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144 Cards in this Set

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  • Back
Neonatal Immunity

Important to remember
1. domestic animals become immunocomptent proir to birth
2. Parturition is associate dwith immumosuppressive levels of stress
3. Colostral immunoglobulin is critical for the survival of the newborn animal

Primary lymphoid organs develop in the 1 trimester followed very quickly by 2 lymphoid organs and phagocytic capabililty by mid gestation

immune responses detected soon after the development of the 1 and 2 lymphoid organs
--> BandT cell responses detectable at about the same time animals can respond to vaccine antigens in utero
Fetal immune responses to intrauterine infections
consequences of intrauterine infections depend on the pathogen and the stage of gestation of the fetus
-fetus is less capable than the adult to fight
-and fetal responses are 1 immune responses (IgM)
-elevated levels can be used as a diagnostic tool
effect of time of gestation
-1 trimester infections more likely to result in death of the fetus
-2 trimester result in variable damage
-3 trimester can provoke effective immune responses, fetus often undamaged
-i.e. congenital infection with toxoplasma gondii or neospora
-i.e. bvd virus
exposure can lead to tolerance and persist infection
Effect of pathogen
bhv-1 can result in death at any time in gestation because the pathogen is very lytic
Parturition is associated with immunosuppression
parturition is triggered by stress of the fetus (high steroid levels)
-result in decreased phagocytosis
-decreased t cell responses
Consequences of neonatal immunosuppression
3-5 days
susceptible to infection which would not cause serious problems in older animals
disease can be caused by organisms and modified live virus vaccines
immunity in the neonate
-passicve protection
maternal immunoglobulins transferred to the fetus or newborn
-active immunity
newborns responses to infection or vaccination:
primary responses
interference of maternal immunoglobulins
transfer of maternal immunity
route determined by nature of placenta:
-hemochorial allows for IgG transfer but not all Ig classes
-endotheliochorial (dogs/cats) allows transfer of low amounts of IgI only
-syndesmochorial (ruminants) no transfer of maternal Ig prior to birth
-epitheliochorial (pigs and horses) no transfer

need to get it from colostrum
first milk, vehicle for transfer of maternal immunoglobulin to fetus, also contains high levels of other anti-microbials and growth factors
you can vaccinate mom and she'll transfer more
passive transfer of colostral immunoglobulin to the neonate
immunoglobulins reach the small intestine intact and functional, they remain intact cuz:
-proteolytic activity in the GIT is low in newborn and high trypsin inhibitor levels in colostrum reduces degradation

intesitnal epithelium allows for absorption of intact immunoglobulins directly into the bloodstream...after 24 hrs gut morphology changes and this no longer occurs
How does colostral immunoglobulin protect neonate
serume Ig protects from viremian and bacteremia

reexcretion of the Igs at mucosal surfaces blocks pathogen invasion

The T1/2 of IgG is 3 weeks, there is a time of vulnerability when colostral Ig has declined and own Ig levels still low
Failure of passive immunity
newborns with inadequate levels of colostral Ig to protect from disease

inadequate colostrum production
inadequate colostrum ingestation
inadequate Ig absorption

Adequate is approx. 10g/L IgG at 24 hrs

fate of FPT:
25% in foals and calves, 50% in dairy bulls*\
factors affecting passive transfer
1. age of the calf at 1st feeding (only those feed before 6 hrs had adequate levels)

2. Mass (gm) of Ig fed: the more Ig fed the higher serum levels achieved

3.Volume and concentration:
newborns comsume a finite volume of colostrumin first few hours, colostrum fed must have high enough Ig concentration to deliver the mass
Colostral immunoglobulins varies widely among cows
colostral immunoglobulin varies widely among cows, due to differences in genes of the receptor in udder that transfers Igs to udder
Diagnosis of FPT
-colostral Ig peaks in serum of newborns in about 24-36 hrs after suckling

-measure serum Ig by radial immunodiffusion (RID)
-need standard curve
Consequences of FPT
less than half normal levels
-serious morbidity/mortality due to bacterial septicemia and or diarrhea
greater than or equal to 1/2 normal levels
-variable morbidity/mortality most often due to diarrhea

having FPT is not necessarily a death sentence

Amount of disease and death losses highly dependent on management
Treatment of FPT
if animal is greater that 12 hrs age serum transfusions and or supportive care
Immune responses in the young
immune responses (primary, IgM) can occur in utero

neonates are unresponsive for about 3-5 days at the time of birth after which they can develop active immunity

colostral Ig interfers with the development of active immunity because
-sequestration fo antigen
-negative feedback on specific B cells

high titers of colostral Ig can block vaccine reponses this is why you vaccinate in series, find window when passive immunity is waining and not extremely vulnerable to infection
Other adverse effects of colostrum and colostral antibody
transfer of antibodies to blood group associated antigens (type 2 hyper)

transfer of cell associated infectious disease
Passive immunity in birds
maternal IgG (IgY) is concentrated in egg in ovary and enters bloodstream of chick

IgM and A enter the albunin in the oviduct and are swallowed by the chick
What di nature intend
fetus and newborn are immunocomptent but immunologically naive

colostral antibodies designed to provide initial high levels of passive protection from pathogens at time of birth

gradual decline in passive protection ant the same tie as exposure to low levels of pathoghens

young gradually replace the passive with active responses

immunologic unresponsiveness to self
Central tolerance
-delection of T cells that have nonfxnal TCRs: apoptosis if no ability to bind self MHC or strong binding to self MHC

however all individual s have a wide array of self reactive T cells which escape deletion in the thymus(not an absolute system)

Peripheral tolerance
-regulatory mechanisms that prevent self-reactive lymphocytes from damaging self
anergy: lack of co-stimulation
suppression: through Th1 and 2 balance
immunological ignorance:self antigens are hidden/cryptic antigens
Physiological Autoimmunity
NORMAL mechanism for removal of aged cells (new immunogenic epitopes and surface proteins are expressed as the cell ages)

i.e. removal of RBCs
-T1/2 is 120 days autoantibodies target a protein called band 3 protein
Autoimmune diseases
pathological condition associated with ongoing tissue damage from self reactive antibodies and/or cytotoxic T cells ( including Th)

-develop spontaneously
-predisponsing causes rarely obvious
-partial or complete failure of tolerance
-result of either an immune response directed to single self antigen or general defect such hat many self antigens are recognized
-results from normal immune response to an abnormal self-antigen or an abnormal immune response to a normal self-antigen (worse)

they are failures of both tolerance and immunoregulation:
-tolerance to self is broken and normal regulatory mechanisms do not fxn to prevent or to down regulate the response to self
What causes loss of tolerance
1. exposure of hidden antigens:
antigens not normally exposed to the cells of the immune system or exposure of previously cryptic epitopes

normally protected from exposure to lymohocytes so no active tolerance (body not used to seein them)

Inflammation: exposure of antigens leading to triggering of immune reponse and AID

i.e. after heart attacks antibodies in cardiac mitochondria
after inflammation of testes antibodies to sperm
in chronic active hepatitis antibodies to liver membrane proteins

2. New epitopes/antigens generated on self proteins by molecular changes
-rheumatoid factor: autoantibodie to the Fc portion of IgG in immune complexes
-immunoconglutinins: autoantibodies to complement components created during complement activation
(low levels of auto antibodies are physiological, high levels are pathological)

3.cross-reactive antigens "molecular mimicry"
immune responses to an infectious agent which shares epitopes to self antigens (important role of Th)

i.e. GpA AID of heart, kidney and joints
Mycoplasma antibodies to normal lung antigens
trypanosomes mammalian cardiac muscle and neurons
epstein barr virus mylein basic protein (MS)
leptospira interrogans immune responses to cornea

4. changes in antigen processing and presentation
once immune response is triggered the APC become activated and have enhanced interactions with Ths
-enhanced antigen processing results in better ability to present self antigens
-high levels of cytokines in enviro results in supplyuing the costimulatory signals needed to trigger self reactive cells

both bacteria and viruses have been impliated in inducing autoimmunity by this means
AID is a failre of tolerance and immunoregulation
Failure of regulatory control once auto reactive lymphocyte looses tolerance
-low level auto-immune responses are normal, general the system can bring the response under control
-when disease develops there is a failure of the regulatory control to self antigens but the factors resulting in this loss are not understood
Factors predisposing to loss of tolerance and immunoregulation
genetic: AID are familial
age: middle aged to older
gender: females
infections: bacteria nd viruses
vaccination: adjuvanted vaccines
altered immune system: lymphoid neoplasia, immunosuppressive therapy, immunodeficiency states
Genetics of Autoimmunity
genes associated with development of AIDs are those of MHC 2(control of immune responsiveness)

-they regulate the ability to respond to antigen, there has been selection for genes that enable effective response to infectious agents

however since AIDs occur after reproductive age no selection pressure against those MHC antigen binding grooves that present self-antigen

-most diseases are associated with a particular combo of MHC genes

-inbreeding can result in high levels of AIDs
OS chickens autoimmune thyroiditis
systemic lupus erythematosus in dogs
Gender and autoimmunity
hormones: females increased risk of AID prevalence in females 10x that of men due to estrogen

microchimerism: exchange of fetal/maternal cells during pregnancy, may cause immune-mediated disease in the recipient
infectious agents as inducers of autoimmunity
molecular mimicry
viruses-> resting Tcell + APC->activated Tcell that is cross reactive with normal tissues->autoimmune response

bystander activation
viruses-> Tcells and APC-> cytokine cascade->activated Tcell (by a non-specific signal)->autoimmune response
Vaccination and autoimmunity
administration of vaccine may trigger transient production of autoantibodies in vast majority of patients no disease results (very rarely does one have an adverse reaction)

i.e. Guillain-Barre syndrome after influenza
Immune-mediated anemia in dogs
altered immune system and loss of immunoregulation
neoplasia of lymphoid tissues associated with AIDs
i.e. autoantibodies to Ach receptors block Ach binding

immunodeficient individual have increase AIDs
i.e. IgA deficient K9 penetrating microbes bearing cross reactive epiptopes allowed to cross
Determinant spreading
-increase in numbers of epitopes recognized in an autoimmune response with time

-response starts out confined to one or a few immunodominant peptide epitopes

-with time immune response spreads to recognize other epitopes on the same protein and then on other proteins
Autoimmune diseases
divided into 2 groups
1. organ specific AID: selective targeting of a single organ or cell type and or related cells or organs. Responses predominately Th2

2.Systemic AIDs: auto reactivity to multiple self anitgens in unrelated tissues, cells, organs. Responses both Th1 and Th2

Some overlap between the two

organ specific AID
-endocrine: hypothyroidism, diabetes
-neurological: polyneuritis, meningitis, myelopahty, myasthenia gravis
-ocular: uveitis, keratitis
-skin: pemphigus, pemphoid
-joints: polyarthritis
-blood cells: rbcs, platelets

can affect any tissues or organ- mild or life threatening

often familial

often mediated by Th2

systemic AID
system lupus erythematosus
in people: rheumatic, connective tissue or collagen diseases

autoreactivity to multiple self antigens many of which are intracellular including nuclear components

circulatin immune complexes are imp. in pathogenesis of the lesions

related systemic AIDs and symptoms often occur in the same individuals and related individuals

i.e. rheumatoid arthritis
sjogrens syndrome
summary of AID
-AID is relatively rare so most of the time tolerance and immunoreg is maintained

-precise mechanisms for loss of tolerance and immunoreg are not understood

-disease usually appear spontaneously and randomly

-few predisposing factors identified however genetics important (but identical twins may not have same degree)

-disease varies in severity, spontaneous exacerbations and remissions common
Mechanisms of autoimmune and other immune mediated disease
immune mediated damage to tissues may be the result of autoimmune attack or secondary to other chronic inflammatory infectious or neoplastic disease

major types of injuries to tissues mediated by immune system are categorized as type 1-4 hypersensitivity
Principles of Vaccination

2 criteria should be satisfied before vaccination can be used to control disease
1. must be established that the immune response can actually protect against the infection disease

2. should be determined if the benefites of vaccination outweigh the risks
basic methods by which animal may be made immune to an infectious disease
1. passive immunity: temporary resistance achieved by transferring antibodies from a resistance to a susceptible individual immunization: adminstering antigen to an animal so that it responds by producing a protective immune response
-->effectiveness depends on how much they have received b/c has a 3 week half life
basic types of vaccines used for active immunization
1. living vaccines (can be modified)

2. dead (inactivated) vaccines
see table for advantages of each
How are pathogen inactivated?
-inactivated ones should be as antigenically similar to the living organism as possible do not want protein denaturation or lipid oxidation (especially surface proteins)

inactivating agents
-formaldehyde cross links proteins (but induced disease)
-alkylating agents cross link nucleic acid chains and leave surface proteins unmodified (but can be very toxic)

don't want an immune response that is irrelevant to protection that is why you want to maintain structural characteristics
how is virulence of pathogens reduced?

-adaptations to growth under unusual conditions

-prolonged growth in culture selects for less virulent, have same antigens but don't cause disease
-growth in cells to which they are not adapted
-quasispecies grow together especially RNA viruses
what technologies are being used or developed to improve vaccines?

see table
-Antigens generated by genetic engineering

Category I
-antigens generated by gene cloning
-identify protein that induces protectie response excised it and put it into a vector to multiply it.
-probably need to use adjuvant
-can use this to produce toxins like leukotoxin from pathogen that causes transport fever
-get a T helper and antibody response
-genetivally attenuated organisms (virulence reduced/removed)
-still want to maintain antigens
-virulence gene removed and therefore will not cause disease

vaccines used for eradication..
i.e. IBR
1. gene for gE deleted allows animal to respond to a lot more than proteins
-if vaccinate all individuals and test for a response to the protein that was deleted, those that have a positive response shows that they have been exposed to the pathogen naturally

2.gD subunits

Category III
-live recombinant organisms
-need to have identified portion that will induce protective response first
- this approach will give you endogenous (T8 cell)response and antibody production
-use canary pox as a vector
-RNA viruse->reverse transcription->cDNA->into pox virus->give vaccine to animal, which undergoes abortive replication in the cell->viral antigen expressed on the surface of target cell-> immune response triggered
-bad... if used sequentially animal will begin to produce antibodies to the vector and it will be killed before it can abortively replicate

Polynucleoide (DNA) vaccines:
body thinks its a live vaccine but its actually dead
-had endogenous pathway, then if eaten by M0 elicit exogenous response
-cloned microbial DNA in plasmid injected-> can get tranfected cell or direct infection of dendritic cell->if transfected that will under go apoptosis, if immature DC cell both will elicit immune response of mature DC cells
-getting into the cell is the problem
How are vaccines administered?
-as single or multiple agent (combo) vaccines intramuscularly or subcutaneously (both parentrally)
-intranasally or by aerosol: stimulate local immunity such as IgA
-in combo with adjuvants
-->any substance that when given with an antigen enhances the immune response to that antigen, early ones were enert, make depot effect and prolong the release of antigen
-cause non-specific immune response=better protection
Types of adjuvants
see table

i.e. liposomes
-vesicles that resemble cell membranes
-induce antibody and in some cases CTL responses
-immunomodulators added to increase efficiency and rxns
What are the types of antiviral vaccines
-mixed parenteral vaccines
modified-live, inactivated
-subunit vaccines
-genetically engineered vaccines
-vecotr vaccines
-intranasal vaccines
what are the types of antibacterial vaccines
1.toxoids-inactivated toxins usually given in combo with adjuvant (alum)
2.bacterins- vaccine containing killed bacteria usually with an adjuvant (alum)
-anaculture is fixed bacterial culture that contains both bacteria and toxoid
-can be imporved by adding purified antigens
-may have problems with strain variation/specificity->autogenous bacterins can be made from isolated from the farm where bacterial disease is occurring
-new generation vaccines against gram- bacteria use common CORE antigen
-can provide cross protection against genera with LPS (endotoxin)

3.Living bacterial vaccines
-modified live not as effective
-i.e. brucella strain 19, anthrax with capsulless mutant
What types of vaccines are available for protozoa?
-babesia transfer of infected blood to young unsusceptible cattle=form f permunition=resistance after primary infection becomes chronic and only effective if parasite persists in the host
-toxoplasa gondi- live vaccine
-recombinant proteins
-infection and treatment
what types of vaccines are available for helminths?
-diversity of life styles makes vaccination hard
-irradiated larva
-recombinant oncosphere antigen and adjuvant
assessing vaccine efficacy
-experimental challenge of vaccinated and unvaccinated animals
-field trials
-laboratory analysis of immune responses in vaccinated animals

efficacy=production of desired results=protection from clinical disease or the reduction of.

*vaccines are mostly able to reduce disease not totally prevent disease and they don't work 100% of the time in 100% of animals

deductive argument
logical reasoning that something must be true b/c it is a particular case of general law that is known to be true

vaccinate animals->challenge animals->assess the vaccine efficacy

evaluating experimental challenge studies in vaccinated and unvaccinated animals
-naive(never been exposed)vs. seronegative (may have been exposed when it had maternal antibody and developed a response)
-relevance of the model to the natural disease
-determine preventable fraction

*did the controls get sick?

evaluating field trials
-pen effect vs. herd immunity effect
-murphy's law in reverse
if something can go right it will

evaluating immunological studies of vaccines
-agents used in assays
-difficulty in comparing serological results among labs
-tests of CMI
-are there correlative challenge data?
why do vaccines fail

adverse reactions to vaccination
vaccine failure
correct administration
incorrect administration

see flow chart for failure

rare adverse reactions get extrapolated to the entire population=problem

see flow chart
variety of defense strategies
1. physical barriers : skine and wound healing
2. self cleaning processes coughing, sneezing, mucus production, urine in UT
3. normal flora to out-compete invaders

Second layer of defense
-temporarily enhanced local defenses
i.e. inflammation
Cells of the immune system
myeloid progenitor cells and lymphocytes
study of immunomodulatory effects of chemicals on the immune system
-an evolving discipline
-an important component of toxicological studies
General principles of immunotoxicity testing
meaningful assessment of immune fxn:
-environmentally realistic exposure to the insult
-requires a battery of tests b/c the immune system is very redunant

-specific (adaptive) and nonspecific (innate) immune fxns play a crucial role in homeostasis and immune regulation

aim of immunotoxicity testing to detect subtle imbalances, to evaluate overall immunocompetence or detect immune imbalance
the immune system has been recognized as a critical target for environmental contaminants

i.e. study conducted to investigate the impacts of gas emissions on beef cattle, human populations and wildlife
immunotoxicological endpoints
-as as biomarkers of exposure or effects from exposure (biological indicators that something is happening)
-are used to evaluate risks to wildlife
-animals serve as sentinels for human risk from chemical exposure
-a term widely used in the context of environmental health
-means foreign compound
-if it gets into a body must be detoxified by and excreted from that body
(chemical compounds effect the animal)
-could cause immunosuppression or immunostimulation
-immune disregulation/immunomodulation

immunosuppression leads to increased incidence or severity of infectious disease and neoplasia from impaired immunosurveillance

-immunostimulation leads to hypersensitivity, autoimmune disease

both are undesirable
what is involved in an immunotoxicology work-up?
Tier 1
based on endpoints already being used in physiology studies
relative organ weights of immune organs
-histopathology: spleen, thymus
-hematology: CBC and differential
--> WBC counts is snapshot of circulating leukocyte population at one moment in time, is not a test of immune fxn
-->WBC differential in clincally sick or stressed birds, heterophils are increased

beware of over interpreting, not very accurate

Tier 2
specific means of testing different aspects of immune fxn
if you get antigenic stimulation the 1st thing that happens is clonal proliferation

in vitro...
lymphocyte proliferation or lymphocyte blastogenesis:
-mitogen-induced proliferation of blood mononuclear cells
-use peripheral blood or splenocytes

Tcell mitogens-concanavalin A, pokeweed mitogen, phytohemagglutinin

Bcell mitogens-lipopolysaccharides, PWM

Enumeration of subpopulations of splenic lymphocytes (Th, T8, serum immunoglobulins)

in vivo
1.PHA skin test (wing web, toe webs, wattles) measure skin thickness before and 24 hrs after PHA injection
-used in avian species and wild rodents, by veterinary toxicologists, biologists and ecologists
-indicates T cells that have proliferated in the area
-stay away from blood vessels
-i.e if animal has a compressed thymus it will have less Tcells

2.DTH test
determine if the animal has been previously exposed
-it is a true indicator of integrated immune fxn
-but it requires species specific optimization
-a comprehensive CM immune response
-dependent upon the interaction of injected antigen, APCs and T lymphocytes
-exposure to an antigen, which is phagocytized by M0, presented through the MHC of the M0 to Tcells, triggers a Th1 response--> memory cells are generated

weeks to yrs later antigen is injected intradermally, it will stimulate the sensitized Th1 cells and initiate the DTH response
-it is the gold standard

3.AB mediated immunotoxicity testing
undifferentiated Bcells--xenobiotics-->Bcells to plasma cells and antibody production
Antibody mediated immunity
1.Tcell independent AB response-lipids
2. Tcell dependent AB response-proteins
3 main assays to measure AB production potential
1. Hemolytic plaque assay (rbc)

splenoces are cultured with srbc and complement, antigen is an RBC protein (making RBC an indicator cell)
bcells and complement bind to rbc surface, lyse rbcs leaving a clear zone

-# of clear lytic spots=#of plasma cells secreting anti-srbc AB

2. Hemagglutination assay (HA)
-serum form sensitized animal is mixed with srbc
-agglutination looks like sheets of rbcs

-ve response the dilution with no more agglutination
+ve response is proportional to [AB]

3. ELISA (most quantitative and sensitive)
-serum is used to determine total IgG vs. specific antigen
-work with serum dilutions of 1/800, 1/1600

HA needs more blood is less sensitive and less refined
SRBC test considerations
higly complex group of antigens
coarse methods to determine AB response
requires 10x more serum than ELISA

???components which stimulate AB production
does not allow detection of subtle differences
may have pre-existing and cross-reacting natural AB
Age specific response to SRBCs
see table
Nonspecific immunity=innate immune response (1st line of defense)
In vitro (leukocytes from spleen or blood or peritoneum)

1.M0 phagocytosis
-culture of M0 with fluorescence labelled antigen
-analyze with flow cytometry or a fluorescence microscope

2. respiratory burst assay
-culture PMNs/heterophils with antigen
-measure the reactive oxygen species/free radicals released

3.natural killer cell fxn, culture with radio or fluorescence labelled antigen
-can be specific and non-specific
immunotoxicity associated with environmental contaminants
see table
most used immunotoxicity test for wild species

in vivo-PHA skin test
-anitbody response (DNP-KLH, foreign RBCs)

In vitro-WBC count and differential
-plasma proteins
-phagocytosis assay
-respiratory burst
-NK assay

post mortem
-spleen, thymus, bursal organ weights
Type I hypersensitivity

Immediate Hypersensitivity
Allergy and anaphylaxis
-acute inflammatory reactions
-mediated by IgE antibody
-effector cells are mast cells, basophils and eosinophils

-Anaphylaxis differs from allergy in that it is systemic and severe (immediately life threatening) while allergy is localized and not usually immediately life threatening
anitigen binding to IgE bound to FcRI on mast cells/basophils triggers cells degranulation
-->this is the usual transduction scenario involving protein kinases

pathogenesis of tissue damage is due to the effects of the released granules (cause vasodilation, puritis, bronchoconstriction)
*made predominantly at body surfaces: skin, intestine and lung
*found bound to mast cells and basophils (almost none in free form
-induced by parasites
-most ind. have low levels
-allergies are a result of IgE production to an antigen
-atopy condition in which IgE produced at abnormally high levels to many antigens

-Th2 cell cytokines(IL4*,5,10,13) elicit Bcell class switch to IgE, if there is an imbalance in Th2 production then increase in IgE
-positive feedback because IL4 promotes production of Th2

-FcRI with very high affinity binding for IgE found on mast cells, basophils, alose found on dendritic cells and monocytes of atopic patients (results in increased cytokines and drives further IgE prdxn)

FcRII with lower affinity for IgE found on NK cells, M0, dendritic cells, eosinophils, platelets and some Bcells

-Th1 cell cytokines (IFN-gamma, IL12 inhibit IL4 production) inhibit IgE production
IgE receptors and the allergy loop
dendritic cells express FcRI and as a result can bind antigen bound to IgE the anitgen once processed, stimulates Th2 responses. These Th2 cells in turn secrete the cytokines which further promote the IgE response
The responses of mast cells to encountering anitgen for which they carry specific IgE
1. cytokine synthesis and secretion

2. granule exocytosis

3. prostaglandin, leukotriene synthesis
soluble mediators released by mast cells
degranulation in seconds-mins
histamine: smooth muscle contraction, exocrine secretions
serotonin: vasodilation
proteases: trypsin, chymotrypsin
arachidonic acid: prostaglandins, throboxanes, leukotrienes

overall effect is acute inflammation, edema, hyptension
role of eosinophils
mobilized and activated preferentially in Type I rxns:

-IL5 from Th2 and mast cells cause mobilization of marrow eosinophils
-mast cell degranulation increase eosinophil chemotaxis
-piecemeal degranulation induced by binding of IgE/antigen to FcRII and by Th2 cytokines (IL5)
--small vesicles of the 2dary granules bud off and move to plasma membrane and release granule contents extracellularly
--large secondary granules contain major proteins (cationic protein, neurotoxin...)
-contents can kill parasites and bacteria but also result in substantial tissue damage
regulation of eosinophil mobilization, chemotaxis and activation
there is excessive interaction btw mast cells and eosinophils in allergic rxns. Eosinophil basic proteins activate mast cells and mast cell factors are chemotactive for and activate eosinophils
development of Type I hypersensitivity
sensitization-phase of exposure to antigen such that IgE immune response is induced
-IgE is produced and will bind to the high affinity receptors on mast cells

Re-exposure-to anitgen results in cross-linking of the IgE on mast cells which triggers degranulation

upon 1st exposure you CANNOT be allergic
Clinical Manifestations of Type I
-symptoms depend on number and location of mast cells affected
-if antigen is administered systemically and rapidly there can be generalized mast cells degranulation (anaphylaxis)
-symptoms of anaphylaxis vary with species most are due to binding of vasoactive molecules to receptors on smooth muscle of vessels, bronchi, gastrointestinal tract
***species differences in mediators, target organ , signs

cattle, sheep: serotonin, kinins, leukotriene main organ is the lung
horse: serotonin and histamine lungs and intestine
dog:histamine, prostoglandin, leukotrienes liver
pigs: histamine lungs
cats: histamine and leukotrienes lungs and skin

drugs that cause it: vaccines, hormones,
milk allergy-jersey cows sensitive to alpha casein delays in milking lead to increased intramammary pressure and milk proteins entering bloodstream
parasites: warble manual removal of pupae from under the skin if they rupture can trigger anaphylaxis in sensitized animals
blackflies, midges, stable flies, mosquitoes symptoms vary from intense pruritus to acute deaths associated with allergy to saliva
local type I events: antigens may be:
-inhaled, ingested, percutaneous exposure
-site of symptoms do not always relate to site of exposure (most result in skin manifestation regardless of entry)
-histological lesions, edema, infiltration of madt cells, eosinophils
-site of exposure and response site do not have to be the same
Allergic disease of the skin
-degranulation of mast cells in the skin result in vasodilation edema and inflammation
-major clinical feature is pruritis
-wide range of allergens: aeroallergens, ectoparasites, food, drugs
-variety of conditions: 30% of all K9 skin disease

hives acute local response manifest as wheals lesions confined to the dermis
more generalized dermal edema which may progress to involve subcutaneous tissue
atopic dermatitis
individual are those that tend to respond with IgE to variety of allergens, most frequent is house dust mites but also provoked by food, environmental antigens
-predisposed by genetics familial in several breeds
-sensitization exposure is believed to be usually percutaneous
-often complicated by secondary infections and or flea allergy due to scratching
-clinical signs: chronically inflamed and itchy skin pruritis self trauma

flea allergy dermatitis
-similar pathogenesis to atopic dermatitis vut most imp predisposing factor is repeated exposure to flease
-causaive antigens are components of flea saliva
-may also involve type 4 reactions
-clinical signs are pruritis self trauma secondary infections

eosinophilic granuloma complex
strange set of conditions in the cat-believed to be type I: ulcerative lesions of skin, mucus membranes characterized by infiltration of eosinophils resulting in ulceration of tissues
food allergy
about 2% of food protein is absorbed in peptide fragments large enough to stimulate an immune response

not equal to food intolerance

IgE responses to food may manifest as either GIT signs or pruritic dermatitis

-signs typically in 4-24 hrs of reexposure symptoms mild to severe
-most common antigens protein rich foods
-diagnosed by response to exclusion diet/symptoms on reintroduction
-may be associated with IgA deficiency
Allergic Rhinitis/asthma
-recognized in dogs/cats but not common
-occurs in families of cattle, cats, basenji dogs, component of chronic obstructive pulmonary disease of horses
Testing for Allergies
intradermal skin test injection of a standard panel of allergens followed by observation of the reaction (wheal)
-limitation is right thing needs to be in syringe

ELISA for allergen specific IgE area of active research, correlation with skin tests and clinical results not too good so far
-very little IgE in serum
Treatment of Allergies
-avoid allergens
-treat secondary infections
-anit-inflammatory agents to prevent mast cell degranulation (stimulate beta or inhibit alpha receptors)
repeated injection of allergen subcutaneously at increasing doses, promotes switch to Th1 cytokines and IgG response, reported to ve about 50-80% effective in dogs (if target antigen known), most dogs require lifelong therapy
Type II hypersensitivity

Antibody mediated immune injury of cells
-destruction of cells due to the binding of antibodies (IgG/IgM) to the cell surface
-effector fxn mediated by either
NK cells, Complement,Phagocytic cells
Classic example
immune mediated destruction of rbcs or platelets
-due to antibody binding to cell surface triggering phagocytosis or complement-mediated lysis
-phagocytosis occurs mainly in the spleen (not alot in blood)
-complement mediated lysis occurs in the bloodstream
-occurs most frequently in dog
-therapy and prognosis depends on the operation of the 2 pathways
immune mediated hemolytic anemia (IMHA)
-AB directed to either:
self rbc antigens-loss of tolerance(cross-reactive to microbial antigen?)
altered self rbc antigen-modified or no longer recognized as self
exposed cryptic antigens-loss of normal structures
alloantigens-occurs in transfusion, antigen expressed on another individual of the same species
-neonatal isoerytrolysis antibodies from maternal colostrum destroy rbcs of the neonate
foreign antigens adsorbed to the cell surface-immune responses destroys the rbc in the process of attacking the foreigner
--penicillin, ASA, quinine, L-dopa, phenacetin, FeLV
expanded neonatal isoerythrolysis
-alloantigens inherited from the sire are expressed in the fetus
-late in gestation the placenta develops small tears whic allow the fetal tissues into mother (expressing alloantigen)
-mother mounts immune resoinse to the foreign blood group antigens
-antibodies concentrate in the colostrum
-colostral anitbodies cause rbc lysis in newborn
diagnosis of immune mediated hemolytic anemia
-clinical symptoms: anemia, jaundice
-CBC: usually regenerative responses with spherocytes and ghost cells
-direct coombs or direct antiglobulin test-to demonstrate AB associated with rbcs
Direct Coomb's Test
agglutination test for IgG, IgM AB binding to rbcs and for fixation of C3
antisera will cross link the rbcs
answering question is AB present

extravascular hemolysis (phagocytosis) IgG, IgM, C3
-steroid therapy
intravascular hemolysis (complement mediated lysis) IgM C3
-nothing can be done therapy wise for this type
Diagnosis of neonatal isoerythrolysis indirect coombs test
check mare in late gestation for rising titer of antibodies to stallion rbcs up to 2% of foals certain blood group antigens are highly immunogenic in an incompatible mare

cats only have 2 blood groups A and B (A dominant) cats of group B have naturally occurring high titer antibodies to blood group A (if A tom breeds a B queen-kitten die)
Transfusion reactions
heterophil antibodies-pigs cattle cats people antibodies to other blood groups occur without exposure to rbc
-induced by cross-reacting epitopes on bacteria
-in these species cross matching of blood is necessary prior to any transfusion of blood
-in species w/o heterophil antibodies animals do not need to be cross-matched on the first transfusion, thereafter cross-matching is necessary

cross-matching test for compatibility of the blood and serum prior to blood transfusion

major cross-match mix recipient serum with donor cells
minor cross match mix donor serum with recipient cells
cold agglutinin disease
clinical signs: necrosis of the tips tail ear toes
-associated with cold-reactive IgM AB to rbcs
-formation of microthrombi in small blood vessels
-results in necrosis of the tissues from ischemia
immune mediated thrombocytopenia
-mechanism similar to disease in rbc
-occurs in conjunction with rbc disease in some patients
-clinical signs associated with hemorrhage, usually petechial on skin and mucus membranes
-diagnosis: often difficult to find sufficient platelets to do testing
-measure either AB bound to the platelets or serum AB binding to normal platelets: ELISA, immunofluorescence, flow cytometer

can be transferred by colostral AB
Skin diseases
Pemphigus and Pemphigoid disease
-target antigens are found in the epithelium of the skin
-damage to the skin due to the AB and complement mediated destruction
-clinical presentation depends on the location of the target antigens, if target is in superficial epithelium the lesion is superficial if deeper in the epithelium erosions or ulcers arises

pemphigus problem high in epidermis
pemphigoid problem at basement membrane

-clinical symptoms
-histological lesions
-immunohistochemical demonstration of deposition of immunoglobulin and or complement in lesions in the pattern consistent with the clinical symptoms and the histology of the lesions
-use a direct or indirect immunoperoxidase method on formalin-fixed biopsies
Immunohistochemical diagnosis of immune mediated skin disease
-direct: usd to demonstrate IgG
-indirect: used to demonstrate IgM, IgA or C3 deposits
other diseases
damage is a component of many of the other documented AID

Addisons disease-AB target cells in adrenal cortex resulting in low levels of glucocorticoids and mineralocorticoids
Diabetes Mellitus-target cells are insulin producing cells of the islets of langerhans in the pancreas
myasthenia gravis-AB to the AchR block the receptor and initiate complement mediated injury to the postsynaptic membrane
Immune mediated destruction of the thyroid-AB directed to thyroid microsomal antigens of thyroid follicular cells and to thyroglobulin
indirect immunofluorescence test for thyroid autoantibodies
lymphoccytic thyroiditis demonstration of serum AB binding to thyroid antigens

immune response is antigen driven: titers decline once the antigen is all removed
other things....
-Type II autoimmune disease generally does not occur in isolation from other forms of immune-mediated damage
-in immune mediated thyroid damage there is damage by type II, type III and IV mechanisms

-cell damage also occurs during beneficial immune/inflammatory conditions
--immune injury associated with infectious agents
Type III hypersensitivity
Immune complex disease
immune complexes are formed
-fixation of the complement cascade (classical pathway)
-complement activation generates chemotxic and activating substances for neutrophils (C3a, C5a)
-neutrophil degranulation leads to release of free radicals and proteolytic enzymes which destroy tissues
a very imp. part of the pathogeesis is that when neutrophils interact with immune complexes on surfaces they can't ingest the degranulate

under natural conditions it is unusual for a single type of immune reaction to occur in isolation, most immune responses are combinations, however in some conditions the immune complex component seems to dominate

how does it differ from type II?
immune complexes are formed btw soluble antigen in the serum or tissues and antibody (not between cell associated antigen and antibody as in type 2 reactions)
classification of type III
-the severity and significance of immune complex reactions depends on the amount and site of the deposition of the complexes
-type 3 reactions are a normal occurrence, disease only occurs if there is large amounts of antigen and or persistence of anitgen

----local reactions immune complexes are confined to single site
----generalized reactions immune complexes are formed in the circulation and damage widespread
-protoype is arthus reaction-antigen injected subcutaneously into an animal with high levels of antibodies
--w/i a few hours the site will contain high numbers of neutrophils, red, edematous and painful
--the blood vessels in the area become thrombosed and local hemorrhage into the tissues occurs.
--peaks in intensity in 6-8 hrs
--ischemic event

-need immune host w/ high antibodies to the injection
-antigen diffuses from injection site into blood vessel walls
-antigen meet AB in the serum within the wall of the blood vessel
-formation of the immune complexes btw and beneath vascular endothelial cells
-immune complexes fix complement in blood vessel walls
-neutrophil chemotaxis and degranulation
-problematic lesion is the vasculitis

Blue-eye: anterior uveitis and corneal edema in dogs
following vaccination with modified live adenovirus vaccine
-virus antigen and AB complexes in the uvea results in 2ndary corneal edema
-blueness due to the opacity of the cornea
-resolves as the virus is eliminated
-similar reaction seen in cats with FIP (develop antibody but don't clear the infection, so antigen persists), toxoplasm, FIV, FeLV

Hypersensitivity pnwumonitis
occurs in the lungs of immune animals after in haling antigens
-inhaled spores encounter AB and form immune complexes within the alveolar walls
-can ve acutely fatal w/i hours of large feed of moldy feed or a chronic condition
-same condition in people is farmers lung

combo of type I and type III
-antigens is molds in hay
-vasuclitis, edema, thickened alveolar walls

staphlococcal hypersensitivity
pruritic pustular dermatitis in dogs
combo of type I and III and IV
histological lesions neutrophil dermal vasculitis
intravenous antigen/antibody complex formation
normally serum immune complexes are removed by binding to either platelets or rbcs

if large and insoluble or bound to rbcs and platelets these are removed by professional phagocytosis
if large number of small soluble complexes are circulating exceeding the cells binding capacity, complexes become deposited in blood vessels
--especially in medium sized arteries of glomeruli, synovia, skin, choroid-plexus areas
i.e. serum sickness
people develop antibodies to all the antigens in horse serum

ten days after treatment generalized erythema of the skin, edema, urticaria, vasculitis, enlargement of joints and lymph nodes
-AB response to foreign species serum proteins resulting in serum immune complexes
-reversible as the foreign proteins are cleared
General Diseases
systemic lupus erythematosus
-development of autoantibodies to many self antigens
-immune complexes are imp part of the mechanism of tissue destruction
--deposition at the vasement membrane zone of the skin, in the glomeruli of the kidney, in small vessels-vasculitis, thrombosis, tissue ischemia, necrosis
Diagnosis of SLE
clinical signs of ANAz are the primary diagnostic criteria for SLE
-anti nuclear antibodies

nuclear antiges are highly conserved body usually won't produce antibodies to DNA, so used as an indicator that something is very wrong
immune mediated arthritis
rheumatoid arthritis:
immune complexe deposition in the synovial membrane of the joint.

1.clinical signs
3.detection of rheumatoid factor

rf is an IgM autoantibody against immune complexed IgG

IgM does not bind to normal free circulating IgG, only IgG that is bound in complex with antigen there is a conformational change allowing RF to bind and increase inflammatory response
other examples of type III
-component of the lesions of infectious disease
i.e. Feline infectious peritonitis virus
-virus forms a persistent infection w/ ongoing release of viral anitgens
-cat mounts a vigorous immune response
-virus specific AB and viral antigen forms large numbers of immune complexes in serum which deposit in blood vessels resulting in generalized vasculitis

i.e. Purpura Haemorrhagica horses recovering from strangles
they develop purpura which are small hemorrhages associated with immune complex vasculitis

Immune complex glomerulonephritis

occurs in a variety of disease other than SLE chronic viral diseases, chronic bacterial diseases, chronic parasitic infections

idiopathic immune mediated polyarthritis
-most common manifestationof immune mediated arthritis in dogs
-sometimes follows known viral or bacterial infections
-transient and reversible
skin diseases
deposition of immunogenic drugs or other antigen and AB complexes at the basement membrane of the skin often apparent as really nasty skin lesions
Summary immune complex disease
-due to soluble antigen (auto or infectious) and AB interaction
-followed by fixation of complement by the classical pathway
-resultin in inflammation and tissue damage by complement and degranulating neutrophils
Type IV hypersensitivity

Delayed type Hypersensitivity
mechanism which involves activated macrophages and cytotoxic T lymphocytes
*antigen activates Th1 cells leading to a cytokine release, M0 and sometimes T8cell destruction of cells

differs from I,II and III reactions in that type IV is cell mediated not mediated through AB

IV reactions can be transferred by Th1 lymphocytes
animal must still ve immune to antigen
Prototype Delayed type hypersensitivity skin test
intradermal injection of antigen for determining exposure to mycobacteria
-if injected into an unexposed animal there is no response
-if injected into previously exposed aminal with a memory population of Th1 cells the DTH reaction occurs

-antigen is phagocytized by APC
-presentation of antigen thru class II MHC to memory Th1 cells along with IL12 prompts release of cytokines
-Th1 cytokines activate M0, increase expression of adherence molecules on local blood vessel endothelium are chemotactic allows extravascularization of neutrophils, lymphocytes and basophils
-tissue damage release of proteases and reactive oxygen from activated M0 and basophils
DTH reaction
-inflammation beginning in 12-24 hrs and peaking in 24-72 hrs
-early stages neutrophils predominate these are replaced by lymphocytes and M0 by the time the reaction peaks
-may later ulcerate
-the bigger the reaction the more immune the animal is
antigen is cleared lesions indurate and resolves
-limits the replication and spreas of viruses
-means of killing of intracellular bacteria protozoa
-the use of this rxn in the dermis is the classical test for CMI

antigen persists granuloma formation (accumulations of M0, some fused to form multi-nucleated giant cell), fibrosis, and pathological consequences
(persistent infections with intracellular organisms which to M0 killing)
pathological consequences
contact hypersenstivity
dermatitis on contact with a wide range of chemical or biological substances
--chemical irritant substance causes direct tissue inflammation
--usually occurs in response to prolonges exposure to small reactive molecules
mechanism of contact hypersenstivity
hapten molecule too small to be antigen is absorbed into the epidermis of the skin, becomes associated with a larger molecules in the skin (carrier)
hapten-carrier complex is phagocytosed by Langerhans cells in the skin and provokes an immune response

DTH rxn in the skin intensely pruritic
diagnosis/therapy of contact hypersensitivity
-patch test removal and reintroduction of suspect allergens
-antigen applied to the skin on a gauze swabtaped in place for 48-72hrs
graft rejection
grafting within an individual (rejection indefinitely)
grafting btw genetically identical ind (aspect as self)
grafting btw genetically different ind of the same species (1-2 wks)
grafting btw ind of different species (rejection after hours)
several mechanisms involving both AB and T cells but much of the response is type IV hypersensitivity

Targets of graft rejection are, the histocompatibility antigens
-MHC I: on all nucleated cells
-MHC II: on APCs, B cells
-blood group antigens: occur on all nucleated cells as well as on rbcs

recognition of MHC II
-helper CD4 Tcells a complex of MHC II and foreign antigen
-foreign MHCII antigens are interpreted as self + foreign and the Th cell is triggered to release helper cytokines

recognition of MHCI
-cytotoxic T8cells recognize a complex of MHCI and endogenously processed peptide: foreigh MHCI is interpreted as self + foreign and the T8cell will be triggered to kill cells with foreign MHC I expression

recognition of blood group associated antigen: these are primarily associated with AB responses and trigger type II destruction of the graft.

even if MHC and blood group mathed ind. most allografts fail w/o potent immunosuppression of the recipient reason is probably the cumulative effects of other minor antigenic differences
-major interest in pigs as source of grafts for people
-big problems with histocompatibility even beyond type IV immune responses
--pre-existing AB to glycoproteins such as those on adhesion molecules results in rejection in mins by fixaton of complement through the classical pathway
--failure of the complement cascade inhibitors to work in heterologous species results also in complement activation by the alternative pathway
graft vs. host disease
-lymphocytes in the graft develop an immune response to the host tissues:
recipient immunosupp. prior to the transplant to try to prevent graft rejection
donor passenger lymphocytes within graft mount a type IV response toward recipient cells
allografts and pregnancy
-fetus in an allograft there are a varitety of mechanisms which prevent rejection
--no expression of immunogenic MHC I or II molecules on the cell layer of the trophoblast in contact with maternal tissue
--fetal antigens entering the maternal circulation initiate an AB response which blocks production of CMI
-placenta and fetus are the source of many immunosupp. factors
-mild immunosupp. and a skewing to AB responses is a consistent feature of pregnancy
-great disparity btw maternal and fetal MHC may result in immune rejection of the fetus: mares reject donkey embryo
Primary immune deficiencies

defect in phagocytosis, in AB production in T cell fxn
-inherited/congenital defects
-rare conditions in out-bred pop. more common if inbreeding has occurred
-**first described thru baby with SCID severe combined immunodeficiency syndrome
signs of primary immunodeficiency
*** increased susceptibility to infections
-opportunistic invaders: wouldn't normally cause disease

other associations
-increased IgE responses
-increased autoimmune diseases
-increased malignancies
defects in phagocytosis
what is required for phagocytic cell function?
-normal cell numvers and morphology
-response to chemotactic factors
-oxidative burst
-killing of micro-organisms

Failure of opsonization
C3 deficiency
--reported in several dog breeds especially brittany spaniels (autosomal recessive)
--highly susceptible to bacterial infection, can be absolute or partial deficiency

Chediak Higashi syndrome: increased susceptibility to certain infections, defect in formation of intracellular granules (huge ones instead of small) related to dilution of coat colors

Peiger-Huet anomaly
usually healthy but pups in affected litters have reduced survival

-neutrophil nuclei doesn't segment
-neutrophils have reduced mobility
-neutrophils with release of immature cells from the bone marrow

defects in phagocytosis: leukocyte adhesion deficiency
-defect in adhesion proteins that enable neutrophils to leave the bloodstream and enter the tissues in response to chemotaxic factor
-clinically recurrent bacterial infections stunted growth, fever, persistent neutrophilia

***canine and bovine leukocyte adhesion deficiency (BLAD)
-deficiency is in the integrin found on neutrophil surfaces(CD11b/CD18)
-CD18 also involved in Tcell adhesion and extravasation so affected cattle have decreased DTH responses
Other phagocytosis defects
canine cyclic hematopoiesis
-autosomal recessive, cyclic loss of neutrophils every 11-12days
-neutrophils also have reduced myeloperoxidase so have diminished fxn
neutrophil function defect
granulopathy syndrome
neutrophil bactericidial defect
lymphocyte defects
B or T cells
-numbers and morphology of cells
-expression of CD markers
-cell fxn assays
-in vivo: AB responses to antigens, DTH reactions
-inherited autosomal recessive
-used to occur frequently in arabs
-absence of component of DNA dependent protein kinase, required to rejoin ends of DNA when the VDJ genes are cut and rejoined to produce the BCR and TCR
-no production of fxnal T or B cells
-can't palpate lymph nodes
-very low circulating lymphocytes, no IgM in presuckle serum
-survive as long as the colostral Ig

X-linked SCID
-lesion differs from other SCID lesionin gene that codes for the gamma chain of IL2R and is also a component of many cytokines result is lymphocytes can't proliferate, not as severe
B and T lymphocyte defects
lethal acrodermatitis
-autosomal recessive
-stunted growth, cutaneous hyperkeratosis and skin and respiratory infections
-low serum IgA and low T cell numbers,partially responsive to zinc therapy
B cell defects
-usually demonstrated as lowered levels of serum Igs
--agammaglobinemia no B cells, no serum Igs
rare disease, lymphoid tissues have no germinal centres, recurrent bacterial infections

Transient Hypogammaglobinemia
-delayed onset in production of Igs
-reccurrent bacterial infections, usually survive

selective IgA deficiency
-infections at surfaces: respiratory, skin, eyes
-increased autoimmunity, cancers
-most complex occurs in German Shepards
-animals can become predisposed to atopy

Selective IgM
-rare disease of arabs'
-IgA, IgG levels are normal or elevated
-recurrent bacterial infections

Selective IgG deficiency
-rare disease
-IgA, IgM levels may be normal
T cell defects
-tend to be incompatible with life so fewer conditions are perpetuated than phagocytic or B cell defects
***nude: congenital hypotrichosis and thymic aplasia
-no thymus
-defect in epithelial cells so hairless aswell
Primary Immunodeficiency
Important in helping understand the functions of the various parts of the immune system

manifest in young usually after colostral protection wanes

often result in opportunistic infections

selective IgA deficiencies may be most prevalence and of greatest clinical important
Secondary Immunological Defects
Virus induced, other agents and conditions, drugs

Virus induced immunosuppression
-usually associated with infection of the lymphocytes resulting in decreased cell numbers and functions
-less often viruses stimulate lymphoid cell activity to pathological extent results in inability to respond to other antigens
-other viruses cause lymphoid neoplasia those cells produced replace normal lymphocytes
viruses that destroy primary lymphoid tissues
chickens: infectious bursal disease virus result in Bcell destruction and inability to make antibodies

retroviruses, CDV, BVBV
--primate retroviruses: symptoms associated w/ decrease in CD4 cells virus enters into cells by CD4 results in no antibody and CMI

-transmitted by saliva, infecs lymphocytes causes many different syndromes lymphoid neoplasia or degenerative conditions

related to HIV, spread by blood and secretions, infects Tcells, megakaryocytes, M0 and dendritic cells, neuronal cells
other viruses
infects and destroys secondary lymphoid organs, depresses the activities of lymphocytes and M0 (decrease IL1 and 2), death do to secondary infecions

virus infects and destroys cells in germinal centers
infectes and can destroy lymphocytes
-may target Peyer
-acute infections result in long term decrease in immune response

Herpes (BHV-1)
other causes of immunosuppression
lymphoid neoplasia
microbial and parasitic infections
malnutrition-starvation affects Tcell functions, complementlevels and neutrophil fxn
exercise-regular moderate exercise increases immune responses, strenuous has the opposite effects because of increased steroid levels
trauma-severe injuries
age-both Band T cell responses decrease, thymic involution, majority of cells in secondary lymphoid are memory,loss in T cell cycle, bone marrow is unaffected by age
stress-increased steroids?
drugs that suppress immune response
nonspecific immunosuppression:
general effects on rapidly dividing cells, amount of radiation that is required to immunosuppress that organism is usually dead

widely used therapeutic in veterinary medicine: mechanism poorly understood steroid directly absorbed into cell and cause synthesis of protein that blocks a range of cell processes, species differences in steroid sensitivity of cells

major effects:
leukocyte circulation is decreased and usually neutrophilic also
immune effector mechanisms-decreased chemotaxis and phagocytosis and cytokine production
modulate inflammatory mediator actions-inhibit acue inflammatory response
cytotoxic drugs
designed to inhibit cell division act on various stages of nucleic acid synthesis
inhibit immune response by inhibiting cell proliferation
toxic effects on bone marrow
i.e alkalating agents, purine analogs and others
drugs that specifically target Tcells
cyclosporin target Th1 cells and blocks IL2 and IFN y, important in graft survival
other ways to deplete lymphocytes
anti-CD3 or 4 or 8
anti IL2R (deplete T activation)
used to reverse graft rejection
summary on secondary immunosuppression
often the result of virus infections that destroy lymphocytes
associated with chronic infections,stress or cancer
can be associated with immunosuppressive therapy for autoimmune disease or neoplasia
antigen specific receptors

recognition, induction, amplification, and effector mechanisms are all phases in development of specific immunity
cellular and molecular evidence for improved responses after primary response
-increase precursor frequency
-increased responsiveness to APC
-shift to broader range of CK
-expression co-receptor molecules
-phenotypic commitment
Effectiveness of memory
more responder cells, more effective recognition, migration and function

antibody peaks laterand than CMI effectors