Lecture 4 ((3) - Week 2B) Flashcards Preview

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Flashcards in Lecture 4 ((3) - Week 2B) Deck (74):

The immune system must protect us against a wide variety of pathogens

eg bacteria, viruses, parasites, fungi
• which pathogens an individual will encounter is not known in advance
• therefore, immune system must maximize its potential to respond to diverse challenges


The immune system must

• recognize and respond to pathogens
(failure = death from infectious disease)
• but not respond to components of our own bodies
(failure = auto-immune disease)
ie must discriminate "non-self" from "self"



anything that binds to a specific receptor on T or B cells
• generates antibody
• can be bits of bacteria, viruses etc (foreign antigen)
• pathogens can also be bits of our own bodies (self antigen)



the portion of the antigen that is recognized and bound by a receptor on an immune cell
• structure of antigen that's recognized
• numerous
• antigens contain many epitopes


Complex antigens (eg proteins) can contain

multiple different epitopes, each of which can be recognized by different antibodies


Epitopes recognized by antibodies are

often shapes formed by the way proteins fold
• different antibodies "fit" different shapes


Cells of innate and adaptive immune systems recognize

non-self in different ways


Innate immune system

• NK cells
• monocytes/macrophages
• dendritic cells
• granulocytes
• a limited number of common microbial structures can be recognized: PAMPs (toll-like receptors)


Adaptive immune system

• T cells
• B cells
• can recognize MANY antigens


Overview of antigen recognition

1. receptor binds to Ag
2. signalling cascade initiated (to nucleus, tell cells to start division)
3. gene transcription
4. production of effector molecules (eg antibodies/cytokines)


Signalling cascade

cell starts dividing


B cells

make antibodies


Antibody is also known as

immunoglobulin (Ig)


Recognition of antigen by B cells

• B cells recognize antigens using the B cell receptor (BCR)
• the BCR is an antibody molecule anchored to the B cell - transmembrane
• antigens are recognized directly (they don't require presentation by other cells)
• epitopes are often conformational (shapes formed by protein folding)

• T cells recognize antigen = complex
• antibody molecules on B cell surface BIND native antigen
--shape and conformation (wrong shape = no binding = no action)


In mamamls, B cells develop in

bone marrow
stem cell -->
pro- B cell -->
pre- B cell (start to express antibody on surface)-->
immature naive B cell -->
mature naive B cell

• naive = hasn't seen antigen


Each new B cell

has a unique receptor
• recognizes a different antigen


Each B cell expresses

only 1 type of receptor
• recognize only 1 antigen


Recognition of antigen by B cells

• activated B cells differentiate into plasma cells - secrete a soluble form of the receptor - antibody
• the antibody recognizes the same antigen as the BCR

• B cell divides, loses antibody from surface --> makes a lot of antibody in solution (not on surface)


Activated B cells differentiate into

plasma cells that secrete a soluble form of the receptor (antibody)


Plasma cells secrete

a soluble form of the receptor (antibody)


Each antibody recognizes

a different antigen
• Ag = antigen
• Ab = antibody


Structure of a typical antibody

Y shaped
Arms of the Y
• light chain on outside of each arm
• heavy chain on inside of each arm
• variable region is distal and made of a combination of shapes of 2 identical heavy (VH) and 2 identical light (VL)
• antigen binds the variable region

The stem of the Y
• constant region
• controls what the antibody does
• heavy chain = γ α μ ε δ

there are 2 types of light chain and 5 types of heavy


2 types of light chain

• kappa κ
• lambda λ


5 types of heavy chain

• mu μ
• gamma γ
• alpha α
• epsilon ε
• delta δ


Variable domains

contains the sequences that interact with antigen


Variable regions of H and L chains

combine to form shape that fits that of the antigen



arms of the Y
binds antigen

Papain digestion (each separately)
Pepsin digestion ( F(ab')2 both parts separated from Fc)


(2 = subscript)

the arms of the Y together



determines function of antibody


V domains contain

areas of hypervariability
• HV regions are also known as complementarity determining regions (CDRs) - 6 combine to form each antibody binding site


HV regions

• hypervariable regions
• also known as complementarity determining regions (CDRs)
• 6 combine to form each antibody binding site


Antibody classes

determined by the constant region of the heavy chain

• IgG = γ heavy chains
• IgE = ε heavy chains
• IgA = α heavy chains
• IgD = δ heavy chains
• IgM = μ heavy chains

all have 2 heavy and 2 light chains, but IgM has 10 heavy and 10 light chains, IgA can have 4 heavy and 4 light chains


IgG =

γ heavy chains
2 heavy 2 light

4 subclasses


IgE =

ε heavy chains
2 heavy 2 light


IgA =

α heavy chains
2 heavy 2 light

Or another Y to get 4 heavy and 4 light

2 subclasses


IgD =

δ heavy chains
2 heavy 2 light


IgM =

μ heavy chains
10 heavy, 10 light


Different classes have

different effector functions


IgG has

4 subclasses in humans
• IgG1
• IgG2
• IgG3
• IgG4


IgA has

2 subclasses
• IgA1
• IgA2


B cells can produce

different classes of antibodies
• IgM and IgD -->
• IgM
• IgG
• IgA
• IgE

• IgD = recognition
• IgE = allergies
• ER makes protein


B cells receptor diversity

• millions of different antigens can be recognized
• each new lymphocyte expresses only 1 type of receptor and recognizes only 1 antigen
• lymphocytes with any given specificity are rare
• an antigen will only activate those lymphocytes with the "right" receptor
• these lymphocytes divide repeatedly - daughter cells express the same receptor
• a large number of useful cells are generated (clonal expansion)


A new lymphocyte expresses

only 1 type of receptor and recognizes only 1 antigen


Lymphocytes with any given

specificity are rare


An antigen will only activate those lymphocytes with

the "right" receptor


Lymphocytes divide repeatedly

clonal expansion
• daughter cells express the same receptor
• a large number of useful cells are generated


How is receptor diversity generated?

• each developing B cell expresses a distinct receptor
• tens of millions of receptors required - how?
• a gene for each receptor? - no, would require tens of millions of genes
• instead, diversity is generated by "mixing and matching" gene segments within the heavy chain and light chain loci


Diversity is generated by

random "mixing and matching" of variable, diversity, and joining segments


Diversity is generated by random "mixing and matching" of

variable, diversity, and joining segments


Making an immunoglobulin heavy chain

• D-J joining: DNA spliced between diversity and joining regions
• V-DJ joining: DNA spliced out between V and DJ
• transcription
• RNA splicing --> chooses constant part and makes different variants

• mediated by RAG recombinase enzymes


Somatic DNA recombination generates

antibody diversity


... generates antibody diversity

somatic DNA recombination


Antibody diversity
2 processes act during B cell development

• combinational diversity
• junctional diversity
~ 5x10^13 antibodies


Combinational diversity

mixing and matching of V, (D), and J segments
• different combinations of H and L chains


Junctional diversity

• addition of P- and N- nucleotides at joins


Antibody responses are dynamic

they evolve DURING immune response
Primary = first time see antigen
• IgM levels in serum up then down
• IgG up

Secondary = second time to see antigen
• IgG down then up

isotype switching and and affinity maturation


Antibody responses are dynamic - they evolve during an immune response

1. class (isotype) switching
2. affinity maturation


Class switching

• a given B cell starts by making IgM (and IgD) but can switch to making IgG (or IgA or IgE)
• class switch recombination allows a given V-D-J unit to be associated with different constant regions
• antibody specificity remains constant whilst biological effector functions are varied

IgM first, then switches primary
secondary made IgG


Class switch recombination

IgM variable (VDJ) followed by constant
• activation induced cytidine deaminase (AID) = DNA chopped out
IgG made
• take out genes that make A and put in genes that make B
• different constant region


Affinity maturation

improves the quality of antibodies during an immune response by increasing their affinity for antigen
(ie makes the antigen binding site a better fit for the antigen)
• changes variable regions
• affinity = strength of interaction


Affinity maturation mechanism

by somatic hypermutation
• individual nucleotides in variable regions are randomly replaced with alternatives
• "tested" against antigen displayed on follicular dendritic cells (FDC) - many mutations are useless
• B cells with the best fit antibodies survive

occurs during an immune response, not during B cell development`


Affinity maturation and class switching occur in

germinal centers (GC) in lymph nodes and spleen
• GC form 3-4 weeks after initial antigen exposure
• rapid initial response is followed by an improved, more effected and diversified, response
• antigen sticks on surface and presents in follicular dendritic cells


What do antibodies do to protect us against infections?

five things:
1. agglutination
2. neutralization
3. opsonisation
4. complement activation
5. antibody dependent cellular cytoxicity (ADCC)



crosslinking by antibodies creates larger particles that are taken up more efficiently by phagocytes
• esp IgA antibody
• multivalvent antibodies and antigens



can block attachment of pathogens to receptor on cells and block the action of bacterial toxins
• keeps shit out
• antibodies bind to pathogens so can't fit into receptor on target cell



FcR mediated uptake enhances pathogen clearance by macrophages and neutrophils
• FcR = receptor for Fc part of antibody
-receptor for heavy chain
• constant part of antibodies attaches to receptor on target cell so pathogens/antigens can't get in


Complement activation

• "trained spotters"
• proteins in blood
• antibody binds to surface of cell enzyme splits C3 into C3a and C3b
• C3b + C5 into C5 convertase to make MAC (membrane attack complex)
• punches hole in cell --> lysis

• classical, alternative, lectin pathways


Antibody dependent cellular cytoxicity (ADCC)

role in killing:
• virally infected cells, helminths, tumour cells
• may be utilized for therapies
• antibody bound to cell
• NK cell or macrophage comes along, recognizes, makes molecules that kill

• viral peptides stick out of target cell surface
• antibodies bind, constant (Fc) region sticks out
• NK cell or macrophage hasFc receptor
• meet up, macrophage/NK cell releases molecules to kill infected cell


Antibody classes and subclasses have

different biological properties


B cells

make antibodies


Each B cell expresses

a single unique receptor for antigen


Somatic recombination contributes to

receptor diversity during B cell development in bone marrow


During an immune response, antibodies

improve and diversify - affinity maturation an isotype switching


Antibodies have 5 main biological activities that

help fight infections