluble proteins produced by host cells that induce the directional migration and activation of leukocytes, as well as other somatic cell types, and thus play major roles in the inflammatory response.

The chemokine CXCL8 (previously known as IL-8) plays a central role in the
migration of neutrophils, including equine neutrophils.

Question 43

How does neutrophil adherence and migration work?

Answer 43

Neutrophil adherence is a two-step process first involving

• endothelial cell surface molecules known as selectins. endothelium exposed to leukotrienes, platelet activating factor (PAF), IL-1, complement protein C5a, histamine, LPSs, TNF-α, or other mediators express P-selectin.

=> P-selectin mediates the process in which neutrophils initially interact with the endothelial surface in a process known as “rolling” (after a few hours: E-selectin)

Endothelial selectins function by binding to carbohydrate ligands present on the leukocyte surface. In the case of neutrophils, the ligand is sialyl-LewisX.

• then tight binding of integrins on the neutrophil surface to intracellular adhesion molecules on the endothelial cell surface.
  Leukocyte integrins are proteins and include functional antigen–1 (LFA-1) and complement receptor type 3 (CR3)
• then migration

Question 44

How do neutrophils phagocytose?

Answer 44

Acitvated neutrophils will actively phagocytose microscopic invaders and attempt to destroy them using reactive oxygen products generated via a nicotinamide adenine dinucleotide phosphate(NADPH)-oxidase–dependent respiratory burst.

Question 45

Who is producing interferones?

Answer 45

production of IFN-α or IFN-β by macrophages

production of IFN-y by NK cells

Question 46

Who is downregulating inflammatory responses?

Answer 46

Deactivation signals include PGE2, cortisol, IL-10, and transforming growth factor–β (TGF-β).

Some of those chemotactic agents responsible for initiating the response
(CXCL8, FMLP, C5a, LTB4, and PAF) also serve to downregulate its intensity by inducing the shedding of IL-1 receptors from neutrophils

Question 47

What are B-cells?

Where are they located?

How long does it take for a B-cell precusor to mature?

What happens to B-cells during the stimulation of a specific antigen?

Answer 47

• Antibodies are produced by B lymphocytes, small lymphoid cells characterized by the cell surface expression of immunoglobulin molecules.
• B cells represent less than 15% of the circulating peripheral blood mononuclear cells but are p_resent in higher proportions in lymph nodes and the spleen._
• B cells are derived from the fetal liver and bone marrow of mammals, developed from a lymphoid stem cell derived from the pluripotent stem cell.
• Under the influence of various cytokines produced by bone marrow stromal cells, the B-cell precursor undergoes its 3-day development into a mature B cell.
• On stimulation with a specific antigen (f.e. by a macrophage presenting an antigen), B cells d_ifferentiate into plasma cells that produce enormous quantities of a specific_ antibody (=gamma globulines) or memory cells.

Question 48

How and where does a T-cell develop?

Answer 48

The T lymphocyte is also derived from the multipotent stem cell and lymphoid
precursor in the bone marrow, though its subsequent development into the mature T cell occurs in the thymus.

Question 49

Describe an immunoglobuline molecule

Answer 49

B cell surface bound immunoglobulin, also known as antibody.

An immunoglobulin molecule is composed of t_wo identical light chains_ and two
identical heavy chains that form a disulfide-linked Y-shaped molecule

• The light chain can be divided into two domains, a conserved carboxy-terminal domain and a highly variable amino-terminal domain.
• Analysis of heavy chains reveals a similar domain structure with the amino-terminal domain being highly variable and the presence of three constant domains.

=>The antigen-binding region of an immunoglobulin molecule is formed by the association of the amino ends of a light and a heavy chain, and the carboxyl end of the heavy chain determines the isotype of the molecule. Similar to most species, five different immunoglobulin isotypes (classes) have been identified in the horse: IgM, IgD, IgG, IgE, and IgA

Question 50

IgM

Where is it found and what does it do?

Answer 50

Surface IgM is found on naive, activated, and memory B cells. Secreted IgM represents the major antibody produced during a primary response.

IgM efficiently mediates agglutination, neutralization, opsonization, and complement activation.

Question 51

Where is IgD found?

Answer 51

IgD = Antigen receptor of naive B lymphocytes.

Question 52

IgG

Where is it found?

major functions?

Answer 52

The principal immunoglobulin found in plasma representing up to 80% of the total immunoglobulin concentration.
The major functions of IgG include opsonization and neutralization reactions.

7 subclasses

• IgG1, IgG3, and IgG4/7 are effective in fixing complement, and
• IgG1, IgG4/7, and IgG3/5 bind Fc receptors so they can function as opsonins and mediate antibody-dependent cellular cytotoxicity.
• IgG6 and IgG5 may play an important role in exotoxin neutralization and immunity to parasites.

Question 53

IgE

Where is it located?

Which are its functions?

Answer 53

Most IgE is found associated with the surface of mast cells and basophils and only very small amounts are present in the plasma.

The cross-linking of two IgE molecules with specific antigen results in the degranulation of the mast cells and basophils.

Thus IgE is the primary antibody responsible for type I hypersensitivity reactions and appears to play a central role in immunity to parasites.

Question 54

IgA

Where is it found?

Major functions?

Answer 54

The most abundant antibody in secretions (tears, mucus, saliva, colostrum, etc.)

IgA antibodies can be neutralizing but do not fix complement efficiently nor do they have efficient opsonization activity.

Question 55

How can T-lymphocytes be differentiated from B-lymphocytes?

Answer 55

T lymphocytes can be differentiated from B lymphocytes in that they do not express surface immunoglobulins but instead express the T-cell receptor (TCR) (involved in antigen-specific recognition). T cells also express another surface molecule called CD3. (The designation CD stands for cluster of differentiation)

2 types of TCRs:

• T cells are mostly αβ T cells
• fewer than 5% of all T cells expressing the γδ receptor.

T cells only recognize processed antigen bound by antigen-presenting molecules (MHC I+II) on the surface of antigen-presenting cells (APCs).

Question 56

What is the purpose of the CD3 complex in the T Lymphocytes?

Answer 56

The five proteins of the CD3 complex are involved in signal transduction following
TCR binding to antigen. (phosphorialted in response to TCR stimulation)

Question 57

Name the 2 types of T Lymphocytes and their purpose

What about immature T-Lymphocytes?

Answer 57

Mature T lymphocytes can be further divided into two distinct populations on the basis of their expression of either the CD4 or CD8 molecule.

• cells expressing CD8 are typically cytotoxic effector cells (cytotoxic T lymphocytes [CTLs]), react to MHC I
• cells expressing CD4 are typically helper cells that produce cytokines that enhance antibody and cell-mediated immune responses. react to MHC II

Whereas the T lymphocytes in the periphery express either CD4 or CD8,
cortical thymocytes (immature T cells in the thymus) express both antigens. During maturation in the thymus, these cells convert to either CD4+ or CD8+ cells or they are eliminated.

Question 58

What are MHCs?

Answer 58

T cells only recognize processed antigen bound by antigenpresenting molecules on the surface of antigen-presenting cells (APCs). These antigen-presenting molecules are glycoproteins encoded by genes within a large gene cluster called
the major histocompatibility complex (MHC)

MHC = group of genes that encode proteins on the cell surface that have an important role in immune response: their main role = antigen presentation

Determines whether transplanted tissue is histocompatible or not.

Question 60

How are intracrellular and extracellular antigens processed?

By which cells? How are they presented to the adaptive immune system?

Answer 60

• intracellular antigens are processed via the endogenouspathway and are associated with MHC I molecules that present them to CD8+ cytotoxic T cells,
• extracellular antigens are processed via the exogenous pathway and are associated with MHC II molecules that present them to CD4+ helper T cells
• endocytosed antigens, such as that phagocytosed by a macrophage, are degraded into peptide fragments within a phagolysosome compartment. Processed peptides then bind with the MHC II molecule. The MHC II molecule is then transported and expressed on the cell surface for subsequent presentation to the helper T cell.

The immune system contains a distinct group of professional antigen-presenting cells called dendritic cells

Question 61

What happens after T-cell recognition of antigen (involving the engagement of a TCR -CD4 or TCR-CD8 complex with processed peptide bound by an MHC II or MHC I molecule)?

Answer 61

The protein tyrosine kinase associated with the cytoplasmic tail of CD4 (or CD8)
phosphorylates the cytoplasmic regions of the CD3 proteins (associated with the TCR) in regions known as immunoreceptor tyrosine–based activation motifs (ITAM).

A series of subsequent phosphorylation events ultimately leads to the release
of stored Ca from the endoplasmic reticulum. The increase in intracellular Ca levels and theactivation of protein kinase Cleads to thephosphorylation of various transcriptional factors that regulate the expression of the genes for various cytokines and/or their receptors.

Question 62

What are T effector cells?

Answer 62

activated T-cells

Question 63

Differences in the trafficking of naive t lymphocytes and memory lymphocytes?

Answer 63

Naive T lymphocytes take the most common route, which involves entry into the lymph node by extravasation from the high endothelial venule (HEV) and return
to the peripheral circulation via the efferent lymphatic. This allows rapid repeated circulation of naive lymphocytes through lymph nodes where there is the greatest
chance of exposure to their specific antigens. naive lymphocyte expresses L-selectin to bind to endothelium -> lost when activated

Memory lymphocytes leave the bloodstream in peripheral vascular beds, particularly in inflamed tissues, and return to lymph nodes via afferent lymphatics. This leads to the exposure of primed memory lymphocytes to the most likely early
sites of antigenic encounter and allows for an early response to recall antigens.

Question 64

What is MALT?

Answer 64

mucosal-associated lymphoid tissue (fe Payer patches and pharyngeal tonsils)

MALT consists of lymphoid follicles containing IgA-committed B cells, surrounded by interfollicular T-cell areas with APCs and HEVs, with an overlying follicle-associated
epithelium (FAE).

Question 65

What is the problem with a newborn foal’s immunity?

Answer 65

• Available studies indicate that innate immunity is intact in foals and leads to functional neutrophil responses similar to those in adults but that adequate levels of immunoglobulins and complement with opsonizing activity are critical (colostrum needed)
• epitheliochorial placentation in horses, transfer of maternal antibodies
  does not occur in utero, and foals are born essentially agammaglobulinemic.
• also, helper T-cytokine expression/production and T-cell responses are quantitatively lower than those of adult horses.

Question 66

How is the immunoglobulin concentration curve in foals?

Answer 66

When foals are vaccinated with antigens against which they have no passively transferred antibody, normal antibody responses have been documented
from at least 3 months of age.

In colostrum-fed foals, serum IgG concentration falls to its lowest level at 1 to 2 months of age as a result of catabolism of maternally transferred immunoglobulin, subsequently rising toward adult levels as a result of endogenous immunoglobulin
production.

Some maternal antibodies stay up to several months making an early vaccination ineffective!

Question 67

What is the half life of maternal antibodies?

Answer 67

The half-life for maternal IgG in foals is estimated at
20 to 30 days.

Question 68

Which hypersensitivity diseases are slow - which ones fast-reacting?

Answer 68

antibody-mediated hypersensitivity diseases (types I, II, and III) are immediate in onset if preformed antibody exists in circulation or tissues, with some variation in time course dependent on the antibody isotype involved.

Cell-mediated hypersensitivity diseases (type IV) are delayed, even in sensitized individuals, for 1 to 3 days, while effector cells are recruited to the site of antigen exposure

Question 69

What is type I hypersensitivity?

Answer 69

mediated by IgE antibody specific for allergens, which are extrinsic antigens normally not recognized by the healthy immune system. IgE is predominantly
found in tissues, where it is bound to mast cells through the high-affinity IgE receptor, which is called FcεRI (basophils and eosinophils also have those receptors when activated)

TH2 response (too much compared to Th1)

f.e. penicillin allergy in humans

Question 70

What is Atopy?

Answer 70

Some individuals are predisposed to IgE-mediated hyperactivity to a wide variety of environmental allergens, and this condition is termed atopy.

Affected individuals have high levels of IgE in the blood and increased eosinophil populations.

Question 71

Release of histamine leads to ?

Answer 71

Histamine causes an increase in local blood flow and capillary permeability

Question 72

Which cells are responsible for the immediate and delayed reaction in type 1 hypersensitivity?

Answer 72

Mast cell degranulation causes an immediate allergic reaction within
seconds, but there is also a sustained late-phase response that develops over up to 8 to 12 hours due to recruitment of TH2 lymphocytes -> eosinophils, and basophils. (activation of the latter causes them to exprime FcERI)

Question 73

What are type II hypersensitivities?

Name examples.

Answer 73

This form of hypersensitivity disease occurs when the causal antigen is associated with cells or tissue components of the body, and there is an IgG antibody response to this antigen. Phagocytes, or other cells expressing Fcγ receptors, mediate destruction of the affected tissue, or removal from the circulation by the reticuloendothelial system in the case of antibody-
positive erythrocytes or platelets.

f.e. Blood transfusion reactions, neonatal isoerythrolysis, immunemediated hemolytic anemia and thrombocytopenia are examples of drug-associated type II hypersensitivities.

Question 74

Explain how penicilline can cause anemia

Answer 74

Type II hypersensitivity:

In the case of the horse, penicillin is an established cause of hemolytic anemia. Diagnosis can be accomplished using a Coombs test. Penicillin binds to the erythrocyte surface and is targeted by antipenicillin antibodies of the IgG isotype. Interestingly, quite large numbers of horses have antipenicillin antibodies of the IgM isotype, but this does not lead to disease.

Question 75

What is a type III hypersensitivity?

Name examples

Answer 75

In type III hypersensitivity the antigen is soluble and present in the circulation. Disease results from formation of antibodyantigen aggregates or immune complexes . Although immune complexes are generated in all antibody responses, they are generally harmless. Large complexes fix complement and are removed from circulation by the reticuloendothelial system. However, small complexes can form at antigen excess, and these can deposit in blood vessel walls and tissues where they ligate Fc receptors on leukocytes, causing an inflammatory response, increased vascular permeability, and tissue injury.

f.e. glomerulonephritis in equine infect anemia, Purpura hemorrhagica following Streptococcus equi infection

Question 76

What is a type IV Hypersensitivity?

Answer 76

Cell-mediated type IV hypersensitivities cause delayed hypersensitivity reactions. A variety of cutaneous hypersensitivity reactions are seen, such as the contact hypersensitivity seen after absorption of haptens such as pentadecacatechol in poison ivy (Efeu) or the local TH1 response seen in the diagnostic tuberculin reaction. When type IV hypersensitivity results in a TH2 response the principal outcomes
are eosinophil activation and recruitment such as in chronic asthma in humans.

Question 77

What is a hapten?

Answer 77

= incomplete antigen

can elicit an immune response only when attached to a large carrier such as a protein

f.e. Penicilline causing hemolytic anemia

Question 78

why is hypersensitivity disease uncommon in horses before puberty?

Answer 78

IgE production in horses does not occur before 9 to 11 months of age and does not reach adult levels before 18 months.

Question 79

What is anaphylaxis?

What are cardinal signs?

Answer 79

Systemic anaphylaxis is a severe immediate type I hypersensitivity reaction mediated by IgE.

reported after administration of a wide range of compounds, including serum, vaccines, vitamin E–selenium preparations, thiamine, iron dextrans, and antibiotics, including penicillin. Target organs in experimental equine anaphylaxis are the lung and the intestine.

Cardinal signs: Sudden dyspnea; hypotension, as evidenced by poor peripheral pulse character; rapid onset of urticaria; collapse

Question 80

Treatment in anaphylaxis?

Answer 80

Hypotension: Epinephrine IM (0.01–0.02 mg/kg, equivalent to 4.5–9 mL of 1:1000 dilution of epinephrine for a 450-kg horse) if dyspnea and hypotension not severe –> otherwise IV, side effects: tachyarrythmia, excitement, myocardial ischemia

Glucocorticoid therapy during the acute phase will aid in preventing the
late-phase reaction.

ideally rapid-acting glucocorticoid: prednisolone sodium succinate (0.25–10.0 mg/kg intravenously),

but dexamethasone may also be used (0.2–0.5 mg/kg intravenously).

Question 81

which type of hypersensitivity reaction is the basis for RAO?

Answer 81

mixed; incompletely understood, although accompanied by an increase in IgE

Question 82

Which type of hypersensibtivity is Insect bite hypersensitivity (IBH)?

Is there a genetic predisposition?

Answer 82

• type I
• In some breeds a genetic predisposition based on an MHC II linkage has been demonstrated.

Question 83

Which test in NI predisposed foals before administration of colostrum?

How long should those foals be muzzled?

Answer 83

jaundice foal agglutination test

• making 1-mL serial dilutions of the mare’s colostrum in saline (1:2–1:128),
• adding 1 drop of the foal’s anticoagulated (EDTA) whole blood to each tube and mixing, centrifuging at medium speed (300–500 × g) for 2 to 3 minutes,
• observing for agglutination of the red blood cell pellet by inverting the tubes.

=> If strong agglutination occurs at or above the 1:16 dilution (≥1:64 for mule foals), the foal should not be allowed to nurse the mare during the first 36 hours.

-> in affected foals: confirmation using a variation of the Coombs test

Question 84

ERU is which type of immune reaction?

Causes?

Answer 84

Equine recurrent uveitis (ERU), also known as moon blindness or periodic ophthalmia is a type IV hypersensitivity reaction

=> development of posterior and anterior synechiae, cataracts, lens opacities, secondary glaucoma, and blindness.
Eyes of affected horses _contain IgG antibodies and autoreactive T cells specific for retinal antigen_s.

potentially associated with the presence of Leptospira: molecular mimicry between the Leptospira antigens and equine intraocular proteins => autoimmune reaction!

Question 85

Purpura hemorrhagica is which type of immune reaction?

Answer 85

Purpura hemorrhagica is an uncommon acute type III hypersensitivity (immune complex) disease in horses characterized by edema of the head and limbs; leukocytoclastic vasculitis; petechial hemorrhages in mucosae, musculature,
and viscera; and sometimes glomerulonephritis.

often associated with infection with

Strep equi and

Corynebacterium pseudotuberculosis

Question 86

Explain the concept of autoimmunity

Answer 86

= tolerance break, f.e.

• break in central tolerance occurs when self reactive B or T cells are not negatively selected during the maturation process in the bone marrow and thymus and are released into the circulation,
• peripheral tolerance mechanisms exist to control autoreactivity. One of these peripheral tolerance mechanisms is the downregulation of self reactive T cells by Tregs. B cells have a higher probability of developing self reactivity than T cells. Thus many autoimmune diseases with known mechanisms involve autoantibodies.
• Autoreactive lymphocytes may respond to self antigens due to molecular mimicry, f.e. Leptospira x ERU, thrombocytopenia x EIA

Question 87

transfer of passive immunity is defined as..

Answer 87

transfer of passive immunity, which is defined as a serum IgG concentration
greater than 800 mg/dL. Serum IgG concentrations less than 400 mg/dL and between 400 and 800 mg/dL have defined complete and partial FTPI

Question 88

Which test is the gold standard for measurement of concentrations
of immunoglobulin classes?

Answer 88

radial immunodiffusion (RID) assay

Question 89

What is a congenital immunodefiency of arabians?

What is the mechanism?

Answer 89

• *Severe combined immunodeficiency (SCID)** is a lethal primary immunodeficiency affecting Arabian foals, characterized by failure to produce functional B and T lymphocytes and resulting in the **complete lack of adaptive immune
  responses. **

vast majority of affected foals are Arabians, in which the condition is inherited as an autosomal recessive trait and results from a lack of DNA protein kinase (DNA-PK) activity –> V(D)J recombination does not occur => developing T cells and B cells do not produce functional TCRs and BCRs and thus fail the positive selection process in the primary lymphoid organs.

Question 90

Severe combined immunodeficiency :

• ante mortem
• post mortem findings

Answer 90

• persistent marked lymphopenia (usually less than 500/μL) and the absence of serum IgM by RID. If presuckle serum is unavailable for testing, serum IgM cannot be used as a diagnostic aid until the foal is older than 3 weeks.
• definitive diagnosis: evaluation if homozygous for the defective SCID gene. (PCR amplification of a specific region of the DNA-PKcs gene) testing with whole blood, pulled hair, or cheek swabs
• post mortem: hypoplasia of the spleen, thymus, and lymph nodes with the
  absence of any normal lymphoid architecture (life expectancy max 5 months, first signs of infection around 1-3 months of life)

Question 91

What is the fell poney syndrome? Diagnosis?

Answer 91

• congenital syndrome caused by a SLA5A3 mutation leading to anemia, immunodeficiency (profound B-cell lymphopenia), and peripheral ganglionopathy
• affected until very recently up to 10% of Fell and 1% of Dales foals, respectively
• diagnosis via PCR based DNA test

Question 92

What is CVID?

Answer 92

Common Variable Immunodeficiency is rare but should be suspected in adult horses with recurrent infections as described previously, hypogammaglobulinemia,
B-cell lymphopenia, and failure to respond appropriately to vaccination.

=> B-cell depletion and inadequate antibody production caused by failure of B lymphocyte maturation in the bone marrow

Question 93

Diagnosis of selective IgM deficiency

Answer 93

serum IgM concentrations persistently less than 2 standard deviations below that of agematched controls (less than 15 mg/dL at 4–8 months; less than 25 mg/dL at greater than 8 months)

coupled with normal concentrations of IgG (≥1000 mg/dL) and

a normal lymphocyte count.

=> exact gene unknown

Question 94

Which molecule is responsible for colostral Ig transport from the intestinal lumen into the systelic circulation?

Answer 94

Although yet to be identified in foals, the neonatal Fc receptor
(FcRn) transports maternal IgG from the intestinal lumen
through enterocytes and into the systemic circulation in
mice

Question 95

What is a subnormal colostral immunoglobulin content?

How do you test for it?

Answer 95

less than 3000 mg/dL

can be estimated by specific gravity or quantitated by RID

Question 96

Which effect does a lymphoma have on Igs?

Answer 96

Lymphoma is often associated with IgM deficiency

Question 97

What happens to foals infected with herpes 1 in late gestation?

Answer 97

Affected foals have profound lymphopenia and generally die, despite therapy. The immunodeficiency is thought to be due to viral-induced lymphoid damage, because necropsy reveals marked necrosis of lymphoid tissue in the thymus, spleen, and lymph nodes.

Question 98

effects of corticoids on the immune system

Answer 98

after crossing the cell membrane they bind to cytoplasmic glucocorticoid receptors. Once activated, glucocorticoid receptors are transported to the nucleus where
they bind to DNA and interact with other transcription factors, resulting in the regulation of as many as 20% of the genes expressed in leukocytes: ↓ expression of cytokines, ↓ Phospholipase A2, cyclooxygenase type 2 =>↓ Protaglandins, leukotrienes, ↓ Adhesion molecules (=> lowering migration of leucocytes)

reduces the numbers of B and T lymphocytes in the peripheral blood of horses

important for allergic reactions:

suppress TH1 responses while sparing TH2 responses

Question 99

Cyclosporine: mechanism of action

Answer 99

= fungal derivative, major immunosuppressive agent for allograft survival.

selectively inhibits proliferation, cytotoxicity, and lymphokine production of T cells by binding to intracellular proteins known as immunophilins and interfering with signaling pathways that are important for clonal expansion of lymphocytes.

CAVE toxic to the kidneys and other organs.

f.e. used for local treatment of keratitis and uveitis

Question 100

Name relevant cytotoxic drugs in equine medicine

Answer 100

azathioprine and cyclophosphamide,

interfere with DNA synthesis and act primarily on dividing cells.
This activity is useful for treatment of cancer and for suppression of dividing lymphocytes.

f. e. Cyclophosphamide + prednisolone as chemotherapeutic protocol to achieve remission of thoracic lymphoma in a horse.
f. e. used to treat immune-mediated hemolytic anemia or thrombocytopenia with success in some cases

Question 101

cytokines as therpeutics?

Answer 101

Interferon-α. antiviral and immunostimulant properties, and oral administration of interferon-α has been shown to reduce inflammatory airway disease in racehorses.

Granulocyte Colony-Stimulating Factor. G-CSF treatment in neonatal foals results in a sustained, dose-dependent increase in neutrophil count and a left shift, by increasing neutrophil production in the bone marrow and shortening the time to release into the circulation while the half-life remains unchanged at 8 hours.

Question 102

Name all leucocytes and their blood and tissue half life

Answer 102

Granulocytes: Neutrophils, Eosinophils, Basophils => 4-5hrs in blood, 4-5 days in the tissue (with serious infection - couple of hours), Phagen;

Monocytes: 10-12 hours in blood => tissue macrophages, in tissue for months

Lymphocytes: life span of months or years, stay in lymph and blood system

Question 103

When and why does leucocytosis and monocytosis occur?

Answer 103

stimulation of the granulocytic and monocytic progenitor cells in the bone marrow –> takes 3-4 days for newly formed granulocytes and monocytes to leave the marow area