Immunology
IMMUNOLOGY
Sherko A Omer
MB ChB, MSc., PhD
1
Immunology
THE ADAPTIVE IMMUNE RESPONSE
An adaptive immune response involves a complex
sequence of events that start with introduction of an
immunogen (or antigen) and a series of reactions that
ultimately leads to an immune response which may
eliminate the provoking material.
The adaptive immune response depends on interaction
of many cells such as antigen presenting cells, T cell, B
cells and other cells all which interact together directly
or indirectly through cytokines.
2
Immunology
THE ADAPTIVE IMMUNE RESPONSE
Antigen Introduction
Intravenous (iv)
Intradermally (id), into the skin
Subcutaneously (sc) beneath the skin
Intramuscular (im)
Intraperitoneally (ip) into the peritoneal cavity.
3
Immunology
THE ADAPTIVE IMMUNE RESPONSE
The administration route strongly influences which
immune organs and cell populations will be involved in
the response.
iv antigen…..spleen
sc antigen …. local lymph nodes
Differences in the lymphoid cells that populate these
organs may be reflected in the subsequent immune
response.
4
Immunology
ANTGEN (IMMUNOGEN) PROCESSING
Recognition of a foreign protein antigen to a T cell
requires that peptides derived from the antigen be
displayed within the cleft of an MHC molecule on the
membrane of a cell.
The formation of these peptide-MHC complexes requires
that a protein antigen be degraded into peptides by a
sequence of events called antigen processing.
5
Immunology
ANTGEN PRESENTATION
The degraded peptides then associate with MHC
molecules within the cell interior, and the peptide-MHC
complexes are transported to the membrane, where they
are displayed (antigen presentation).
6
Immunology
ANTGEN PROCESSING & PRESENTATION
7
Immunology
ANTGEN PROCESSING & PRESENTATION
8
Immunology
ANTGEN PROCESSING & PRESENTATION
9
Immunology
ANTGEN PROCESSING & PRESENTATION
10
Immunology
ANTGEN PROCESSING & PRESENTATION
11
Immunology
ANTGEN PROCESSING & PRESENTATION
Presentation of nonpeptide (lipid and glycolipid) antigens
derived from bacteria involves the class I–like CD1
molecules.
TCR react with glycolipid antigens derived from
bacteria such as Mycobacterium tuberculosis.
These nonprotein antigens are presented by members of
the CD1 family of nonclassical class I molecules.
12
Immunology
ANTGEN PROCESSING & PRESENTATION
The CD1 family of molecules associates with 2-
microglobulin and has general structural similarity to class
I MHC molecules.
There are five genes encoding human CD1 molecules
(CD1A-E, encoding the gene products CD1a-d, with no
product yet identified for E).
13
Immunology
B CELL ACTIVATION AND PROLIFERATION
APCs present antigens to TH cells and at the same time
naïve B cells recognize the antigens through their mIgM
or mIgD.
B cell activation occurs either with aid of TH cells in
thymus- dependent antigens TD or without TH cells in
thymus independent antigens TID.
Activation leads proliferation and differentiation. Some
B cells will develop in to memory B cells while other
develops to form antibody producing plasma cells.
14
Immunology
B CELL ACTIVATION AND PROLIFERATION
15
Immunology
B CELL ACTIVATION AND PROLIFERATION
16
Immunology
B CELL ACTIVATION AND PROLIFERATION
17
Immunology
B CELL ACTIVATION AND PROLIFERATION
B- and T-cell activation share many parallels, including
compartmentalization of function within receptor subunits.
Activation by membrane-associated protein tyrosine
kinases; assembly of large signalling complexes with
protein–tyrosine-kinase activity; and recruitment of
several signal-transduction pathways.
The B-cell coreceptor can intensify the activating signal
resulting from crosslinkage of mIg, This may be
particularly important during the primary response to low
18
concentrations of antigen.
Immunology
B CELL ACTIVATION AND PROLIFERATION
19
Immunology
B CELL ACTIVATION AND PROLIFERATION
20
Immunology
B CELL ACTIVATION AND PROLIFERATION
21
Immunology
B CELL ACTIVATION AND PROLIFERATION
Transmission electron micrographs of initial contact between a T cell and B
cell (left) and of a T-B conjugate (right). Note the broad area of membrane
contact between the cells after formation of the conjugate.
22
Immunology
B CELL ACTIVATION AND PROLIFERATION
23
Immunology
PHASES OF HUMORAL IMMUNE RESPONSE
24
Immunology
PHASES OF HUMORAL IMMUNE RESPONSE
The primary response has a long lag period, a
logarithmic rise in antibody formation, a short plateau,
and then a decline.
IgM is the first antibody class produced, followed by a
gradual switch to other classes, such as IgG.
The secondary response has a shorter lag time, a more
rapid logarithmic phase, a longer plateau phase, and a
slower decline than the primary response.
25
Immunology
PHASES OF HUMORAL IMMUNE RESPONSE
Mostly IgG and other isotypes are produced in the
secondary response rather than IgM, and the average
affinity of antibody produced is higher.
Within a week or so of exposure to a TD antigen,
germinal centres forms.
Germinal centres are sites of somatic hypermutation of
rearranged immunoglobulin genes. Germinal centres are
the sites of affinity maturation, formation of memory B
cells, class switching, and plasma-cell formation.
26
Immunology
PHASES OF HUMORAL IMMUNE RESPONSE
27
Immunology
PHASES OF HUMORAL IMMUNE RESPONSE
Class switching allows any given VH domain to
associate with the constant region of any isotype.
This enables antibody specificity to remain constant while
the biological effector activities of the molecule vary.
A number of cytokines affect the decision of what Ig
class is chosen when an IgM-bearing cell undergoes the
class switch.
28
Immunology
PHASES OF HUMORAL IMMUNE RESPONSE
The humoral response to TD antigens is marked by
extensive class switching to isotypes other than IgM,
whereas the antibody response to TID is dominated by
IgM.
In the case TD antigens, membrane interaction between
CD40 on the B cell and CD40L on the TH cell is essential
for the induction of class switching.
29
Immunology
PHASES OF HUMORAL IMMUNE RESPONSE
Class switching
30
Immunology
PHASES OF HUMORAL IMMUNE RESPONSE
The average affinity of the antibodies produced during the
course of the humoral response increases remarkably
during the process of affinity maturation.
Experimentally, the affinity of the serum anti-DNP
antibodies produced in response to the antigen was then
measured at 2, 5, and 8 weeks after immunization.
The average affinity of the anti-DNP antibodies increased
about 140-fold from 2 weeks to 8 weeks. Subsequent
work has shown that affinity maturation is mainly the
result of somatic hypermutation.
31
Immunology
T CELL RESPONSES
TH cell activation is initiated by interaction of the TCR-
CD3 complex with a peptide-MHC complex on an
antigen-presenting cell.
Activation also requires the activity of accessory
molecules, including the coreceptors CD4 and CD8.
Many different intracellular signal-transduction pathways
are activated by the engagement of the TCR.
32
Immunology
T CELL RESPONSES
T cells that express CD4 recognize antigen combined
with a class II MHC molecule and generally function as TH
cells.
T cells that express CD8 recognize antigen combined
with a class I MHC molecule and generally function as TC
cells.
Interaction of a TH cell with antigen initiates a cascade of
biochemical events that induces the resting TH cell to
enter the cell cycle, proliferating and differentiating into
memory cells or effector cells.
33
Immunology
T CELL RESPONSES
ICAM intercellular adhesion molecule; LFA lymphocyte function-associated antigen 34
Immunology
T CELL RESPONSES
Gene activation
immediate genes, expressed within half an hour of
antigen recognition, encode a number of transcription
factors, including c-Fos, c-Myc, c-Jun, NFAT, and NFB.
Early genes, expressed within 1–2 h of antigen
recognition, encode IL-2, IL-2R (IL-2 receptor), IL-3, IL-
6,IFN-, and numerous other proteins.
Late genes, expressed more than 2 days after antigen
recognition, encode various adhesion molecules.
35
Immunology
T CELL RESPONSES
These profound changes
are the result of signal-
transduction pathways
that are activated by the
encounter between the
TCR and MHC-peptide
complexes.
36
Immunology
T CELL RESPONSES
T cells (peripheral T cell) are not MHC restricted.
Most in humans bind free antigen, and most have the
same specificity.
They may function as part of the innate immune system.
37
Immunology
MECHANISMS OF ANTIGEN ELIMINATION
The adaptive immune response, whether humoral or cell
mediated lead to elimination of the provoking agents by
different mechanisms:
Direct killing of target cells which carry foreign antigens
by activated Tc* cells through cytotoxicity via two
mechanisms, the perforin granzyme pathway and the
Fas/FasL pathway.
Toxin neutralizing antibodies can neutralize bacterial
toxin or insect venom forming immune complex.
38
Immunology
MECHANISMS OF ANTIGEN ELIMINATION
Virus neutralization, anti-viral antibodies can block
attachment of viruses to their receptors.
Opsonization, antibodies coated antigen can be
removed by macrophage as macrophages have
receptors for Fc portions of antibodies.
Humoral immune response may lead to activation of
complement which will eliminate the antigen by various
methods.
39
Immunology
MECHANISMS OF ANTIGEN ELIMINATION
ADCC, NK cell can kill IgG coated cells through
cytotoxicity.
LAK (lymphokine activated killer) cells can kill after
being activated
CD4+ T cells can produce several cytokines resulting in
delayed type reaction and inflammation.
40
Immunology
SUPERANTIGENS
Viral or bacterial proteins that bind simultaneously to the
V domain of a TCR and to the chain of a class II MHC
molecule.
Exogenous (exotoxins secreted by gram-positive
bacteria, such as staphylococcal enterotoxins, toxic-
shock-syndrome toxin, and exfoliative-dermatitis toxin)
and endogenous (cell-membrane proteins encoded by
certain viruses that infect mammalian cells)
superantigens have been identified.
41
Immunology
SUPERANTIGENS
Crosslinkage of a TCR and class II MHC molecule by
either type of superantigen produces an activating signal
that induces T-cell activation and proliferation.
42
Immunology
REGULATION OF IMMUNE RESPONSE
Suppressor T cells (Ts) were believed to be CD8+ T
cells. However, the cellular and molecular basis of the
observed suppression remained obscure, and eventually
great doubt was cast on the existence of CD8+
suppressor T cells.
Recent research has shown that there are indeed T cells
that suppress immune responses. Unexpectedly, these
cells have turned out to be CD4+ rather than CD8+ T
cells.
43
Immunology
REGULATION OF IMMUNE RESPONSE
Within the population of CD4+ CD25+ FoxP3+ T cells,
there are regulatory T cells that can inhibit the
proliferation of other T cell populations in vitro.
The suppression by these regulatory cells is antigen
specific because it depends upon activation through the
TCR.
Cell contact between the suppressing cells and their
targets is required, if the regulatory cells are activated by
antigen but separated from their targets by a permeable
barrier, no suppression occurs.
44
Immunology
REGULATION OF IMMUNE RESPONSE
Regulatory T cell Activation, as immune response
progresses, the activity of T cells with suppressor activity,
such as T regs, starts to predominate.
IL-10, the major immunosuppressive cytokine released
by activated CD4+ CD25+ FoxP3+ T cells, downregulates
both TH1 and TH2 cells, thus reducing the delivery of
costimulatory signals to B cells.
T cells with suppressor activity persist after the antigen is
eliminated, either as a consequence of their late
activation or of a longer life span. 45
Immunology
REGULATION OF IMMUNE RESPONSE
Several regulatory mechanisms will operate in order to
turn off antibody production after the infectious agent (or
any other type of immunogen) has been eliminated.
Antigen Elimination, the most obvious downregulatory
mechanism is the elimination of the antigen, which was
the primary stimulus of the immune response.
46
Immunology
REGULATION OF IMMUNE RESPONSE
Immunoregulatory effects of soluble antigen-antibody
complexes and anti-idiotypic antibodies.
47
Immunology
TOLERANCE
State of antigen-specific immunological unresponsiveness.
At the cellular level, tolerance can result from
clonal deletion or
clonal anergy.
48
Immunology
TOLERANCE
Experimental demonstration of clonal anergy versus clonal expansion. (a,b) Only signal 1 is generated when resting T H
cells are incubated with glutaraldehyde-fixed antigen-presenting cells (APCs) or with normal APCs in the presence of
the Fab portion of anti-CD28. (c) The resulting anergic T cells cannot respond to normal APCs. (d,e) In the presence of
normal allogeneic APCs or anti-CD28, both of which produce the co-stimulatory signal 2, T cells are activated by fixed 49
APCs.
Immunology
TOLERANCE
Acquired tolerance can be induced in experimental
animals, under the right conditions, known as tolerogenic
conditions, these condition include:
The host
Genetic predisposition
Antigen (soluble, small-sized antigen) and antigen
structurally similar to self protein.
Administration route (intravenous administration of antigen)
Antigen dosage (high- or low-dose of antigen).
50
Immunology
TOLERANCE
The clinical significance of understanding acquired
tolerance is reflected in the need to re-establish tolerance
in autoimmune diseases.
Re-establishing tolerance limited only to antigens that lead
to autoimmune pathology represents the only hope for
specific treatment.
51