Immunoglobulins (Antibodies)
Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology
Antigen
An antigen is a molecule that is recognized by the immune system - [anti]body [gen]erator.
Superantigen is an antigen that activates a large number of polyclonal T lymphocytes. Superantigens bind to the Vβ chain of the T cell receptor (TCR) bypassing the need for MCH.
Different antigens according to their structure
- Proteins are excellent immunogens, they are "classic" antigens and are T-cell-dependent antigens. Vaccines which are protein based antigens include diphtheria and tetanus.
- Polysaccharides are T-cell-independent antigens. Meningococcal and 23-valent pneumococcal vaccines are examples of T-cell independent antigens
- Nucleic acids - DNA and RNA
- Lipids - MHC-like CD1 molecules bind lipid antigens that are recognized by natural killer T lymphocytes (NKT cells) and γδ T lymphocytes.
The genes encoding immunoglobulins (Ig) heavy chains are on chromosome 14, κ light chains on chromosome 2, and λ light chains on chromosome 22.
2 - κ light chains
22 - λ light chains
14 - heavy chains
Light chains κ and λ are encoded on diffrent chromosomes - κ is encoded on chromosome 2 and λ is encoded on chromosome 22. An immunoglobulin molecule has either κκ (60%) or λλ (40%) but never one of each. An individual B lymphocyte will produce only κ or λ chains but never both.
Gene Recombination. This video shows how gene recombination affects immunoglobulins. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.
Controls of Ig type switch
IgA switching: APRIL, BAFF, TGF-beta
IgE switching: IL-4
IgG switching: IFN-gamma
The earliest B cell that produces immunoglobulins is the pre-B lymphocyte. An adult produces 2-3 grams of immunoglobulin every day
There are 5 immunoglobulin classes remembered by the mnemonic GAMED: Ig G, A, M, E, D. B-cells are the only cell types that synthesize antibody molecules.
Five immunoglobulin classes (mind map)
In order of their serum concentrations:
IgG 1000 mg/dL
IgA 200 mg/dL
IgM 150 mg/dL
IgD 4 mg/dL
IgE 0.005 mg/dL (extremely low serum concentration compared to other Ig in (GAMED)
IgG and A are divided in subclasses: 4 for IgG -- IgG1, IgG2, IgG3, IgG4, and 2 for IgA -- IgA1 and IgA2.
The shortest half-life of all IgG subclasses is IgG3.
Antibody function: each antibody binds to a specific antigen; an interaction similar to a lock and key. Image source: Wikipedia.
Structure of IgG:
Each antibody has an Ag-binding region (Fab), a hinge region, and a region that determines the class or subclass of the antibody (Fc).
The Fc portion of the IgM and the IgG molecule binds to the first component of complement (C1q), to activate the classical complement pathway.
Ig order of their serum half-life in days:
IgG 21
IgM 10
IgA 6
IgD 3
IgE 2 (shortest half-life among other Ig in GAMED)
Ig structures. Image source: Wikipedia.
IgG
IgG provides the majority of antibody-based immunity against pathogens. It has the most sub-classes (4), the highest serum concentration (1000 mg/dL) and longest half-life (21 days). IgG is involved in the secondary response to Ag while IgM is involved in the primary response. Subclasses concentration: IgG1 60-70%, IgG2 20-30%, IgG3-4 are in single digits.
Ig
G
Greatest serum concentration, half-life and number of sub-classes
Mnemonic: Dose of IVIG in PIDD
400-600 mg/kg/month
4 letter words:
IVIG
CVID
SCID
IgM
IgM is expressed on the surface of B cells and in the serum. It binds Ag the early stages of B cell mediated (humoral) immunity before there is sufficient IgG. Thus, IgM is involved in the primary response to Ag while IgG is involved in the secondary response. IgM has the second longest half-life among the Ig (GAMED). IgM forms polymers where multiple immunoglobulins are covalently linked together with disulfide bonds, mostly as a pentamer. The pentameric IgM has the largest molecular mass at 900 kD.
Structure of the pentameric IgM: 1. Base unit, 2. Heavy chains, 3. Light chains, 4. J chain, 5. Intermolecular disulfide bonds. Image source: Wikipedia.
Role of IgE and mast cells in allergy. Image source: Wikipedia.
Omalizumab binds to Cε3 region of IgE.IL-4 and IL-13
IL-4 and IL-13 are cytokines produced by Th2 cells. They up-regulate IgE production and thus increase allergic inflammation. IL-4 is much more potent than IL-13.
IL-4
IL-13
Increase
IgE production
Inflammation promoters
Receptors for IgE
High-Affinity IgE Receptor (FcεRI)
The high affinity receptor for IgE (FcεRI) is expressed on mast cells (fixed in tissues) and basophils (circulating in blood). The level of FcεRI expression is regulated by levels of IgE. FcεRI molecule consists of 4 chains: alpha, beta and 2 gamma.
Low-Affinity IgE Receptor (FcεRII)
The role of FcεRII is not clear. Variations in the low-affinity IgE receptor gene (FCER2 or II) are associated with an increase in severe exacerbations in children with asthma. There are several reasons that a patient may not respond to inhaled corticosteroid therapy in asthma and genetics, including FCER2 variants, may be an important one.
Variations in some of the SNPs were associated with increased IgE levels and increased risk of severe exacerbations of asthma during inhaled corticosteroid treatment. Therefore, FCER2 variations may lead to asthma exacerbations despite inhaled steroids. Personalized medicine via pharmacogenetics can lead to genetic studies guiding therapeutic decisions in the future.
Anti-IgE (omalizumab, Xolair) is approved for treatment of severe persistent asthma. There are occasional case reports of anti-IgE (omalizumab) use as a new therapeutic approach for chronic rhinosinusitis.
There is a correlation between IgE titres and the severity of clinical reaction to egg after the diagnosis has been established. A cut-off level of 8.20 kU/l had a 90% probability of clinical reactivity. IgE titres may help determine which patients are at risk of a reaction to eggs.
Higher levels of IgE are associated with more severe asthma (the cut-off level is 100 IU/mL). IgE level is inversely correlated with baseline lung function and asthma severity.
References
Allergy and Immunology MKSAP, 3rd edition.
Related Reading
Medical Immunology Syllabus. Columbia University.
In the Clinic - Dr. Robert Wood, MD, Discusses the IgE Blood Allergy Test. InsiderMedicine.ca (video).
Variations in Receptor Gene Contribute to Asthma Exacerbations. Medscape, 01/2008; J Allergy Clin Immunol 2007;120:1285-1291.
Anti-IgE (omalizumab): A new therapeutic approach for chronic rhinosinusitis. JACI, Volume 121, Issue 1, Pages 257-258 (January 2008).
FIT Corner Q & A from 5th edition of Cellular and Molecular Immunology, edited by Abul K. Abbas and Andrew H. Lichtman. ACAAI, 2004.
Chapter 5: Immunoglobulin Structure and Function. Allergy and Immunology Review Corner: Chapter 5 of Middleton’s Allergy Principles and Practice, 7th Edition, edited by N. Franklin Adkinson, et al. FIT Corner Q&A.
Video
3D Medical Animation: Antibody Immune Response
Published: 12/13/2007
Updated: 08/25/2010
Antibody function: each antibody binds to a specific antigen; an interaction similar to a lock and key. Image source: Wikipedia.
Structure of IgG:
1. Fab region
2. Fc region
3. Heavy chain with one variable (VH) domain followed by a constant domain (CH1), a hinge region, and two more constant (CH2 and CH3) domains.
4. Light chain with one variable (VL) and one constant (CL) domain
5. Antigen binding site (paratope)
6. Hinge regions.
Image source: Wikipedia.
2. Fc region
3. Heavy chain with one variable (VH) domain followed by a constant domain (CH1), a hinge region, and two more constant (CH2 and CH3) domains.
4. Light chain with one variable (VL) and one constant (CL) domain
5. Antigen binding site (paratope)
6. Hinge regions.
Image source: Wikipedia.
Somatic hypermutation changes V but not C region. Class switching changes C but not V region.
Each antibody has an Ag-binding region (Fab), a hinge region, and a region that determines the class or subclass of the antibody (Fc).
The Fc portion of the IgM and the IgG molecule binds to the first component of complement (C1q), to activate the classical complement pathway.
IgG 21
IgM 10
IgA 6
IgD 3
IgE 2 (shortest half-life among other Ig in GAMED)
Ig structures. Image source: Wikipedia.
IgG
IgG provides the majority of antibody-based immunity against pathogens. It has the most sub-classes (4), the highest serum concentration (1000 mg/dL) and longest half-life (21 days). IgG is involved in the secondary response to Ag while IgM is involved in the primary response. Subclasses concentration: IgG1 60-70%, IgG2 20-30%, IgG3-4 are in single digits.
Ig
G
Greatest serum concentration, half-life and number of sub-classes
Mnemonic: Dose of IVIG in PIDD
400-600 mg/kg/month
4 letter words:
IVIG
CVID
SCID
IgM
IgM is expressed on the surface of B cells and in the serum. It binds Ag the early stages of B cell mediated (humoral) immunity before there is sufficient IgG. Thus, IgM is involved in the primary response to Ag while IgG is involved in the secondary response. IgM has the second longest half-life among the Ig (GAMED). IgM forms polymers where multiple immunoglobulins are covalently linked together with disulfide bonds, mostly as a pentamer. The pentameric IgM has the largest molecular mass at 900 kD.
The best complement fixation is IgM.
Structure of the pentameric IgM: 1. Base unit, 2. Heavy chains, 3. Light chains, 4. J chain, 5. Intermolecular disulfide bonds. Image source: Wikipedia.
Ig
M
Macro -- largest Ig
IgA
IgA is found in mucosal secretions and protects mucosal surfaces by neutralizing bacterial toxins and inhibiting adhesion to epithelial cells. IgA is found in the GI, respiratory tract and
urogenital tract, also in saliva, tears, and breast milk.
Structure of the dimeric IgA: 1. H-chain, 2. L-chain, 3. J-chain, 4. secretory component. Image source: Wikipedia.
Ig
A
Adhesion prevention
Aggregates -- 2 units linked together
Alternative pathway of complement
Activation
IgD
IgD functions mainly as an Ag receptor on B cells and it also has a role in class switching.
IgE
IgE is involved in immediate hypersensitivity (allergy). It binds to allergens and triggers histamine release from mast cells. It has the lowest serum concentration (mcg rather than mg) and the shortest half-life (2 days) among Ig (GAMED).
M
Macro -- largest Ig
IgA
IgA is found in mucosal secretions and protects mucosal surfaces by neutralizing bacterial toxins and inhibiting adhesion to epithelial cells. IgA is found in the GI, respiratory tract and
urogenital tract, also in saliva, tears, and breast milk.
Structure of the dimeric IgA: 1. H-chain, 2. L-chain, 3. J-chain, 4. secretory component. Image source: Wikipedia.
Ig
A
Adhesion prevention
Aggregates -- 2 units linked together
Alternative pathway of complement
Activation
IgD
IgD functions mainly as an Ag receptor on B cells and it also has a role in class switching.
IgE
IgE is involved in immediate hypersensitivity (allergy). It binds to allergens and triggers histamine release from mast cells. It has the lowest serum concentration (mcg rather than mg) and the shortest half-life (2 days) among Ig (GAMED).
Role of IgE and mast cells in allergy. Image source: Wikipedia.
Omalizumab binds to Cε3 region of IgE.
IL-4 and IL-13 are cytokines produced by Th2 cells. They up-regulate IgE production and thus increase allergic inflammation. IL-4 is much more potent than IL-13.
IL-4
IL-13
Increase
IgE production
Inflammation promoters
Receptors for IgE
High-Affinity IgE Receptor (FcεRI)
The high affinity receptor for IgE (FcεRI) is expressed on mast cells (fixed in tissues) and basophils (circulating in blood). The level of FcεRI expression is regulated by levels of IgE. FcεRI molecule consists of 4 chains: alpha, beta and 2 gamma.
Low-Affinity IgE Receptor (FcεRII)
The role of FcεRII is not clear. Variations in the low-affinity IgE receptor gene (FCER2 or II) are associated with an increase in severe exacerbations in children with asthma. There are several reasons that a patient may not respond to inhaled corticosteroid therapy in asthma and genetics, including FCER2 variants, may be an important one.
Variations in some of the SNPs were associated with increased IgE levels and increased risk of severe exacerbations of asthma during inhaled corticosteroid treatment. Therefore, FCER2 variations may lead to asthma exacerbations despite inhaled steroids. Personalized medicine via pharmacogenetics can lead to genetic studies guiding therapeutic decisions in the future.
Anti-IgE (omalizumab, Xolair) is approved for treatment of severe persistent asthma. There are occasional case reports of anti-IgE (omalizumab) use as a new therapeutic approach for chronic rhinosinusitis.
There is a correlation between IgE titres and the severity of clinical reaction to egg after the diagnosis has been established. A cut-off level of 8.20 kU/l had a 90% probability of clinical reactivity. IgE titres may help determine which patients are at risk of a reaction to eggs.
Higher levels of IgE are associated with more severe asthma (the cut-off level is 100 IU/mL). IgE level is inversely correlated with baseline lung function and asthma severity.
References
Allergy and Immunology MKSAP, 3rd edition.
Related Reading
Medical Immunology Syllabus. Columbia University.
In the Clinic - Dr. Robert Wood, MD, Discusses the IgE Blood Allergy Test. InsiderMedicine.ca (video).
Variations in Receptor Gene Contribute to Asthma Exacerbations. Medscape, 01/2008; J Allergy Clin Immunol 2007;120:1285-1291.
Anti-IgE (omalizumab): A new therapeutic approach for chronic rhinosinusitis. JACI, Volume 121, Issue 1, Pages 257-258 (January 2008).
FIT Corner Q & A from 5th edition of Cellular and Molecular Immunology, edited by Abul K. Abbas and Andrew H. Lichtman. ACAAI, 2004.
Chapter 5: Immunoglobulin Structure and Function. Allergy and Immunology Review Corner: Chapter 5 of Middleton’s Allergy Principles and Practice, 7th Edition, edited by N. Franklin Adkinson, et al. FIT Corner Q&A.
Video
3D Medical Animation: Antibody Immune Response
Published: 12/13/2007
Updated: 08/25/2010
Labels: Immunology
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