Immunology by liamei12345

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									Immunology




             IMMUNOLOGY


              Sherko A Omer
               MB ChB, MSc., PhD




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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.

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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.




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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.
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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.



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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).




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Immunology


  ANTGEN PROCESSING & PRESENTATION




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Immunology


  ANTGEN PROCESSING & PRESENTATION




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Immunology


  ANTGEN PROCESSING & PRESENTATION




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Immunology


  ANTGEN PROCESSING & PRESENTATION




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Immunology


  ANTGEN PROCESSING & PRESENTATION




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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.


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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).




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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.
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Immunology


  B CELL ACTIVATION AND PROLIFERATION




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Immunology


  B CELL ACTIVATION AND PROLIFERATION




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Immunology


  B CELL ACTIVATION AND PROLIFERATION




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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
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 concentrations of antigen.
Immunology


  B CELL ACTIVATION AND PROLIFERATION




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Immunology


  B CELL ACTIVATION AND PROLIFERATION




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Immunology


  B CELL ACTIVATION AND PROLIFERATION




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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.
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Immunology


  B CELL ACTIVATION AND PROLIFERATION




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Immunology


  PHASES OF HUMORAL IMMUNE RESPONSE




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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.

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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.
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Immunology


  PHASES OF HUMORAL IMMUNE RESPONSE




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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.


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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.



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 Immunology


     PHASES OF HUMORAL IMMUNE RESPONSE
Class switching




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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.
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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.


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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.
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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 NFB.

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.
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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.




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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.




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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.


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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.



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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.




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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.
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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.




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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.

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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.
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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.




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Immunology


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




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Immunology


                     TOLERANCE
State of antigen-specific immunological unresponsiveness.

At the cellular level, tolerance can result from

clonal deletion or

clonal anergy.



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   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).

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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.




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