Download Immunology Lecture 6 Feb 12 2013

B cell immunity
B-cell activation requires crosslinking of surface
immunoglobulin
 Activation of B cells usually requires
1) Crosslinking of BCR
2) CD19 co-receptor on B cell
3) CD40 receptor on B cell
B-cell activation requires crosslinking of surface
immunoglobulin

1) Crosslinking of BCR
IgM molecules in the B cell receptor
(BCR) on the surface of the B cell are
crosslinked when they bind the
epitope on the surface of the pathogen.
(Crosslinking of surface Ig is
analogous to T cell receptor
clustering in T cell activation.)
B-cell activation requires crosslinking of surface
immunoglobulin
 2) CD19 co-receptor on B cell
The B cell has a co-receptor that is required to
give a signal for activation.
 The co-receptor is composed of CD19
and 2 other surface molecules.
 Binding of the co-receptor to
complement components increases the
BCR signal by 1,000 to 10,000 fold.
B-cell activation requires crosslinking of surface
immunoglobulin
 3) CD40 receptor on B cell
A co-stimulatory signal from a T cell, given
when CD 40 ligand on the T cell binds CD40
receptor on the B cell, is usually needed for the
B cell to be activated.
Thymus-independent antigens
 Thymus-independent antigens (TI
antigens)–can stimulate B cells to
produce antibodies without T cell help.
 TI antigens are usually bacterial
surface molecules with highly repetitive
epitopes.
 The need for the co-stimulatory signal is
overridden for one of two reasons:
• bacterial components like LPS bind
to other receptors on B cells
• repetitive epitopes of TI antigens
crosslink many BCRs on the cell
surface.
Thymus-independent antigens
 However, because Thymus independent (TI) response doesn’t
involve T cells, they do not have the attributes that require T
cell help:
 No isotype switching.
 No somatic hypermutation.
 No memory B cell formation.
Most TI antigens activate B cells regardless of their
antigenic specificity
 Mitogens – Nonspecifically activate T and/or B cells
 At high concentrations
 Polyclonal in nature
B cells
T cells
B and T cells
Bacterial
polysaccharides
Plant glycoproteins
Pokeweed mitogen
- Lipopolysaccharide (LPS)
-
Concanavalin A (Con A)
Phytohemagglutinin (PHA)
Nonspecific activation of T cells
 Superantigens – Antigens that bind simultaneously to TCR and
MHC-II of APC in the absence of a specific peptide antigen.
Example: a) Toxic Shock Syndrome
Staphylococcus aureus
Elicits massive T cell activation
Induces large cytokine release
Thymus-dependent antigens
Interaction with T cells is required for isotype switching
in B cells.
 Isotype Switching:
 Is initiated by T cell cytokines.
 The isotype that a B cell switches to is determined by cognate interactions
with helper T cells.
 The particular isotypes are determined by cytokines released by the helper T
cell.
Interaction with T cells is required for isotype switching
in B cells.
 Isotype switching requires interaction between CD40 receptor on the B cell with
CD40 ligand on the T cell.
 Hyper-IgM syndrome–a condition in which there are unusually high amounts of
IgM and very few other isotypes.
 Hyper-IgM is caused by a failure to isotype switch due to the absence of CD40
ligand on T cells.
Antibody Effector Functions
 Isotype switching diversifies the constant region (Fc region) of the Ig.
 The Fc region has 2 functions:
 To deliver antibodies to sites that would otherwise be inaccessible.
 To link antigen to proteins or cells of the immune system that will
cause its destruction.
IgM, IgG, and IgA antibodies protect the blood and
extracellular fluids.
 IgM and IgG predominate in the plasma where they
protect the body from septicemia–infections of the
blood.
 IgG and monomeric Ig A made in the lymph nodes or
spleen predominate in the extracellular spaces.
 Dimeric IgA is made in the secondary lymphoid
tissue underlying mucosal surfaces and
predominates in secretions across epithelium
including in breast milk.
Transfer of antibodies from mother to child
 A newborn is protected from pathogens that it will encounter in the environment
after birth by passive immunity – the transfer of pre-formed Igs from one
individual or organism to another.
 Antibodies are transferred from the mother to the baby in two ways:
 1) IgA against pathogens to which the mother has been exposed are
secreted in breast milk and protect the baby from pathogens in the gut.
 2) IgG is transported across the placenta from the mother directly into the
blood stream of the fetus.
Antibody production is deficient in very young
infants.
 The mother's IgG is gradually broken down in the infant.
 The infant only begins making its own Igs after about 6 months.
 Consequently IgGs are lowest in infants between 3 and 6 months.
High affinity IgG and IgA are used to neutralize microbial
toxins and animal venom.
 Toxoids – modified forms of microbial toxins that are used as a vaccination to
stimulate a protective response against toxins. Examples: diphtheria toxin,
tetanus toxin
 High affinity antibodies to toxins prevent them from binding to receptors on the
cell surface.
High affinity IgG and IgA are used to neutralize microbial
toxins and animal venom.
 People who have been exposed to animal venoms can be protected through
passive immunity by injection with antibodies against the venom.
 In this case the pre-formed antibodies are isolated from the serum of large
domesticated animals that have been vaccinated with venom.
High affinity neutralizing antibodies prevent viruses and
bacteria from infecting cells.
 High affinity Igs prevent:
 Viruses from binding to receptors on cell surfaces.
High affinity neutralizing antibodies prevent viruses and
bacteria from infecting cells.
High affinity Igs prevent:
•Bacteria from adhering to and colonizing the surface of epithelial cells.
The Fc receptors of hematopoietic cells are signaling
receptors that bind Fc regions of antibodies.
 Several different types of hematopoietic cells express Fc receptors that
function as signaling receptors that induce a variety of responses.
Phagocyte Fc receptors facilitate the recognition, uptake, and
destruction of antibody-coated pathogens.
 The constant regions of circulating antibodies have low affinity for Fc receptors.
 Once antigen is bound the region is capable of forming a strong interaction with Fc
receptors on phagocytic cells. These interactions facilitate phagocytosis.
 Some bacterial pathogens have adapted to evade phagocytosis and can only be
phagocytosed if they have been opsonized with a coating of antibody.
IgE binds to high affinity Fc receptors on mast cells,
basophils, and activated eosinophils.
 The Fc receptor on mast cells, basophils, and eosinophils has such a high
affinity for free IgE that they are almost always coated with IgE that is not bound
to antigen.
 Mast cells are like sentinels posted underneath the mucosa and the skin.
 Mast cells, basophils, and eosinophils are filled with granules containing:
 Histamines- bronchoconstriction, vascular permeability, gastric and mucus
secretion
 Inflammatory mediators–molecules that increase vascular permeability
allowing molecules of the immune system to move out of the blood and into
tissue
A mast cell becomes activated when antigens
crosslink at least two IgE molecules on its surface.
IgE is effective against multicellular pathogens
 Multicellular pathogens such as intestinal worms cannot be controlled by the
mechanisms that work on microorganisms. However mechanisms involving
IgE can be effective.
 Inflammatory mediators cause smooth muscle contraction that can expel
parasites from airways and the gut.
 Increased blood vessel permeability supplies fluid to help flush out the
pathogen.
Eosinophils can bind IgE on pathogens
 If the pathogen stimulates an immune response and becomes coated with IgE,
eosinophils will bind IgE (via Fc receptor) causing them to pour out their toxic
contents on the parasite.
 In developed countries IgE most frequently lead to detrimental responses to
antigens that result in allergic responses or even anaphylaxis–a systemic life
threatening allergic response.
 Anaphylaxis: common signs include difficulty breathing and drop in blood
pressure
Natural Killer Cells
NK cells provide an early defense against intracellular
infections
 Natural killer (NK) cells–a second type of
cytotoxic lymphocyte.
 Do not have T cell receptors or surface
Ig.
 Have cytotoxic granules.
 NK cells:
 Provide innate immunity against
intracellular infections.
 Are activated by cytokines released by
macrophages early in infections.
 Can terminate or contain infections
during the time a CD8 cytotoxic T cell
response is developing.
2 things that can target cells for destruction by NK cells
1) Antibodies bound to the cell are recognized by Fc receptors on the NK cell and
stimulate antibody-dependent cell-mediated cytotoxicity (ADCC)–the
recognition and killing of cells coated with antibody.
2 things that can target cells for destruction by NK cells
2) Reduced levels of MHC class I expression.
Complement
Complement Tags microorganisms for destruction
•
Complement system–a system of blood proteins that permanently marks a
pathogen or antigen as foreign and targets it for removal by the immune system.
Complement components are plasma proteins with
various functions.
 The complement components are soluble proteins that are produced by the liver.
 Many complement components are zymogens–an inactive form of an
enzyme.
 The initiation of the complement reaction starts a chain reaction that results
in successive activation of zymogens by cleavage at specific sites.
 Cleavage usually produces two fragments:
 The larger fragment usually has enzymatic
activity (activates the next component in
the reaction.)
 The smaller fragment stimulates
inflammation.
Complement components are plasma proteins with
various functions.
 The complement system uses 3 different strategies to recognize pathogens,
each of which activates the complement pathway:
 Classical pathway–triggered by antibodies bound to the surface of the
pathogen.
 Alternative pathway–triggered directly by components of bacterial cell
surfaces.
 Lectin-mediated pathway–triggered by mannose binding proteins that are
bound to molecules on the surface of pathogens.
(Mannose associated serine protease)
(Mannose binding lectin)
C3a
 The most important and
abundant complement
molecule is C3.
 All 3 complement pathways
generate enzymes that act as
C3 convertase–an enzyme
that cleaves C3.
Small peptides released during complement activation
induce local inflammation.
The smaller complement components C3a, C4a and C5a are known as anaphylatoxins
Anaphylatoxins induce anaphylaxis, an acute systemic inflammatory response
Order of potency: C5a > C3a > C4a
Complement Aids in Phagocytosis
Regulatory proteins in plasma limit the extent of
complement activation
•
Various proteins inactivate enzymes
at key steps in the complement
pathways keeping the chain reaction
from getting out of control
e.g. C1INH (C1 esterase inhibitor)
•
Deficiency of C1 esterase inhibitor
can cause Hereditary angioedema
Hereditary angioedema