- an extracellular hydrophillic "spacer" sequence composed of 26 amino acid residues
- a hydrophobic transmembrane sequence
- a short cytoplasmic tail
Immunoglobulin G (IgG)
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| IgG (Kuby et al.) |
Properties
- IgG is the most versatile immunoglobulin because it is capable of carrying out all of the functions of immunoglobulin molecules
- It is the major Ig in serum (75% of serum Ig is IgG) and in extra vascular spaces
- It is the only class of Ig that crosses the placenta. The transfer is mediated by receptors on placental cells for the Fc region of IgG. IgG1, IgG3 and IgG4 readily cross the placenta and protect the developing fetus.
- Complement activation - IgG3 is the most effective followed by IgG1. IgG2 is less efficient while IgG4 does not fix complement at all.
- Binding to cells - Macrophages, monocytes and some lymphocytes have Fc receptors (FcR) for the Fc region of IgG. IgG4 has intermediate affinity and IgG2 has very low affinity. A consequence of binding to the Fc receptors on monocytes and macrophages is that the cells can internalize the antigens better. 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).
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| IgM Pentamer (taken from http://www.allerresponz.com/) |
IgM primarily exists as a pentamer (19S immunoglobulin) but it can also exist as a monomer (180,000 MW). In its pentameric form, all heavy and light chains are identical. It also has an extra domain on the μ-chain (CH4) and has another protein called the J-chain which is disulphide bonded to the cysteine residues at the C-termini of two μ-chains. This chain functions in polymerization of a single molecule into a pentamer.
Properties
- IgM is the third most common serum Ig. IgM is the first Ig to be made by the fetus and the first Ig to be made by virgin B cells during a primary response to an antigen.
- As a consequence of its p-ntameric structure, IgM is a good complement fixing Ig. Thus, IgM antibodies are very efficient in leading to the lysis of microorganisms.
- It is also a good agglutinating Ig . Thus, IgM antibodies are very good in clumping microorganisms for eventual elimination from the body.
- It can bind ten small hapten molecules. However, due to steric hindrance, only 5 or few larger antigens can be bound simultaneously.
- It binds to some cells via the Fc receptors (FcRs)
- Surface IgM exists as a monomer and lacks J-chain but it has an extra 20 amino acids at the C-terminus to anchor it into the membrane.
- Cell surface IgM on B-cells functions as a receptor for antigen and is noncovalently associated with two additional proteins in the membrane of the B-cell called Ig-alpha and Ig-beta. These additional proteins act as signal transducing molecules since the cytoplasmic tail of the Ig molecule itself is too short to transduce a signal. Contact between surface immunoglobulin and an antigen is required before a signal can be transduced by the Ig-alpha and Ig-beta chains.
- IgM also plays an important accessory role as a secretory immunoglobulin
Immunoglobulin A (IgA)
- IgA is the second most common serum Ig (10-20 % of total immunoglobulin in serum). The daily production of secretory IgA is greater than any other Ig class.
- It is the major class of Ig in secretions - breast milk, tears, saliva, colostrum, mucus. Since it is found in secretions, secretory IgA or sIgA is important in local (mucosal) immunity and is sometimes referred to as 11S immunoglobulin.
- Serum IgA is a monomer but IgA found in secretions is found to be dimeric. When IgA exits as a dimer, a J-chain is associated with it.
- When IgA is found in secretions, it has another protein associated with it called the secretory piece or T piece which is a 70,000 (MW) polypeptide made in epithelial cells and added to IgA as it passes into the secretions. It helps IgA to be transported across mucosa and also protects it from degradation in the secretions by masking sites succeptible to protease cleavage (the hinge region of secretory IgA).
- The poly Ig receptor interacts with J-chain of the polymeric IgA and IgM antibodies.
- Secretory IgA serves as an important effector function at mucous membrane surfaces which are the main entry sites for most pathogens.
- The polymeric property of secretory IgA is associated with crosslinking large antigens with multiple epitopes
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| IgA dimer (taken from http://www.invivogen.com/) |
Immunoglobulin E (IgE)
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| IgE (taken from http://www.allerresponz.com/) |
- It is the least common serum Ig since it binds very tightly to Fc receptor on basophils and mast cells even before interacting with antigen
- It is involved in allergic reactions. Binding of the allergen to the IgE on the cells results in the release of various pharmacological mediators that result in allergic symptoms like asthama, hay fever, hives and anaphylactic shocks. IgE also plays a role in parasitic helminth diseases. Since serum IgE levels rise in parasitic diseases, measuring IgE levels is helpful in diagnosing parasitic infections. Eosinophils have Fc receptors for IgE and binding of eosinophils to IgE-coated helminths results in killing of the parasite. IgE does not fix complement.
Immunoglobulin D (IgD)
- It is primarily found on B-cell surfaces where it functions as a receptor for antigen. IgD on the surface of B-cells has extra amino acids at C-terminal end for anchoring to the membrane.
- IgD together with IgM is the major membrane bound immunoglobulin expressed by mature B-cells. It is thought to function in the activation of B-cells by antigens.
- No biological effector function has been identified for IgD and it does not fix complement.
Antigenic determinants on Immunoglobulins
- Since antibodies are glycoproteins, they can themselves function as potent immunogens. Such anti-Ig antibodies are powerful tools for the study of B-cell development and humoral immune responses. The antigenic determinants or epitopes on immunoglobulin molecules fall into three major catogories:
- Isotypic determinants
- Allotypic determinants
- Idiotypes determinants
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| Antigenic Determinants |
- These are constant region antigenic determinants (epitopes) that characterize classes and subclasses of heavy chains and types and subtypes of light chains within a species. Each isotype is encoded by a separate constant region gene which is same for all the members of the same species.
- If human IgM is injected into a rabbit the rabbit will recognize antigenic determinants on the heavy chain and light chain and make antibodies to them. If that anti-serum is absorbed with human Ig of all other classes, the antibodies to the light chain determinants and any determinants in common with human IgM will be removed and the resulting anti-serum will react only with human IgM. Indeed, the antibodies will only react with the constant region of the μ chain. The determinants that are recognized by such antibodies are called isotypic determinants and the antibodies to those determinants are called anti-isotypic antibodies. Each class, subclass, type and subtype of immunoglobulin has its unique set of isotypic determinants.
- Location → heavy chain isotypes are found on the Fc portion of the constant region of the molecule while light chain isotypes are found in the constant region
- Occurrence → isotypes are found in all normal individuals in a species. The prefix Iso means same in all members of the species. Some individuals with immunodeficiencies may lack one or more isotypes but normal individuals have all isotypes.
- Importance → antibodies to isotypes are used for the quantitation of Ig classes and subclasses in various diseases, in the characterization of B-cell leukemia and in the diagnosis of various immunodeficiency diseases. For example, P-K reactions were basis for the first biological assay for IgE activity. Anti-isotypic antibodies for IgE was able to completely block P-K reactions.
Allotypes
- Allotypes are antigenic determinants specified by allelic forms of the Ig genes and represent slight differences in the amino acid sequences of heavy or light chains of different individuals. Even a single amino acid difference can give rise to an allotypic determinant, though in many cases several amino acid substitutions take place.
- Allotypic differences are detected by using antibodies directed against allotypic determinants. These antibodies can be prepared by injecting the Ig from one person into another. In practice however, anti-allotype antisera is obtained from women who have had multiple pregnancies (antibodies are produced in response to paternal allotypic determinants on fetal Ig). Antibodies to allotypic determinants can also arise from a blood transfusion.
- In humans, allotypes have been characterized for all four IgG subclasses, for one IgA subclass and and for the κ-light chain.
- Location → in humans, the allotypic differences are localized to the constant region of the heavy and light chains
- Occurrence → individual allotypes are found in individual members of a species. All allotypes are not found in all members of the species. The prefix Allo means different in individuals of a species
- Importance → (1) Monitoring bone marrow grafts - Bone marrow grafts that produce a different allotype from the recipient can be used to monitor the graft, (2) Forensic medicine - Km and Gm allotypes are detectable in blood stains and semen and are useful in forensic medicine can be used as markers and (3) Paternity testing - The immunoglobulin allotypes are one of the characteristics used in legal cases involving paternity.
Idiotypes (Id)
- Unique antigenic determinants present on VH and VL individual antibody molecules.
- Antigenic determinants created by the combining site of an antibody are called idiotypes and the antibodies elicited to the idiotypes are called anti-Id antibodies. Idiotypes are the antigenic determinants created by the hypervariable regions of an antibody and the anti-idiotypic antibodies are those directed against the hypervariable regions of an antibody.
- Location → idiotypes are localized on the Fab fragment of the Ig molecules. Specifically, they are localized at or near the hypervariable regions of the heavy and light chains. In many instances the actual antigenic determinant (i.e. idiotype) may include some of the framework residues near the hypervariable region. Idiotypes are usually determinants created by both heavy and light chain HVR's although sometimes isolated heavy and light chains will express the idiotype.
- Importance → (1) V region marker - Idiotypes are a useful marker for a particular variable region, (2) Regulation of immune responses - there is evidence that immune responses may be regulated by anti-Id antibodies directed against our own Id's, (3) Vaccines - In some cases anti-idiotypic antibodies actually stimulate B-cells to make antibody and thus they can be used as a vaccine. This approach is being tried to immunize against highly dangerous pathogens that cannot be safely used as a vaccine and (4) Treatment of B-cell tumors - Anti-idiotypic antibodies directed against an idiotype on malignant B-cells can be used to kill the cells. Killing occurs because of complement fixation or because toxic molecules are attached to the antibodies.
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