Antibody classes

Antibodies are divided into groups according to their constant regions. The term constant region may be misleading as these regions are not identical in all immunoglobulins (Igs), although they basically are similar among broad groups. Igs that share the same basic kinds of constant domains in the heavy chains belong to the same Ig class. Five main classes of Igs exist; IgG, IgM, IgA, IgD and IgE, some of which include a number of distinct subclasses. 

Besides from differing in the constant region, each antibody class differ in their functional activity and distribution as well, which is directly determined by the structural variation of the heavy chains. Moreover, 2 basic kinds of light chains exist (lambda and kappa), which can be associated with any of the heavy chains, thereby increasing the diversity of Igs but without interfering with the functionality of the Igs.

Most individuals have fairly constant levels of IgG in the blood, representing the critical balance between antibody production and continuous breakdown. Approximately 4 times as much IgG (including its subclasses) is found as IgA, 10-15 times as much as IgM, 300 times as much as IgD, and 30,000 times as much as IgE. The amount of Ig produced and secreted represents the daily respons to antigenic stimulation, which happens continually.

During initial B cell stimulation, most B cells secrete IgM. Some B cells continue to secrete IgM, but others switch to produce IgG, IgA or IgE at some point. Memory B cells specialized for responding to repeated infections by a given antigen, produce and secrete IgG or IgA immediately. What determines the balance among the specific antibody classes is not completely understood, however it is influenced by the nature and the site of deposition of the antibody. Moreover, their production is mediated by cytokines secreted locally by surrounding T cells. 

Immunoglobulin G

IgG is the most common class of Ig, which is present in the largest amounts in tissue fluids such as blood. Each IgG molecule consists of two identical heavy chains and two identical light chains, carrying two identical antigen-binding sites. 

Four subclasses of IgG exist (IgG1-4), each with minor differences in the heavy chains but with distinct biological properties. The greatest differences are found in the number of amino acids in the hinge region (IgG1: 15, IgG2: 12, IgG3: 62, IgG4: 21) and the number of cysteine residues involved in inter-heavy chain disulfide bridges (IgG1: 2, IgG2: 4, IgG3: 11, IgG4: 2). The IgG subclasses circulate in the following relative percentages: 60-70% IgG1, 14-20% IgG2 and 4-8% IgG3, 2-6% IgG4. 

The structural differences between the 4 subclasses result in different biological effector functions involving complement activation and cell Fc receptor binding. While IgG1 and IgG3 activate the complement system effectively, is IgG2 less effective whereas IgG4 does not bind to C1 or activate the complement system at all.  

IgG is the only Ig capable of crossing the placenta, consequently, it provides some degree of immune protection to the developing fetus. In addition, IgGs are found in the mother’s milk, and when ingested by an infant, they confer immunity to the infant as well.

Immunoglobulin M

IgM is the first class of Ig made by B cells as they mature, and it is the form most commonly present as the antigen receptor on the B-cell surface. IgM is composed of 2 heavy chains and 2 light chains, however each of the heavy chains has an extra constant domain (CH4) compared to IgG. When IgM is secreted, five IgMs typically are joined together to make a large pentamer molecule with 10 antigen-binding sites. This large IgM complex is particularly effective at attaching to antigenic determinants present on the outer coats of e.g. bacteria or vira and opsonize them for phagocytosis. Moreover, IgM is specialized to activate the complement system upon antigen binding.  

Immunoglobulin A

IgA is primarily produced by B cells in the mucous membranes of the body and is mainly found in body secretions, including tears, saliva, respiratory and intestinal secretions, and colostrum (the first milk produced by lactating mothers). In secretions, IgA serves to protect the mucosal tissues from microbial invasion and to maintain immune homeostasis with the microbiota. In contrast to secretions, very small concentrations of IgA is present in the serum. The molecular structure of IgA resembles IgG, except that IgA usually assembles as a dimer and associates with a special protein that enables the newly formed IgA dimer to be secreted across epithelial cells that line various ducts and organs. Although IgG is the most common class of Ig, more IgA is synthesized by the body daily than any other class of antibody. However, IgA is not as stable as IgG, and therefore it is present in lower amounts at any given time.

Immunoglobulin D

IgD is primarily present on the surface of the majority of B cells early in their development and only limited amounts of IgD is released into circulation. If secreted, IgD is found as a single molecular structure similar to IgG. The functions of IgD is not clear, although it has been proposed to primarily function as an antigen receptor on B cells ant bo be involved in regulating B cell function upon antigen encounter. Moreover, IgD has been proposed to play an elusive function in blood, mucosal secretions and on the surface of innate immune effector cells, by binding to basophils and mast cells and activating these to produce antimicrobial factors that are functional in the respiratory immune defence in humans. 

Immunoglobulin E

IgE is produced by a small proportion of B cells and is found in low concentrations in the bloodstream. IgE consists of one four-chain unit and has two identical antigen-binding sites, but similar to IgM, each of the heavy chains contains an extra constant domain (CH4), which mediates binding to the surface of basophils and mast cells. Upon antigen binding to IgE antibodies, cells become stimulated to release chemicals such as histamines, which are involved in allergic reactions. Although IgE commonly is involved in allergic reactions, IgE antibodies also help protect the host against parasitic infections. Similar to IgD, only limited amounts amount of IgE are secreted.

Immunoglobulin functions and distribution

Functional activity

Neutralization

Opsonization

Sensitization for killing by NK cells

Sensitization of mast cells

Activates complement

Distribution

Transport across epithelium

Transport across placenta

Diffusion intro extravascular sites

Mean serum level (mg/mL)

IgG1

++

+++

++

+

++

 

–

+++

+++

9

 

IgG2

++

+

–

–

+

 

–

+

+++

3

IgG3

++

++

++

+

+++

 

–

++

+++

1

 

IgG4

++

+

–

–

+


–

+/-

+++

0.5

    IgA        IgD       IgE       IgM

  ++          –         –          +

  +           –         –           +

 –           –         –            –

 –           –       +++          –

  +           –         –          +++


 +++         –         –            +

  –           –         –            –

    ++          –         +          +/-

   2.1         0.4     0.0003     1.5