See also “Fc receptors” under “signal transduction”  See also antibody glycosylation under glycosylation.  See also IgA  

Introduction:

The term “isotype” refers to the classificaiton of an antibody’s heavy or light chain constant region. For example, the two types of light chains, kappa and lambda, are referred to as isotypes. Isotypic determinants typically reside in the constant region of the light chain, also referred to as the CL in general, and C kappa or C lamba in particular. Likewise, the constant region of the heavy chain molecule, also known as CH, determine the isotype of the antibody. 

There are 5 major classes of heavy chains in humans (alpha, beta, gamma, delta, sigma, and mu) which determine the class or “isotope” of the antibody: Each isotype is distinguished by unique amino acid sequences in the heavy chain constant region that result in structural and functional differences among different isotypes. The 5 antibody classes have different effector functions such as opsonization or the promotion of phagocytosis of antigens by macrophages and neutrophils, antibody dependent cell-mediated cytotoxicity (ADCC) which can kill antibody bound target cells.

Among the four isotypes, IgG1 molecules exhibit predominant effector functions. The IgG2, IgG3 and IgG4 isotypes contain very minimal effector functions. The N-linked oligosaccharides present in the constant CH2 domain of the Fc also have greater influence on the effector functions of IgG1 molecules.  In IgG1 the disulfide bond linking the light and heavy chains goes to the hinge region, whereas in the IgG2, IgG3 and IgG4 subclasses the disulfide bond linking the light and heavy chains goes to the junction between the variable and constant region. (Raju, BioProcess International, 44, April 2003).

The genes encoding the heavy chain immunoglobulin constant region of human chromosome 14 arose through multiple rounds of gene duplication and natural selection and provide the constant regions for the five main immunoglobulin classes: IgG, IgA, IgD, IgE and IgM. (Salfeld “isotype selection in antibody engineering” Nautre Biotechnology, 25,(12), 2007).

Antibody Isotypes:

IgA  (see outline)

IgD was discovered when a patient developed multiple myelomas whose myelomas protein failed to react with anti-isotype antisera against the then known isotypes. When rabbits were immunized with this myeloma protein, the resulting antisera identified this same class of antibody at low levels in normal human serum. Ig D, with IgM, is the major membrane bound immunoglobulin expressed by mature, B cells and is thought to function in the activation of a B cell by an antigen.

IgE antibodies mediate the immediate hypersensitivity reactions that are responsible for the symptoms of hay fever, asthma, hives and anaphylactic shock. IgE is the least common serum Ig since it binds very tightly to Fc receptors on basophils and mast cells even before interacting with antigen. Binding of the allegergen to the IgE on the cells results in the release of various pharmacological mediators that result in allergic symptoms. EgE also plays a role in parasitic helminth diseases. Because IgE levels rise in parasitic diseases, measuring IgE levels is also helpful in diagnosing parasitic infections. Eosiophils have Fc receptors for IgE and binding of eosinophils to EgE coated helminths results in killing of the parasite. IgE does not fix complement. Mayer, G., Immunology, Chapter 4, Section VI, 2009, The board of Trustees of the Unviersity of South Carolina.

IgG  See outline

IgM moleules make up 10% of the total serum content.

IgM can be found as a monomer on the surface of B lymphocytes but in circulation it exists mainly as a pentamer after being secreted from plasma cells. The IgM pentamer has a M mass of about 85–1,000 KDa while each monomer is about 180 kDa. The monomers form a pentamer by disulfide bonds between adjacent heavy chains. IgMs are described in US 7,442,783. 

IgM is the first class produced in a primary response to an antigen. IgM often has a lower affinity than IgG which means that the combined strenght of the noncovalent interactions between a single antigen binding site on IgM and a single epitope is lower for IgM. However, IgM can still bind antigen more effectively than IgG due to its high avidity which is the strenght of multiple interactions between a multivalent antibody and an antigen. IgM is pentameric which means that it has a higher valency (number of binding sites per antibody molecule) than IgG. The monomers form a pentamer by disulfide bonds between adjacent heavy chains. Thus IgM antibodies typically can bind multiple antigens. IgMs are described in US Pat 7,442,783.

IgM is predominantly active in antibacterial and antitoxin immune resposnes whereas IgG participates in defending against viral antigens (US2013/0052208). 

How Class Switching Occurs:

The V and C region of the Ig receptors are encoded by two separate genes on the same chromosome and joined together by  a prcoess called class switch recombination (CSR). CSR enables expression of antibodies with the same antigen specificity but different isotypes of the Ig Recetpor which means different effector functions by chaning the C reigon part of the antibody molecule. The IgH gene carries several alternate C reigon exons. The mu region is in clsoest proximity to the V region. Antibodies with mu H chains can be expressed without a class switch. Therefore, the intron between the V(D)J exon and the first mu exon is removed from a long primary transcript by splicing. This elads to the isotype IgM. There exists several other C regions fruther downstream. Each of these C regions is preceded by a switch region that enables recombination. Swithc regions are highly repetitive GC rich sequences of 1-10 kb lenght. An interplay of sIgM, CD40 signaling and cytokeins (like IL-4) induces isotype switching by initating DNA double strand breaks. The DNA strands are joined toether by the proteins of the NHEJ pathways as in V(D)J recombination. Switch regions can also be affect y hypermutation indicating that both processes share a common mechanism. (Ulrike Schotz. “Diversificaiton of the immunoglobulin genes: analysis of the molecular mechanisms in the chicken B cell line DT40” Disseration, 2009). 

Antibodies with Alterered Effector function

Reduced Immunogenicity:

Moore (US 2006/0275282) describes antibodies and Fc fusion proteins with reduced immunogicity such as having reduced ability to bind one or more human class II MHC molecules.