W12 Adaptive immune system - focus on B cells Flashcards
Innate immune system
Rapid response
Non-specific (generic anti-bacterial or anti-viral mechanisms)
Most often fails to completely eliminate the infection
Adaptive immune system
Delayed response Highly specific Usually eliminates infection Memory Long term immunity, but specific to that particular pathogen
Adaptive Immunity
Humoral immunity
Mediated by B-lymphocytes
Cellular immunity
Mediated by CD8+ cytotoxic T- lymphocytes
Both branches regulated by CD4+ helper T-lymphocytes
(T-helper cells)
Humoral immunity
Humor = fluid
Following an infection
Plasma contains substances- “antibody (Ab)” -which neutralise that specific infectious agent
Demonstrate in vitro
Or in vivo, e.g. treatment of rabies by infusion of antibody
“adoptive immunotherapy”
What is antibody?
Protein- “immunoglobulin (Ig)”
Migrates in the γ-globulin fraction on serum electrophoresis
Each antibody binds to a specific antigen (most often a protein) on the infectious agent
But plasma contains many different Abs
Note how diffuse the γ-globulin band is.
Antibody - structure
Immunoglobulin protein Y-shaped Tetrameric 2 identical heavy chains 2 identical light chains Held together by non-covalent interactions and by –S-S- crosslinks between cysteine a.a. residues
Light Chains
There are two types of light chain
Kappa (κ) and lambda (λ)
But any B-cell will only make one type
Any Ig molecule will contain either kappa or lambda, never both
This phenomenon is called “light chain restriction”
Each chain has a variable region
Amino acid sequence varies from one Ig molecule to another
Binds antigen
And a constant region
Responsible for effector functions
E.g. activating complement, binding to phagocytes
antibody (Ab) - structure
Each Ig molecule has two antigen binding sites
And a flexible hinge region
Ig is a glycoprotein
Carbohydrate added in the Golgi
Fab and Fc Antibody fragments
Ig treated briefly with protease. Cuts molecule at hinge region
Fab- fraction
Antigen binding
Fc- fraction
crystallisable
How does antibody fight infection?
By coating and neutralising a pathogen
E.g. if a virus is coated with Ab it cannot bind to its receptors on the cell surface
By activating complement
Which can then blow holes in a bacterial cell membrane
By opsinisation
Phagocytes have Fc receptors on their cell membrane
Bind to pathogens coated with Ab, and phagocytose them
How does an Ab bind to antigen?
Non-covalent interactions
- Electrostatic, hydrophobic, van der Waals forces, hydrogen bonds
- Depends on the antibody binding site being exactly complementary, sterically and chemically, with a site on the surface of the antigen
- The binding site on the Ag for one specific Ab is called an epitope
Different types of B cells
The body generates over 100,000,000 different B-cells each making a different “random” Ig
Each B-cell only makes one specific Ig
These naïve B-cells sit around in lymph nodes doing not very much
During an infection - B cells
During an infection, a small number of B-cells will, by chance, be making an Ig that binds one of the foreign antigens
These B-cells are activated and begin to multiply- “clonal selection”
Clone
a group of cells (or organisms) that are genetically identical
Descendants of the original activated B-cell make the same Ig
Therefore they are a clone
Lymphocyte Development in the Bone Marrow
HSC into CLP + CMP (Neutrophils, red cells, platelets etc)
CLP into Pre-T (further development in thymus) + Pre-B
Pre-B into imm-B
HSC: haematopoietic stem cell
CMP: common myeloid progenitor
CLP-:common lymphoid progenitor
Pre-T: T-cell precursors
Primary and Secondary Lymphoid Organs
HSC into Pre-B into Imm B-cells
Imm B-cells into follicles containing resting B-cells (secondary lymphoid organs, lymph nodes, spleen, gut etc)
B-cell activation
Functional Ig is first expressed as IgM on the cell surface
(sIgM)
This acts as a “B-cell receptor” in a similar way to a growth factor receptor. The IgM does not have intrinsic tyrosine kinase activity, but associates with other tyrosine kinases
Binding of antigen to IgM activates the tyrosine kinases and their signal transduction pathways
B-cell activation requires
Antigen binding to the B-cell receptor (sIgM), resulting in stimulation of signal transduction pathways
Co-stimulation by T-cells
The activated B-cell begins to secrete soluble IgM
Activated B cells
B cells activated
Multiply rapidly
Differentiate to become Ig secreting cells
First make IgM
Then undergo class switching to make Igs with
the same Ag specificity
but different heavy chain constant regions
E.g. IgG, IgA etc
Ig secreting cells e.g. plasma cells
Memory B- cells
Memory B-cells
Memory B-cells allow a very rapid response to a second exposure
Immediate production of IgG rather than IgM
Natural immune responses are polyclonal
More than one clone of B-cells is generated
More than one Ig is synthesised
Because
Multiple antigens on organism
Multiple epitopes on each antigen
More than one Ig may recognise the same epitope
Class (or isotype) Switching
Once a B-cell starts making an Ig which binds a specific Ag:
It can switch to make Igs with the same Ag binding site
But different constant regions
To carry out different functions in different parts of the body
Classes (isotypes) of Ig
The body can make different classes of Ig
IgG, IgM, IgA, IgD, IgE
differ slightly in heavy chain constant region amino acid sequence
Have different functions
note: there are actually 4 types of IgG (subclass IgG1 – IgG4) And 2 types of IgA (subclass IgA1 and IgA2)
Heavy chain isotype
gamma = IgG
miu = IgM
alpha = IgA
delta = IgD
epsilon = IgE
IgM
Always the first class of Ig made by B-cells during the primary response
First made as a membrane bound protein on B-cell surface
Activates B-cell by signal transduction
Later made in secreted form
Activates complement
Acts as opsonin
IgM - presence of specific IgM antibodies
Presence of specific IgM antibodies to an antigen indicates a recent primary response to that antigen
Implies a current primary infection
Presence of IgG antibodies may be due to past exposure to antigen
IgM Structure
Membrane bound IgM is formed of a single Ig tetramer
In secreted IgM five molecules of the basic Ig tetramer polymerise to form a pentamer
IgG
Major class of Ig in the circulation
Very good at activating complement system
Good as an opsonin
Formed of a single Ig tetramer
IgA
Most abundant class in external secretions Milk, sweat, tears, gut secretions Protects mucosal surfaces Does not activate complement Does bind Fc receptors triggering Phagocytosis Inflammatory reactions
IgA structure
In serum, occurs as a single Ig molecule
In secretions, most IgA is present as a dimer of two whole Ig molecules (+ accessory proteins)
IgE
Physiological role in protection against parasitic worms
Binds to Fc receptors on mast cells and basophils
Triggers release of histamine
BUT also involved in allergies!
IgE produced in response to allergens (pollen, peanuts etc)
Release of histamine causes symptoms of allergies
Over response can cause anaphylactic shock
IgD
Extremely low concentration in circulation
Also found on B-cell membrane
Role is unknown
