The Adaptive Immune Response
IMM250F Immunity and Infection (Ch. 4)
Jasty Singh
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The Adaptive Immune Response
Video 1: Introduction
o Overview/review of innate and adaptive immune responses
o Lymphocytes: Cells of the adaptive immune system
— How B and T cells recognize and respond to host threats — Introduction to lymphocyte subsets and antibody classes
Video 2: Hallmarks of the adaptive immune response
— Specificity, Diversity, Tolerance, Clonal selection, Memory
Overview/review of innate and adaptive immune systems
The microbial world we face 24/7
Microbes (= microorganisms)
• Organisms so small, they cannot be seen with the naked eye • Goal is to replicate
Microbiota (microflora, commensals)
• Microbes that colonize our body surfaces • Normally harmless or even beneficial
• Changes to microbiota can affect health
• Microbes that can cause disease (‘pathology’) • A small subset of microbes
• Establish infection in the host
Images: Left, CDC/ , ; middle, Wikimedia Commons, BlastOButter42; right: CDC,
General approach of innate and adaptive immune cells to recognition and response
Stages of the immune response
Entry of a pathogen
Recognition
Return to resting
Immune cells (innate and adaptive) have receptor molecules on their surfaces that can attach to (‘recognize’) the internal threat
When receptor molecules recognize a threat the cell is activated and defense functions are triggered (‘effector functions’)
Earlier in the course…
Innate and adaptive immune systems provide complementary internal defenses
In Chapter 2
Cytokines: Soluble molecules secreted by one cell type that act on another (e.g. activate or inhibit certain functions)
‘Adaptive Immune Cells’
Lymphocytes: Cells of the Adaptive Immune System
RBC, platelet, lymphocyte (left to right) seen through a scanning electron microscope
Credit: Electron Microscopy Facility at The National Cancer Institute at Frederick (NCI Frederickdomain, https://commons). Public .wikimedia.org/wiki/File:Red_White_Blood_cells.png
All immune cells are formed from the hematopoietic stem cell
Earlier in the course…
Lymphocytes are the immune cells responsible for adaptive immunity
In bone marrow there are ‘common lymphoid progenitor cells’ that develop (‘mature’) into either B or T lymphocytes
o Some mature in the bone marrow become mature B cells
o Others travel to the thymus and develop into mature T cells
B lymphocyte (‘B cell’)
Maturation
Lymphoid progenitor cells
Maturation
T lymphocyte (‘T cell’)
Primary and secondary lymphoid tissues
Primary lymphoid tissues
Where lymphocyte maturation occurs • B cells – Bone marrow
• T cells – Thymus
Secondary lymphoid tissues
Where mature lymphocytes become activated to respond to pathogens
• Lymphnodes
• Mucosa-associated lymphoid tissue
• Skin-associatedlymphoid tissue
Adapted from Cancer Research UK (Original email from CRUK) [CC BY-SA 4.0 (http://creativecommons.org/lic enses/by-sa/4.0)], via Wikimedia Commons unmodified.
Immune recognition: Comparison of immune and adaptive immune systems
DAMP (not shown) (Damage- associated molecular pattern)
Present in host when there is tissue injury
– Complex molecular structures
Innate leukocytes have pattern recognition receptors (PRRs) that recognize PAMPs and DAMPs
→Recognition of general pathogen types (e.g. virus vs bacteria)
Lymphocytes have antigen receptors that recognize antigens
→ Recognition of unique pathogens (e.g. influenza virus vs measles virus; or, influenza virus ‘strain X’ vs ‘strain Y’)
Lymphocyte antigen receptors
B cell receptor (BCR)
T cell receptor (TCR)
(Recognition)
Also known as Immunoglobulin (Ig)
(Response)
Antigen recognition by B and T cells is fundamentally different
B cell receptors recognize antigen on its own
Any type of molecule (e.g. carbohydrate, protein, lipid, nucleic acids)
T cells recognize protein antigens ‘presented’ by another host cell
Recognize only a fragment of the protein (peptide) displayed an ‘MHC’ molecule
A host cell presenting antigen to a T cell
MHC = major histocompatibility complex (more about this later)
Antigen recognition by B and T cells is fundamentally different
A host cell presenting antigen to a T cell
Molecules that neutralize Pathogens/Toxins
“Antibodies”
Molecular messengers
“Cytokines”
Molecular Killers
Secreted products
Secreted products
MHC = major histocompatibility complex (more about this later)
B cell receptors recognize antigen on its own
Any type of molecule (e.g. carbohydrate, protein, lipid, nucleic acids)
T cells recognize protein antigens ‘presented’ by another host cell
Recognize only a fragment of the protein (peptide) displayed an ‘MHC’ molecule
Division of labour in lymphocyte responses
APC = antigen presenting cell Antigen uptake (e.g. via PRRs)
Activated CD4+ T cells Differentiate into helper T cells (Th) that secrete cytokines needed for activation of B, CD8+ T, some innate leukocytes
→Overall defense
Activated B cells
Differentiate into plasma cells that secrete antibody → Extracellular
Activated CD8+ T cells
Differentiate into cytotoxic T lymphocytes (CTL) that kill infected cells
→Intracellular defense
A cell is said to ‘differentiate’ when it acquires new characteristics (structural and/or functional) that distinguish it from its earlier form and/or function
Plasma cells, Th, and CTL are the ‘effector cells’ of adaptive immunity
Summing up lymphocyte recognition and response
Cell Type Antigen Receptor Antigen Effector Effector Cell Recognized Cell Response
CD4 T TCR Peptide/MHC II T Helper Cytokine Cell Complex (Th, TH) Secretion
CD8 T TCR Peptide/MHC I Cytotoxic T Lysis of Cell Complex Lymphocyte Infected
(CTL) Cells
B Cell BCR Any Type of Plasma Cell Antibody (Immunoglobulin Molecule Secretion on B cell surface)
Even further division of labour: CD4+ T cells subsets and antibody classes
Major CD4+ T cell subsets
Major antibody classes (‘IgX’ = ‘Immunoglobulin X’)
Hallmarks of the adaptive immune response
A lymphocyte
NAIAD, USA; Electron Microscopy Facility at National Cancer Institute, USA
o Specificity
o Diversity
o Tolerance
o Clonal selection o Memory
One antigen specificity per lymphocyte
BCRs (or TCRs) on a given B or T lymphocyte are:
• Identical; thousands of copies • Unique to that lymphocyte
• Highly specific for a particular
Diversity of antigen recognition by lymphocyte population is vast
Different BCR or TCR specificities in the B cell or T cell population = ‘repertoire’
Antigen receptor ‘repertoire’
Different antigens
Diversity of BCR and TCR repertoires is always greater than diversity of antigens
Rough estimate? BCR repertoire ~ 100,000,000 specificities
Recall: Central dogma of molecular biology
Exon = part of a gene that is expressed in the corresponding protein Intron = part of a gene that is NOT expressed in the corresponding protein
(Amino Acids)
Mystery of lymphocyte receptor diversity
Human genome has around 25,000 genes
Your immune system can produce over 100,000,000 different BCRs/TCRs
Each BCR and TCR has two different protein chains (heavy, light; alpha, beta)
How is this possible???
Answer: ‘Gene rearrangement’
won the 1984 in Physiology and Medicine: “for his discovery of the genetic principle for generation of antibody diversity”
“There are hundreds of millions of different antibodies, which vastly outnumber the combined total of human genes. In 1976 showed how this is possible through the redistribution of genes in a cell during its development into an antibody-producing B lymphocyte.”
” – Facts”. Nobelprize.org. AB 2014. Accessed 15 Aug 2016. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1987/tonegawa-facts.html
Lymphocyte antigen receptors
B cell receptor (BCR)
T cell receptor (TCR)
(Recognition)
(Response)
Researchers studied genes that encode antibody light chain, antibody heavy chain, TCR alpha chain, TCR beta chain (but light chain gene was studied first)
Also known as Immunoglobulin (Ig)
Multiple V, D and J segments in antigen receptor gene loci allow the generation of diversity
Genomic DNA in IgH and TCR beta gene loci
Gene segments
… V1 V2 ……. Vn Gene
rearrangement
D(1-n) J(1-n)
V = ‘variable’ D = ‘diversity’ J = ‘joining’
One of each type of gene segment ‘recombines’ to form a complete V exon
Adapted from Fig. 4-13 Primer to The Immune Response, 2e. Copyright © 2014 Elsevier Inc. All rights reserved.
Choice of V, D, J that form complete V exon is RANDOM
→ ‘VDJ recombination’ creates diversity of immunoglobulin genes
Multiple V, D and J segments in antigen receptor gene loci allow the generation of diversity
Genomic DNA in IgL and TCR alpha gene loci Gene segments
… V1 V2 ……. Vn Gene
rearrangement
V = ‘variable’ D = ‘diversity’ J = ‘joining’
One of each type of gene segment ‘recombines’ to form a complete V exon
Choice of V, J that form complete V exon is RANDOM
Adapted from Fig. 4-13 Primer to The Immune Response, 2e. Copyright © 2014 Elsevier Inc. All rights reserved.
BCR (and TCR) diversity is created by VDJ recombination
Combinatorial diversity:
Diversity arising due recombination of V, D and J segments that are each selected randomly from a collection of gene segments
Chain pairing diversity:
Diversity arising from the random production and pairing of immunoglobulin heavy and light chain specificities
Diversity is generated during T and B cell development (before antigen encounter)
Toronto TCR connection
Dr. Dept of Immunology University of Toronto
First to clone the gene for the human TCRβ chain
Ebola virus
Advantages of limitless antigen receptor repertoires
Effective protection against:
• Newly emerging pathogens
(e.g. COVID-19, protective antibody in Ebola virus survivors)
• Quickly evolving pathogens
(e.g. mutating surface proteins of influenza, HIV)
• Cellular mutants (e.g. all cancers)
Influenza virus
HIV budding from infected cell
Images:: Public Image Library, National Institutes of Health
The possible downside of a limitless receptor repertoire?
If BCRs and TCRs can recognize ‘anything’, they can recognize ‘self’
→Potential for ‘autoimmune’ responses • Autoreactive Th and CTL cells
• Autoreactive B cells→autoantibodies
Autoimmune responses can cause damage and/or dysfunction
→‘Autoimmune disease’
Tolerance mechanisms eliminate or control self-reactive lymphocytes
B cells – bone marrow
T cells – thymus
Where lymphocytes first express antigen receptor genes
Eliminate autoreactive lymphocytes while they are still immature
A key advantage of adaptive immunity: Clonal selection phenomenon
F. Mac ( , 1960)
Vast circulating pool of lymphocyte clones
Cell division (‘proliferation’) of selected clone
Example shown for B cells
Plasma cells (secrete antibody)
‘Clone’ (noun) = genetically unique cell (and any progeny of that cell if it divides)
Every step is antigen-specific
The memory response provides protective immunity upon subsequent exposure to a pathogen
o Develops faster o Reaches a higher
o Specific for same antigen that triggered primary response
o Responsible for long- lived immunity to pathogens
Hallmarks of the adaptive immune response
A lymphocyte
NAIAD, USA; Electron Microscopy Facility at National Cancer Institute, USA
o Specificity
o Diversity
o Tolerance
o Clonal selection o Memory
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