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Immunoglobulin
Immunoglobulins are glycoproteinmolecules that are produced by plasmacells in response to an immunogen andwhich function as antibodies TERM 2
Antigen binding
DEFINITION 2 Antigen binding by antibodies is theprimary function of antibodies and canresult in protection of the host. Thevalency of antibody refers to the number ofantigenic determinants that an individualantibody molecule can bind. The valency ofall antibodies is at least two and in someinstances more TERM 3
Effector Functions
DEFINITION 3
- Fixation of complement - This results in lysis of cells andrelease of biologically active molecules2. Binding to various cell types - Phagocytic cells,lymphocytes, platelets, mast cells, and basophils havereceptors that bind immunoglobulins. This binding canactivate the cells to perform some function. Someimmunoglobulins also bind to receptors on placentaltrophoblasts, which results in transfer of theimmunoglobulin across the placenta. As a result, thetransferred maternal antibodies provide immunity to thefetus and newborn TERM 4
Heavy and Light Chains
DEFINITION 4 All immunoglobulins have a four chain structure as their basic unit.They are composed of two identical light chains (23kD) and twoidentical heavy chains (50-70kD) TERM 5
Disulfide bonds
DEFINITION 5 Inter-chain disulfide bonds - The heavy and light chains andthe two heavy chains are held together by inter-chaindisulfide bonds and by non-covalent interactions Thenumber of inter-chain disulfide bonds varies among differentimmunoglobulin molecules. Intra-chain disulfide binds - Within each of the polypeptidechains there are also intra-chain disulfide bonds.
Variable (V) and Constant (C) Regions
When the amino acid sequences of many differentheavy chains and light chains were compared, itbecame clear that both the heavy and light chaincould be divided into two regions based on variabilityin the amino acid sequences. These are the: Light Chain
- VL (110 amino acids) and CL (110 amino acids) Heavy Chain - VH (110 amino acids) and CH (330-440 aminoacids) TERM 7
Hinge
Region
DEFINITION 7 This is the region at which the arms of the antibodymolecule forms a Y. It is called the hinge regionbecause there is some flexibility in the molecule atthis point. TERM 8
Domains
DEFINITION 8 Three dimensional images of the immunoglobulinmolecule show that it is not straight as depicted infigure 2A. Rather, it is folded into globular regionseach of which contains an intra-chain disulfide bond.These regions are called domains.
- Light Chain Domains - VL and CL 2. Heavy Chain Domains
- VH, CH1 - CH3 (or CH4) TERM 9
The Prototype Immunoglobulin Molecule
DEFINITION 9 Heavy Chains(five types: , , , , ) Light Chains (two types: and ) Fab fragment Fc fragment Constant and variable regions Carbohydrate Disulfide linkages TERM 10
The antibody molecule can readily be cleaved
into functionally distinct fragments.
DEFINITION 10 Intact IgG treated with papain --> Fab + Fab + FcIntact IgG treated with pepsin --> Joined Fab + Fc degraded Fab region binds antigen C-fixation requires Fc Precipitation and Agglutination require bivalency
Ig Classes
5 Subclasses of Ig based on differences in the aminoacid sequences in the constant region of the heavychains. All immunoglobulins within a given class willhave very similar heavy chain constant regions.1. IgG - Gamma heavy chains2. IgM - Mu heavy chains3. IgA - Alpha heavy chains4. IgD - Delta heavy chains5. IgE - Epsilon heavy chains TERM 17
Ig Sub-classes
DEFINITION 17
- IgG Subclasses IgG1 - Gamma 1 heavy chains - highest frequency IgG2 - Gamma 2 heavy chains IgG3 - Gamma 3 heavy chains- shortest half-life IgG4 - Gamma 4 heavy chains- no comp fixation2. IgA Subclasses IgA1 - Alpha 1 heavy chains IgA2 - Alpha 2 heavy chains TERM 18
Lock and Key concept
DEFINITION 18 The combining site of an antibody islocated in the Fab portion of the moleculeand is constructed from the hypervariableregions of the heavy and light chains.Thus, our concept of antigen-antibodyreactions is one of a key (i.e. the antigen)which fits into a lock (i.e. the antibody). TERM 19
Non-covalent Bonds
DEFINITION 19 The bonds that hold the antigen to theantibody combining site are all noncovalentin nature. These includehydrogen bonds, electrostatic bonds,Van der Waals forces and hydrophobicbonds. Multiple bonding between theantigen and the antibody ensures thatthe antigen will be bound tightly to theantibody. TERM 20
Reversibility
DEFINITION 20 Since antigen-antibody reactions occurvia non-covalent bonds, they are by theirnature reversible.How to Antibodies become highlyspecific?
AFFINITY
Antibody affinity is the strength of thereaction between a single antigenicdeterminant and a single combining site onthe antibody. It is the sum of the attractiveand repulsive forces operating between theantigenic determinant and the combiningsite of the antibody. Most antibodies have a high affinity fortheir antigens TERM 22
Avidity
DEFINITION 22 Avidity is a measure of the overall strength ofbinding of an antigen with many antigenicdeterminants and multivalent antibodies. To repeat, affinity refers to the strength ofbinding between a single antigenicdeterminant and an individual antibodycombining site whereas avidity refers to theoverall strength of binding betweenmultivalent antigens and antibodies. TERM 23
Cross reactivity
DEFINITION 23 Cross reactivity refers to the ability of an individual antibody combining site to react with more than one antigenic determinant orthe ability of a population of antibody molecules to react with more than one antigen. Cross reactions arise because the cross reacting antigen shares an epitope in common with the immunizing antigen orbecause it has an epitope which is structurally similar to one on the immunizing antigen (multispecificity). TERM 24
Biological Consequences of Antibody
Affinity/Avidity
DEFINITION 24 Neutralization of toxins Complement activation Immune elimination of antigen Virus neutralization More intense immune complex disease in animals higher levels of circulating antigen-antibodycomplexes more intense localization of immune complexeson basement membranes. more severe impairment of organ function TERM 25
The T cell antigen receptor
DEFINITION 25 Resembles an Ig Fab fragmentNo alternative constant regionsNever secretedVery short intracytoplasmic tailPositively charged amino acids in theTM regionAntigen combining site made of juxtaposed Va and Vb regions
STRUCTURE OF CLASS II MHC MOLECULES -
A cytoplasmic region containing sites for phosphoylation andbinding to cytoskeletal elements A transmembrane region containing hydrophic amino acidsby which the molecule is anchored in the cell membrane A highly conserved 2 domain and a highly conserved 2 domain to which CD4 binds A highly polymorphic peptide binding region formed from the1 and 1 domains TERM 32
STRUCTURE OF CLASS II MHC MOLECULES -
DEFINITION 32 A cytoplasmic region containing sites for phosphoylation and binding to cytoskeletal elements A transmembrane region containing hydrophic amino acids by which the molecule is anchored in the cell membrane A highly conserved 2 domain and a highly conserved 2 domain to which CD4 binds A highly polymorphic peptide binding region formed fromthe 1 and 1 domains TERM 33
STRUCTURE OF CLASS II MHC MOLECULES
The antigen-binding groove
DEFINITION 33 MHC class II molecule is most variable in the 1 and 1 domains, which comprise the peptide binding region. The groove of Class II molecules can accommodate longer peptides of approximately 13-25 amino acids long with some of the amino acids located outside of the groove. TERM 34
STRUCTURE OF CLASS II MHC MOLECULES
The antigen-binding groove
DEFINITION 34 Within the MHC there are 5 loci that encode class II molecules, each of which contains a gene for an chain and at least one gene for a chain. The loci are designated as HLA- DP, HLA DQ, HLA-DR, HLA-DM, and HLA-DO. Among these, HLA-DP, HLA DQ, and HLADR are the most important and are most polymorphic. TERM 35
Important aspects of MHC
DEFINITION 35 Although there is a high degree of polymorphism for a species, an individual has maximum of six different class I MHC products and only slightly more class II MHC products (considering only the major loci). Each MHC molecule has only one binding site. The different peptides a given MHC molecule can bind all bind to the same site, but only one at a time. Because each MHC molecule can bind many different peptides, binding is termed degenerate.
Important aspects of MHC 2
MHC polymorphism is determined only in the germline. There are no recombinational mechanisms for generating diversity. MHC molecules are membrane-bound; recognition by T cells requires cell-cell contact. Alleles for MHC genes are co- dominant. Each MHC gene product is expressed on the cell surface of an individual nucleated cell. TERM 37
Important aspects of MHC 3
DEFINITION 37 A peptide must associate with a given MHC of that individual, otherwise no immune response can occur. That is one level of control. Mature T cells must have a T cell receptor that recognizes the peptide associated with MHC. This is the second level of control. TERM 38
Important aspects of MHC 4
DEFINITION 38 Cytokines (especially interferon-) increase level ofexpression of MHC. Peptides from the cytosol associate with class I MHCand are recognized by CD8 Tc cells. Peptides fromwithin vesicles associate with class II MHC and arerecognized by CD4 Th cells. Polymorphism in MHC is important for survival of thespecies. TERM 39
How do peptides get in MHC groove?
DEFINITION 39 Class I: peptides are loaded in the ER Class II: molecules formed with aninvariant chain in the ER (a place holderfor the peptide). The invariant chain iscleaved and removed inside a vesiclewhere peptides in the same vesicleassociate with MHC II. Both Class I and II when associated withpeptide are exported to cell surface. TERM 40
Role of CD3 complex
DEFINITION 40 The TCR is closely associated with a group of 5 proteins collectively called the CD3 complex. The proteins of theCD complex do not contribute to the specificity in any way. The CD 3 complex is necessary for cellsurface expression of the TCR during T celldevelopment. the CD3 complex transduces activationsignals to the cell following antigeninteraction with the TCR.
