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Immunology > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

characteristics of the immune system

A
  • a network of interacting cells that communicate through direct contact and release of soluble proteins (cytokines)
  • end result is to generate cells that fight infection (anti microbial activity)
  • may also result in host tissue destruction (collateral damage)
  • may also result in misdirected and anti-host responses (autoimmunity)
  • by understanding the immune response we can use it to protect ourselve against infection (vaccines)
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2
Q

vacination

A

inoculation with a small amount of pathogen or a harmless variant of the pathogen triggers an immune response that protects against full blown infection

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3
Q

extracellular pathogens

A
  • cellular: bacteria and protozoa

- multicellular: helminths

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4
Q

intracellular pathogens

A
  • cellular: bacteria and protozoa

- subcellular: viruses

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5
Q

central question in immunology

A

how do cells of the immune system discriminate between self and dangerous non self molecules

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6
Q

two essential events in immune defense

A
  • recognition

- destruction

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7
Q

innate mechanisms establish inflammation at sites of infection

A
  • surface wound introduces bacteria, activates resident effector cells to secrete cytokines
  • vasodilation and increased vascular permeability allow fluid, protein, and inflammatory cells to leave blood and enter tissues
  • the infected tissue becomes inflamed, causing redness, heat, swelling, and pain
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8
Q

cytokine

A

messenger protein molecule secreted by an immune cell

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9
Q

inflammation

A

redness, swelling, heat, pain caused by the immune response

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10
Q

neutrophil storage

A
  • large reserves in bone marrow, released when needed to fight infection
  • travel to and enter infected tissue
  • engulf and kill bacteria
  • die in the tissue and are engulged and degraded by macrophages
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11
Q

macrophage receptors

A
  • binding of bacteria to phagocytic receptor induces engulfment and degredation
  • binding of bacterial components to signaling receptors on macrophages induces the synthesis of inflammatory cytokines
  • macrophages can have both
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12
Q

innate immune system qualities

A
  • evolutionarily ancient
  • all multicellular organsims process innate
  • limited number of specificities
  • defined by cells that possess primitive mechanisms of killing
  • respoonse stays the same upon pathogen re-encounter
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13
Q

adaptive immune system qualities

A
  • evolutionarily more recent
  • arose in jawed verts
  • large number of specificities
  • b cells and t cells
  • response gets better and more effective upon reencounter
  • memory
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14
Q

selection of lymphocytes by a pathogen

A
  • proginator cells give rise to large numbers of lymphocytes each with a different specificity
  • during infection, lymphocytes with receptors that recognize the pathogen are activated
  • proliferation and differentiation of pathogen-activated lymphocytes give effector cells that terminate the infection
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15
Q

Nonspecific defense against infection

A
  • barriers: skin, epithelial cells in gut, mucus

- our normal microbes: prevent colonization by pathogenic microbes by competing for living

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16
Q

antibiotics interfere with natural ecology and defense in the intestine

A
  • the colon is colonized by large numbers of commensal bacteria
  • antibiotics kill many of these commensal bacteria
  • pathogenic bacteria gain a foothold and produce toxins that cause mucosal injury
  • red and white blood cells leak into gut between injured epithelial cells
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17
Q

complement system

A
  • family of soluble proteins consitutively synthesized by the liver and found in blood, lymph and extracellular fluids
  • when complement is activated extracellular pathogens become coated with complement making them susceptible to phagosytosis and cuasing direct pathogen destruction
  • approx 30 complement proteins present in inactive form (zymogen)
  • activated by proteolytic cleavage in sequential fashion
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18
Q

cleavage of C3

A
  • exposes reactive thioester bond that covalently attaches the C3b fragment to the pathogen surface.
  • either attacked by water and made soluble
  • or attacked by R-OH or R-NH2 and bound to pathogen surface
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19
Q

Alternative pathway of complement activation

A
  • spontaneous hydrolysis of thioester bond in C3. Promoted by physiochemical changes in the local environment brought about by infection
  • B is recruited and then cleaved by D into Bb and Ba
  • Bb remains on C3 and makes a iC3Bb convertase
  • convertase activates C3 by proteolytic cleavage
  • C3b is highly reactive and covalently attaches to microbial surface
  • reacts with hydroxyl and amino group on the pathogen surface.
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20
Q

Convertase loop

A
  • C3b can feed back into the reaction cascade making more membrane bound C3b
  • positive amplification loop
  • pathogen rapidly becomes coated with C3b
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21
Q

Regulation of C3b deposition on surfaces

A
  • preperdin: released by neutrophils at site of the infection and stabilizes convertase
  • factor H: changes conformation of convertase and makes it vulnerable to cleavage by factor I
  • factor h accumulates around host cells because of affinity for glycosaminoglycans not present on microbial surfaces
  • DAF; and MCP; membrane bound molecules on human cells so complement activation is avoided
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22
Q

Complement receptors on macrophages trigger phagocytosis and degradation of C3b-coated microbes

A
  • complement activation leads to deposition of C3b on bacterial cell surface
  • CR1 on macrophage binds C3b on bacterium
  • endocytosis of the bacterium by the macrophage
  • macrophage membranes fuse creating a membrane bound vesicle called the phagosome
  • lysosomes fuse with the phagosomes forming phagolysosome
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23
Q

The terminal complement proteins create a membrane pore complex on pathogens

A
  • alternative C3 convertase binds another C3b to create C5 convertase
  • C5b initiates assembly of the MAC
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24
Q

The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane

A
  • C6 and C7 bind to C5b
  • complex inserts into membrane via C7
  • C8 binds and inserts into membrane
  • Bound C8 initiates polymerization of C9 in membrane forming a pore
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25
Q

Regulation of the MAC on human cells

A
  • CD59 prevents assembly of the membrane attack complex
  • on the cells of pathogens complement components C5-C9 assemble a complex the perforates the cell membrane
  • CD59 binds to C5b678 and prevents the recruitment of C9
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26
Q

cleavage proteins of complement cascade induce local inflammation

A
  • anaphylatoxin act on blood vessles to increase vascular permeability
  • increase perm allows increased fluid leakage from the blood vessels and extravastion of complement and other plasma proteins at the site of infection
  • migration of monocytes and neutrohpils from blood into tissue is increased
  • microbial activitiy of macs and neutrophils is also increased
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27
Q

Serum protease inhibitors: a2-macroglobulin

A
  • protease and a2 macroglobulin
  • protease cleaves bait region, causing conformational change
  • a2 macro enshrouds the protease and is covalently bonded to it
  • many bacterial pathogens express proteases aid in tissue destruction
  • humans have inhibitors such as a2 macroglobulin
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28
Q

Direct killing of microbes by anti-microbial peptides (AMPs)

A
  • largest family of AMPS are defensins
  • alpha and beta
  • defensins are amphipathic allowing thme to insert into membrane and cause disrtuption
  • const secreted at mucosal surfaces
  • neutrophils are major source
  • synthesized as longer inactive pepetides that must be cleaved to activate
  • work best in low ionic strength environement
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29
Q

Paneth cells in intestine are an important source of defensins

A
  • HD5 and HD6 are a-defensins produced by Paneth cells
  • Also called cryptidins
  • Paneth cells also secrete other anti-microbials (lysozyme, phospholipase A2)
  • Protect gut epithelium from infection
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30
Q

Pentraxins are plasma proteins that bind microbes and target them to phagocytes

A
  • cyclin pentameric structure
  • Pentraxins are bridging molecules that bind to pathogen surface and cell surface molecules like CD89 on human phagocytes
  • Pathogen targeted for phagocytosis and destruction
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31
Q

short pentraxin

A
  • serum amyloid p component
  • liver hepatocytes
  • bacteria, virus, fungi, parasite ligands
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32
Q

long pentraxin

A
  • PTX3
  • source: monocytes, macrophages, DC, endo and epitheial cells
  • bacterial, viral, and fungi ligands
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33
Q

Three phases of immune response

A
  • immediate innate
  • induced innate
  • adaptive immune response
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34
Q

Tissue macrophages

A
  • stationed to guard against infection
  • express large array of receptors that recognize commonly expressed microbial lipids and carbs
  • PAMPs: pathogen associated molecular patterns that are recognized by PRRs
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35
Q

two kinds of mac receptors

A

phagocytic and signaling

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36
Q

phagocytic receptors (macs)

A
  • mediate uptake and degredation
  • recognize components of microbial surfaces
  • microbs bound by receptor on the mac surface
  • internalized by receptor mediated endocytosis
  • fusion of the endosome with a lysosome forms a phagolysosome in which they are degraded
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37
Q

Signaling receptors: toll like

A
  • family of approx ten receptors
  • homodimers or heterodimers
  • recognize diverse microbial molecules
  • sensor domain with leucine repeats LRR
  • toll interleukin receptor signaling domain to change gene txn
  • can be on inside and outside of human cells
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38
Q

Recognition of bacterial LPS by TLR4

A
  • LPS recognized by complex of TLR4, MD2, CD14
  • LPS binding protein delivers LPS to CD14
  • now recognized by TLR4 and MD2 and signals host nucleus
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39
Q

signaling pathway triggered by TL4 leading to mac activation

A
  • complex of TLR4 MD2 CD14 and LPS on mac surface
  • MyD88 binds to TLR4 and activates IRAK4 to Phos TRAF6 which leads to P of IKK
  • IKK P IKB leading to degredation and release of NFKB which enters nuc
  • activates genes for inflammatory cytokines
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40
Q

Five major cytokines secreted by macs

A
  • IL1B and TNFa: induce blood vessels to become permeable so effector cells and fluid with effector cells can pass through to tissues
  • IL6: induces fat and muscle cells to metabolize to raise the temperature
  • CXCL8; recruits neutrophils from the blood and guides them to the tissue
  • IL12: recruits and activates NK cells that secret cytokinds that strengthen the mac response
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41
Q

Detection of infection in cytoplasm via nod like receptors

A
  • bind components of bacteria cell wall (pep)
  • leads to activation of NFKB
  • dimerize and bind RIPK2
  • then recruits TAK1 and P cascade to activate NFKB
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42
Q

IL1B and the inflammasome

A
  • synthesized in the cytoplasm as an inactive precursor called proIL1B
  • cleaved by the protease caspase 1
  • caspase 1 is made as an inactive precursor that also must be cleaved
  • IL1B can control its own production in a positive feedback loop through cell surface IL1 receptor
  • needs two signals
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43
Q

assembly of the inflammasome

A
  • IL1B binds to receptor
  • change in ionic conditions via entrance of ATP stimmulates assemby
  • also stimulates NFKB pathway
  • inflammasome is made up of NLRP3 (nod like), procaspase and adapter proteins
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44
Q

Neutrophils are directed to sites of infection by adhesion molecules and chemokines

A
  • weak selectin mediated adhesion allow to roll along endothelium
  • done by vascular addressin CD34
  • CXCL8 recepter allows for tight binding and then diapedesis through ICAM 1
  • TNFa induces expression of ICAM
  • neutrophils release enzymes that degrade laminins and collagens facilitating movement in response to chemokine gradient
45
Q

neutrophil kill

A
  • bacterium is phagocytosed
  • phagosome fuses with azurophillic and specific granules
  • ph of phagosome rises, antimicrobial response is activated and the bacterium is killed
  • ph of phagosome decreases, fusion with lysosome allows acid hydrolysis to degrade bacterium completely
  • neutrophil dies by apoptosis and is phagocytosed by macrophage
46
Q

cytotoxic granules

A
  • azurophilic: primary; myeloperoxidases, lysozyme, nuetrophil proteases, defensins
  • specific: secondary; lactoferrin (binds iron req for bacteria growth), NADPH oxidase (resp. burst)
47
Q

Respiratory burst

A
  • characterized by rapid burst of oxygen consumption
  • important neutrophil killing mechanism
  • end result: highly interactive molecules that disrupt bacterial metabolism (Superoxide, hydrogen peroxide)
48
Q

Dying neutrophils release NETs that trap and kill microorgansim

A
  • Neutrophil extracellular traps
  • composed of chromatin and anti-microbial enzymes
  • release DNA and enzymes
49
Q

inflammatory cytokines IL1B IL6 and TNFa cause fever and trigger acute phase response in liver

A
  • produced by active macrophages
  • increase body temperature (pyrogens) which slows down viral and bacterial infection
  • act on liver and hepatocytes to induce acute phase proteins
50
Q

IL1/IL6/TNFa effects

A
  • liver: acture phase proteins (C reactive, manose binding lectin), complement opsonization
  • bone marrow and epithelium: neutrophil mobilization, phagocytosis and NET
  • hypothalmus: increased body temp; decreased viral and bacterial replication
  • fat/muscle: protein and energy mobilization to generate increased body temperature; decreased viral and bacterial replication
51
Q

mannose binding lectin activates the complement pathway

A
  • MASP2 is activated and cleaves itself
  • MBL binds to mannose residues on microbes
  • lectin; a protein that has carb binding properties
52
Q

Lectin pathway of complement activation

A
  • activated MBL complex cleaves C4 and C2 to produce C4b and C2a which associate to form C3 convertase
  • MASP 2 cleaves C4 to C4b and binds to microbial surface.
  • MASP 2 cleaves C2 to C2a and C2b
  • C2a binds to C4b forming a C3 convertase
  • binds C3b to surface
53
Q

C reactive protein triggers the classical pathway of complement activation

A
  • initiated by C1 has C1q
  • C1 first component of complement binds to CRP and becomes active through cleavage of C1s
  • classical pathway of complement activation start with C1
54
Q

C reative steps

A
  • CRP binds to phosphorylcholine, C1q binds to CRP
  • C1r is activated and cleaves C1s
  • C1s cleaves C4
  • C1s cleaves C2 to generate C4bC2a convertase
55
Q

Detection of viral infection from within cells

A
  • cells posses internal sensors of viral infection that results in production of type I interferon (IFNa and B)
  • interferes with viral replication
  • RIG 1 like receptors sense viral RNA
  • MAVS: mitochondrial antiviral signaling protein
56
Q

Steps for in cell detection

A
  • Viral replication in cytoplasm produces uncapped RNA with 5’ triphosphate
  • RLR binding to viral RNA induces association with MAVS and dimerization
  • dimerization initiates signaling pathways that activate IRF3 and NFKB
  • IRF3 causes synthesis and secretion of type I interferons, and NFKB causes synthesis and secretion of inflammatory cytokines
57
Q

Interferon effects

A
  • (IFNa and B)
  • Induce resistance to viral replication
  • increase expression of ligands for receptors on NK cells
  • activate NK cells to kill virus-infected cells
58
Q

Natural killer cells

A
  • Kill cells infected with virus and produce inflammatory cytokines
  • Killing function minimizes replicaiton
  • mechanism to prevent off target killing: only can kill when in close contact, committee decision, inhibitory signals given by host cells
59
Q

NK cell killing of virally infected cell

A
  • virus infection triggers interferon response
  • Type I interferon drives NK proliferation
  • drives differentiation into cytotoxic effector cells
  • effector NK cells kill by inducing apoptosis
60
Q

Communication between mac and NK

A
  • mac activated by viral infection secretes inflammatory cytokines that recruit and stimulate NK cells
  • NK cell and macrophage form a conjugate pair with a synapse in which IL12 and IL15 activate NK cell
  • NK cells proliferate and differentiate into effector NK cells secreting IFNy
  • IFNy binds to receptor on macrophages and activates them to increase phagocytosis and secretion of inflammatory cytokines
  • positive feedback loop
61
Q

timeline of viral infection

A
  • innate: production of IFNa IFNB, TNFa, and IL12
  • Innate: NK cell killing of infected cells
  • adaptive: t cell killing of infected cells
62
Q

small lymphocyte function

A

production of antibodies (B cells) or cytoxic and helper functions (T cells)

63
Q

plasma cell function

A

fully differentiated form of B cell that secretes antibodies

64
Q

B cells/lymphocytes

A
  • part of the acquired immune response
  • function of B cells is to secrete antibody/immunoglobulin
  • antibody also expressed on the B cell surface where it is referred to as the Bcell receptor for Ag
  • Abs are specific for antigens (proteins and carbs mostly)
  • The repertoire of Ab specificities that can be made by an individuals is at least one billion.
65
Q

What is an antigen?

A

a molecule or a fragment of a molecule that is recognized by an Ab made by a B cell; or by a recptor expressed by a T cell

66
Q

Plasma cells secret Ab of the same that is expressed on unstimulated B cell

A
  • Resting B cell: has membrane bound Ig; not encountered Ag
  • Encounter with Ag: binding of Ag chooses B cell for proliferation: called clonal selection
  • Stimulated B cells gives rise to Ab secreting plasma cell: antibody factory
67
Q

Basic structure of an immunoglobulin

A
  • 5 types of antibodies: IgM, IgG, IgD, and IgE
  • called isotypes
  • they all have the same Y shape structure
  • different effector functions
  • each Ab molecule is composed of 2 identical heavey changes and 2 identical light chains
  • differences concentrated in N termini: variable region
  • each antibody molecule can bind two identical antigens
68
Q

Hinge region of Ab

A

gives flexibility in binding antigens on microbial surfaces

69
Q

Antibody isotypes

A
  • G,M,D,A,E
  • determined by the peptide sequence of the C region of the heavy chain
  • heavy chain constant regions of each isotype referred to as the mu, gamma, delta, alpha, and epsilon
  • determine effector function for each Ab isotype
  • light chains can be either kappa or lambda
  • no known differences in function
70
Q

Variability in V regions

A
  • not evenly distributed but concentrated within hypervariable regions
  • CDR1-3 hypervariable regions
  • make up the binding surface that is complementary to shape of the antigen
71
Q

Nature of antibody-antigen binding

A
  • multivalent ag with different epitopes or repeated epitopes
  • the part of the ag bound to antibody is the antigenic determinant or epitope
  • an ag can have many epitopes, these can be different or repeated
  • eptiope can be single aa sequence or can be discontinuous dependent on shape
  • non covalent interaction
  • ab differ in affinities depending upon how strongly they bind Ag
72
Q

Affinity vs avidity

A

-affinity: strength of binding between ag and single ab binding site
-avidity: overal strength of ab binding at multople sites
-

73
Q

How antibodies work

A
  • Direct effect on microbes: interfere with function, neutralize toxins, and activate MAC
  • Effects mediated by Fc receptor: recognize specific isotypes, trigger responses in the cell, one is phagocytosis and degranulation
74
Q

Function of IgE

A
  • specialized to activate mast cells in epithelium, eosinophils at mucosal surfaces and basophils in blood
  • IgE binds to surface of these cells through Fc receptors
  • Binding of Ag to surface bound to IgE causes explosive degraulation of bioactive molecules
  • important in defense against parasitic worms
  • also cause of allergy and asthma
75
Q

IgG and its isotypes

A
  • IgG overal very flexible molecules: easier to access to antigenic determinants
  • aa differences between isotypes tend to be concentrated in Ab hinge regions
  • disulfide bonds between cysteine residues hold ab molecules together
76
Q

IgA

A
  • specialized for secretion into gut lumen and other areas of mucus secretion
  • IgA present as a monomer in the blood
  • in mucus secretions it is present in large amounts in dimeric form linked by J chain
  • functions by neutralization
77
Q

mAb as tools

A
  • flow cytometry in immunology research
  • immunize mouse using human mac as ag
  • monoclonal ab production, secretion of ab specific for human macs
  • label mAb with flurochrome of choice using standard biochemical tech
  • bunch of antibody
78
Q

Generation of diversity in Ab before encounter with ag

A
  • immunoglobulin genes are fragmented into gene segments

- during b cell development in bone marrow, the segments are assembled to form a complete gene

79
Q

Germ line organization of human heavy chain and light chain loci

A
  • L=leader peptide
  • three gene segments
  • Light chain made of V and J
  • heavy chains made of V D J
80
Q

V region sequences are made from gene segments

A
  • VDJ are cut and spliced together by DNA editing enzymes
  • this is called somatic recombination- only occurs in developing B cells
  • the selection of VDJ used in assembly occurs randomly
  • for light chain single recomb occurs (VJ)
  • for heavy two recomb events (d to j then DJ to V)
  • creates huge diversity
81
Q

Mechanisms of gene arrangement

A
  • DNA rearrangement directed by recombinations signal sequences (RSS) which are enzyme recognition sites
  • Two types
  • 23 spacer or a 12 spacer
  • recombination must occur between the two different types in an inverted orientation
82
Q

Role of RAG enzyme

A
  • the enzyme complex mediating recombination is valled VDJ recombinase also called RAG (recombination activating gene complex)
  • RAG binds to one RSS and recruits the other (J to V)
  • DNA is cut and ends are joined
  • same for VDJ too
83
Q

recombination enzymes introduce additional diversity

A
  1. Cleavage by RAG
  2. Ends are covalently joined to generate hairpins
  3. DNA is nicked on 1 stain of the D and J segments. Position of the nick can vary= more diversity
  4. hairpins open generated new sequence that is palidromic
  5. nucelotides randomly added to the termini by terminal deoxynucleoty transferase. called N nucleotides because they are not coded by the germline
  6. strands pair through random matching of complementary base pairs
84
Q

arrangement of the heavy chain locus

A
  • naive B cells express IgM and IgD on the cell surface
  • VDJ, Cmu and C delta are expressed as a sinlge RNA transcipt which is spliced to generate IgM and IgD mRNA with the same V region
85
Q

Allelic Exclusion

A
  • every B cell has two copies of the heavy and light chain loci
  • only one locus of each are expressed in rearranged form
  • as soon as one locus undergoes successful rearrangement, rearrangement at the other locus in switched off
  • consequently B cells express Ab of one and only on specificity
  • in a population of B cells, the same functional light chain rearrangement is found with different functionaly heavy chains
  • random association of heavy and light chaings is another source of diversity
86
Q

Ab diversification after encounter with Ag

A
  • gene rearrangement leads to naive B cells that express membrane bound IgM and IgD
  • encounter with ag stimulates the B cell to secrete IgM and IgD
  • secreted vs membrane bound Ab is the result of alternative RNA splicing
  • All ab isotypes are produced in these forms
87
Q

further diversitfication of V genes through somatic hypermutation

A
  • ag activated b cells express the enzyme activation-induced cytidine deaminase (AID)
  • b cells activated by ag proliferate
  • AID randomly converts C to U during DNA repilcation
  • U converted randomly to one of the 4 bases normally found in DNA
  • occurs only in V regions of heavy and light chains
88
Q

affinity maturation

A
  • as immune response progresses, ab increase in binding efficiency
  • by chance some ab bind ag with higher affinity after AID expression
  • somatic hypermutation gives rise to mutant Ab
  • by chance some also bind with lower affintiy
  • cell binding ag with higher affinity receive stronger signal for proliferation
89
Q

How are different Ab isotypes produces

A
  • isotype switching
  • naive B cells express IgM and IgD on surface
  • after activation they secrete IgM and IgD
  • during the immune respose cells switch to other isotypes that retain the original V region (alterred by hypermutation)
  • switching involves splicing out intervening DNA sequences. Conceptually similar to VDJ recomb. occurs after Ag encounter
90
Q

Isotype switch mechanism

A
  • switch region is a repeptive sequence that facilitates recombination
  • same enzyme as used in somatic hypermutation converts C to U which is removed leaving a nick in the DNA
  • looped out
  • switching occurs from C mu to other C loci
  • cells can sequentially switch in a 5’ to 3’ direction
91
Q

Similarities of B cells and T cells

A
  • express Ag specific receptor. B cells, antibody; T cells T cell receptor
  • The Ag specific receptors are made using similar mechanisms
  • T cells and B cells undergo clonal expansion in response to antigen
92
Q

Differences of T and B cells

A
  • T cells recognize Ag associated with host cells surface molecules (MHC proteins)
  • T cells recognize degraded fragments (peptides) of protein Ag
  • TCR expressed in membrane bound form. Never secreted
93
Q

TCR generation of diversity

A
  • no post ag exposure increase in diverstiy
  • only had two D segments
  • VJ segments
  • P and N nucleotides
  • TCR gene rearrangement occurs in the thymus
94
Q

evolution of VDJ recombination/ evolution of adaptive immunity

A
  • Transposon cleaves gene encoding receptor of innate immunity
  • transposone inserted with segments of repetitive DNA
  • moved to different xsomes
  • RAG1/2 genes resemeble transposase gene of transposon
  • Transposons are ancient mobile genetic elements. Encode a transposase and possess terminal repeats recognized by transposes protein
  • may ultimately have derived from viruses
95
Q

aB and yd t cells

A
  • some t cells express yd along with CD3
  • some express aB
  • T cells never express both
  • yd T cell recognition of Ag and yd T cell function varies between species
  • yd T cells found more abundantly in tissues like skin and intestinal epithelium
96
Q

organization of yd TCR loci

A
  • yd TCR and aB use same gene rearrangement mechanisms to generate diversity
  • Organization is different: d chain locus is located within the a chain locus. during d chain rearrangement two D segemnts can be incorporated
  • any recombination of V to J at the a locus deletes d chain
97
Q

Antigen processing and presentation to T cells

A
  • pathogen protein in cell
  • antigen processing by breakdown of protein
  • presentation of pep by MHC molecule
  • recognition of Ag MHC complex by TCR
  • protein AG must first get into cells
  • inside it is cleaved by proteases to generate antigenic peps
  • inside the cell, the pep bind to major histocompatibility glycoproteins
  • MHC + pep travel to cell surface where it is presented to a T cell
  • The TCR recognizes the combinatio of MHC and Ag
98
Q

MHC class I and class II

A
  • Class I: heavy chain a chain, peps bind in the groove; B2 microglobulin stabilizes the molecule
  • Class II: has a and B chain
  • only certain cells express MHC II
  • Virtually all cells express MHC I
99
Q

subsets that recognize MHC 1 and 2

A
  • II: T cell expressing CD4; helper T cell; assist immune responses, help macrophage activation and help B cell responses
  • I: t cell expressing CD8; cytotoxic T cell; kills cell infected with virus or other intracellular pathogens
100
Q

function of T cells

A
  • change behavior of other cells
  • CD8: kill virus infected cell
  • CD4: release cytokines to activate macrophages to release cytokines
  • CD4: release of cytokines to activate B cells to become plasma cells to release antibody
101
Q

Antigen presentation by MHCs in different compartments

A
  • Compartment 1: cytoplasm and nucleus; peptides generated in cytoplasm loaded onto MHC1 in DR
  • Compartment 2: vesicular system contiguous with outside. ER, golgi, endosome, lysosmes. Proteins from outside are degraded and loaded on the MHC II in loading compartment
102
Q

MHC class I presentation pathway

A
  • peptides produced in the cytosol are transported into the ER
  • Proteosome concept: large % proteins produces by a cell are misfolded and therefore are nonfunctional. The proteosome is a large barrel shaped structure and enzymatically degrades useless proteins. In addition the proteosome works with TAP to translocate peptides into ER for antigen presentation
  • TAP: transportor associated with Ag processing
103
Q

MHC class II presentation pathway

A
  • ag is taken up from the extracellular space
  • in early endosomes of neutral pH, endosomal proteases are inactive
  • acidification of vesicles activates proteases to degrade antigen into peptide fragments
  • vesicles containing peptides fuse with vesicles containing MHC class II
  • MHC2 pathway samples the extracellular environment
  • Macs and DC phagocytosed Ag
  • B cells also bind to Ag through surface immunoglobulin then internalized ag-ab complex by receptor mediated endocytosis
  • macs, DC, and B are the only ones that express MHCII
104
Q

Cross presentation

A
  • enables exogenously derived peptides to enter the class I presentation pathway
  • a mechanism for peptides to cross from MHC2 to the MHC1 presentation pathway
  • mechanism unknown
  • transfer of exogenously derived peptides into cytoplasm, can fuse with vescile containing MCH1
105
Q

The major histocompatibility complex

A

MHC1 and MHC2 as well as proteins involved in antigen processing and presentation are encoded by a cluster of genes called the major histocompatibility complex

Mismatches between MHC genes during transplantation cause tissue rejection (hence the name)

MHC genes are highly polymorphic – consequently they differ in the peptides they bind and therefore the TCR specificities with which they interact

Polymorphism defined by multiple alleles for each MHC gene

From genetics: a child will inherit a different allele from each parent and will therefore be heterozygous for each MHC gene

However, note: Individual MHC genes may be possess high polymorphism, low polymorphism (oligomorphic), or may be non-polymorphic

Human MHC is called the human leukocyte antigen (HLA) complex

106
Q

MHC isotypes

A
  • HLA-A,B,C present Ag to CD8 cells and bind to receptors on NK cells
  • HLA-E and HLA-G bind to NK cells
  • HLA-F chaperone for surface HLA that looses their peptides
  • HLA DM and DO supervise peptide loading on MHC2
  • HLA-DP, DQ, DR present Ag to CD4 t cells
107
Q

Map of the human MHC

A

For HLA DO, A and B genes are separated

Class III regions encodes additional genes we will not consider here

Pattern of alleles expressed across the MHC complex is called the haplotype
The encoded protein of one specific allele is called an allotype

Low meiotic recombination frequency across MHC locus

Therefore, the parental HLA haplotype inherited as a unit across generations

Over long term human history, genetic recombination is significant and results in many 1000’s of haplotypes

108
Q

Polymorphisms in MHC molecules

A
  • concentrated in regions that bind peptide and TCR
  • allotypic variation is in the binding groove (CLass I)
  • in class II the alpha chain is nonvarient
109
Q

MHC restriction

A
  • T cells recognize combination of peptide and MHC

- don’t respond unless recognize specific ag with MHC

Immunology (4 decks)

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