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Summary IMM250 Review Final Exam
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IMM250Final Review Notes
Immune Cells
B-lymphocyte
1) They employ a modular design, in that they use relatively few genes (V,D,J, and C) to create enough different antibody
molecules to recognize any possible invader.
2) B cells are made on demand. We have 3 billion B cells circulating in our bodies and this population is heterogeneous for
every possible antigen out there. This means that for every collection of B cells which are monoclonal for a specific antigen,
on average, there are about 30 of them. Normally we start off with a relatively small number of B cells, and then select the
particular B-cells that will be useful for an invader’s antigen, and expand that group through clonal selection and
proliferation. This is economical in that we save space in our bodies by limiting the total number of B cells, while retaining
the capacity to respond to any type of antigen out there.
3) After proliferation, the B cells begin to secrete nuff antibodies which are specific for the antigen in question that triggered
the clonal selection process.
4) When the invader has been conquered, most the B cells which were actively secreting antibodies will die. As a result, we
don’t fill up with B cells that are appropriate to defend against yesterday’s invader, which would be useless for invaders of
the future.
5) During B cell proliferation, some of them actually develop into memory B cells for long-term immunity to the specific
antigen or invader in question.
6) Antibodies can bind to both viruses and bacteria. Antibodies can bind to both types and opsonize them, tagging them for
destruction. Opsonize = to prepare for eating (German).
7) When antibodies opsonize bacteria or viruses, they do so by binding to the invader with their Fab regions (variable region),
leaving their Fc tails (constant region) available to bind to Fc receptors on the surface of cells like macrophages. This is done
to mark the pathogen for cell-death as the macrophage comes in for phagocytosis.
8) Fc binding to Fcr makes the phagocyte more prone to phagocytosis. Macrophages have an innate ability to directly bind to
many pathogens and engulf them. However, the ability of antibodies to opsonize almost all pathogens leaving their Fc
regions exposed to binding to macrophage Fcr’s, macrophages increase their range of targets and are able to phagocytise
many more pathogens.
Lymphocyte development: “Growing an adaptive immune system”.
Ø Innate immunity:
Ø First to respond to foreign antigen
Ø Phagocytic cells are key components of innate response (macrophages and neutrophils)
Ø There is a very limited scope of antigen recognition via direct contact, but antibody-opsonisation can help increase the
number of targets that macrophages and other phagocytes can engulf.
• Adaptive immunity – all T and B cell activity
• B cells produce antibodies
• T cells help B cells to produce antibodies and can also directly kill pathogens (CTLs)
• Adaptive immunity confers lifelong protective immunity to re-infection with the same pathogen.
• B and T cells comprise a pool of lymphocytes with a large number of specificities for “antigens” – can cover virtually all
antigens that we can possibly encounter
• Both innate and adaptive immune responses are dependent on the activities of leukocytes (WBCs)
• Only vertebrates have an adaptive immunity.
• All other species and genera have innate immunity
, • The adaptive immune system comprises the Lymphoid stem cell derivatives except natural killer cells (NK cells bridge the
gap between innate and adaptive immune system). This includes: B cell progenitors which develop into plasma cells and
memory B cells, and T cell progenitors which develop into CD8+ cytotoxic lymphocytes (CTLs) and CD4+ helper T cells and
regulatory T cells (Tregs)
• T lymphocytes secrete cytokines to signal and activate other immune cells
• B lymphocytes secrete antibodies which neutralize pathogens/ toxins
[1]
• The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is responsible for
recognizing antigensbound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen is
of relatively low affinity and isdegenerate: that is, many TCR recognize the same antigen and many antigens are recognized
by the same TCR.
• The TCR is composed of two different protein chains (that is, it is a heterodimer). In 95% of T cells, this consists of an alpha
(α) and beta (β) chain, whereas in 5% of T cells this consists of gamma and delta (γ/δ) chains.
• When the TCR engages with antigen and MHC, the T lymphocyte is activated through a series of biochemical events
mediated by associated enzymes, co-receptors, specialized accessory molecules, and activated or released transcription
factors.
• The B-cell receptor or BCR is a transmembrane receptor protein located on the outer surface of B-cells. The receptor's
binding moiety is composed of a membrane-bound antibody that, like all antibodies, has a unique and randomly
determined antigen-binding site. When a B-cell is activated by its first encounter with an antigen that binds to its receptor
(its "cognate antigen"), the cell proliferates and differentiates to generate a population of antibody-secreting plasma B cells
and memory B cells. The B cell receptor (BCR) has two crucial functions upon interaction with Ag. One function is signal
transduction, involving changes in receptor oligomerization. The second function is to mediate internalization for
subsequent processing of Ag and presentation of peptides to helper T cells. BCR functions are required for normal antibody
production, and defects in BCR signal transduction may lead to immunodeficency, auto-immunity and B-cell malignancy.
• T and B cells recognize antigens in different manners
• TCR has only 1 antigen binding site, but eventually that triggers the release of cytokines
Antigens
• Antigens can come from bacteria, viruses, parasites/ helminthes
• Less obvious: self-antigens = autoimmune disease
• Tumour-antigens,
• Neo-antigen = tissue injury which reveals an otherwise obscured normal body antigen (think of seminiferous vesicles and
damage to the basal layer exposing spermatozoa to the immune system). This antigen is normally invisible to the immune
system, but it can be exposed to the immune system through tissue changes.
• Transplanted tissue (foreign)
• Allergens from the environment = antigen over-response
• Antigen = any substance that can bind to a specific antibody
• Epitope: the structural component of the antigen actually recognized by an antibody or antigen receptor (a.k.a. the
antigenic determinant).
• Many pathogens display multiple epitopes resulting in a polyclonal immune response (more than one population of B and T
cells are activated through clonal selection and proliferation).
• A polyclonal response is induced by multiple epitopes involving multiple clones of different specificities.
• B cell antigens must be on the pathogen surface (pathogen’s antigen can bind directly to the BCR)
• T-cell antigens need not be on the pathogen surface (infected cells have MHC class I which are present on all nucleated
cells, or MHC class II (APCs)) because CTLs in particular are used to kill virally infected cells through assisted suicide.
• B cells see exposed particles (antigens) on the surface of a pathogen or exposed parts of soluble proteins = direct binding to
the Fab region of the BCR (transmembrane antibody)
• T cells see antigens that are buried within the pathogen. These are processed by antigen-presenting cells and loaded onto
and antigen-presenting molecule called the major histocompatibility complex (MHC). Antigen presenting cells may be virally
, infected, and some viral proteins may be digested to form degraded viral peptides which combine with MHC class II
molecules within the ER that end up in the PM, and then recognized by T cell TCR. T cells recognize peptides – bits of
protein that can be inside of the pathogen or virally infected cell.
• The antigens which T cells recognize are in the context of the MHC class I or II depending on the cell type and these
peptides which are loaded into the MHC are often conserved peptides which are less likely to mutate. This is why T cells are
important for fighting off pathogens as it is highly efficient.
Diversity of B cells
• The clonal selection hypothesis (Frank McFarlane Burnet – 1956)
• Clonal selection and proliferation take 7-10 days therefore the adaptive immune system is delayed, whereas the innate
immune system is rapid.
• The clones of the original activate naïve B cell or T cell all have identical receptors (BCR or TCR) with the same specificity
from the original ancestor. There are minor differences though
• 1 B cell only has one type of BCR or antibody.
• There are roughly 3 billion B cells circulating in our bodies, and they are extremely diverse because in total, our adaptive
immune system can respond to any type of antigen.
• Development and diversification of B cells: early maturation and expansion of the lymphoid progenitor stem cells and pro-B
cells occurs in the bone marrow
• The appearance of the BCR on the cell surface is an important development checkpoint. Expression of BCR during
development in the bone marrow is an important checkpoint that is selected to see if it will mature and join circulation.
• The presence of the B cell receptor on pre-B lymphocytes is essential for further development
• Mature B cells circulate in the blood and lymphoid organs
• After clonal selection and expansion you get the development of Ab-secreting plasma cells and long-term memory B cells
• In our blood, we have approximately 10 billion unique B cells, each expressing a distinct BCR. Each BCR is capable of binding
a distinct antigen
• There are only about 25,000 genes in the human genome + <1 million proteins
Development and diversification of B cells: VDJC recombination
• Around 40 V gene regions. V = variable, D= diverse, J= joining, C= constant
• Multiple possible combination for the heavy chain alone
• Several gene segments that are randomized and combined in different ways to be expressed.
• Pairing with a light chain leads to another layer of diversity
• Addition of junctional modification (adding and deleting nucleotides) can also increase diversity
• The VDJC recombination event is totally stochastic, and nothing external influences the rearrangement. VDJ recombination
occurs in the bone marrow.
• VDJ recombination causes the B cell receptor variation, more specifically, the variation in amino acid sequence of the 2
proteins making up the BCR ( heavy+ light chain)
• The first protein, the Heavy chain, is a combination of one of each of the V, D, and J segments
• The second protein, the light chain, is a combination of one of each of the V, and J segments. There is no D region in the
light chain of an antibody.
• Once these 2 genes are transcribed, translated and made into proteins, the two bind together and form the BCR.
• C regions do not contact the antigen so it does not have to be hyper-variable. The C regions of the heavy chain dictate the
isotype of antibody – there are around 5 choices of C region only corresponding to the different types of antibodies.
• The combination of the heavy and light chain V regions forms the Ag binding site or Fab
• The C regions of the heavy chain dictates the BCR class (isotype) = antibody class: IgG, IgA, IgM, IgE, and IgD
• DNA that is not needed in the constant region (C) forms a secondary structure (loop) and is cut out of the naïve B cell
genome.
• the heavy and light chains bind to each other via disulphide bonds
, Antibodies
• antibody = immunoglobulin
• antibodies can be purified and used as a therapy to treat infection
• Each tip of the "Y" of an antibody contains a paratope (a structure analogous to a lock) that is specific for one particular
epitope (similarly analogous to a key) on an antigen’
• Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune
system, or can neutralize its target directly (for example, by blocking a part of a microbe that is essential for its invasion and
survival). The production of antibodies is the main function of the humoral immune system
• Antibodies are secreted by a type of white blood cell called a plasma cell.
• Antibodies can occur in two physical forms, a soluble form that is secreted from the cell, and a membrane-bound form that
is attached to the surface of a B cell and is referred to as the B cell receptor (BCR).
• BCRs have transmembrane domains located in the heavy chains, which tether the antibody in the cell surface membrane
• The BCR is only found on the surface of B cells and facilitates the activation of these cells and their subsequent
differentiation into either antibody factories called plasma cells, or memory B cells that will survive in the body and
remember that same antigen so the B cells can respond faster upon future exposure.
• Membrane-bound immunoglobulins are expressed as monomers (BCRs = monomers), and secreted antibodies can be
monomers or pentamers (polymers).
• In most cases, interaction of the B cell with a T helper cell is necessary to produce full activation of the B cell and, therefore,
antibody generation following antigen binding
• There are several different types of antibody heavy chains, and several different kinds of antibodies, which are grouped into
different isotypes based on which heavy chain they possess. Five different antibody isotypes are known in mammals, which
perform different roles, and help direct the appropriate immune response for each different type of foreign object they
encounter.
• Though the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable,
allowing millions of antibodies with slightly different tip structures, or antigen binding sites, to exist. This region is known as
the hypervariable region. Each of these variants can bind to a different antigen
• The large and diverse population of antibodies is generated by random combinations of a set of gene segments that encode
different antigen binding sites (or paratopes), followed by random mutations in this area of the antibody gene, which create
further diversity
• Antibody genes also re-organize in a process called class switching that changes the base of the heavy chain to another,
creating a different isotype of the antibody that retains the antigen specific variable region. This allows a single antibody to
be used by several different parts of the immune system.
• The antibody molecules come in 5 different classes, and they may have the same antigen binding site, but the different
constant region allows for different types of immunological responses to the invader.
Antibody secreting cells: Plasma cells
- Naïve B cells must express membrane-bound antigen-specific immunoglobulin to mature, and only mature B cells circulate
in the blood and lymphoid organs
- Many B cells are discarded due to lack of maturation, as if they don’t express a BCR.
- Each B cell is committed to express immunoglobulins with the same hyper-variable region or Fab region, such that they all
have the same specificity for a single epitope
- An encounter with a pathogen (clonal selection) stimulates the proliferation and differentiation of resting B cells into
plasma cells and memory B cells.
- Plasma cells secrete antibodies of the same specificity as the membrane-bound immunoglobulin expressed by the B cell
precursor
- Plasma cells do not have membrane-bound antibodies or BCRs because they are specialized to secrete soluble antibodies
- Only resting, mature B cells express BCRs
- Most proliferating and developing naïve B cells eventually turn into plasmablasts and then plasma cells
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