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Final

IMM250H1 Study Guide - Final Guide: Innate Immune System, Adaptive Immune System, Hematopoietic Stem Cell


Department
Immunology
Course Code
IMM250H1
Professor
Dana Philpott
Study Guide
Final

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IMM250 Lecture 5Introduction to the adaptive immune system
Innate and adaptive immunity are interdependent systems
Innate immune system
First line of defense
Recognize common molecular patterns (PAMPs/MAMPs)
Innate leukocyte/WBC responses
No ‘memory’ (always same response)
Not smart immune system, it reacts but does not remember
Adaptive immune system
Second line of defense
Recognize molecular structures (has the capacity to recognize any molecular structure)
Lymphocytes (kind of leukocyte, are 2 types = T cells + B cells)
Yes ‘memory’ of threat
Stronger/faster immune response to subsequent infections from same pathogens
Adaptive system requires innate system activation
Adaptive system can feedback to innate system
Innate & adaptive immunity
1. Pathogen encounter
2. Pre-existing innate immunity
= non-specific
= 0-4 hours, immediate
= physical barriers (skin)/chemical barriers (pH)/biochemical barriers to keep pathogens out
(skin, saliva, mucosal barriers)
3. Induced innate response
= broad recognition
= within 4-6 hours
= triggers inflammation, complement, phagocytosis, targeted cell lysis
= activates induce adaptive system
4. Induced adaptive response
= specific recognition
= 4 days later
= B cells (antibodies), Th cells (cytokines), Tc cells (cytolysis = kill targets)
Entry of internal threat recognition response return to resting (homeostasis)
Homeostasis important because: do not want adaptive system to be focused on specific pathogens, need adaptive system to retain broad specificity
Immune recognition
Innate immune recognition
o PAMPs = mol’c on surface of pathogens that activate innate immune system
o Recognized by PRRs on innate immune cells = TLRs, Nod receptors
Adaptive immune recognition
o Antigen = macromolecule/protein/carbohydrate expressed exclusively by ONE pathogen, each pathogen has MULTIPLE antigens
o H1N1, the H and the N are antigens on flu virus, recognized by the adaptive immune systems
o Recognized by lymphocytes that have antigen receptors
Only vertebrates of animal kingdom have evolved an adaptive immune system
Adaptive immune system comprised of 2 kinds of immunity:
1. Cellular immunity
Cells of innate immune system can also mediate cellular immune response (e.g. phagocytosis)
Adaptive immune cells also cause phagocytosis, and kill pathogens directly with microbicidal molecules
2. Humoral immunity
Generation of antibodies, secreted and floating in blood, can be detected in blood tests
Antibodies bind pathogens and toxins (i.e. tetanus) exclusively
also activate OTHER processes e.g. complement (coat & kill pathogens)
Some pathogens do not need both cellular and humoral immunity (most do)
Hematopoietic stem cells give birth to all cells of the immune system
(myeloid progenitor granulocytes neutrophil, eosinophil, basophil, mast cell, monocyte
monocyte dendritic cell, macrophage)
(lymphoid stem cell lymphocytes B cell, T cell, NK cell
B cell plasma cell, memory cell
T cell CD4+ Th cell, CD8+ Tc cell)
Antigens
Unique, presented on different bacteria, different viruses (even within a virus, different strains of viruses have different antigens displayed)
e.g. each season, new type of influenza put out different antigens so pre-existing immunity does not work as well
Antigens within yourself
e.g. tumor (tumours display antigens/proteins that are malformed, will look like antigen to immune system = tumor surveillance)
Immunocompromised = higher rates of cancer b/c less tumour surveillance
Autoimmune diseases like MS, rheumatoid arthritis, have inappropriate responses to own antigens
e.g. proteins part of myelin sheath that protect neurons attacked by immune system = MS
e.g. transplants need immunosuppressant to prevent attack on donor organ’s protein antigens | e.g. allergies like hay fever/pollen as antigen

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Antigens that trigger CELLULAR immunity trigger response through T-CELLS (T-CELL RECEPTOR = TCR)
Antigens that trigger HUMORAL immunity trigger responses through B-CELLS (B-CELL RECEPTOR = BCR)
T-cell will bind to antigen that fits TCR secrete products (cytokines = molecular messenger of immune system, and molecular killers = perforin, poke holes in target cells)
B-cell will bind to antigen that fits BCR secrete products (antibodies that are soluble version of B-cell receptors same as on surface
can check “titers against X pathogen through blood test, titrating/diluting blood and looking for dilution at which they can detect signal of antibody
BCR
2 blue heavy chains, 2 orange light chains, total of 4 proteins
Y shape, binds 2 antigens at once
Spans membrane
Releases antibody same except cut off TM domain
Recognizes PAMPs (protein/carbohydrate) on surface of pathogens, in native/folded shape
TCR
2 proteins, alpha chain and beta chain
Binds 1 antigen
Also spans membrane
Recognizes peptides = small linear sequences of amino acids
Good way to see different bits of a pathogen
Peptides can come from proteins INSIDE pathogen i.e. not necessarily on pathogen surface
Proteins on surface can mutate seasonally, but proteins INSIDE are usually more important for organism function = less likely to mutate = retain more immunity
T-cell receptor diagram
Small peptide T-cell sees (small red line), need antigen-presenting molecule on host cell
Viral proteins are broken down into peptides inside an infected host cell, loaded onto host’s antigen-presenting molecule
Immune system diversity
Every lymphocyte (B-cell or T -cell) has ONE antigen specificity
Multiple copies of BCRs/TCRs, more change of sticking to antigen
BCRs/TCRs are unique to specific lymphocytes
BCRs/TCRs are highly specific for particular antigen
Antigen receptor ‘repertoire’ has to be bigger than possible antigens you can throw at it
100 million specificities of BCRs
BCR level 1
Has 2 light chains (kappa or lambda light chain) and 2 heavy chains
Random whether antibody has kappa chain or lambda chain (express one or other)
Each of 100 million BCRs bind specific antigen
gene transcribed into RNA translated into unfolded protein folded/modified into finished protein (central dogma)
Only have 25,000 genes in genome, how do you get 100 million heavy chains and light chains
Gene rearrangement VDJ recombination
Immunoglobulin/antibody gene locus (V = variable D = diversity J = joining C = constant)
Within gene locus, have 3 gene loci in germline DNA in developing B cells:
(V + D + J segments = V exon, + C exon = heavy chain protein) + kappa light chain + lambda light chain
VDJ rearrangement in bone marrow, B-cell precursor cells
V, D, J region randomly selected intronic DNA looped out unique V exon = 100 million specificities
Light chain locus has no D segment, 1 V exon + 1 C exon
Heavy chain locus has D segment, 1 V exon + 3 C exons
Germ-line cells have different DNA than mature lymphocytes and lymphocyte precursor cells
V regions from heavy chain and light chain = antibody binding site
C site = constant site, no V D J recombination, but indicates class of antibody molecule (IgM, IgG, IgA, Ig = immunoglobulin)
BCR level 2
V domain = variable domain, high structural variability, antibody binding site
C domain = class of antibody, low structural variability, dictates antibody’s function (activating complement, allergic response)
Both light/heavy chains encoded by same rearranged IgL/IgH genes, light chain either kappa OR lambda gene
BCRs have 2 identical binding sites
TCRs have V, C region, alpha chain, beta chain, 1 binding site = alpha V region + beta V region
Developing B cell chooses kappa OR lambda light chain, VJ recombination occurs at both genes
3 loci in germline DNA: heavy chain loci, kappa light chain loci, lambda light chain loci
(2 light chains in case the heavy and light chains don’t pair well, have another chance-- never express both)
BCR level 3
V region is made up of 3 micro domains = CDR1, CDR2, CDR3
CDR = complementarity determining region
CDRs stick out more interact with antigens more, most protein variability of V domains
TCR has CDR1, CDR2, CDR3 too
Combinatorial diversity: diversity due to VDJ recombination
Modifies germline DNA in adaptive immune cells (B cells & T cells), no in innate immune cells
Receptors more evolutionarily ancient in innate immune cells
Chain pairing diversity: diversity due to random pairs of heavy + light chains (alpha + beta chains)
Combinatorial + chain pairing diversity: during B/T cell devo in marrow, before cells see antigen

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VDJ rearrangement exclusive to adaptive immunity, only in vertebrates (evolutionarily recent)
No VDJ rearrangement in cells of innate immune system, receptors in innate system are “germline encoded” more evolutionarily ancient
Adaptive immune system ss a survival advantage, people who lack ability to make adaptive immune system, affected by antigens die
Bubble Boy David Vetter, Severe Combined Immunodeficiency Syndrome (SCID), mutation prevents adaptive immune system from functioning
Had older sibling with disease who passed away, had bubble ready for him, died after bone marrow transplant
Emerging pathogens capacity to respond to threats we have not seen before, do not need to evolve pathogen-specific antigen receptor sequences in germline
Evolving pathogens change antigens, e.g. influenza virus seasonal strains swap antigens H an N; e.g. HIV mutation rate high;
e.g. trypanosome parasite, sleeping sickness/Chagas’ disease, hundreds of genes encoding cell surface protein (attack with T cell to attack intracellularly)
Immunosurveillance of tumours can develop tumours b/c humans live longer, lack immune system/immunosuppressed
Normal cell mutates (random or exposed to mutagen) expresses tumour antigens Immunosurveillance
emergence of resistant variant, different antigens less recognized
T cell/B cell response co-evolves with new antigens
1. Elimination adaptive immune response destroys newly emerging tumour cells
2. Equilibrium if elimination incomplete, tumour cells evolve, held in-check by BCRs/TCRs detecting new tumour antigens (co-evolve)
3. Escape tumour variants resistant to adaptive immune response, clonal selection, tumour growth
Advantages of limitless antigen receptor repertoire
1. Protect against newly emerging pathogens e.g. Ebola virus survivors have protective antibody
2. Protect against quickly evolving pathogens e.g. influenza surface proteins, HIV, trypanosomes
3. Protect against cellular mutants with Immunosurveillance e.g. all cancers/tumours
Clonal Selection & Expansion
Want more than one cell to generate adaptive immune response, innate response holds things at bay
but need adaptive immune cells to deal w/ quickly-replicating pathogens
Course of typical immune response
Time 0: introduction of pathogen, innate immune system responding
1. Establish infection
2. Induction of adaptive response, logarithmic expansion (few clones will divide/expand) & differentiate to plasma cells
3. Adaptive immune response clears pathogen (plasma cells = fully-differentiated B cells, secrete antibody)
4. Immunological memory, have memory cells
Clonal selection hypothesis, Frank McFarlane Burnet
Immune cells have own unique antigen receptors
Population of lymphocytes with correct antibody-antigen specificity will be signalled to divide
Germ-line DNA changed/rearrangements = unique receptor, expressed by all daughter cells too
1. Each mature lymphocyte has many copies of a single antigen receptor w/ unique specificity
2. Antigen receptor on lymphocyte + complementary antigen required for lymphocyte activation
3. Lymphocyte activation induces cell division, daughter cells have same antigen as parent cell
4. Lymphocyte whose antigen receptor specificity allows binding to ‘self’ antigen is eliminated
gets rid of those potentially harmful lymphocytes
Secondary immune response
Pathogens display multiple antigen (influenza has H and N), small pool of lymphocytes respond
= big enough pool of lymphocytes that you can detect them in the blood
Antigen-specific lymphocytes expand, peak, come back down
= do not want immune system dominated by few clones, need diversity
Most cells will die once infection is cleared, but retain more than baseline
Naïve cells respond, multiple B/T cells = primary immune response
Memory cells respond, one B/T cell = secondary immune response
Secondary immune response (more starting cells, respond more potently)
1. Faster
2. Higher magnitude (more expansion)
3. Same antigen as primary response
4. Responsible for long-lives immunity to pathogens
Vaccination work by triggering primary response memory secondary memory
Exposed to pathogens in history
developed herd immunity
Depending on pathogen
parasite vs. virus,
infection location (mucosal, skin)
dictate which response generated
(has to do with C region)
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