Estrous, Immunology

• proestrus
• estrus
• diestrus
• anestrus
• OR 
• follicular stage (influence of estrogen produced by maturing follicle)
• luteal phase (progesterone produced by corpus luteum)

estrus is when a female will stand for a male.  Any other behavior is proestrus

gonadotropin releasing hormone from hypothalamus, stimulates pituitary to release FSH and LH

• Follicle stimulating hormone, released from anterior pituitary
• controls growth and maturation of follcile in ovary (releases estrogen, enough causes ovulation/LH release)
• Proestrus and estrus

ovulation

luteinizing hormone, causes ovulation (diestrus)

what's left of follicle after ovulation, relases progesterone which readies uterus for pregancy and maintains environment for fetus if pregnancy occurs.

released from corpus luteum, readies uterus for pregnancy and maintains environment to allow fetus to grow

at end of pregnacy/diestrus, fetus releases ACTH, cortisol increases, uterus releases prostaglandins and estrogen, which sensitize uterus to oxytocin

starts uterine contractions, stimulated by prostaglandins and estrogen

causes breakdown of corpus luteum, causing end of diestrus.  Otherwise, persistent anestrus and animal can't cycle again.

• caused by prostaglandin F2a, signals end of diestrus.  
• Otherwise persistent anestrus and animal won't cycle again, so CL MUST be broken down.

• actions like endogenous GnRH, FSH or LH.  
• Gonadorelin (GnRH)
• Chorionic Gonadotropin (hCG)

• gonadotropin, normally endogenous from hypothalamus (from slaughtered animals)
• causes release of FSH and LH
• used in cattle and guinea pigs for cystic ovaries
• horses and cats to induce estrus (limited success)

• gonadotropin, endogenously secreted by uterus.  Obtained from urine of pregnant women.  
• Mimics LH activity with limited FSH
• Used in cattle and guinea pigs for cystic ovaries
• in males, cryptorchidism and infertility (also makes testosterone)
• causes abortion in mare early (pre-35 days) pregnancy.  Some hypersensitivity reactions

• synthesized by ovaries, adrenal cortex, placenta and testicles from cholesterol
• development of female gonads and secondary female sex charateristics (birth control pills)
• inhibits ovulation, increase uterine tone, cause endometrium proliferation
• Estradiol, diethylstilbestrol (DES)

• Cattle for persistent CL, expel purulent material, retained placenta or mummified fetus, promote weight gain
• dogs to induce abortion, incontinence (low estrogen causes urethral sphincter problem)
• horses for estrus induction
• DES banned in food animals due to cervical cancer in humans

• compounds similar to progesterone, some secreted by CL
• anti-insulin effect and adrenal suppression
• increase endometrium secretions, decrease uterine motility, increase mammary gland secretion, inhibits release of gonadotropins from pituitary to prevent ovulation (during pregnancy)
• Megestrol acetate

• Progestins
• Dogs, as appetite stimulant, control estrus, treate false pregancy, male behavior issues, male galactorrhea (milk glands in male)
• Cats for dermatitis, behavior (urination and territorial), suppress heat cycle instead of spay
• Adverse: hyperglycemia, Addisons (GI, bradycardia, electrolytes), endometrial hyperplasia, increased appetite

• Group of long-chain fatty acids called icosenoids
• Regulates and treats conditions of female reproductive tract IF there is a luteum to lyse
• Lutalyse

• salt of endogenous prostaglandin F2a.  
• lyses luteum, uterine contractions, cervix relaxation
• Cattle, sheep goats: estrus sync, pyometra, silent heat, abortion
• swine: parturition induction
• horses: control of estrus cycle timing, anestrus mares with CL
• dogs/cats (off-label): pyoetra, endometrial hyperplasia, abortion

• bronchoconstriction
• increses smooth muscle contraction (early labor)
• sweating (horses)
• abdominal pain/cramps (h/d/c/p)
• urination/defecation(d/c/p)
• dyspnea, panting (d/c)
• tachycardia (d)
• increased vocalization (c/p)

• uterine contractility (neurohormonal).  Comes from posterior pituitary, increases contractility.
• Uterus must be primed first for a time by progesterone and estrogen
• dystocia (makes contractions stronger), retained placenta, uterine prolapse, induce milk letdown, agalactia in pigs
• NO birth canal obstruction! Can rupture uterus

Kids get allergies because they grow up in a sterile environment

• physical barrier
• innate
• acquired

• defends body against invasion by pathogens and minimize damage caused by them
• includes primary (thymus, bone marrow, Peyer's Patches, Bursa of Fabricus) and secondary (WBC, lymph nodes, lymphatic vessels, spleen, tonsils, other tissues).

• intact skin, first defense
• self-cleaning of other surfaces (sneeze, cough, v/d, UTI, etc)
• COmmensal bacteria (synergistic effect) (skin and GI), out-compete poorly adapted bad guys

• general, non-specific immune mechanisms that defend body against first and subsequent exposures to pathogens.
• LACK MEMORY. Every response is the same.
• Activated immediatly, rapid elimination. Lasts minutes to hours. 
• Reacts against common carb component most microbes have (different from "self" tissues)

• cells: detect, eat, kill pathogens and virus-invaded cells
• Molecules: bind and kill, coat so other cells can kill, block growth, prevent spread, mobilize defenses

• Natural killers, macrophages, dendritic cells
• Sentinel Cells: recognize and respond to invading pathogen/microbe, recruit WBC to phagocytize.  Usually mast or dendritic
• Compliment: set of enzymatic paths that activate proteins that kill invaders

set of enzymatic paths in innate immunity that activate proteins that kill invaders

kill invaders directly or promote destruction by defense (bind to pathogen and increase chances/ease of phagocytosis).

• Protective, localized response of tissue to damage.
• Begins immediatly at site of damage.
• dilutes, destroys or walls off agent and damaged tissue, lets blood components into damaged site. induces phagocytosis and cleans damaged tissue
• acute is protective, chronic becomes damaging/disease

• 1. increases vascular caliber (diameter of vessels), allows more blood to site. Vascular structure changes, allows plasma proteins and cells to get into tissue and form exudate
• 2. exudate: accumulation of plasma/protein rich fluid at site, causing swelling
• 3. WBCs are chemically attracted, emerge from blood to get tissue, eat and produce chemicals to clean tissue and attract other things

• inflammation is triggered by chemical mediators released by injured tissues and migrating WBCs. 
• Cause vasodilation, increased blood flow, vasopermeability.  Plasma dilutes and fibrin tries to immobilize, WBC are phagocytic for tissues and microbes
• Prostaglandins (PGs)
• leukotrienes (LTs)
• Histamine
• Serotonin (5-HT)
• Bardykinin

• diverse family of fatty acids collectively, effecting everything
• Come from cell membranes.  Phospholipases release arachadonic acids (essential) after damage (trauma or immune)

• with cyclooxygenase 1 or 2, prostaglandins
• with lipoxygenase, leukotrienes
• Platelet-activating factor

• present in normal healthy animals
• made by arachadonic acid and COX 1

• not detectible without injury and inflammation
• made by arachadonic acid and COX2
• abundant in macrophanges activated by inflammation

• increase vascular permeability
• increases smooth muscle contraction
• attract neutrophils

• huge with blue granules and big round nucleus
• Found especially in skin, respiratory, GI (where they'll find invaders), close to blood vessels
• Regulate blood flow and influence cellular migration.  
• Histamine, seratonin

when WBC, attracted to damage in a tissue, line endothelium.  Endo cells contract, WCB migrate, release chemical mediators, phagocytize

• comes from mast cells, basophils and platelets
• Increases vascular permeability and causes pain (increases nocioceptor sensitivity) in acute inflammation

• comes from mast cells, basophils, platelets
• increases vascular permeability in acute inflammation

• B cell covered in receptors binds to antigen (can be allergen), processes, presents to T-helper cell.  
• T produces lymphokines (cytokines specific to lymphocytes) that differentiate B cell into memory cell or plasma cell (produce antigen-specific antibody = IgE)
• IgE binds to FC receptor on mast cell (irreversible), causes "sensitized" mast cell
• Cross link, bind to 2 IgE, degranulates to release histamine and seratonin, cause effect.  
• Can include increased secretions, constriction, sensitized nerves, attract eosinophils.

mast cell degranulation, caused by cross link of 2 IgE, so must happen twice

• redness (vasodilation)
• swelling (permeability)
• heat (vasodilation)
• pain (pressure from swelling, histamine release)

• Protect against infection, regulate inflammation, remove damaged cells, send danger signals, regulate acquired
• 2 pathways, classical and pattern recognition
• innate defense, network of inactive serum proteins and cell surface receptors

activation of compliment by molecules in microbes (usually carbs), activated innate immunity

• evolutionarily recent
• associated with acquired immunity
• compliment becomes activated when antibodies bind to surface, work with acquired to destroy microbe

• alter cell membranes or induce inflammation
• hastens elimination of invader
• induces bacterial lysis, opsimization (makes pathogen more susceptible to phagocytosis)

• makes pathogen more susceptible to phagocytosis
• microscopic molecule can bind to surface of large pathogen so other cells can more easily eat invader

• alter membranes (bacterial lysis, opsimization)
• inflammation (mast cell degranulation, neutrophil chemotaxis to attract phagocytes)
• other (immune regulation, angiogenesis, removal of apoptotic cells
• blood coagulation

• antigen-SPECIFIC immune response to a particular substance that the body IDs as "non-self"
• directed against specific pathogen
• Slower, but LEARNS, long-lasting
• does not fully develop unless body has been previously exposed to that specific pathogen
• 2 types: Cell-mediated (T and B cells) and Humoral (antibody-mediated)

acquired immune system

• innate: macrophages, dendritic, neutrophils, natural killers (sentinel and phagocytic)
• adaptive: T and B cells

• any substance that can induce a specific immune response
• usually a large protein molecule recognized by cells of acquired

• usually macrophage, dendritic cell, some B cells
• Traps and processes antigen
• presents antigen to immune system cells who take care of it.  
• Process antigen, present it on surface, T-helper recognizes, B cell coated in receptors binds to same antigen, tell B to become memory or plasma, plasma cell produces antibodies specific to antigen, make antibody-antigen complex.

• exogenous antigens openly proliferate, can be found by antibodies (humoral)
• intracellular pathogens proliferate in cell and are taken care of by cell-mediated immunity (not accessible to antibodies)

lymph nodes, sometimes in secondary lymph organs like spleen

• glycoproteins.  Antibodies.  
• Antigen-specific, usually not seen for at least a week after exposure (can't test right away)
• Bind to antigen they are specific to, cause antigen/antibody complex

• test.  Apply electric field to sample, molecules separate by size and charge.  Run when see hyperproteinemia characterized by hyperglobulinemia.  
• Albumin most negative, rest separate into alpha, beta and gamma. 
• Gamma is immunoglobulins.  
• Look for spike--is it one Ig or several? Monoclonal vs polyclonal gammopathy

GMADE

• highest concentration in serum, longest half life (in circulation longest), smallest molecule (escapes vaso in inflamm)
• defense of tissues, can bind to pathogens and specific antigens, causes bacteria to clump and activates opsimization (more susceptible to phagocytes) in classical compliment pathway
• Produced in spleen, lymph, bone marrow (1 and 2 lymph tissue)
• Predominant transferred from mom to offspring in colostrum

• 2nd highest concentration in serum, largest molecule so stays in circulation
• antibody produced on initial exposure to antigen
• primary immune response (also 2 but less)
• More efficient than IgG in activation of opsimization, activation of compliment and neutralizing viruses
• produced by plasma cells in 2 lymph organs (NOT bone marrow)
• Shaped like a polygon, not linear like other Igs

• third highest concentration in serum, predominate Ig found in body secretions of nonruminents
• produced in body surfaces (guard at the gate), makes pathogens and viruses clump to each other and body surfaces "not sticky", major in preventing pathogen invasion.  
• Bord IN (airborne pathogens)
• NOT increase opsimization or activate compliment
• produced in respiratory, skin, urogenital, GI, cornea, mammary glands

• B-cell receptor, very little in blood
• Not yet found in rabbits, chicken, cats
• not sure what does.  
• Found attached to B cells only

• 1. immediate allergic reaction, red, swollen, itchy, sneezy
• 2. antibodies attack self (auto-immune)
• 3. deposition of antibody/antigen complex in tissue creates inflammation (glomerulonephritis, for example)
• 4. delayed, very slowly developing, mediated by T cells and natural killer cells.  Takes 24-96 hours to develop.

• low concentration in serum (shortest half life)
• mediate allergic reactions, especially type I.  Causes degranulation of mast cells if cross-linked, more than 1 IgE on surface
• enhances local defenses, triggers acute inflammation (FC on mast and basophils) and compliment in PARASITIC WORM IMMUNITY
• produced by plasma cells beneath body surfaces (respiratory, skin, urogenital, GI, cornea, mammary)

• LOTS of Igs.  
• monoclonal could be cancer
• polyclonal suggests infection (FIP?)

• fragment receptor crystallized.
• Steadier part on stem of antibody, antigen binding sites can change, FC is more constant

• Administer pre-formed antibodies from another immune animal (inject Ig)
• Immediate but not long-lasting
• artificial: antiserum, antitoxin
• natural: colostrum/placenta, from mom

• IV organism (killed or modified live if artificial), animal fights.  
• Takes longer to develop, lasts longer
• artificial: vaccination
• natural: infection
• Repeated exposure makes immunity stronger, booster vaccines

• administration of antigen to stimulate immune so individual can develop immunity
• 1st: development of effector T and B cells (helper, killer, suppressor), temporary protection
• 2nd: development of memory T and/or B cells, re-exposure (3rd), recognition, clonal expansion and differentiation into effector T and B cells, kill invader.

T or B cell that stops allergic response from going on, spares "self".

• Inactivated vaccine: virus or bacteria grown in culture then killed (formaldehyde or heat). Proteins remain intact enough to be recognized by immune (exogenous antigen) and stimulate mostly T helper cells (CD4)
• Modified live vaccine: attenuation (goldilocks) to reduce virulence, stimulates response of mostly cytotoxic T cells (CD8), act as endogenous, cell-mediated immunity.
• viral purified subunit: inject into another species
• viral recombinant product: inject into another species
• viral DNA vaccine: most recent, protein off capsid, purified

DNA that encodes antigen is injected into the individual

take gene responsible for coding of antigen, inject into another species or virus (cat rabies = canary pox)

most recent, take protein off capsid, purify and make vaccine from that

• attenuated, strong enough to stimulate, too weak to replicate.  
• Response primarily cytotoxic T cells (cell-mediated, get into cells and replicate, endogenous)
• fewer smaller doses required, more effective, adjuvents unnecessary, less chance of hypersensitivity, cheaper, given with natural route, stimulate humoral and cell mediated response, lover-lasting (3 year)

• killed with formaldehyde or heat, mostly T helper cell response (acts as exogenous)
• Stable on storage, safer, unlikely to cause disease, do not replicate, will not spread, safe in immunodeficient patients, easier to store, no risk of reversion

process that reduces virulence of virus in vaccine (goldilocks).

additives to enhance effectiveness so you need less.  Often causes reactions.

vaccine for bacteria, almost always killed

1940s, with smallpox

• defense inside cells where antibody can't reach.  
• Eliminate abnormal cells and intracellular organisms (endogenous)
• cytoxic T cells (CD8) cause forced apoptosis
• Cells leave lymph organs and seek abnormal cells.  Don't wait to be presented.
• Cancer

• most common primary binding test
• Detect and measure antibodies.
• Well is pre-coated with antigen, serum goes in well, makes a/a complex if present.  Add anti-globulin (protein that binds to Ig, which is bound to a/a complex, sandwich), causes color change.

• Fluoresce when irradiated with blue or UV light
• tests serum for antibodies
• Direct and indirect
• Direct: label antibody specific for antigen, antibody fluoresces
• indirect: fluoresce on anti-globulin

• indirect. Tests infection based on post-exposure (not definitive, or straightforward. current? May not be active)
• false + can be post-clinical, exposure without disease, vaccination, colostrum.
• 2 samples (acute and convalescent later)
• Lyme, toxoplasmosis (problematic)
• Most common in alive animal

fourfold increase in antibody titer (between acute and convalescent sample) consistent with recent antigenic stimulation

• IgM indicates recent exposure, usually seen first in immunoresponse
• IgG is produced later in response, indicates exposure several weeks to months previously