Transcript Immunology

Immunology
IMMUNOLOGY
Sherko A Omer
MB ChB, MSc., PhD
1
Immunology
MOLECULES THAT RECOGNIZE ANTIGEN
Recognition of foreign antigen is the character of
adaptive immune response.
Two different molecules can recognize antigens:
 Immunoglobulins (Ig)
 T cell receptors (TCR)
2
Immunology
IMMUNOGLOBULIN
Antibodies (Immunoglobulin) are glycoproteins with
antibody activity.
They combine specifically with the substances that may
elicit them (immunogen or antigen).
Immunoglobulin form the humoral arm of immune
response.
Immunoglobulin constitute 20% of total plasma proteins
and are produced by plasma cells.
3
Immunology
IMMUNOGLOBULIN
Immunoglobulins consist from 82-96% polypeptide and
4-18% carbohydrate (glycoproteins).
Immunoglobulins are bifunctional molecules that can
bind specifically with an antigen and initiate a variety
of secondary functions like complement fixation and
attachment to other cells, and these secondary functions
are independent of their specificity for antigens.
4
Immunology
IMMUNOGLOBULIN
5
Immunology
IMMUNOGLOBULIN
Basic unit (monomer), each Immunoglobulin molecule
contains at least one basic unit and this basic unit
consists from four polypeptide chains.
Heavy chain, each basic unit contains two identical
heavy polypeptide chains each with approximately 400*
amino acids.
Light chain, each basic unit contains two identical light
polypeptide chains each with approximately 200 amino
acids.
6
Immunology
IMMUNOGLOBULIN
Each polypeptide chain of immunoglobulin have an
amino terminal region (V) variable and a carboxyl
terminal region (C) constant region, these terms
describe the considerable variability in amino acid
sequence in these regions.
The polypeptide amino acids of are linked non adjacently
to form globular regions called domains, heavy chain
domains includes VH, CH1,CH2 and CH3 while the
domains of light chain are VL and CL. An additional
domain CH4 is seen in IgM and IgE.
7
Immunology
IMMUNOGLOBULIN
Paratope (antigen binding) consist from small numbers
of amino acids in the V region of both heavy and light
chains.
Hinge region, an area in the heavy chain between CH1CH2, this area is more exposed to enzymes and it is
more flexible for movement of Fab arms, IgM and IgE
have no hinge regions.
8
Immunology
IMMUNOGLOBULIN
Fab and Fc, digestion of IgG by the enzyme papain
produce 2 Fab (Fragment antigen binding) and one Fc
(Fragment crystallisable).
F(ab`)2, digestion of IgG by the enzyme pepsin produce
one F(ab`)2 which consist from 2 Fab and hinge region
and 1 P Fc` that consist of a small peptide (small
fragment).
9
Immunology
IMMUNOGLOBULIN
10
Immunology
IMMUNOGLOBULIN
Disulfide bond, chemical disulfide bonds (S-S) are
formed between cysteine residues, the bonds are
essential for normal three dimensional structure of the
immunoglobulin, disulfide bonds may be inter-chain
(between H and H, H and L, or L and L chains) or intrachains
11
Immunology
IMMUNOGLOBULIN
Five classes of Immunoglobulins are present according
to the structure and antigenic characteristic of the
constant C region of the heavy chain:
 IgG (G for Gamma )
 IgA (A for Alpha )
 IgM (M for Muta )
 IgD (D for Delta )
 IgE (E for Epsilon )
IgG have four subclasses (IgG1, IgG2, IgG3 and IgG4)
IgA have two subclasses (IgA1 and IgA2).
12
Immunology
IMMUNOGLOBULIN
13
Immunology
IMMUNOGLOBULIN
Light chains are divided into two types on the basis of
antigenic structures, these are Kappa () and Lambda
(), subtypes are present for lambda chain.
S value, a value for sedimentation coefficient of
immunoglobulin according to Svedberg’s technique, the
bigger molecular weight of that immunoglobulin the
bigger the S value.
Ig polymer, some Immunoglobulin consists from more
than one basic unit such as like dimeric IgA and
pentameric IgM.
14
Immunology
IMMUNOGLOBULIN
15
Immunology
IMMUNOGLOBULIN
J chain, a polypeptide chain present in polymeric
Immunoglobulins such as pentameric IgM and dimeric
IgA .
Secretary component (SC), a small polypeptide present
in secretory IgA.
16
Immunology
IMMUNOGLOBULIN
Immunoglobulin isotype, antigenic differences that
characterize the class and subclasses of heavy chain and
type and subtypes of light chain.
17
Immunology
IMMUNOGLOBULIN
Immunoglobulin allotype, genetically determined
antigenic differences in Immunoglobulins that varies in
different members of the same species, these differences
are located in C region so that a particular isotype may
have several alternative allelic structure.
18
Immunology
IMMUNOGLOBULIN
Immunoglobulin idiotype, the antigenic determinant that
distinguish variable region of Immunoglobulin from other
variable region of other immunoglobulins.
19
Immunology
IMMUNOGLOBULIN
20
Immunology
IMMUNOGLOBULIN
Glycosylation, carbohydrates are present in different
amounts as simple or complex side chains of the C
region of heavy chain, J or SC chain. Carbohydrates play
role in secretion of Immunoglobulins by plasma cells.
Complementarity-determining regions (CDRs), most of
the differences among antibodies fall within areas of the
V regions called CDRs on both light and heavy chains,
that constitute the antigen binding site of the antibody
molecule.
21
Immunology
IgG
Major immunoglobulin in human serum accounting for
80% of total serum Immunoglobulins
There are 4 subclasses IgG (IgG1, IgG2, IgG3 and IgG4)
each with either two  or two  light chains.
IgG (IgG1, IgG3 and IgG4) are only Immunoglobulins that
pass placenta so play an important role in protecting the
developing fetus.
22
Immunology
IgG
IgG except IgG4 can fix complement through the classic
pathway (lgG3 more than IgG1 and IgG2) using their CH2.
IgG1 and IgG3 bind with high affinity to Fc receptors on
phagocytic cells and thus mediate opsonisation.
IgG4 has an intermediate affinity for Fc receptors, and
IgG2 has an extremely low affinity
23
Immunology
IgM
IgM accounts for 5% –10% of the total serum
immunoglobulin, with an average serum concentration of
1.5 mg/ml.
Monomeric IgM, with a molecular weight of 180 000 Da,
is expressed as membrane-bound antibody on B cells
(mIg).
IgM is secreted by plasma cells as a pentamer in which
five monomer units are held together by disulfide bonds.
24
Immunology
IgM
IgM is the first immunoglobulin class produced in a
primary response to an antigen.
It is the first immunoglobulin to be synthesized by the
neonate, its presence fetal blood indicates intra-uterine
infection.
Due to its pentameric structure, serum IgM has a higher
valency than the other isotypes in binding antigens with
many repeating epitopes such as viral particles.
IgM is also more efficient than IgG at activating
complement
25
Immunology
IgM
Because of its large size, IgM does not diffuse well and
therefore is found in very low concentrations in the
intercellular tissue fluids.
The presence of the J chain allows IgM to bind to
receptors on secretory cells, which transport it across
epithelial linings to enter the external secretions that
bathe the mucosal surfaces.
IgM plays an important accessory role as a secretory
immunoglobulin.
26
Immunology
IgA
Constitutes only 10%–15% of the total immunoglobulin in
serum.
Predominant immunoglobulin class in external secretions
such as breast milk, saliva, tears, and mucus of the
bronchial, genitourinary, and digestive tracts.
In serum, IgA exists primarily as a monomer, but
polymeric forms (dimers, trimers, and some tetramers)
are sometimes seen, all containing a J chain.
27
Immunology
IgA
Binding of secretory IgA to bacterial and viral surface
antigens prevents attachment of the pathogens to the
mucosal cells, thus inhibiting viral infection and bacterial
colonization.
Complexes of secretory IgA and antigen are easily
entrapped in mucus and then eliminated by the ciliated
epithelial cells of the respiratory tract or by peristalsis of
the gut.
28
Immunology
IgA
Secretory IgA has been shown to provide an important
line of defense against bacteria such as Salmonella,
Vibrio cholerae, and Neisseria gonorrhoeae and viruses
such as polio, influenza, and reovirus.
Breast milk contains secretory IgA and many other
molecules that help protect the newborn against infection
during the first month of life. Because the immune system
of infants is not fully functional, breast-feeding plays an
important role in maintaining the health of newborns.
29
Immunology
IgE
The potent biological activity of IgE allowed it to be
identified in serum despite its extremely low average
serum concentration (0.3g/ml).
IgE antibodies mediate the immediate hypersensitivity
reactions that are responsible for the symptoms of hay
fever, asthma, hives, and anaphylactic shock.
Localized mast-cell degranulation induced by IgE also
may release mediators that facilitate a build up of various
cells necessary for anti-parasitic defense.
30
Immunology
IgD
IgD, has a serum concentration of 30g/ml and
constitutes about 0.2% of the total immunoglobulin in
serum.
IgD, together with IgM, is the major membrane-bound
immunoglobulin expressed by mature B cells, and its role
in the physiology of B cells is under investigation.
No biological effector function has been identified for IgD
31
Immunology
GENETICS OF IMMUNOGLOBULINS
The genes for Immunoglobulin molecules are located on
different chromosomes.
Heavy chain genes are on chromosome 14.
 light chain gens are on chromosome 22.
 light chain are located on chromosome 2.
32
Immunology
GENETICS OF IMMUNOGLOBULINS
The enormous numbers of Immunoglobulins are formed
by somatic recombination of different genes.
For heavy chain there are different variable (V), diversity
(D), joining (J) and constant (C) genes.
For light chain there are different V, J and C genes.
Different recombination of these genes gives different
Immunoglobulins.
33
Immunology
GENETICS OF IMMUNOGLOBULINS
34
Immunology
MONOCLONAL ANTIBODIES
35
Immunology
MONOCLONAL ANTIBODIES
Uses:
Measurement of proteins and drugs in the serum.
Tissue and blood typing.
Identification of infectious agents.
Identification of CD that can be used for classification and
follow-up of leukaemia and lymphoma.
Identification of tumour antigens.
Identification of autoantibodies in a variety of diseases.
36
Immunology
B CELL RECEPTOR (BCR)
The mIg have very short cytoplasmic
tails which are too short to be able to
associate with intracellular signalling
molecules.
(BCR) is a transmembrane protein
complex composed of mIg and disulfidelinked heterodimers called Ig-/Ig-.
37
Immunology
B CELL RECEPTOR (BCR)
Molecules of this heterodimer associate
with an mIg molecule to form a BCR.
The Ig- chain has a long cytoplasmic tail
containing 61 amino acids; the tail of the
Ig- chain contains 48 amino acids.
The tails in both Ig-/Ig- are long
enough to interact with intracellular
signalling molecules.
38
Immunology
BCR
Some of the many signal-transduction
pathways activated by the BCR
39
Immunology
T CELL RECEPTORS (TCR)
Cells that express TCRs have approximately 105 TCR
molecules on their surface.
TCR are exist as either  and  -T cell receptors.
Each chain in a TCR has two domains containing an
intrachain disulfide bond that spans 60–75 amino acids.
The amino-terminal domain in both chains exhibits marked
sequence variation, but the sequences of the remainder of
each chain are conserved.
40
Immunology
T CELL RECEPTORS (TCR)
TCR domains include one variable (V) and one constant
(C) that are structurally homologous to the V and C
domains of immunoglobulins.
The TCR variable domains have three hypervariable
regions, which appear to be equivalent to the CDRs in
immunoglobulin light and heavy chains.
The majority of T cells in the human express  T-cell
receptors.
41
Immunology
T CELL RECEPTORS (TCR)
The T-cell receptor is closely associated with the CD3, a
complex of polypeptide chains involved in signal
transduction forming the TCR-CD3 membrane complex.
CD3 is a complex of five invariant polypeptide chains that
associate to form three dimers: a heterodimer of gamma
and epsilon chains (), a heterodimer of delta and epsilon
chains (), and a homodimer of two zeta chains () or a
heterodimer of zeta and eta chains ().
42
Immunology
T CELL RECEPTORS (TCR)
Schematic diagram of
the TCR-CD3 complex,
which constitutes the Tcell antigen-binding
receptor.
43
Immunology
GENETICS OF (TCR)
TCR germ-line DNA is organized into multigene families
corresponding to the , ,  and  chains. Each family
contains multiple gene segments.
The mechanisms that generate TCR diversity are
generally similar to those that generate antibody diversity.
The  chain, is encoded by V, J, and C gene segments.
The  chain is encoded by V, D, J, and C gene segments.
44
Immunology
GENETICS OF (TCR)
45
Immunology
CYTOKINES
Low-molecular-weight proteins that are produced and
secreted by a variety of cell types.
They play major roles in the induction and regulation of
the cellular interactions involving cells of the immune,
inflammatory and hematopoietic systems.
Cytokines bind to specific receptors on the membrane
of target cells, triggering signal-transduction pathways
that ultimately alter gene expression in the target cells.
46
Immunology
CYTOKINES
The susceptibility of the target cell to a particular cytokine
is determined by the presence of specific membrane
receptors.
A particular cytokine may bind to receptors on the
membrane of the same cell that secreted it, exerting
autocrine action; it may bind to receptors on a target cell
in close proximity to the producer cell, exerting paracrine
action; in a few cases, it may bind to target cells in distant
parts of the body, exerting endocrine action.
47
Immunology
48
Immunology
CYTOKINES
Cytokines fall into one of the following families:
hematopoietins, interferons, chemokines, and tumor
necrosis factors.
Cytokines act by binding to cytokine receptors, most of
which can be classified as immunoglobulin superfamily
receptors, class I cytokine receptors (also known as
the hematopoietin receptor family) , class II cytokine
receptors (also known as the interferon receptor family),
members of the TNF receptor family, and chemokine
receptors.
49
Immunology
CYTOKINES
50
Immunology
CYTOKINES
51
Immunology
CYTOKINES
52