Immunology Exam 2

MHC promiscuity: The MHC binding pocket is much more _____________ than the Ab or T cell receptor binding pocket. Essentially, there are many peptides that fit, requiring only conservation of the ___________ _______________ that interact with the antigen contact residues within the MHC binding pocket.

"flexible"; anchor residues

C5 convertase: • The Classical and lectin pathways generate a different C5 convertase than the alternate pathway. • C5 binds to the C3b component, allowing cleavage by _________ (classical) or _______ (alternate). • C5b does not bind surfaces covalently. • C5b initiates formation of the ________________ ______________ _____________ • C5a leads to _____________________

C2b; Bb; membrane attack complex (which leads to cell lysis); inflammation

pathways converge: • All pathways form a ______/______ __________________, which cleaves and activates ______ and ______. • After this formation, the pathways overlap and use the same proteins.

C3/C5 convertase; C3 and C5

Complement Deficiencies: Loss of ___________ severely impairs migration of neutrophils and macrophages from the blood into sites of inflammation. This molecule is an ___________, and also turns out to be _________

CD18; integrin (transmembrane receptor); CR3 (which binds C3b which does opsonization)

The TCR complex is associated with _________, a multisubunit complex which is NOT Ag-specific nor variable but which serves to transmit intracellular signals if the TCR is engaged. Undergoes ________________________ if TCR is bound by antigen.

CD3; phosphorylation

__________ cells are required to create and maintain memory CD8+ T cells

CD4+

MHC class I pathway: ___________________ break down endogenous proteins (into peptides 12-15 amino acids long); the epitopes go to the ______ because that's where the MHC I molecules are; MHC molecules with epitopes bound can leave and go over to the ___________ where it is delivered to the cell surface

proteosomes; ER; golgi

when an MHC molecule with an epitope binds to a TCR (T cell receptor) there is also a coreceptor on the T cell that binds to the MHC molecule; what are the 2 versions of this coreceptor?

CD4+ and CD8+

T cell maturation in the thymus requires antigen presentation to the differentiating T cells. If class I presentation is missing, __________ T cells cannot be selected for, and vice-versa.

CD8+

MHC 1- only interacts with ___________ T cells, and only presents ___________________ antigen MHC 2- only interacts with ___________ T cells, and only presents ___________________ antigen

CD8+ T cells (cytotoxic T cells) ; endogenous; CD4+ T cells (helper T cells); exogenous

In animals, the MHC is linked to both immune and production traits. what are some traits in Cattle, sheep/goats, pigs, and horses that are linked to MHC?

Cattle - Blood neutrophil counts - Mastitis frequency, esp. coliform mastitis susceptibility - BLV susceptibility Sheep/Goats - Resistance to T. colubriformis - Incidence of scrapie - Susceptibility to caprine arthritis-encephalitis - Resistance to Cowdria Pigs - Litter size, ovulation rate, piglet viability - Growth performance - Muscle larval burdens for T. spiralis Equine - Risk of recurrent uveitis - Sarcoid tumors - Insect bite allergies - Response to Equine Infectious Anemia Virus

B cells against self antigens are deleted in the bone marrow. B cells can try to rearrange ________________ (antibody genes) such that they don't bind self

receptors

what is the clinical criteria for a dog or cat with SIRS: (temp., heart rate, respiratory rate, WBC ranges?; and how many of these categories = SIRS in cats/dogs)

DOG: 1. temp. <99 or >102.6 2. heart rate >140 3. respiratory rate >40 4. WBC >19,000 or <6,000 (3%) -2 out of 4 = SIRS CAT: 1. temp. <100 or >103.5 2. heart rate <140 or >225 3. respiratory rate >40 4. WBC <5,000 or >19,500 (5%) -3 our of 4 = SIRS

Cardinal clinical signs of acute/early inflammation (localized) (5 signs):

redness, heat, swelling, pain, and loss of function *redness and heat caused by vasodilation (more RBC's) and swelling caused by increased vascular permeability

Disruption of the epithelial tight junctions allows access to the host; what's one pathogen that's good at this?

E. coli

-Following uptake of bacteria, neutrophils and macrophages are induced to make free radicals that damage cell membranes -The activity is triggered by decreased pH of the phagosome

respiratory burst

MHC _______________: T cells only recognize MHC molecules by which they were educated in the thymus; because T cells recognize not only the epitope but the MHC molecule; has to recognize both at the same time in order for the T cell to become active

restriction

some tumors escape clearance by Tc cells using the same strategies as immune privileged sites (such as engaging ________-__________ or expressing __________________ cytokines)

Fas-FasL (which leads to apoptosis of T cells); inhibitory (such as TGFB2 and G-TsF)

what is the receptor for phagocytosis you should know and what does it do?

Fc receptors- bind antibodies; phagocytes can have Fc receptors for the Fc part of the antibody and the top part of the antibody (variable part) can bind an antigen (ex. bacteria)

Antibody produced during an immune response also removes the stimulus (antigen). This means there is less antigen to stimulate further specific responses. Moreover, immune complexes can block activation by binding to inhibitory receptors. For instance, ____________ signals are inhibitory for B cells.

FcγRII

___________ have unique structures that bind certain TLR

Fungi

how are organisms attenuated?

Growing the organism in vitro until it loses virulence. However, rDNA can be used to directly remove or mutate virulence genes such that virulence is directly attenuated.

where are T cells activated by APC's?

secondary lymphoid organs

ACUTE INFLAMMATION - vascular effects: 1. _________________: The process of stopping blood leakage from a damaged blood vessel, which involves vasoconstriction and clot formation (coagulation and platelet aggregation) 2. __________________: increases net blood flow resulting in heat, redness, and swelling/edema. Fluid escaping the blood vessels during vasodilation is referred to as __________________ (extravascular fluid with low protein). 3. Increased _________________ _______________________: Endothelial cells contract permitting the passage of protein rich fluid (____________). 4. Increased endothelial cell _______________________: Endothelial cells become sticky allowing for leukocyte attachment and migration.

Hemostasis; Vasodilation; transudate; vascular permeability; exudate; adhesiveness

Class ___ and ____ MHC molecules actually physically present the antigen on the surface of a cell. Class ______ is a loose term for all other genes in the MHC region.

I and II; III

cytotoxic T cells: -CD8+ T cells which recognize Ag presented in the context of MHC class ____ -Are highly selective in that they will not kill surrounding cells of the host (Polar release of the _______________ ______________ accounts for this) -Have rearranged _______ as do TH cells -secrete _________ which can block viral replication. -Th cells augment Tc cells via secretion of _________ and by increasing MHC class ____ gene expression.

I; cytolytic granules ; TCR; IFN-α; IL-2; MHC class I

• The C5 convertases can be inactivated by displacing C3b and cleaving it by Factor ___ or displacing C3b by Factor ____

I; H

what is the MHC gene order for humans, pigs, dogs, rabbits, chimps?

II, III, then I

Cytokines: mainly produced by leukocytes. ___________, ___________, and __________ tend to be very proinflammatory.

IL- 1β, IL-6, and TNFα

TSLP activated dendritic cells (turn self reactive T cells into Treg cells) do not produce Th1-polarizing or pro-inflammatory cytokines such as (4 examples)

IL-1 a/b; IL-12; IFNs; eotaxin 2

Treg cells produce anti-inflammatory cytokines such that they inhibit the activity of other cells, including activated T cells. The cytokines responsible for this are ___________ and __________

IL-10 and TGF-B

-_______ class switching in B cells is initiated by TH2 cells which develop in the presence of _________. Naive T cells differentiate along a TH2 pathway. When TH2 cells interact with B cells, they stimulate switching to _______. The interaction also induces the B cells to proliferate, thereby generating many copies of this _______-producing B cell clone. -this happens in ____________ ______________

IgE; IL-4; IgE; IgE; lymph nodes

natural passive immunity: antibodies transferred from mom to baby; _______ is transferred across the placenta and _______ is transferred through breast milk

IgG; IgA

which antibody is always on surface of B cell and the first type of antibody made

IgM

what 2 antibodies are the best at activating the complement system?

IgM and IgG

B cell receptor ITAM • B cell receptors require ________ and ________ to transmit signal to indicate IgM has bound antigen. • __________/__________ co-receptors also amplify the signal. • Thus, complement further stimulates B cells that have bound antigen

Igα and Igß; CD21/CD19

______________ _____________: By arbitrarily splicing nucleic acids together within the region, different reading frames are generated leading to different amino acid structure at the Ag binding pocket. This process occurs at all V-D-J junctions during recombination. This is the same as what process in antibodies?

Imprecise joining; junctional diversity

Acute inflammation begins within _______________ to ________________ following tissue injury via trauma or infection.

seconds to minutes

Acute phase proteins are produced by liver cells in response to inflammatory signals such as _______, ____________, and _________. Acute Phase Proteins include serum amyloid A (SAP), C-reactive protein (CRP), fibrinogen, and mannan-binding lectin (MBL). SAP and CRP are pentraxins that form 5-member disks. Their expression is an indicator of systemic inflammation, often chronic.

LPS, TNF-α, and IL-6

the lymphoid organ where the lymphocyte finds its antigen causes them to prefer to return to that tissue (ex. if becomes effector cell in ________ then prefer to return to mucosal surfaces..)

MALT

The _________ is the structure used to "talk" to T cells - The _____________ is presented to T cells which have a receptor for various ones - The T cell receptor actually binds both the ______________ and _________ molecule

MHC (Major Histocompatability Complex); epitope; epitope and MHC

the MHC molecules of an antigen presenting cell present ________ epitopes as well as ____________ ones but T cells should only recognize foreign epitopes as being dangerous

self; foreign

• Both MBL and ficolins bind _____________ ___________________ that cleave ______ and _______ • then _________ and __________ combine to form C3 convertase • C3 convertase then produces C3b that binds to bacteria

serine proteases (ex. MASP-2); C4 and C2; C4b and C2a

Signals are transmitted through both the _________ molecules and the ____ _________ ________________. This (usually) activates both cells.

MHC; T cell receptor

lectin pathway: • The lectin pathway uses proteins very similar to the C1q component from the classical pathway. There are two major host-derived serum proteins that bind to bacterial surfaces to start the cascade: - _____________ _____________ ___________- binds to mannose residues and several other sugars present on many pathogens but not on mammalian cells. It is also produced by the liver in low quantities that are increased during an acute phase response. - ___________- a family of proteins that binds to carbohydrate structures on bacterial and fungal cells to activate the cascade. They are present at higher levels in serum. Animals lacking an adaptive immune response have larger families of ficolins to provide broader recognition of pathogens.

Mannose binding lectin (MBL); Ficolins

Linkage of MHC alleles with specific disease susceptibility traits or autoimmune pathologies is widely recognized. Various alleles can lead to presentation/non-recognition of certain epitopes. MHC loci are inherited in classical _________________ fashion, just like every other locus

Mendelian

_______________ increases with increase in number of SIRS symptoms and in severity of the disease process

Mortality

• ROP are formed within the phagolysosome by activation of ______________ ____________ • The enzyme generates highly reactive oxygen ions that damage cell membranes (ex. superoxide, hydrogen peroxide, hydroxyl radicals, and hypochlorite) • Nitric oxide can also assist in killing the pathogen, but is formed via a different enzyme system (__________ ____________ _________________).

NADPH oxidase; nitric oxide synthetase

neutrophils can kill bacteria with or without oxygen; 1. oxygen dependent- _____________ donates electron to oxygen to make ________ to kill bacteria; 2. oxygen independent- bags of ________________ within neutrophils can be released into the phagosome to kill bacteria

NADPH; ROS; proteases (proteasomes)

danger signals: The main family of proteins that signal damage are the ___________ which are activated only in stressed cells. These signals are induced by __________ ______________________ following loss of cytoplasmic ______

NALPs; NALP dimerization; K+

__________: -Networks of extracellular fibers, primarily composed of chromatin (DNA and histones) and released granule proteins. released by neutrophils -appear to provide a high local concentration of antimicrobial components that trap and/or kill extracellular microbes independent of phagocytic uptake.

NETs (Neutrophil extracellular traps)

____________: TLRs predominantly detect PAMPs acquired via endocytosis. However, cells have similar mechanisms to detect PAMPs within the cytoplasm. These are even more ancient evolutionarily than are TLR, but also activate __________. ALL work together with TLRs to give immediate recognition of PAMPs.

NOD's (Nucleotide binding oligomerization domain proteins); NF-kB

passive immunization: -Defined as the protection of one individual via transfer of Ab (or B cells or T cells) from another individual - Usually __________-lived (no memory) - Can induce _____________________ reactions - Can transfer other infectious agents

short; hypersensitivity

• The most important action of complement deposition onto bacterial surfaces is _______________________ which enhances uptake by phagocytes. • Many blood cells have receptors for certain activated complement proteins, the most important being ________ on _____________________ and ____________________. • Uptake via complement receptors can activate the phagocyte.

OPSONIZATION; C3R (C3 receptor) (this receptor recognizes C3b); macrophages and neutrophils

______________________: If the connective tissue framework and/or parenchymal cells are excessively destroyed then the inflammatory lesion is essentially bonded together by fibroblast cells and collagen.

Organization (scarring/fibrosis)

____________: -structures and molecules not found in higher eukaryotes -we have evolved receptors (on innate cells) to specifically bind those "patterns"

PAMPs (pathogen associated molecular patterns)

___________ ________________ 1994- proposed the "Danger Signal" hypothesis to explain self vs non-self immune recognition _____________ _______________ 1996- showed that innate immune cells have "pattern" receptors that detect non-self pathogens by their unique components

Polly Matzinger; Charles Janeway

The system recognizes a wide variety of epitopes: • _______________- several genes exist for a given MHC class • __________________- a large number of alleles exist for a given gene • ___________________- will bind a range of similar epitopes

Polygenic; Polymorphic; Promiscuous

immune privileged sites vs. immune privileged tissues

sites- sites where foreign tissue grafts can survive for a long time; inhibit immune response tissues- organs that have extended survival when transplanted to conventional sites on a mismatched recipient; are resistant to immune clearance

Lipid mediators: _____________________ and ____________________ mainly produced by leukocytes that attract more leukocytes as well as induce various vascular effects.

Prostaglandins and leukotrienes

TCR generates diversity by _________________ ___________________________ and Each T cell expresses _____-_____ thousand receptors of IDENTICAL specificity.

somatic recombination; 10-30K

how does antigen processing relate to the adaptive immune system?

some of the broken down antigen is presented by MHC molecules to T cells

NETs are only released if neutrophils are stimulated to produce _________.

ROS

Rather than expressing or purifying an antigen to create a subunit vaccine, one can insert the gene for that antigen into a harmless vector. The vector is a live organism that does not cause disease.

Recombinant Vector Vaccine

when the lymphocyte recognizes its antigen it undergoes clonal expansion and proliferates; these cells are temporarily retained in lymphoid tissue as they expand; how?

S1P- draws naive lymphocytes into the efferent lymphatics if they don't find their antigen S1PR1- is downregulated when the lymphocyte recognizes its antigen so that the lymphocyte will be retained in the lymphoid tissue for a while

sepsis definition

SIRS + infection = sepsis -Systemic response to infection with bacteria, viral or protozoal organisms -infection is the process, sepsis is the response

ONCE A TCR IS SUCCESSFULLY REARRANGED (BY _______________ ____________________________), NO FURTHER __________________ ___________________________ OCCURS; THIS IS DIFFERENT FROM ANTIBODIES; DON'T WANT T CELLS TO RESPOND TO YOUR OWN EPITOPES (IF THERE WAS ________________ _____________________________ THIS MIGHT HAPPEN)

SOMATIC RECOMBINATION; SOMATIC HYPERMUTATION; SOMATIC HYPERMUTATION

The multi-step process is mediated by various adhesion proteins and chemokines. Key groups/families of adhesion proteins include what 4 molecules?

Selectins, mucin-like molecules, Integrins, and the Immunoglobulin superfamily; *chemokines activate the lymphocyte and other adhesion molecules

diseases associated with SIRS/sepsis

Septic peritonitis Pyelonephritis Pyometra Pyothorax Septic arthiritis Abscesses: liver, renal pancreatic Severe wound infections Pneumonia Bacterial endocarditis Prostatitis Severe enteritis: bacterial translocation Neoplasia Severe pancreatitis Diskospondylitis

Some bacteria can avoid the barrier functions of the immune system altogether by existing within infected cells, right in the cytoplasm. _____________ and ______________ are two examples of bacteria that can escape the vacuole to access the cytoplasm.

Shigella and Listeria

some bacteria produce their own Fe+2 binding proteins called _____________________ to compete with the host proteins

Siderophores

when T cells die they are removed by phagocytosis in the ____________

spleen

MHC class II pathway (8 steps)

Step 1- binding of antigen non-specific receptor mediated (CR3, FcR, mIg) Step 2- Endocytosis (B cells), phagocytosis (macrophages and dendritic cells), or pinocytosis (all cells) Step 3- Endosome (phagosome) formation Step 4- Endosome pH decreases to activate proteases Step 5- Endosome-lysosome fusion contains more proteolytic enzymes and MHC class II molecules Step 6- Association of processed Ag with MHC class II Step 7- Fusion of phagolysosome with plasma membrane Step 8- Ligand interaction with CD4+ T cells

-These vaccines contain only defined proteins from an infectious agent rather than the whole organism. -include those in which an antigen is complexed with a carrier protein to increase immunogenicity.

Subunit or component vaccines

SIRS definition

Systemic (whole body) Inflammatory Response to a variety of severe clinical insults including: microbial invasion, severe injury, neoplasia or any disease process that causes severe inflammation

The T cell receptor chains are composed of discrete segments that are generated by somatic rearrangement during development of the T cell. For the alpha chain, after a V-J joining occurs, the gene is transcribed. The J chain segments remaining between the new VJ and the constant region exon are _____________ out of the RNA transcript as tho they were introns.

spliced

Nasal delivery is increasingly common route of exposure - Improved antigen ________________ and _________________

stability and retention

3 things that inhibit lipid mediators

steroids and COX-1 and COX-2 inhibit this process (and therefore inflammation)

-Memory T cells allow the adaptive immune response to start again very quickly without requiring full __________________ and selection of naïve T cells. -which interleukin is important in generating memory T cells?

stimulation (don't need all 3 stimulatory parts); IL-7

T cells are lymphocytes that begin development in the bone marrow through interactions with _____________ cells and __________________

stromal cells and cytokines

job of Th1 vs Th2 cells

T helper 1- activate macrophages and dendritic cells T helper 2- used to activate B cells *both types use cytokines to complete these activities

____ cells that recognize antigen presented by dendritic cells in the lymph nodes are activated and proliferate (divide) a bunch and can then activate ____ cells specific for that antigen

T; B

MHC class I (more details) -________ _______________ move peptide fragments into ER - Processing completed by ________________________

TAP proteins; aminopeptidase

In the absence of infection, __________ production by dendritic cells in draining lymph nodes drives differentiation of Treg cells (sometimes called Tr1 cells)

TGF-B

what factors (4) promote immune privilege in the eye?

TGFB2; VIP; MIF; and CD59 (all located in aqueous humor)

Complement receptor stimulation can work with ________ signals to induce a very strong expression of proinflammatory cytokines.

TLR

How do TLR activate phagocytes?

TLR signal the cell via overlapping cascades of kinase reactions. Most lead to activation of several transcription factors, but NF-kB is the most important concerning which genes are turned on. This is especially important for activating which cytokine genes are turned on and how strongly the genes are expressed.

_________: -(membrane associated cells that can be on the outside of a cell or inside in a lysozome) recognize PAMPs and then send signals to the cell's nucleus by affecting transcription factors -suggests that the innate immune system can recognize evolutionarily conserved structures and patterns on different types of pathogens.

TLR's (toll-like receptors)

_________-derived dendritic cells in the thymus (generated near ________________ _______________), interact with some self-reactive T cells to make them ________ cells capable of muting response to those self antigens in the peripheral tissues such as lymph nodes

TSLP; hassall's corpuscle; Treg; **hassall's corpuscles- secrete TSLP; as T cells move to the thymus and start to differentiate they can be rescued from apoptosis by hassall's corpuscles if they're autoreactive

MHC class II Codominant Expression and MHC class I polymorphism & polygeny:

The MHC cells are able to present a wide variety of processed peptides by having several loci which code for molecules of the same function, and by having many alleles within the population. Both alleles from each locus can be expressed by the same cell type. The binding pocket is promiscuous and can bind many different epitopes

the transcription factors produced generate ______________ ____________________ (non-reversible)

terminal differentiation

sepsis- bacteria are spread to the circulatory system and then spread to the entire body; supportive care for sepsis =

Vasopressors, fluids, oxygen, antibiotics, organ protection.....

what are lysosomes?

they contain enzymes/proteins and fuse with phagosomes to break down antigen

what is a haplotype

a collection of alleles

what's special about high endothelial venules?

they have no tight junctions

what cells accumulate during acute vs. chronic inflammation?

acute- neutrophils chronic- macrophages and lymphocytes

In reality, many different _______________ _______________, ____________________, and _________________ __________________ are involved in controlling lymphocyte migration from the blood into tissue sites.

adhesion proteins, chemokines, and chemokine receptors

________________ are substances that enhance the immunogenicity of an antigen.

adjuvants

needleless vaccines (advantages and disadvantages)

advantages: - No risk of disease transfer between individuals - Better disbursement of antigen - No "sharps" waste - No risk of needle breakage in carcass - Can be used for any type of vaccine disadvantages: -more expensive

live vaccines: advantages and disadvantages

advantages: -induce Th1 and Th2 response (viral vaccines also CTL response) -few innoculating doses required -adjuvants unnecessary -induction of interferon -relatively cheap -usually contain attenuated organism (limited virulence, causes infection but not disease) disadvantages: -could potentially get the disease -could infect immunosuppressed person

DNA vaccines (advantages and disadvantages)

advantages: • Very stable • Very safe • Inexpensive to produce disadvantages: • Still a subunit vaccine • Risk of transgenesis (dna integrating into the chromosome and causing a mutation) • Public acceptance?

there are many ____________ of the T cell receptor genes; this is what creates the high level of diversity of T cell receptors

alleles *TCR diversity is about equal to antibody diversity

Only the TCR from 1 chromosome is expressed within a given T cell; the remaining chromosome rearrangement is suppressed by a mechanism called ____________ __________________

allelic exclusion

T cell receptor structure

alpha and beta chains with variable regions (where the epitope/MHC molecule binds; and the part that is rearranged similar to antibody gene rearrangement), constant regions, and hinge regions (little part between membrane and constant region)

B cells can also be rendered _____________ in the periphery if they don't receive enough positive signal, including ____ cell help

anergic; T

What might be the benefit of lymphocyte homing? A. To direct lymphocytes to tissue sites where they will most likely re-encounter antigen. B. To separate effector lymphocytes from naïve lymphocytes to prevent competition for antigen.

answer is A

What might be the benefit of constant recirculation by naïve lymphocytes? A. To prevent secondary lymphoid organs from overfilling with lymphocytes. B. To increase the likelihood that lymphocytes will encounter antigen they can recognize.

answer is B

Any molecule capable of inducing antibody generation

antigen

The display of antigens as peptide fragments bound to MHC molecules on the surface of a cell

antigen presentation

Highly specialized cells that can display processed antigen as peptide fragments on the cell surface.

antigen presenting cells

The degradation of proteins into peptides that can bind MHC molecules for presentation to T cells.

antigen processing

MHC class II process

antigen taken in by phagocytosis and processed; peptide bound by MHC class II molecule and travels to surface

peripheral tolerance: T or B cells that recognize self antigens out in the periphery can either undergo ___________________ or ____________

apoptosis or anergy

________________: A process of programmed cell death involves an orchestrated series of biochemical events leading to a characteristic cell morphology and death. The apoptotic process is executed in such a way as to safely dispose of cells, such as neutrophils. Not to be confused with ______________, which is a form of cell death that results from cellular injury.

apoptosis; necrosis

the thymus has a cortex (outer region) and medulla (inner region) and also has hassall's corpuscle cells; why does the thymus stain lighter in the medulla and darker in the cortex?

as you get closer into the medulla it stains less dark because there are less T cells that rearrange successfully and become mature (express receptors); then can leave the thymus and circulate through the blood and secondary lymphoid organs

having different diseases/ disorders (ex. diabetes) gives one a greater risk of developing ____________________ disease

autoimmune

which organ gets smaller with age?

thymus; still have thymic remnants when you get older; can't produce as many naiive T cells but still have all the memory T cells; bone marrow is always producing more T cells

MHC class II presentation is a __________ and _____________ dependent process

time and energy

disadvantage of autogenous vaccine?

time between detecting infection in the herd and availability

in evaluating the dog annie who had 2 bullet wounds; what did they use to see if there was any leaks from the respiratory/GI tract into the tissues?

barium (looked on radiograph and didn't see any leakage)

immunologically privileged sites (5)

brain, eye, testes, uterus, hamster cheek pouch

_____________ _______________ _____________________ (mast cells, macrophages, dendritic cells) recognize the warning signals from pathogens (PAMPs) and damaged cells (DAMPs) and then dump out a ton of chemicals and signals to signal ___________ inflammation to start

tissue resident leukocytes; acute

positive/negative selection of T cells in the thymus is a form of _____________ __________________

central tolerance

central tolerance vs. peripheral tolerance

central- T (in thymus) and B (in bone marrow) cells that bind self antigens are deleted by clonal deletion peripheral- T and B cells that bind self antigens are inhibited from effector function (by anergy, cell death, or immune deviation)

____________ memory T cells- stay in lymph nodes ____________ memory T cells- travel into the tissues -both types are stimulated by IL-7

central; effector

the movement of dendritic cells to lymph nodes is mediated by what?

chemokine receptor expression.

Once circulating lymphocytes enter secondary lymphoid organs or sites of inflammation, their migration is controlled by specific ________________ that guide them to specific locations (e.g., T cell or B cell areas).

chemokines

_________________-tells the leukocytes where to go within the tissue once they exit the blood vessels (mediated by chemicals/cemoattractants that attract the leukocytes; there are more and more cemoattractants the closer you get to the antigen/invader)

chemotaxis

what does each MHC class molecule encode (MCH class I, class II, and class III)

class I- encode a single chain class II- encode 2 chains (α and ß) class III- encode cytokines, heat shock proteins, Ag processing and transport proteins, and complement proteins (this is not another way to present epitopes)

which MHC class is present on most cells and which one is present only on antigen presenting cells

class I- most cells class II- only antigen presenting cells

For self-reactive T cells in the periphery, tolerance is induced by lack of _______________________. Without this, the T cells is actually induced to _____________, or lack of responsiveness.

co-stimulation; anergy

why is the complement system highly regulated?

complement system is not antigen specific so it has to be highly regulated

____________________ molecules are produced when the cell is stressed (infected by virus or bacteria); the cytotoxic T cell binds to these and ________ _______________ released in polar fashion only at the interface of the damaged cell without killing the neighboring cells

costimulatory; CTL (cytolytic) granules

some Dø can activate CD8+ T cells even though that requires class I presentation of exogenous antigens via a process called __________-__________________, also called __________________________.

cross-presentation; retrotranslocation

TLRs specifically recognize microbial components unique to their pathogen class. By triggering different responses in phagocytes (mostly Dø and Mø), they determine which ______________ are produced. This provokes a specific adaptive immune response. TLRs ARE THE OTHER LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY.

cytokines

Many vaccines now include __________________ or _______-_______________ that directly stimulate the APC to improve immunogenicity

cytokines or TLR-agonists

memory T cells (both CD4+ and CD8+): • Some memory T cells have a phenotype where they rapidly produce ________________ and enter inflamed tissue. • Other memory T cells express ___________ which suggests they would migrate quickly to lymph nodes.

cytokines; CCR7; *some memory cells are out to the periphery (this leads to faster response because don't have to wait for antigen to travel to the lymph nodes)

_______________ turn on transcription factors which favor differentiation of a certain type of T cell (ex. Th1); the T cell goes on to produce _______________ which favor their same pathway (ex. Th1) and slow down the other pathway (ex. Th2)

cytokines; cytokines

______________ cells are the most potent stimulators/activators of naive T cells!

dendritic

-How did the B cell get a hold of the antigen? -Is the epitope recognized by the antibody the same as the epitope recognized by the Th2 cell?

dendritic cells; doesn't need to be (as long as the epitopes are from the same antigen)

best chance for surviving sepsis = early _________________ and early __________________

detection; intervention

-apoptosis caused by Tc cells (cytotoxic T cells) does/does not trigger further inflammation -Granzymes activate ____________ in the target cell to start the process of apoptosis

does NOT! caspases

want TCR's to bind just the right amount to MHC molecules; tight enough to recognize that the receptor binds to the epitopes that are there but not super tight, why?

don't want TCR's to bind too tightly to the epitopes in the thymus because they are self epitopes; and if the TCR binds too tightly then it will bind to self epitopes out in the periphery

why are neutrophils killed by apoptosis and what happens during apoptosis?

don't want neutrophils around for a long time because they might start killing host cells; during apoptosis the neutrophil kind of collapses in on itself without releasing all its toxic chemicals (which is good because the toxic chemicals would kill your own cells) and then macrophages come and eat them; once neutrophil gets into the tissue it dies there and is removed there (can't reenter blood vessels)

what is the difference between an MHC class I molecule presenting antigen to an effector CD8+ T cell vs. a naive CD8+ T cell?

effector- the T cell kills the cell with the MHC class I molecule naive- the antigen presenting cell (usually dendritic cell) activates the naive T cell to become an effector T cell

Circulating lymphocytes attach to and trans-migrate through ________________ cells lining post-capillary venules by a multi-step process. This provides precise control over the rate and levels of lymphocyte accumulation. What are the 4 steps to this process?

endothelial; 1. capture/rolling 2. activation 3. adhesion 4. trans-migration

Also called an antigenic determinant, it is the portion of a larger antigenic molecule that is recognized by antibodies or T cell receptor

epitope

examples of differences between eukaryotic and prokaryotic cells

eukaryotic- have organelles, big, 80s ribosome, no cell wall, longer replication (18 hrs), diploid, more chromosomes prokaryotic- no organelles, small, 70s ribosome, peptidoglycan cell wall, short replication (30 min), haploid one circular chromosome

dendritic cells efficiently take up immune complexes, then shed immune complex bodies (________________) containing antigen for uptake and processing by B cells (by specific recognition by IgM).

exosomes

T/F: neutrophils express antigen

false (?)

Tregs can be generated in the thymus or locally (in secondary lymphoid organs) during Th0 cell polarization through activation of the __________ transcription factor; _____________ ____________ in the gut- is often where Th0 cells in the periphery become Treg cells; can only do this in a normal (no infection) environment

foxp3; peyer's patch

T cells: • Recognize foreign antigens ONLY in the context of MHC of same _______________ • Produced by __________ ______________, educated in the _____________.

haplotype; bone marrow; thymus

conjugate vaccine: -If you are trying to raise antibodies against a "poor" antigen, you can covalently link the antigen to a carrier that is highly immunogenic. - This is the _____________-_____________ effect

hapten-carrier

The high number of alleles assures that most individuals are _____________________ at each of the MHC loci.

heterozygous

naive T cells travel from thymus through blood and into lymphoid tissues via _________ ____________________ _________________

high endothelial venules

kitasato and bering pioneered tentanus and diphtheria passive immunization in humans; how?

horse antibodies were transferred to humans to protect against tetanus

Complement is a primary contributor to transplant tissue damage through a process called ___________________ _________________. but ___________ can block membrane attack complex and allow the transplant to be accepted

hyperacute rejection; CD59

MHC ______________________ sites: In order to generate populations with the ability to present almost every possible antigen, the MHC has a high rate of mutation (many _____________) in the peptide binding cleft. This changes the specificity between _____________ as to the exact structure that will fit into the cleft.

hypermutation; alleles; alleles

_______________ ____________________: certain tissues are capable of restricting the extent of an immune response or the activation of immune cells. Typically, antigens from these sites can be immunogens if exposed to the adaptive immune system in the proper context, such as following trauma. However, these tissues often have very tight blood brain barriers to block access of pathogens.

immune privilege

Acute and chronic inflammation - a physiological process involving various systems, such as the ______________ system, the ___________________ system, and the ______________ system.

immune, circulatory, and nervous

is the absence of or failure to mount an immune response to antigens.

immunological tolerance

Like Ab gene rearrangement, further diversity is gained from _______________ _________________ and from random addition of ______________________ to splice junctions.

imprecise joining; nucleotides

cancer vaccines: Multiple approaches will be necessary, and ______________________ medicine will be required in many instances

individualized

Many of the antibody-based medications seek to target and interfere with specific receptor-ligand interactions as a way of controlling _____________________

inflammation

• Regulatory proteins can protect host cells from complement mediated damage that occurs secondary to _____________________ • Regulatory proteins can be associated with the host cell _____________ or are secreted in ___________ • Nearly every step of the complement cascade(s) is regulated to prevent damage to your own cells and tissues.

inflammation; surface; serum

acute inflammation- response to ___________ (anything that destroys cells; burn, cut...); normal process to remove pathogens and initiate tissue repair but can be detrimental if it's too excessive or re-occurring; ____________ inflammation- immune system can't remove the pathogen and continues to try to respond to the pathogen

injury; chronic

self-nonself discrimination in innate vs. adaptive cells

innate- TLR's have perfect recognition of microbes (don't recognize self antigens) adaptive- imperfect, selected in individual somatic cells

The Complement System • A series of ~20 heat labile plasma proteins synthesized in the __________ (Kupffer cells and hepatocytes). Complement functions in a ______________ to attack extracellular pathogens. They do this via: - ____________ bacteria - _________________ bacteria - Promoting ____________________

liver; cascade; - lysing bacteria - opsonizing bacteria - Promoting inflammation

An ideal vaccine will: - Induce immunity in most individuals - Give _________-lived immunity to all strains/variants - Not be _________ or induce illness at any level -vaccine should be harmless, but seen as an enemy by the immune system!!

long; toxic

if blood glucose is ________ that means something has ruptured and animal needs surgery

low

what are marker vaccines used for?

to tell which animals created antibodies as a result of the vaccine vs. as a result of exposure/infection

The pathway down which a Th0 cell differentiates is determined by which __________________ ___________ is activated. This is determined in part by which _________________ are present, which is determined in part by which stimuli have triggered the antigen presenting cells.

transcription factor; cytokines

T/F: Both self and non-self antigens are constitutively processed and presented by antigen presenting cells

true

T/F: CD8+ cells kill the MHC 1 cells when they recognize an epitope that the cell is presenting

true

T/F: DNA vaccines are subunit vaccines

true

T/F: all septic patients have SIRS but not all SIRS patients have sepsis

true

T/F: one receptor can bind to more than one type of chemokine as long as its in the same class (ex. CXCR2 can bind to CXCL8, CXCL7, CXCL6...)

true

T/F: you can make vaccines for anything, not just viruses?

true

what type of vaccine is an autogenous vaccine?

usually killed whole organism vaccines

artificial introduction of antigens (under conditions where disease will not result) to stimulate a long term adaptive immune response; The name comes from the vaccinia virus (cowpox), used by Jenner to stimulate immunity against smallpox.

vaccination

vaccination vs. immunization

vaccination- give the body antigens immunization- provide body with defense against an antigen (vaccine or injecting antibodies)

fluid is forced out and can't return to the blood vessel during inflammation (in normal vessels a little fluid leaks out of arterioles but can enter back into the ______________)

venules

Class I recognition is particularly important for __________-infected cells and ___________ cells.

virus; tumor

how do you generate antibodies against endogenous antigens?

when viral cells die they release things (like proteins) that get dumped out and can be picked up by B cells and chewed up to present epitopes on the surface that T cells can recognize and then the T cells activate the B cell to make antibodies

In the ER, the MHC class I molecules first assemble with _____-____________________ and a stabilizing protein (_______________). When a peptide binds, the ________________ is released and the MHC class I molecule adopts a different conformation.

ß2-microglobulin; calnexin; calnexin

Pathophysiological effects: Extensive tissue damage:

• Acute inflammation. -Excessive inflammation (e.g., sepsis, trauma) -Re-occurring inflammation (e.g., allergies) • Chronic (prolonged) inflammation (e.g., autoimmunity)

-macrophages and neutrophils have receptors which recognize opsonins -3 major opsonins are:

• Antibodies • Complement C3b • Lectin binding proteins (MBL, acute phase proteins)

alternate pathway (4 steps)

• C3 can be spontaneously activated by bacterial cell surfaces or in plasma, forming C3b attached covalently to the surface. • C3b binds factor B, forming C3bB • C3bB is now ready to be cleaved by factor D, yielding C3bBb on the surface of the cell. C3bBb is the C3/C5 convertase! • C3bBb can cleave many molecules of C3, just as in the classical pathway. • C3b that is produced by the C3/C5 convertase then binds to the bacterial surface

Complement Deficiencies: Several genetic deficiencies in complement are noted in humans and animals. Affected individuals usually present at an early age with recurring bacterial infections and are diagnosed by low levels of the specific complement protein. Most prominent examples include (2 examples):

• C3 deficiency in Brittney Spaniels • C3 receptor deficiency in cattle (bovine leukocyte adhesion deficiency)

Membrane attack complex (4 steps)

• C3b binds to C5 and permits cleavage by C4bC2b (or C3bBb in the alternate pathway). The resulting C5a is chemotactic for inflammatory cells. C5b deposits on the bacterial membrane. • C5b will bind C6 and C7 causing it to release from C3b. • The C5bC6C7 complex attaches and binds C8 and multiple C9's. • C9 forms a ring structure causing a pore to form (which causes cell lysis) - Many bacteria are resistant to this aspect of complement

3 species with limited MHC diversity:

• Cheetahs • Tasmanian devils • Giant pandas

MHC class I structure

• Constitutively expressed on the surface of all nucleated cells • Single chain (45 kDa) non-covalently associated with ß2-microglobulin (ß2m) • One transmembrane part (a3), one part for stability (b2), and 2 parts for binding the epitope (a1 and a2)

what 3 ways do adjuvants work in?

• Convert soluble proteins into particulate material • Stimulate cytokine production by APC • Depot effect to maintain Ag half life

peripheral tolerance is induced and maintained by

• Exclusion of inflammatory/cytolytic cells from the tissue. • Expression of ligands on target cells that turn off or kill autoreactive Th and B cells (PD-1 receptor). • Expression of anti-inflammatory cytokines and immunosuppressive factors in the tissue • Reduced expression of MHC class I molecules

how does nomenclature work in the alternate pathway?

• For proteins that are not also part of the classical pathway, they are designated by a letter only. Thus, B is complement component B. • When cleaved during activation, they acquire a lower case "a" or "b" as in the classical pathway. Thus, Bb is complement component B, active form.

To induce disease, a pathogen must be able to (5 things):

• Have access to a host (direct contact, fomites, vectors...) • Adhere to, and colonize or invade the host • Successfully evade host defense mechanisms • Replicate within or on the host whilst continuing to evade host defenses • Be directly or indirectly capable of causing damage to host cells or tissues!!!!!!!

classical pathway (6 steps)

• IgG or IgM antibodies bind to antigens on surface of bacteria • C1q binds to the antibodies and becomes active • Activated C1s can cleave C4, yielding C4a which has no proteolytic activity, and C4b which binds covalently to the microbial surface near C1. • The C4b binds to C2, making it susceptible to cleavage by C1. This yields C4bC2a on the surface of the bacterium. C4bC2a is the C3/C5 convertase! • C4bC2a can now cleave many (up to 1000) molecules of C3, yielding C3a and C3b. • C3b (lots of it!) binds covalently to the bacterial surface.

benefits of adjuvants

• Improved immediate response to antigen(s) • Fewer boosters required • Overcoming immunosenescence or immunosuppression • Targeting antigens to APC • Activating APC • Improved response to targets with low antigenicity

PERIPHERAL Tolerance encompasses many processes (6) that inhibit activation of self-reactive B cells and T cells in the tissues:

• Lack of T cell co-stimulation induces anergy • The self antigens may be sequestered • Immune privileged tissues express FasL to kill autoreactive T cells • Treg cells make anti-inflammatory cytokines or express anti-inflammatory ligands • Inhibit both Th0 cells and dendritic cells • Immune privileged tissues express little classical MHC class I but also express non-classical MHC class I to inhibit NK cells

Killed/Inactivated vaccines (3 disadvantages and 2 advantages)

• Mostly induce antibodies only. Since they cannot get into the cytoplasm, it is difficult to induce CTL responses. • Because the organism doesn't multiply, these vaccines require large amounts of antigen • Usually protection is shorter term - Poor induction of memory B cells - Boosters required - Usually include an adjuvant to boost immune response - Usually very little IgA put onto mucosal surfaces • Advantages include: - More stable storage - Unlikely to cause disease or illness in immunosuppressed people

DNA vaccines (what are they and how do they work?)

• Plasmids carry the genetic information for the antigen • Injection into muscle cells results in temporary production of the encoded protein - MHC class I presentation - Cell-mediated immunity

Many factors may influence the immune response to vaccination (5 examples)

• Presence of maternal antibody • Nature and dose of antigen • Route of administration • Presence of adjuvants • Host factors (age, nutritional factors, genetics, coexisting disease)

antigen presentation on B cells (5 steps)

• Step 1- antibody on surface of B cells bind to epitopes on native antigen • Step 2- antibody "caps" and the antigen is internalized • Step 3- The antigen is processed similarly as in macrophages • Step 4- Peptide-MHC class II complex is exported to the cell surface • Step 5- Ligand interaction with CD4+ T cells

3 main types of vaccines

• Whole organisms - Killed or inactivated - Attenuated live strain • Subunit or component vaccines - toxoids • DNA vaccines

what is the classical pathway activated by?

• activated by IgG or IgM antibodies binding to surface

how is the lectin pathway activated?

• activated by opsonins binding to bacterial cell surface

Many bacteria have outer structures which can do what 3 things?

• can block neutralizing Ab formation • prevent lysis by complement membrane attack complex formation • inhibit phagocytosis

2 direct mechanisms of tissue damage by pathogens and 3 indirect ones

• direct -endotoxin production -direct cytopathic effect • indirect -immune complexes -anti-host antibodies -cell-mediated immunity

Stages at which complement is inhibited by the host include (4 things):

• dissociation of C1r and C1s to inactivate the initiation complex • displacement of C2b from the C3/C5 convertase • cleavage and inactivation of C3b in the C3/C5 convertase • inhibition of the membrane attack complex (by CD59)

macrophages can be referred to as highly __________________ (4 things)

• highly phagocytic: present processed antigens to CD4+ T cells • highly secretory: regulate immunocytes, mediate killing of pathogens, stimulate tissue repair • highly activational: respond quickly to changes in microenvironment. • highly polymorphic based on tissue site: (ex. blood-monocytes; brain- microglial cells)

routes of infection (4 mucosal surface ones and 3 external epithelial ones)

• mucosal surfaces: -mouth and respiratory tract -GI tract -reproductive tract -opportunistic infection • external epithelial: -external surface -wound -insect bite

how is the alternate pathway activated?

• spontaneous activation in the blood or bacterial surfaces

Immune privilege sites: -extracellular fluid does not mix into _________________ system -few naive lymphocytes in the tissue -high expression of ___________________________ ___________________ and _______________ _________________

lymphatic; immunosuppressive cytokines and surface ligands

-T cells that do not encounter their specific Ag reenter the circulation via the __________________; -T cells that do encounter their Ag are activated to proliferate and differentiate into armed ______________ T cells. Once activated, they also leave via the __________________ and enter circulation through the _____________ __________; -activated T cells travel to extralymphoid organs (like lungs, skin, GI tract....) and can home to inflamed organs/tissues

lymphatics; effector; lymphatics; thoracic duct

advantage (1) and disadvantages (5) of giving vaccines through injections

- Advantage is ease of anatomic site access - Disadvantages are: • Cost of needles • Artificial route of entry for most pathogens • Typically induce primarily IgG responses • Culturally unacceptable in parts of the world • Capture of animal

MHC class II pathway: what 2 molecules break down antigen in the proteolysosome?

- Cathepsins - Endopeptidases

Complement proteins are present in inactive forms in the serum and are triggered via either of 3 pathways:

- Classical Pathway - Alternate Pathway - Lectin Pathway

MHC class II structure

- Expressed predominantly on immunocytes. - Consist of two polymorphic chains (α and ß) that fold together to form a binding pocket for processed antigens -2 transmembrane subunits (a2 and b2) and 2 subunits that make up the peptide binding cleft (a1 and b1)

examples of why a vaccine might fail (no or few Ab produced)

- Interference with maternal antibodies - Senescence (has to do with age) - Improper application of vaccine - Physiologic state of recipient - Host genetics - Pathogen strain antigenic variation - Extremely virulent pathogen strain encountered - Insufficient time for immune response to occur - Poor technique!

different routes of exposure for vaccines (5)

- Subcutaneously - Intramuscularly - Orally (edible or drinking water) - Intranasal - In ovo or in utero

what is the result of promoting inflammation? (3 things)

- leakage of antibodies and other factors (such as complement proteins!) into the site of immune challenge - migration of cells of the innate immune system into inflammatory lesions - activation of phagocytes entering the lesion

what are the 2 proteosomes found in cells?

-20s proteasome -immunoproteosome

what happens with the C3a and C3b produced at the end of these 3 pathways?

-C3a- leads to inflammation -C3b- leads to opsonization -or- leads to production of C5b (which leads to cell lysis) and C5a (which leads to inflammation)

chemokines are specialized cytokines; -4 main groups: -how do the receptors for chemokines work?

-CL#, CCL#, CX3CL#, and CXCL# (CCL# and CXCL# have the most members) -CR# receptors only bind to CL# chemokines; CCR# receptors only bind to CCL# chemokines and so on..

conjugate vaccines (what are they and what are they commonly used to fight against?)

-Conjugate vaccines are a type of subunit vaccines. Here, you are taking something that is not very immunogenic and attaching it to something that is. Common for making vaccines against bacteria with capsules (polysaccharides).

Physiological benefits of acute inflammation (3):

-Dilute toxins -Isolate or destroy invading microorganisms -Initiate repair

toxoid vaccines (what are they and how are they made?)

-For pathogens in which a secreted toxin is the cause of disease or clinical illness, targeting just the toxin can be efficacious. -Can be made by treating toxins with chemical inactivators such as formalin or by heat to denature it -Toxoid is an inactivated toxin

how does IgG and IgM bind to bacterial surface?

-IgG binds to antigens on bacteria in the "staple" form and C1 binds to one of these "staple" forms -IgM bings to antigens on bacteria and C1 binds to at least 2 of these molecules

explain the process of lymphocyte "imprinting"

lymphocytes have a preference of which tissue to go to (skin, mucosal...) because of the different adhesion molecules and chemokine receptors they express on their surface (they express these specific adhesion molecules and chemokine receptors after they become effector lymphocytes); the endothelial cell has to have the correct complement to bind to the adhesion molecules/chemokine receptors to allow the lymphocyte to enter the peripheral tissue

progression of out of control inflammation (4 things)

-SIRS (Systemic Inflammatory Response Syndrome) -Sepsis -Severe sepsis -Septic shock

septic shock definition

-Severe sepsis complicated by persistent hypotension refractory to early fluid therapy (patient doesn't respond to fluid therapy) -Based on HR, RR, CRT, mentation, urine output, CVP

-Effector (and memory) lymphocytes migrate to tissue locations in a more selective manner (homing), which is dictated by where they initially encountered antigen. what are the 2 types of lymphoid tissues that lymphocytes first encounter antigen?

-Skin-associated lymphoid tissue (SALT): Peripheral lymph nodes and inflamed skin. or -Mucosal-associated lymphoid tissue (MALT): e.g., Peyer's patch

central tolerance- removes B and T cell clones that might recognize self antigens centrally during ____________________

lymphopoesis

what is a FAST?

-focused assessment sonographic technique -take an ultrasound and look for fluid or air -tFAST = thoracic; aFAST = abdominal

cytotoxic T cell receptor structure

-has constant alpha and beta regions -has variable alpha and beta regions -has CD8+ dimer that binds to a3 subunit of MHC class 1 molecule -has CD3 molecule associated with it at the membrane

subunit/component vaccine huge disadvantage?

-huge disadvantage of only stimulating immunity against a single protein which may not impart full protection. - Must carefully choose antigen to target!

Th1 cells: -The principal function of TH1 cells is __________________ activation; -Secrete cytokines which augment nonspecific immune responses (ex. __________); -Secrete factors which inhibit TH2 differentiation (ex. ___________ and ____________)

macrophage; IFN-y; IFN-y and TNF-a

different examples of adjuvants (6)

-incomplete freunds adjuvant (delayed release of antigen, increased uptake by macrophages) -complete freunds adjuvant (delayed release of antigen, increased uptake by macrophages, induction of macrophage co-stimulators) -freunds adjuvant with MDP (same as complete) -alum -alum plus -ISCOMs (delivers antigen to cytoplasm, allows induction of Tc cells because of MHC class I presentation)

-3 complement factors that lead to inflammation (they are anaphylatoxins) -1 complement factor that leads to opsonization -5 complement factors that lead to lysis (membrane attack complex)

-inflammation: C3a, C4a, and C5a -opsonization: C3b -lysis: C5b, C6, C7, C8, C9

which vaccine is the least safe but most effective? which vaccine is the most safe but least effective?

-live-attenuated virus -nucleic acid vaccines

dendritic cells: -where are they primarily found? -where are they found in low numbers? -are poorly phagocytic in ____________ _____________ -are ____________- they sample the environment and bring antigen to the lymph nodes where they can be taken up by B cells

-lymphoid tissue ("Interdigitating" cells in T cell areas "Follicular" dendritic cells in B cell areas) -skin, spleen, and blood -lymph nodes -mobile

what are 6 qualities of good vaccines?

-offer protection (sometimes lasts a lifetime, sometimes only lasts a season) -cost -ease of application (boosters required) -multivalent vaccines -stability -reduce disease

what 4 things are needed for Antigen Processing and Presentation?

-phagocytic cells (dendritic cells, macrophages, B cells) -Means for degrading larger antigen molecules • Proteosomes (endogenous Ag) • Phagolysosomes (exogenous Ag) - Molecules to present peptide fragments on cell surface (MHC class I and II molecules) - Receptors to distinguish foreign epitopes (T cell receptors)

RECIRCULATION

-process by which T and B cells circulate through the body -afferent lymphatics- entering secondary lymphoid organs; efferent lymphatics- exiting lymph nodes; thoracic duct- returns the lymph to the blood; blood vessels- deliver lymphocytes to nonlymphoid (peripheral) tissues; then blood vessels or afferent lymphatics deliver the B/T cells back to lymphoid organs

what do neutrophils do if they encounter a bacteria too big to phagocytize?

-release NET's (fibers made of chromatin (histones and DNA) decorated with antimicrobial proteins) -NETs are released during a novel form of cell death that requires ROS produced by the NADPH-oxidase complex. During this process, the nucleus decondenses and intracellular membranes disintegrate allowing the mixing of nuclear and cytoplasmic components. Eventually, the plasma membrane ruptures to release NETs, structures that contain chromatin and granule proteins.

severe sepsis definition

-sepsis with evidence of organ dysfunction - > 1 organ system -AND lactate >4 mmol/L (hypoperfusion) -OR Systolic BP <90 mmHg (hypotension)

how does nomenclature work in the classical pathway?

-the components are C plus a number (ex. C4 is complement factor 4) -when the proteins are cleaved during activation, the smaller fragment is "a" and the larger fragment is "b" ("b" usually sticks around and participates in the next step)

APC and T cell activation: signals are derived from what 3 types of receptors?

-toll-like receptors -cytokine receptors -Fc receptors

future of inflammation:

-would be nice to have biomarkers to tell you how far along the inflammation is and if there is sepsis (ex. in polytrauma patients and lung epithelial injury

which 2 antigen presenting cells are inducible by co-stimulatory factors?

macrophages; B cells

what are the 3 best antigen presenting cells?

macrophages; dendritic cells; B cells

3 types of defects in neutrophil function:

1. Defects of adhesion: -LFA-1 and Mac-1 subunit defects lead to impaired adhesion (leukocyte adhesion deficiency-1). neutrophils can't get into periphery. Occurs in humans, cattle, dogs. 2. Defects of chemotaxis/phagocytosis: -Microtubule assembly defect leads to impaired locomotion and lysosomal degranulation [Chediak-Higashi Syndrome]. neutrophils can't move to site of inflammation or phagocytize things. Occurs in humans and cattle. 3. Defects of microbicidal activity: -Deficiency of NADPH oxidase that generates superoxide, therefore no oxygen-dependent killing of bacteria (chronic granulomatous disease).

allergy shots work on what 2 principles?

1. Exposes allergen to immune system in a way that favors IgG production over IgE • Usually via adjuvants and changing route of exposure 2. Inducing Treg cells that inhibit allergen-specific B cells and T cells

acute inflammation systemic effects (very severe) inflammation factors released into the blood. what are 5 results of this?

1. Fever 2. Increased blood pressure 3. Loss of appetite 4. Leukocytosis 5. Acute-phase proteins (released from liver during severe inflammation)

Amines and peptides: mainly produced by leukocytes and other cells that induce vasodilation and vascular permeability. (3 examples, their source and what they're derived from)

1. Histamine: Source - Leukocytes and platelets. Derived from the amino acid histidine. 2. Serotonin: Source - platelets. Derived from the amino acid tryptophan and is stored inside platelet granules. 3. Neuropeptides: Source - Nerve cells. Peptide products from nerve cells that function directly and indirectly in inflammation (substance P).

reasons to intervene surgically (2)

1. Leaking organ: (trachea, esophagus, bladder, urethra, stomach, intestines, gall bladder) -Intestinal contents, bile contents, urine (bladder) --> immediate surgery -Air (chest), urine (urethra) --> monitor closely --> progressive --> surgery 2. Bleeding organ Monitor closely --> progressive --> surgery

what are the 3 "signals" that happen between antigen presenting cells and T cells to activate the naive T cells?

1. MHC class I or II is bound to T cell receptor 2. co-stimulation (ligand-receptor binding) (CD28 on T cells binds to B7 on the APC to deliver a co-signal) 3. cytokines

-Lymphoid compartments: secondary lymphoid organs at portals of antigen entry (3 examples)

1. Mucosal-associated lymphoid tissue- Peyer's patch, mesenteric lymph nodes, lung lymph nodes... collect antigens crossing mucosal epithelial surfaces. 2. Skin-associated lymphoid tissue- peripheral lymph nodes - collects antigens crossing the skin epithelium 3. Spleen - filters blood.

Exudate composition can vary and are useful for diagnostic purposes. what are the 4 types of exudate?

1. Serous exudate: Watery with no cells (e.g., blister fluid). 2. Purulent/suppurative exudate: Thick fluid that contains WBC, bacteria, cellular debris. 3. Hemorrhagic exudate: Contains blood. 4. Fibrinous exudate: Contains high concentrations of fibrinogen and fibrin resulting in a sticky meshwork.

_______________ vaccines: • Sometimes called _____________ - Very useful in eradication purposes (when using serology) • These vaccines typically elicit identical immunity as a live vaccine, but have - An additional protein not found on the pathogen, OR - Are missing a protein not essential to pathogen growth but is recognized by the immune system

marker; DIVAs- differentiate infected from vaccinated animals

4 examples of TLR's and what their ligand is (what they recognize)

1. TLR-2 TLR-6 heterodimer: ligand is cell wall beta-glucans (bacteria and fungi) and zymosan (fungi) 2. TLR-3: ligand is double stranded RNA (viruses) 3. TLR-4: LPS (gram - bacteria) and lipoteichoic acids (gram + bacteria) 4. TLR-9: DNA with unmethylated CpG (bacteria and herpesviruses)

what do the 4 types of Th cells defend against?

1. Th1 = defends against intracellular pathogens 2. Th2 = defends against extracellular parasites; allergens; and asthma 3. Th17 = defends against extracellular bacteria; produces IL-17 (inflammatory) 4. Treg = immunosuppression (suppresses T cell responses)

what are the 4 main T helper cells that a Th0 cell can differentiate into? what is the stimulus that leads to that differentiation? and what does each different T helper cell act on?

1. Treg- stimulus = TGF-beta!!, IL-10, and IL-2; acts on = T cells & macrophages (destroy intracellular pathogens) 2. Th17- stimulus = IL-23!!, TGF-beta, IL-6, and IL-21; acts on = neutrophils (destroy intracellular pathogens) 3. Th1- stimulus = IL-12!!, IL-18, and IFN-gamma; acts on = macrophages (destroy intracellular pathogens) 4. Th2- stimulus = IL-4!!, IL-10, and IL-2; acts on = B cells (make antibodies to help destroy pathogens)

Clinical importance of tissue-specific homing by lymphocytes (2 examples)

1. Vaccine development: Antibodies target the microbe (e.g., free virus particles and bacteria) and cytotoxic T cells target infected cells. It may be possible to enhance immunity by delivering vaccines at sites where infection occur, such at mucosal surfaces (e.g., rotavirus, norovirus, enteric bacteria, influenza). 2. Use adhesion molecule and chemokine receptor inhibitors to block lymphocyte accumulation at sites of chronic inflammation (e.g., autoimmune disease, inflammatory bowel disease...)

Th1 cell activities to remember (4) *Th1 cells are primary activators of macrophages

1. activates macrophage to destroy engulfed bacteria 2. induce macrophage differentiation in bone marrow 3. activate endothelium to induce macrophage binding and exit from blood vessel at site of infection 4. causes macrophages to accumulate at site of infection

5 mechanisms antibodies use to protect against infectious agents

1. agglutination 2. opsonization 3. neutralization 4. antibody dependent cell mediated cytotoxicity 5. activation of compliment

what 2 things does tissue regeneration require?

1. an intact connective tissue framework 2. parenchymal cells (essential cells required for organ function - e.g. muscle cells); must be labile (e.g., epithelial) or stable (e.g., hepatocytes), but not permanent (e.g., cardiac muscle cells). *not permanent because permanent ones aren't good at proliferating and reproducing so if they are destroyed it will most likely result in scarring (aka organization)

vicious cycle when inflammation goes out of whack (5 steps to the cycle)

1. bacteria causes inflammation of the tissue 2. Immune system chemicals attack tissue to contain infection 3. More tissue damage from collateral damage of immune system attack 4. More immune system chemicals released 5. More inflammation

Engagement of TLRs leads to variable production of cytokine sets, which directly impacts Th0 cell differentiation. give 4 examples of which pathogens cause release of which cytokines to drive differentiation towards Th1, Th2, Th17, or Treg

1. bacteria recognized by TLR-4 and TLR-5 cause release of IL-12 which drives differentiation towards Th1 2. helminths recognized by TLR-1/2 cause release of IL-10 which drives differentiation towards Th2 3. fungi recognized by dectin-1 cause release of IL-6 and IL-23 which drives differentiation towards Th17 4. fungi recognized by TLR-2/6 cause release of IL-10 and TGF-B which drives differentiation towards Treg

neutrophil adhesion: neutrophils have to leave blood vessels just like lymphocytes; what are the steps (3) the neutrophil follows to get out into the tissue and what are the factors that help with these processes?

1. capture and rolling: selectins (specifically L, P, and E selectins) help with this 2. firm adhesion: integrins (specifically Mac-1, VLA-4, and LFA-1) help with this 3. diapedesis (when neutrophil squeezes through endothelial cells): immunoglobin superfamily (specifically ICAM-1, ICAM-2, VCAM-1, and PECAM) helps with this

Several mechanisms contribute to maintain tolerance (5)

1. deletion of self-reactive clones 2. 2 signals required to activate T cells 3. Treg cells block activation of autoreactive T and B cells 4. immune "privileged" sites and tissues 5. ignoring self-antigens by the immune system

4 main groups of inflammatory factors

1. derived from the coagulation and complement cascades 2. Lipid mediators 3. Amines and peptides 4. cytokines

immune privilege is induced and maintained by what 3 things?

1. expression of ligands that block access/effector function of Tc cells or induce apoptosis (Fas-FasL) 2. reduced expression of MHC class I 3. expression of anti-inflammatory cytokines and immunosuppressive factors

subunit/component vaccine antigens can be produced in what 2 ways?

1. gene put into plasmid is put into bacteria which makes the antigen 2. vector put in cell culture

3 ways to kill/inactivate antigens for vaccines and do they work or not?

1. heat denatures protein (not useful) 2. Chemical inactivation common (formaldehyde or ßpropriolactone), but must be removed to avoid toxicity 3. Inactivated vaccines can be live organisms that are unable to replicate. These often give better immunization.

7 steps to produce DNA vaccine

1. identify and culture organism 2. sequence DNA 3. identify immunogenic peptide motifs 4. identify DNA sequences that code for the immunogenic peptides 5. put that DNA that codes for the immunogenic peptides in a plasmid 6. purify plasmid DNA 7. administer DNA vaccine

4 additional mechanisms to induce tolerance

1. immunologically immature (if neonate is exposed to antigen they become tolerant to it) 2. clonal exhaustion (tolerance induced by high doses of antigen) 3. oral tolerance (induced by feeding antigens) 4. tolerance to fetal antigens (placenta is "hidden" during pregnancy, moms antibodies cant get to the fetus, presence of Treg cells, inhibitor Crry, enzyme IDO depletes tryptophan and starves autoreactive T cells)

many adjuvants do what 2 main things to macrophages?

1. increased cytokine synthesis by macrophages 2. enhanced antigen presentation by macrophages

Treg cells mediate peripheral tolerance by:

1. inhibiting APC activation 2. secreting cytokines that suppress T cell function in the peripheral tissues 3. binding cytokines needed by normal T cells for survival

steps of an antigen presenting cell presenting an epitope

1. internalization of antigen by antigen presenting cell 2. antigen processing 3. processing makes multiple peptides (epitopes); one of which can bind to class II (or class I?) allele 4. T cells respond to immunodominant epitope

Antimicrobial peptides in innate immunity (4 main ones and what do they do?)

1. lactoferrin- Iron binding; amphipathic with affinity toward bacterial and fungal lipids 2. lysozyme- Cleaves bond between N-acetylglucosamine and Nacetylmuramic acid in peptidoglycan molecule 3. cathelicidins- Family of membrane-binding proteins that disrupt the bacterial and fungal membrane 4. defensins- Cationic, basic, pore-forming proteins that bind to bacterial and fungal membranes

neutrophil swarming

1. large #'s of neutrophils in bone marrow, released when needed to fight infection 2. travel to infected tissue where they engulf/kill bacteria. die in the tissue and engulfed/degraded by macrophages

Timing is everything! • Must avoid interference by _______________ Abs • Must apply at a time when the neonatal immune system can mount an adaptive immune response • Vaccination in the face of an outbreak may be too late • ________________ must not occur too quickly

maternal; Boosters

immature B cells can differentiate in the bone marrow and have 4 outcomes

1. no self reaction (migrates to periphery) 2. multivalent self molecule (clonal deletion or receptor editing leads to apoptosis or generation of non-autoreactive mature B cell) 3. soluble self molecule (migrates to periphery and leads to anergic B cell) 4. low-affinity non cross-linking self molecule (migrates to periphery and creates a mature B cell)

many Acute Phase Response Proteins are pattern recognition factors that bind to structures found on bacteria. CRP and MBL do what 2 things?

1. opsonize 2. activate complement

what 3 things did louis pasteur invent?

1. rabies vaccine for humans 2. cholera vaccine for chickens 3. pasteurization

TCR diversity: -alpha chain can choose from about _______ variable regions -beta chain can choose from about _______ variable regions -Additional variability is gained by recombination of variable regions with ____ (and ____) regions.

100; 30; J; D

sepsis mortality is about _______-________%

35-50%

if potentially autoreactive T cells are deleted in the thymus, how do the APC in the thymus present all possible self epitopes that the T cells will see out in the periphery?

medulary epithelial cells in the thymus express transcription factor (AIRE) that let them express most of the genes in the body so it has most of the self epitopes from the body; AIRE = autoimmune regulator (gene that drives expression of most self antigens); deficits in AIRE gene function can lead to autoimmune disease (because self reactive T cells escape to the periphery)

Tc cells can kill _____-______ cells before they die

50-100

how long is the average processed antigen (epitope) that the a1/a2 peptide binding cleft of an MHC class I molecule binds

8-12 amino acids long

how long is the average processed antigen (epitope) that the a1/b1 peptide binding cleft of an MHC class II molecule binds

8-16 amino acids long (later in the lecture it says 13-20??)

_____% of T cells don't rearrange successfully in the thymus and they die

95

some Th cells differentiate into _______________ cells

memory

T cells have memory (like B cells); once they are differentiated, some of the cells become ____________ cells and stick around for a long time in case the host becomes infected by the same antigen again; makes for a much faster and stronger response the second time around; The _____________ and ________________ of the B and T cell response improves with each subsequent exposure.

memory; strength and specificity

Most pathogens are encountered at ______________ surfaces - But it is difficult to predict whether oral delivery will induce an immune _______________ or __________________!

mucosal; response or tolerance

________ lymphocytes- restrict their circulation to pretty much just secondary lymphoid organs until they find their antigen

naive

what are the active and passive components of natural and artificial immunity?

natural immunity: passive- maternal antibodies, active- post infection artificial immunity: passive- injection of antibodies, active- exposure to antigen (vaccine)

Inflammation: • Several complement cleavage fragments, esp. C5a, are _________________________ that promote inflammation locally by doing what 5 things

ANAPHYLATOXINS; - increase vascular permeability ( "leaky"; vasodilation of blood vessels) -contraction of smooth muscle - mast cell degranulation (release granules containing histamine) - increase adherence of phagocytes to endothelial cells (activation of phagocytes) -establishing a chemotactic gradient to recruit immune cells.

-Most numerous leukocyte in the blood (in most animals) and at sites of acute inflammation. -A short lived cell with a life span of ~ 2 days.

neutrophils

Th17 Cells: -primary activity is to activate ___________________

neutrophils

-most important accessory cells in the innate defense against bacteria are PHAGOCYTES (mostly _____________________ and ______________________) -when lysosomes fuse with phagosomes the contents of the lysosome do what 5 things?

neutrophils and macrophages; - acidify the phagolysosome - generate an oxidative burst - release cationic peptides and defensins - release proteases such as lysozyme - activate competitors such as ferritin

examples of non-specific and specific surface defenses

non-specific: -skin/mucus -microflora -low pH -flushing action -Lysozyme, lactoferrin, defensins -phagocytic cells -complement proteins specific: -Tc -IgA (milk or mucus)

About 50-100,000 MHC class I and class II molecules are on the surface of a typical cell, Most are occupied by ____________ or ________ antigens. Empty MHC molecules are not stable on the cell surface.

normal or self

*MHC class I molecules are expressed by every ________________ cell. *MHC class II molecules are expressed primarily by __________ ___________ __________.

nucleated; white blood cells

Many of the class III genes encode proteins involved in antigen processing and transport. Other genes encode complement factors and cytokines. Interestingly, several ________________ receptors are encoded in this region and may influence mate selection.

olfactory

what is the alpha TCR chain gene rearrangement rescue pathway?

only 1/3 chance that the joining between V and J regions is successful (in frame) so this rescue pathway is another chance for the chain to make a successful rearrangement; The T cell receptor gene rearrangement can occur several times if one rearrangement is nonfunctional, but the DNA in between the chosen V and J's is lost each time

which TLR's are on the outer membrane and which are on the lysozomal membrane?

outer- TLR-2, TLR-6, TLR-4 lysozomal- TLR-3 and TLR-9

some TLR's are on the __________ membrane, others are on the wall of the _________________ inside the cell (all are membrane bound though)

outer; lysozome

Anti-microbial activities of phagolysosomes are categorized as _________________ and _______-_________________

oxidative and non-oxidative.

The pathway down which a T helper cell differentiates is determined by the cytokines encountered at first activation. We don't always understand what drives production of certain cytokines. In some cases, the same ________________ can induce different responses (cytokines) depending on form or anatomic location which can lead to differentiation of different ______ cells

pathogen; Th

Each MHC allele recognizes different ______________. This potentially results in one individual being able to mount an effective immune response to a given pathogen, while another (who has a different allele) presents a different, less important epitope of that pathogen.

peptides (or epitopes)

how cytotoxic T cells kill cells: Cytolytic mechanism involves rapid release of granules containing cytotoxins (3 main cytotoxins)

perforin: polymerizes on cell membrane to form a pore granzymes: serine proteases which cleave proteins on target cell membrane Lymphotoxin-α (LT-α): induces cell death via apoptosis, a programmed cell death involving cleavage of genomic DNA

TLRs are constantly recruited to ____________________ to sample the contents.

phagosomes

which animal is an exception to the regular process of recirculation?

pig is an exception- lymphocytes leave and return straight to the blood instead of efferent lymphatics then thoracic duct and then blood

Exceptions- _________, ________________, and some ________________ have CD4+/CD8+ double positive cells. These are actually memory Th cells (CD4+) that gained low CD8+ expression after immunoactivation.

pigs, chickens, and some monkeys

B cells process and present Ag via class II MHC, _____________ ___________ do not because they are fully activated and all they do is make antibodies

plasma cells

______________ _______________- only T cells that can interact with MHC molecules in the thymus are allowed to continue to develop; ones that interact too strongly are killed (_______________ _________________)

positive selection; negative selection

lymphocytes leave through ________ ________________ ________________ and then stick to the venule wall and leave to enter the peripheral tissues to find the pathogen that they're specific to

post capillary venules (aka high endothelial venules)

MHC Class I-Function

present endogenous antigen to CD8+ T cells; This signals cytotoxic T cells to destroy host cells which display abnormal Ag

MHC Class II- Function

present exogenous antigen to CD4+ T cells; This activates T helper cells for the purpose of inducing the immune response, including antibody production, macrophage activation, and cytokine cascades.

• Microorganisms can stimulate tissue macrophages (and dendritic cells) to release _________________________ ___________________ • This event initiates local inflammation (vasodilation, leukocytes move to infection)

proinflammatory cytokines

plasma protein that stabilizes the C3bBb convertase on bacterial cells during alternate pathway

properdin

__________________ vaccines are an important herd health tool. They fill a void when new disease agents emerge for which there are no vaccines, or when antigenic variation occurs that is outside the spectrum of protection afforded by commercially available vaccines. - It is made from the microorganisms specific to a ___________, usually by a licensed facility. - Can be used with USDA approval on neighboring farms - Takes ~_____ weeks for bacterial vaccines, _______ weeks for viral vaccines

Autogenous; farm; 6; 12

what are some possible pros and cons of inflammation

pros- fibrin formation, delivery of nutrients and oxygen, entry of antibodies cons- inappropriate inflammatory response, digestion of normal tissue, increased coagulation, decreased oxygen to edematous tissue

pros and cons of surgery

pros- grossly visualize, take care of the problem and/or biopsy cons- invasive (tissue trauma), anesthesia risk, delayed healing

Inflammatory factors derived from the coagulation and complement cascades: -These are inactive proteins circulating in the blood that become activated by _________________ during inflammation. (5 examples)

proteases; -thrombin (pro-inflammatory) -bradykinin (pro-inflammatory) -fibrin-split products (important in clotting -C3a and C5a (attract leukocytes)

What's the advantage using cell culture vs bacteria to produce recombinant proteins?

protein folding and glycosylation (bacteria won't do this so it has less of an effect in a vaccine)

Th2 cells: -The primary activity of TH2 cells is to activate and differentiate ____ cells -Are inefficient activators of ____________________ -Secrete factors which drive ____ cell growth. -Secrete factors which regulate ____________ switching (IL-4 & IL-5). -Secrete factors which inhibit _______ differentiation (IL-4 & IL-5)

B; macrophages; B; isotype; Th1