Immunoglobulins (Antibodies)

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

Immunoglobulin Genes

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

The rearrangement in Ig chains is mediated by recombination activating genes (RAG1 and RAG2).


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.

Antibodies (immunoglobulins, Ig)

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.


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.

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.

Classical and alternative complement pathways. Image source: Wikipedia.

C1 protein, showing subunits C1r, C1s, and the C1q tails. Image source: Wikipedia.

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.

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).

Role of IgE and mast cells in allergy. Image source: Wikipedia.

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: 10/05/2009