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Part IIImmunology
Cara Mestdag
KULEUVEN
Part II
, 1
Inhoud
The structure of a typical antibody ................................................................................................................................... 4
IgG antibodies consist of four polypeptide chains ........................................................................................................ 4
Immunoglobulin heavy and light chains are composed of constant and variable regions. .......................................... 4
The domains of an immunoglobulin molecule have similar structures ........................................................................ 5
The antibody molecule can readily be cleaved into functionally distinct fragments .................................................... 5
The hinge region of the immunoglobulin molecule allows flexibility in binding to multiple antigens ......................... 6
Structural variation in immunoglobulin constant regions ................................................................................................ 7
Different classes of immunoglobulins are distinguished by the structure of their heavy-chain constant regions ....... 7
The constant region confers functional specialization on the antibody ....................................................................... 7
IgM and IgA can form polymers by interacting with the J chain ................................................................................... 7
The interaction of the antibody molecule with specific antigen ...................................................................................... 8
Localized regions of hypervariable sequence form the antigen-binding site ............................................................... 8
Antibodies bind antigens via contacts in CDRs that are complementary to the size and shape of the antigen ........... 8
Antibodies bind to conformational shapes on the surface of antigens using a variety of noncovalent forces ............ 9
Antibody interaction with intact antigens is influenced by steric constants ................................................................ 9
Antigen recognition by T cells ......................................................................................................................................... 10
TCRαβ heterodimer is very similar to a Fab fragment of immunoglobulin................................................................. 10
T-cell receptor recognizes antigen in the form of a complex of a foreign peptide bound to an MHC molecule ........ 10
There are 2 classes of MHC molecules with distinct subunit compositions but similar 3D structures ...................... 10
Peptides are stably bound to MHC and also serve to stabilize the MHC molecule on the cell surface ...................... 11
MHC class I molecules bind short peptides of 8-10 amino acids by both ends .......................................................... 11
Peptides that bind MHC class II are variable in length and their anchor residues lie at various distances from the
peptide ends ............................................................................................................................................................... 12
The CD4 and CD8 cell-surface proteins of T cells directly contact MHC molecules and are required to make an
effective response to Ag .............................................................................................................................................. 12
The expression of MHC classes molecules differ among cells .................................................................................... 13
Primary immunoglobulin gene rearrangements and expression.................................................................................... 14
Complete immunoglobulin genes are generated by the somatic recombination of separate gene segments. ......... 14
Multiple contiguous V gene segments are present at each Ig locus ........................................................................... 15
Rearrangement of V, D and J gene segments is guided by flanking DNA sequences.................................................. 15
IgM and IgD are derived from the same pre-mRNA transcript and are both expressed on the surface of mature B
cells. ............................................................................................................................................................................ 18
Transmembrane and secreted forms of immunoglobulin are generated by alternative heavy-chain mRNA
transcripts ................................................................................................................................................................... 18
T-cell receptor gene rearrangement ............................................................................................................................... 19
The T-cell receptor gene segments are arranged in a pattern similar to that of immunoglobulin gene segments and
are rearranged by the same enzymes. ........................................................................................................................ 20
T cells receptors concentrate diversity in the third variable region (CDR 3) ............................................................... 20
, 2
T cell receptor γ-loci and T cell receptor δ-loci in humans ......................................................................................... 20
Evolution of the adaptive immune response .................................................................................................................. 20
The generation of αβ T-cell receptor ligands .................................................................................................................. 21
Antigen presentation functions both in arming effector T cells and in triggering their effector functions to attack
pathogen-infected cells. .............................................................................................................................................. 22
Peptides are generated from ubiquitinated proteins in the cytosol by the proteasome ........................................... 24
Peptides from the cytosol are transported by TAP into the endoplasmic reticulum and further processed before
binding to MHC class I molecules ............................................................................................................................... 25
Newly synthesized MHC class I molecules are retained in the ER until they bind a peptide ...................................... 25
Peptide: MHC class II complexes are generated in acidified endocytic vesicles from proteins obtained by
endocytosis, phagocytosis and autophagy ................................................................................................................. 26
Premature binding of peptides to MHC II in the ER is prevented by assembly of the MHC class II associated
invariant chain or Ii or CD74........................................................................................................................................ 27
Regulation of Peptide Loading by HLA-DM and HLA-DO ............................................................................................ 27
The major histoncompatibility complex and its function ............................................................................................... 29
Many proteins involved in Ag processing & presentation are encoded by genes within the MHC. ........................... 29
Recognition of nonpeptide ligands by unconventional T-cell subsets ............................................................................ 32
A variety of genes is with specialized functions is also encoded in the MHC ............................................................. 32
Members of the CD1 family of MHC class I-like molecules present lipid-based antigens to NKT cells ...................... 32
γ:δ T cells can recognize a variety of diverse ligands .................................................................................................. 32
, 3
4: Antigen recognition by B-cell and T-cell receptors
Innate Immune Responses: Initial defence against infection. & Controls pathogens with specific molecular patterns or
those inducing interferons and nonspecific defences.
• Adaptive Immune System
o Lymphocytes recognize a variety of antigens1, which are recognized by specialized proteins on
lymphocytes.
o B cells have immunoglobulins2 (Igs) as recognition proteins.
o B-cell receptor (BCR) 3is a membrane-bound form of immunoglobulin.
o B cells produce antibodies 4with the same specificity as BCR.
• Antibody Structure and Function
o Antibodies have two functions: specific binding (to pathogens or their products in extracellular
spaces) and recruiting other cells to destroy pathogens.
o Variable region (V region) 5binds antigen, while the constant region (C region) 6engages elimination
mechanisms.
o Antibody variability allows recognition of a wide range of antigens.
o C region has five isotypes7, each activating different effector mechanisms.
• T-Cell Receptors (TCRs)8
o Membrane-bound proteins associated with intracellular signalling.
o Recognize short peptide fragments of protein antigens presented by MHC molecules9 on host cells.
o MHC molecules=transmembrane glycoproteins encoded in the major histocompatibility complex
(MHC)10 and are highly polymorphic11, increasing the range of bound peptides.
o TCR recognizes both peptide antigen and the MHC molecule (MHC restriction12).
• Despite different antigen recognition methods, both B and T cells use structurally similar receptor molecules.
➔ Basic structure accommodates variability in antigen specificity.
1
Any molecule that can bind specifically to an antibody or generate peptidefragments, recognized by a T-cell receptor
2
The protein family to which antibodies and B-cell receptors belong
3
The cell-surface receptor on B cells for specific antigen; composed of transmembrane immunoglobulin molecule (which
recognizes antigen) associated with the invariant Igα and Igβ chains (which have a signalling function). On activation by antigen,
B cells differentiate into plasma cells producing antibodies of the same antigen specificity as this receptor.
4
A protein that binds specifically to a particular substance (antigen). Each antibody molecule has a unique structure that enables
it to bind specifically to its corresponding antigen, but all antibodies have the same overall structure and are known collectively
as immunoglobulins. Antibodies are produced by differentiated B cells (plasma cells) in response to infection or immunization
and bind to and neutralize pathogens or prepare them for uptake & destruction by phagocytes.
5
The region of an immunoglobulin or T-cell receptor that is formed of the amnio-terminal domains of its component polypeptide
chains. These are the most variable parts of the molecule and contain the antigen-binding sites.
6
That parts of an immunoglobulin or a T-cell receptor that is relatively constant in aminoacid sequence between different
molecules. Also known as the Fc region in antibodies. It determines its particular effector function.
7
The designation of an immunoglobulin chain with respect to the type of constant regio it has. Light chain scan be of either
kappa or lambda isotype. Heavy chains can be of µ, δ, γ, α or ε isotype. The different heavy-chain isotypes have different effector
functions and determine the class and functional properties of antibodies (IgM, IgD, IgG, IgA, IgE)
8
The cell-surface receptor for antigen on T lymphocytes. It consists of a disulfide linked heterodimer of the highly variable α and
β chains in a complex with the invariant CD3 and ζ proteins, which have a signaling function. T cells carrying this type of receptor
are often called αβ T cells. An alternative receptor made of variable γ and δ chains is expressed with CD3 and ζ on a subset of T
cells.
9
Highly polymorphic cell-surface proteins encoded by MHC class I and MHC class II genes involved in presentation of peptide
antigens to T cells. They are also know as histoncompatibility antigens.
10
A cluster of genes on human chromosome 6 that encodes a set of membrane glycoproteins called the MHC molecules. The
MHC also encodes proteins involved in antigen processing and other aspects of host defese. The genes fort he MHC molecules
are the most polymorphic in the human genome, having large numbers of alleles at the various loci.
11
Existing in a variety of different forms; applied to a gene, occuring in a variety of different allels
12
That fact that a peptide antigen can only be recognized by a given T cell i fit is bound to a particular self MHC molecule. MHC
restriction is a consequence of events that occur during T-cell development.
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