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immunology

Terms in this set (117)

what are the differences between primate, dog, cat, horse, cows, and birds in transfer of maternal antibodies across placenta
what are Ig classes in colostrum & milk amount ruminants and non
ruminants: mainly IgG
non-ruminants: IgA

*most Ig in milk is produced in udder (not transferred from serum like colostrum)
what is gut closure?
after 24 hours new layer of enterocytes form preventing absorption from lack of FcRn
what are reasons for failure of passive transfer of maternal antibodies (3)
1. production failure (premature lactation or neonate, insufficient secretion/poor quality)
2. ingestion failure (inadequate intake from multiple births, miss 6 hour optimal window, poor suckling drive)
3. intestinal absorption of maternal immunoglobulins failure (suckling occurred after gut closure)
what are tests used to determine adequacy of maternal antibodies in foals & calves (4)
1. total protein (protein electrophoresis)
2. salt precipitation (sodium sulfite & zinc sulafte in foals)
3. ELISA/enzyme linked immunosorbent test
4. radial immunodiffusion assay/RID or precipitation test
what are treatment options for FPT (failure of passive transfer)
<15 hours then give 2-3 liters of colostrum
>15 hours but <3 wks old give plasma infusions
>3 weeks old give antibiotics and put under observation
why give serial vaccinations of young domestic animals?
due to the maternal antibody interference with active immunization
puppies and kittens immune mature at 6-9 w. of age
calves and foals immune mature at 6 months
what is ontogeny?
what develops when?
the development of individuals over their life span

thymus is first then secondary lymphoid organs (b cells in ln, antibodies not until late gestation)
when does the ability to mount cell-mediated immune responses develop?
at same time as antibody production
what impact does a short gestation have on immune system ontogeny?
leads to incomplete development of immune system at birth (ex. rodents lymphoid organs develop after birth)
what impact does a long gestation have on immune system ontogeny?
leads to full development of immune system at time of birth but highly vulnerable due to naivety
when are the first lymphoid cells seen in foals & when does fetal thymus develop in calves and piglets
lymphoid cells circulate 60-80 post conception in foals

fetal thymus develops 40 days post conception
response to pathogens is determined by what and is common in what disease?
determined by state of immunological development of fetus

BVD (persistently infected)
why are neonates vulnerable to infection? (3)
1. innate immunity suppressed by fetal cortisol released during birth (suppressed phagocytic function)
2. adaptive immunity is naïve and dependent on exposure of antigens
3. neonatal immune response are biased toward Th2 immune response & suppress Th1 (neonatal Th1 are highly sensitive to apoptosis by Th2 IL4)
what are the advantages and disadvantages of neonatal Th2 immune suppression of Th1
adv: IFNy damages placenta so you want that suppressed; CTLs could recognize MHC1 expressed by fetus
dis: increased susceptible to intracellular bacteria (ex. rhodococcus equi in foals <6 mo. )
when are peak serum immunoglobulin levels of passive maternal immune protection normally reached?

over what time frame do they decrease?
12-24 hours after birth

15 weeks ( in the same time the foals antibodies are being synthesized to compensate)
when are the foals antibodies reach protective levels ?
2 months
minimum IgG requirements for calves and foals?
calves: >1,000 mf/dL or 2-4 L
foals: >800 mg/dL ( partial failure is 200-800 & complete failure is <200)
what are the causes of congenital and acquired immunodeficiency

consequences?

categories?
defects in lymphocyte maturation, activation, or from defects in effector mechanisms in innate & adaptive immunity

increased susceptibility to microbial infections & cancer

congenital (primary/genetic - inherited traits / innate & adaptive) and acquired (secondary, microbial infections/retroviruses)
what are autosomal recessive vs. x linked inherited genetic disorders?
ar: parents carry gene defect, 25% of offspring from 2 carrier parents will have disease
x: mutations in x chromosome, no male to male transmission
what is leukocyte adhesion deficiency type 1 primary immunodeficiency of innate immunity
- decreased/absent expression of b2/CD18 integrins
-recurrent bacterial/fungal infections
- defective adhesion & migration
what is leukocyte adhesion deficiency type 2 primary immunodeficiency of innate immunity
defective adhesion & migration due to decreased/absent ligand for E & P selectin decreasing leukocytes in tissues
-recurrent bacterial/fungal infections
- GDP- fructose transporter mutation; can't slow down to engage & migrate
What is Chediak-Higashi syndrome?
A protein trafficking defect characterized by impaired phagolysosome formation
-defective vesicle fusion & lysosome function in neutrophils, macrophages, DCs, NKC, cytotoxic T cells
-recurrent bacterial infections
-can't exocytose granules, mutation in lysosomal trafficking regulator protein
-autosomal recessive (prevalent in cats & cattle)
-consequences= susceptibility to disease leading to early death (can't fight off simple infections)
what are the common complement deficiencies of primary immunodeficiency (innate)
- chronic granulomatous disease: defected ROS production by phagocytes (phox-91)
- toll like receptor signaling defects: recurrent infections because defects in TLR & CD40 signaling (NEMO, Ik8a)

>10% of primary immunodeficiencies
-no MAC attack
-susceptible to meningococcal disease (c5-c9 components)
what are primary immunodeficiencies of the adaptive variety?
what is SCID?
primary immunodeficiency (adaptive)
-severe combined immunodeficiency
-defects in both antibody & t cells immune response (T,B, NK)
-low circulating lymphocytes
-failure to synthesize Ig
-hypoplasia (lack of developing lymphoid tissues)
how is SCID inherited?
autosomal recessive - DNA dependent protein kinase catalytic subunit & recombination activating gene (RAG1 & 2)
- decreased T, B, & functional NK; cant recombinate to create diversity; no VDJ

X LINKED- IL2 receptor; decreased T & NK ; normal B cell # but decreased function; STAT (IL2 drives t cell proliferation)
what animals more commonly get SCID
Arabian horses- born healthy, sick when maternal antibodies wear off & can't produce their own (autosomal recessive)
jack Russell terriers (x linked)- not responsive to IL2 but can produce IL2, normal # of IgM but lack IgG & IgA due to decreased B cell function (thymus weight greatly decreased)
mice
what are secondary (acquired) immunodeficiencies?
what is agammaglobulinemia?
b cell deficiency common in SB, TB, & quarter horses
- x linked (all males)
-mutations in BTK
-decreased serum Ig isotypes & b cell #
-pre-b receptor checkpoint defect
what is common variable immunodeficiency?
present in >3 yr old horses & miniature dachshunds
-lack of B cells in blood, bone marrow, or spleen
lymphocytes nonresponsive to LPS of bacteria
What is hypersensitivity?
undesirable reactions produced by normal immune system including allergies & autoimmunity (can be damaging, uncomfy, or fatal)
T/f: hypersensitivity reactions require a pre-sensitized immune state of the host
true
what Ig's does each type of hypersensitivity correlate to?
type 1: IgE
type 2: IgG, IgM
type 3: IgG, IgA
type 4: none
what is the timing of clinical signs, cell involved, Ig class, and clinical syndromes of type 1 hypersensitivity
timing- immediate/minutes
cells- mast, baso, eosinophils
Ig-IgE
clin.- allergies, asthma, & anaphylaxis
what are clinical syndromes of type 2 hypersensitivity & Ig class?
cytolysis of antibody coated cells leading to anemia, thrombocytopenia, or neutropenia

IgG & IgM
what are cells involved in type 3 hypersensitivity, Ig class, & clinical syndrome?
neutrophils

IgG & IgA
complement activation leading to vasculitis & arthritis
what are cells involved in type 4 hypersensitivity?
Th1, CTLs, & macrophages
what is the purpose of type 1 hypersensitivity?
self eliminate/cure (round worms in gut) & eliminate allergen/antigen from muco-cutaneous surfaces (involves mast cells & IgE)

clinical signs= mucus, runny nose, sneezing, itching, coughing, vomiting, diarrhea, smooth muscle contraction/bronchoconstriction, & vascular permeability/edema formation
of mast & eosinophils which is a antibody dependent cell cytotoxicity for parasite destruction & which has high affinity for the FceR1 for IgE and releases vasoactive substances like histamine, heparin, and serotonin (in ruminants)?
mast cells have high affinity for FcR1 for IgE & release vasoactive substances

eosinophils are phagocytic and use antibody dependent cell cytotoxicity
what is the sequence of events for type 1 hypersensitivity?
what cell is involved in the late phase reaction?
eosinophils (mobilize, chemotaxis, & activate in response to mast cell degradation & Th2 cytokines)
which cell in type 1 contributes to acute inflammatory process & exacerbates the inflammation triggered by mast cells?
eosinophils
how are mast cells activated & degranulated?
what are localize allergic reactions? type1
what is atopic dermatitis? type1
high levels of circulating IgE (6x)
- genetically predisposed in terriers, westies, & setters
what is anaphylaxis?
systemic allergic response
-vascular permeability leads to massive edema (epiglottal swelling/tracheal compression, fluid in lung shock organ decreases bp & Q)
-bronchiole constriction leads to asphyxiation
- dogs have fluid loss from GI
how do you treat anaphylaxis?
-inhibit mast cell degranulation (epi relaxes smooth muscle, cromolyn sodium inhibits intracellular calcium increase)
- inhibit histamines (anti-histamines bind receptors)
-corticosteroids (stabilize membranes & prevents arachidonic acid break down and inflammation)
what is desensitization therapy of type 1 hypersensitivity?
preventative hypo-sensitization therapy
what diagnostic tests do you use for type 1 hypersensitivity?
radio immunosorbent test (RIST): measures nonspecific IgE
radio allergosorbent test (RAST): measures specific IgE (dog specific antibody)
flea IgE test: ELISA
intradermal skin test: inject small amounts of allergen into dermis and observe reaction
how does infection of Giardia occur?

what are symptoms?
consumption of water, food, or by hands contaminated w/ infective cysts which transform into trophozoites causing illness (passed through stool)

(adheres to gut epithelium but doesn't invade/go in deeper)

watery diarrhea, anorexia, abdominal cramps, bloating, increased belching
what are innate barriers that help protect against giardia?
(mouth to stomach to intestines)
mechanical barriers - epithelial cells, mucus, peristaltic movement
chemical barriers- HCl, proteases, lysozymes, bile, defensins, cathelicidins
cell barriers- intraepithelial t lymphocytes, APCs/Mcells, competition w/ other gut microbes
what are adaptive immune responses against giardia
inductive site: peyers patches/ mesenteric ln (CD4 t cells, plasma b cells)
effector sites: intestinal mucosa/lamina propria (IgA)
Giardia induces what t helper immune response? & what antibody?
Th2 response to secrete cytokines

IgA
what is feline immunodeficiency virus (FIV) ?
retrovirus uses reverse transcriptase to copy viral RNA to DNA
expect low levels of CD4 but high levels of CD8
what test do you run for FIV and what phase of disease would you expect a response?
IDEXX snap assay looking for FIV specific antibodies & do a confirmatory test looking for presence of viral genome by PCR

sub-clinical
what is role of B cells & what is most effective response to kill FIV

why is it immunodeficiency
b cells: produce antibodies against virus but they aren't protective
most effective: CD8

cd4 & b cells get depleted over time creating immunodeficiency & lymphoid organ atrophy
when does type 2 hypersensitivity occur?
when antibodies & complements destroy normal/healthy cells ex. transfusing wrong blood type or hemolytic disease of newborn where mom makes anti fetus antibodies and then they are delivered in colostrum
what are the types of type 2 antibody mediated disease?
1. antibodies ( not IgE) cause disease by binding to target antigens (autoantibodies against self antigens)
2. antibodies form immune complexes that deposit in blood vessels causing vasculitis or organs (anti-streptococcal deposits in kidney leads to renal failure)
what are the mechanisms of antibody mediated disease? (type2) (3)
1. opsonization & phagocytosis: antibodies bind & promote destruction of cell or interfere w/ normal functions so entire cell is phagocytosed (ex. autoimmune mediated anemia (IMHA): erythrocyte epitopes autoimmune mediated thrombocytopenia (IMT): platelet epitopes)
2. complement & FcR mediated inflammation: neutrophil activation, inflammation & tissue injury; MAC attack
3. antibodies specific for tissue antigens deposit intissue interfering w/ normal cellular function: antibody stimulating receptor w/o hormone (Graves Disease TSH leads to hyperthyroidism) and antibodies against Ach receptor cause paralysis (myasthenia gravis)
what are causes of type 2 hypersensitivity?
1. allo-immune reactions caused by incompatibility between donor and recipient (blood transfusion & erythrocyte glycoproteins)
2. anti-glycoprotein antibodies react w/ RBC antigen (blood type a makes antiB and vice versa type o makes anti A & b has no antigens)
3. secondary immune mediated (altered epitopes)
4. secondary to infectious agents (tick borne diseases)
5. primary immune mediated hemolytic anemia IMHA due to autoimmunity
what are the blood types of cats?
you would use an agglutination test to determine blood type
what test would you do for IMHA?
coombs anti-globulin test
precipitation & agglutination assay
direct immunofluorescence flow cytometry
indirect immunofluorescence
which type of hypersensitivity is related to immune complex mediated tissue injuries?
type 3
what are the 3 phases of type 3 sensitivity?
1. immune complex deposits in tissue/vessel
2. complement cascade activated
3. activation of neutrophil/mast cells (release enzymes & ROS that damage tissue/vessels)
what is the arthus reaction?
a local subacute antibody mediated hypersensitivity reaction. Intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in skin
(repeated injections)

type 3 hypersensitivity
what is farmers lung?
type 3 sensitivity
post strept. equi vasculitis lesions (strangles), rheumatoid arthritis & lupus are what type of hypersensitivity?

what is blue eye
type 3

local type 3 reaction; corneal edema, ag/ab complexes deposit in cornea
what are systemic reactions of type 3 hypersensitivity
pneumonitis (farmers lung or heaves)
serum sickness (hepatitis, glomerulonephritis, & arthritis)- causes antivenom or antitetanus
peritonitis (vasculitis)
dermal vasculitis (strangles)
glomerulonephritis (lyme's disease)
how do you treat type 3 hypersensitivty?
treat underlying condition & suppress immune system (glucocorticoids & cyclophosphamide)
what type of hypersensitivity is related to cell mediated tissue injuries? what is it known for?
type 4
delayed hypersensitivity
what is the immune mech. & response of type 4 hypersensitivity
mech: Th1, CD4, CD8 accumulate & release cytokines (IFN, TNF); activates macrophages & cytotoxic t cells

response occurs at 72 hours; swelling, induration, granuloma at site of antigen due to accumulation of macrophages & lymphocytes (cytotoxic t cells destroy cells expressing target antigen)
describe the type 4 immune response to TB skin testing
reaction is a memory Th1 response to bacteria- if persists 48-72 hours post procedure then positive
poison ivy oil is an example of what type of hypersensitivity?
4 (hapten binds to skin and stimulates CTLs to induce apoptosis of keratinocytes)

its contact dermatitis like topical drug reactions, formaldehyde, & nickel
what are the immunological aspects of organ graft rejection?
what are multiple sclerosis, polymyositis, insulin deficient diabetes mellitus, lymphocytic thyroiditis examples of?
type 4 autoimmune reactions
T/F: lymphocytes are made tolerant to self antigens + very high antigen doses cause tolerance?
true (accomplished by central and peripheral tolerance)

still true because very high and very low doses cause tolerance
True/false: regulatory t cells control immune response by secreting IL10 & TGFB & T17 regulates inflammation by secreting IL17
T
where are self reactive lymphocytes destroyed?

where are they just turned off?
destroyed by negative selection in primary lymphoid organs

turned off in secondary lymphoid organs later in life
define tolerance
unresponsive to antigen; can occur if immature lymphocytes are exposed to antigen early & lymphocytes remain tolerant when exposed later in life
define autoimmunity
reactive against self; characterized by specific antibody or cell mediated immune response against constituents of body's own tissue (autoantigens); results in autoimmune disease
what are 2 examples of tolerance?
1. non-identical (dizygotic) twin share placenta & bone marrow cells colonize each other so they become tolerant to twin's cells & can get skin graft regardless of genetic differences (CTLs won't reject)
2. BVDV intrauterine infection: cow with BVD will pass it on to calf in utero and the calf will be persistently infected
what are the mechanisms of tolerance induction?
where does T cell selecting for central tolerance occur?
thymus via expression of AIRE transcription factors to promote self protein expression
what are the mechanisms of b cells central tolerance?
what is t cell peripheral tolerance?
mature self-reactive cells leave thymus and can be suppressed by 3 mechanisms in periphery
1. anergy: functional inactivation (due to loss of secondary signal/costimulation)
2. deletion: induced apoptosis (Fas/FasL)
3. suppression: by tregs (TGF OR IL10)
What is b cell peripheral tolerance?
self-reactive b cells can occur in secondary lymphoid tissues; antibody diversity is generated by VDJ rearrangement in primary lymphoid organs, then random somatic mutation in germinal centers of ln or spleen
what are mechanisms of b cell induction (peripheral tolerance)?
what is autoimmunity?
tolerance failing; condition characterized by specific AB or cell mediated immune response against the constituents of the body's own tissue

consequence of adaptive immunity evolved, sometimes triggered by immune stimulants (virus, vaccine, drugs)

clinical signs & lesions are results of hypersensitivity reaciton
what is initiation of autoimmunity?
1. abnormal immune response to self: loss of tolerance due to genetic predisposition via AIRE mutations, apoptosis failure, of MHC genes
2. normal immune response to abnormal/unusual antigens: hidden antigens released from aged cells/damaged tissue (brain, eye, testes, uterus); molecular alterations in AG; molecular mimicry cross reacting epitopes
what does MHC have to do with autoimmunity?
genetic predisposition; loss of MHC polymorphism (less resistance=more susceptible to autoimmune disorders)

examples: sheepdogs & IMHA
MHC1 lupus in German shepherds
MHC 1 insulin dependent diabetes mellitus
what's an example of normal response to hidden self antigen (part of autoimmunity initiation)

what's an example of molecular alterations by antigens
aged RBCs exposing new epitopes and IgG autoantibodies marking for removal

distemper; AB binds to virus changing AB shape so new Fc epitopes are exposed resulting in an autoantibody IgM to patients IgG (rheumatoid factor which leads to macrophages & pro-inflammatory cytokines & neutrophils causing TNF to destroy cartilage and bone)
what is molecular mimicry?
sharing epitopes between infectious agents or drugs and self antigens
what is the difference between molecular mimicry & bystander activation?
what is type 1 autoimmune condition?
milk allergy (casein) in cattle stimulates type 1 hypersensitivity reaction leading to delayed milking & induces Th2 & IgE to self casein (cows develop acute anaphylaxis)
what is type 2 autoimmune conditions?
autoimmune mediated anemia (IMHA): autoantigen is erythrocyte epitope
autoimmune mediated thrombocytopenia (IMT): autoantigen is platelet epitope
Myasthenia gravis: anti-acetylcholine receptor antibodies; block nerve impulses of striated muscle (affects german shepherds, retrievers, & dachshunds)
graves disease: anti-thyroid stimulating hormone receptor antibodies resulting in hyperthyroidism
autoimmune hypothyroidism: antibodies to Thyroid hormones or thyroglobulins (affects beagles & great danes)
pemphigus complex: antibodies to desmosomes/basement membranes
go into pemphigus (type 2 autoimmune condition)
skin blistering; autoantibodies to desmosome adhesion molecule in stratum granulum; sloughing keratinocytes; complement activation
what are type 3 autoimmune conditions?
antibody-antigen complexes on tissues (rheumatoid arthritis or systemic lupus) (german shep. common for lupus detect with anti-nuclear antibody test which uses UV light & flourescein)
what is type 4 autoimmune conditions?
polymyositis: progressive muscle weakness not associated w/ exercise (lymphocytes & macrophages infiltrate muscle)
insulin dependent diabetes mellitus: T cells and AB
lymphocytic thyroiditis: CTLs against thyroid epithelium
how do you treat autoimmunity?
immunosuppressive drugs: -glucocorticoids alter cytokine production & inhibits inflammation by inhibiting break down of arachidonic acid; azathioprine inhibits nucleic acid synthesis inhibiting replicating cells/lymphocytes; cyclosporine A inhibits clonal expansion of T cells by blocking IL2 (proliferation component)
what is immunotherapy?
the prevention or treatment of disease with substances that stimulate the immune response.
what is the most widely used drug that can suppress immune response? (hint: prevents NF kB activation which blocks immune function)
corticosteriods
what class of drug is used to prevent allograft rejection/treat autoimmune disease?
immunosuppressive drugs (blocks T cell activation & interferes w/ signal transduction)
T or F: PAMPS that activate PRRs in a nonspecific fashion are immune system inhibitors
false they are stimulants not inhibitors
is cytokine therapy the best way to modulate the immune system? why?
no because of its toxicity & cost
what are biological response modifiers? (BRMs)
substances employed by stimulants & inhibitors on innate & adaptive immune systems for immunotherapy

monoclonal antibodies, cytokines, & PAMPS use them for anti-TNFa/ENBREL, IL2, & CpGs (same order)
what are the the targets of immunotherapy?
hypersensitivity reactions, cancer, & infectious agents
what is ENBREL (etanercept)
biopharmaceutical that treats autoimmune diseases like arthritis, psoriasis, & ankylosing spondylitis by acting as TNFa inhibitor

(type of mAbs & cytokine like IL2 & IFNa)
what is Eqstim?
stimulates TLR9 receptors in cytosol activating sentinel cell killing mechanisms

biologic drug/PAMPs that treats horses prior to transport
what is the anti-inflammatory effect of glucocorticoid?
what are corticosteroids?
(lipid soluble)steroid hormone produced in adrenal cortex that acts as a synthetic analogue of glucocorticoids (prednisone= anti-inflammatory/immunosuppressive/antiproliferation & vasoconstriction) & mineralocorticoids (aldosterone: regulate electrolyte & water balance)

modulate transcription of genes
how do glucocorticoids enter & attack cells?
their mechanism of action is triggered by immune stimulus & NFKB dissociates from inhibitor IKBa (which under normal circumstances would increase transcription & cytokine synthesis) & would normally be degraded but corticosteroids stimulate synthesis of excessive amounts of IKBA which binds to NFKB & continues preventing activation

outcome: controls immune mediated diseases, autoimmune diseases, & lymphoid cancers
what is azathiprine/imuran?
-cytotoxic drug
-inhibits nucleic acid (purine) synthesis, targets S phase of cell cycle, affects T cell proliferation
-used for treatment of immune mediated & autoimmune diseases
what is cyclophosphamid?
-cytotoxic drug
-alkylating agent that cross-links DNA helices
-toxic for resting & dividing cells!
-impairs B & T cell responses
-used for lymphoid neoplasia, autoimmunity, immune mediated disease
-suppresses bone marrow
which drugs prevent activation of Calcineuride (signaling molecule) which then inhibits NFAT transcription factor & activation genes (IL2)? typically used in kidney transplants & autoimmune diseases
cyclosporine & tacrolimus
what is the drug rapamycin (mTOR) used for?
regulates cellular metabolism, growth, & proliferation by blocking mTOR activation
what are NSAID drugs for?
provide analgesic (pain-killing) and antipyretic (fever reducing) effects and in high doses anti-inflammatory effects; common for dermatitis / allergy cytokines

apoquel inhibits JAK
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