STRUCTURE AND FUNCTIONS OF IMMUNOGLOBULINS Flashcards
What is an immunoglobulin?
Immunoglobulins are glycoprotein molecules that are produced by plasma cells in response to an immunogen and which function as antibodies.
They are the critical components of humoral acquired immune response
The immunoglobulins derive their name from the finding that they migrate with globular proteins when antibody-containing serum is placed in an electrical field
What are the GENERAL FUNCTIONS OF IMMUNOGLOBULINS?
- The primary function of immunoglobulins is to bind specifically to closely related antigens, which can result in protection of the host
- In addition to antigen binding, immunoglobulins mediate a variety of effector functions
- Frequently the binding of an antibody to an antigen has no direct biological effect.
- The significant biological effects are a consequence of secondary “effector functions” of antibodies
- The ability to carry out a particular effector function requires that the antibody bind to its antigen.
- Not every immunoglobulin will mediate all effector functions
Discuss the Antigen binding function of immunoglobulins
Immunoglobulins bind specifically to one or a few closely related antigens.
Each immunoglobulin actually binds to a specific antigenic determinant
Antigen binding by antibodies is the primary function of antibodies and can result in protection of the host.
The valency of antibody refers to the number of antigenic determinants that an individual antibody molecule can bind.
The valency of all antibodies is at least two and in some instances more
Discuss the Effector functions of immunoglobulins
- Fixation of complement - This results in lysis of cells and release of biologically active molecules
- Binding to various cell types
- Phagocytic cells, lymphocytes, platelets, mast cells, and basophils have receptors that bind immunoglobulins.
- This binding can activate the cells to perform some function.
- Some immunoglobulins also bind to receptors on placental trophoblasts, which results in transfer of the immunoglobulin across the placenta. As a result, the transferred maternal antibodies provide immunity to the fetus and newborn
What is the BASIC STRUCTURE OF IMMUNOGLOBULINS?
- Heavy and Light Chains
All immunoglobulins have a four chain structure as their basic unit.
They are composed of two identical light chains (23kD) and two identical heavy chains (50-70kD) - Disulfide bonds
Inter-chain disulfide bonds: The heavy and light chains and the two heavy chains are held together by inter-chain disulfide bonds and by non-covalent interactions The number of inter-chain disulfide bonds varies among different immunoglobulin molecules.
Intra-chain disulfide binds: Within each of the polypeptide chains there are also intra-chain disulfide bonds.
- Variable (V) and Constant (C) Regions
The heavy and light chain could be divided into two regions based on variability in 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 amino acids) - Hinge Region
This is the region at which the arms of the antibody molecule forms a Y. It is called the hinge region because there is some flexibility in the molecule at this point. - Domains
Three dimensional images of the immunoglobulin molecule show that it is not straight. Rather, it is folded into globular regions each of which contains an intra-chain disulfide bond. These regions are called domains.
Light Chain Domains - VL and CL
Heavy Chain Domains - VH, CH1 - CH3 (or CH4) - Oligosaccharides
Carbohydrates are attached to the CH2 domain in most immunoglobulins. However, in some cases carbohydrates may also be attached at other locations.
Discuss the STRUCTURE OF THE VARIABLE REGION
- Hypervariable (HVR) or complementarity determining regions (CDR)
Comparisons of the amino acid sequences of the variable regions of immunoglobulins show that most of the variability resides in three regions called the hypervariable regions or the complementarity determining regions.
Antibodies with different specificities (i.e. different combining sites) have different CDR while antibodies of the exact same specificity have identical CDR (i.e. CDR is the antibody combining site). CDR are found in both the H and the L chains. - Framework regions
The regions between the CDR in the variable region are called the framework regions.
Based on similarities and differences in the framework regions the immunoglobulin heavy and light chain variable regions can be divided into groups and subgroups.
These represent the products of different variable region genes.
Immunoglobulin fragments
Immunoglobulin fragments produced by proteolytic digestion have proven very useful in elucidating structure/function relationships in immunoglobulins.
How is the immunoglobulin digested with papain?
Digestion with papain breaks the immunoglobulin molecule in the hinge region before the H-H inter-chain disulfide bond. This results in the formation of two identical fragments that contain the light chain and the VH and CH1 domains of the heavy chain.
- Fab
Antigen binding - These fragments were called the Fab fragments because they contained the antigen binding sites of the antibody. Each Fab fragment is monovalent whereas the original molecule was divalent. The combining site of the antibody is created by both VH and VL. An antibody is able to bind a particular antigenic determinant because it has a particular combination of VH and VL. Different combinations of a VH and VL result in antibodies that can bind a different antigenic determinants. - Fc
The fragment contains the remainder of the two heavy chains each containing a CH2 and CH3 domain. This fragment was called Fc because it was easily crystallized
Effector functions - The effector functions of immunoglobulins are mediated by this part of the molecule. Normally the ability of an antibody to carry out an effector function requires the prior binding of an antigen; however, there are exceptions to this rule.
What occurs in the Treatment of immunoglobulins?
Treatment of immunoglobulins with pepsin results in cleavage of the heavy chain after the H-H inter-chain disulfide bonds resulting in a fragment that contains both antigen binding sites.
- F(ab’)2 -This fragment was called F(ab’)2 because it is divalent. The F(ab’)2 binds antigen but it does not mediate the effector functions of antibodies.
- Fc-The Fc region of the molecule is digested into small peptides by pepsin.
What are the Immunoglobulin classes?
IgG - Gamma heavy chains (γ)
IgM - Mu heavy chains (µ)
IgA - Alpha heavy chains (α)
IgD - Delta heavy chains (δ)
IgE - Epsilon heavy chains (ε)
What are the IMMUNOGLOBULIN SUBCLASSES?
- IgG Subclasses
a) IgG1 - Gamma 1 heavy chains
b) IgG2 - Gamma 2 heavy chains
c) IgG3 - Gamma 3 heavy chains
d) IgG4 - Gamma 4 heavy chains - IgA Subclasses
a) IgA1 - Alpha 1 heavy chains
b) IgA2 - Alpha 2 heavy chains
What are the immunoglobulin types?
- Immunoglobulins can also be classified by the type of light chain that they have.
- Light chain types are based on differences in the amino acid sequence in the constant region of the light chain.
- These differences are detected by serological means.
Kappa light chains
Lambda light chains(Lambda 1- 4 subtypes)
Structure of IgG
- All IgG’s are monomers (7S immunoglobulin).
- The subclasses differ in the number of disulfide bonds and length of the hinge region.
Properties of IgG
IgG is the most versatile immunoglobulin because it is capable of carrying out all of the functions of immunoglobulin molecules.
- gG is the major Ig in serum - 75% of serum Ig is IgG
- IgG is the major Ig in extra vascular spaces
- Placental transfer - IgG is the only class of Ig that crosses the placenta. Transfer is mediated by a receptor on placental cells for the Fc region of IgG. Not all subclasses cross equally well; IgG2 does not cross well.
- Fixes complement - Not all subclasses fix equally well; IgG4 does not fix complement
- Binding to cells - Macrophages, monocytes, PMNs and some lymphocytes have Fc receptors for the Fc region of IgG.
- Not all subclasses bind equally well; IgG2 and IgG4 do not bind to Fc receptors.
- A consequence of binding to the Fc receptors on PMNs, monocytes and macrophages is that the cell can now internalize the antigen better. The antibody has prepared the antigen for eating by the phagocytic cells.
- The term opsonin is used to describe substances that enhance phagocytosis. IgG is a good opsonin.
- Binding of IgG to Fc receptors on other types of cells results in the activation of other functions.
What are the Clinical Implications of IgG?
Increases
a) Chronic granulomatous infections
b) Infections of all types
c) Hyperimmunization
d) Liver disease
e) Malnutrition (severe)
f) Dysproteinemia
g) Disease associated with hypersensitivity granulomas, dermatologic disorders, and IgG myeloma
h) Rheumatoid arthritis
Decreases
a) Agammaglobulinemia
b) Lymphoid aplasia
c) Selective IgG, IgA deficiency
d) IgA myeloma
e) Bence Jones proteinemia
f) Chronic lymphoblastic leukemia
