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IMMUNOLOGY

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Title: IMMUNOLOGY


1
IMMUNOLOGY
  • Sherko A Omer
  • MB ChB, MSc., PhD

2
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.

3
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.

4
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.

5
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.

6
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).

7
ANTGEN PROCESSING PRESENTATION
8
ANTGEN PROCESSING PRESENTATION
9
ANTGEN PROCESSING PRESENTATION
10
ANTGEN PROCESSING PRESENTATION
11
ANTGEN PROCESSING PRESENTATION
12
ANTGEN PROCESSING PRESENTATION
  • Presentation of nonpeptide (lipid and glycolipid)
    antigens derived from bacteria involves the class
    Ilike 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.

13
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).

14
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.

15
B CELL ACTIVATION AND PROLIFERATION
16
B CELL ACTIVATION AND PROLIFERATION
17
B CELL ACTIVATION AND PROLIFERATION
18
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 proteintyrosine-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 concentrations of
    antigen.

19
B CELL ACTIVATION AND PROLIFERATION
20
B CELL ACTIVATION AND PROLIFERATION
21
B CELL ACTIVATION AND PROLIFERATION
22
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.
23
B CELL ACTIVATION AND PROLIFERATION
24
PHASES OF HUMORAL IMMUNE RESPONSE
25
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.

26
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.

27
PHASES OF HUMORAL IMMUNE RESPONSE
28
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.

29
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.

30
PHASES OF HUMORAL IMMUNE RESPONSE
  • Class switching

31
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.

32
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.

33
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.

34
T CELL RESPONSES
ICAM intercellular adhesion molecule LFA
lymphocyte function-associated antigen
35
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 NF?B. Early genes,
expressed within 12 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.
36
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.
37
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.
38
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.

39
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.

40
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.

41
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.

42
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.

43
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.

44
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.

45
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.

46
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.

47
REGULATION OF IMMUNE RESPONSE
  • Immunoregulatory effects of soluble
    antigen-antibody complexes and anti-idiotypic
    antibodies.

48
TOLERANCE
  • State of antigen-specific immunological
    unresponsiveness.
  • At the cellular level, tolerance can result from
  • clonal deletion or
  • clonal anergy.

49
TOLERANCE
  • Experimental demonstration of clonal anergy
    versus clonal expansion. (a,b) Only signal 1 is
    generated when resting TH 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 APCs.

50
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).

51
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.
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