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Immunology

VIEWS: 22 PAGES: 52

									Immunology




             IMMUNOLOGY


              Sherko A Omer
               MB ChB, MSc., PhD




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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)




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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.



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Immunology


             IMMUNOGLOBULIN




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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.
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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.
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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 CH1-
 CH2, this area is more exposed to enzymes and it is
 more flexible for movement of Fab arms, IgM and IgE
 have no hinge regions.



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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).


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Immunology


             IMMUNOGLOBULIN




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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 intra-
 chains




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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).

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Immunology


             IMMUNOGLOBULIN




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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




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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.




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Immunology


             IMMUNOGLOBULIN
 Immunoglobulin isotype, antigenic differences that
 characterize the class and subclasses of heavy chain and
 type and subtypes of light chain.




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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.




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Immunology


             IMMUNOGLOBULIN
Immunoglobulin idiotype, the antigenic determinant that
distinguish variable region of Immunoglobulin from other
variable region of other immunoglobulins.




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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.

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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.

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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


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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.
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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.


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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.

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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.


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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.
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  GENETICS OF IMMUNOGLOBULINS




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Immunology

      MONOCLONAL ANTIBODIES




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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.


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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 disulfide-
linked heterodimers called Ig-/Ig-.




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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.

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 Immunology


    BCR




Some of the many signal-transduction
pathways activated by the BCR




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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.

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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 ().


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Immunology


            T CELL RECEPTORS (TCR)




Schematic diagram of
the TCR-CD3 complex,
which constitutes the T-
cell 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.

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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.

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Immunology




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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.

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Immunology


             CYTOKINES




                         50
Immunology


             CYTOKINES




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Immunology


             CYTOKINES




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