Immunoglobulins (Antibodies): Structure and the Five Classes

The immune system faces an impossible-looking demand: it must make a different antibody for almost every molecule it could ever meet, millions of distinct targets, yet each antibody must also plug into the same small set of killing machinery. Evolution solved this with a modular design.

Every antibody is built from the same Y-shaped frame, but two tips of the Y are endlessly variable (to grip any target), while the base is one of only a few fixed types (to trigger the response). Understanding that one design, a variable grabbing end and a constant signaling end, unlocks everything about how antibodies work and why there are exactly five classes. This article covers that structure and the five classes it produces.

Immunoglobulins, also known as antibodies, are special types of glycoprotein molecules that are secreted by well-differentiated B cells, called plasma cells. Antibodies specifically react with the antigens which stimulated their production. They are released from lymph nodes and spleen into the blood where they serve as the effector of humoral immunity.

Antibodies are part of the serum proteins and are found in the gamma (γ) globulin fraction when serum proteins are separated by electrophoresis so also called immunoglobulins.

The two-part logic of every antibody

Before the details, hold on to one idea. Every antibody has two functional parts, and they answer the two things an antibody must do.

The variable part decides what the antibody binds. It differs from one antibody to the next, which is how the body makes millions of different specificities. It sits at the two tips of the Y.

The constant part decides what the antibody does once it has bound, and which class it belongs to. It is the same across all antibodies of a given class. It forms the stem of the Y.

This is why the same structure appears again and again below: the variable region for recognition, the constant region for function and class. Keep this split in mind and the rest of the article organizes itself.

Basic Structure of an Antibody

Figure: Basic Structure of antibody molecule

Antibodies are Y-shaped four-chain molecules consisting of two identical heavy (H) chains and two identical light (L) chains, held together by disulfide bonds. Each light chain is bound to a heavy chain by a disulfide bond to form a heterodimer(H-L). Two identical heavy and light (H-L) chain combinations are also held together by disulfide bridges forming a basic four-chain (H-L)2 antibody structure, a dimer of dimers. The exact number and precise locations of these interchain disulfide bonds differ among antibody classes and subclasses.

Light chains are called light chains because their molecular weight is less i.e. about 25,000. Molecular weight of heavy chains is 50,000 to 70,000 depending upon antibody isotype/class.

Basically, an antibody molecule has two functions i.e., antigen binding and effector functions. The binding of an antibody with an antigen is very specific (i.e., a single antibody can not bind with different antigens/epitopes) which is determined by the structural configuration of the antigen-binding region of that antibody.

Immunoglobulins have two Fab (“fragment, antigen-binding”) fragments and one Fc (“fragment, crystallizable) fragment.

A simple way to hold the geometry: the two arms of the Y are the two Fab regions (fragment, antigen-binding), each ending in a variable tip that grabs antigen. The single stem is the Fc region (fragment, crystallizable), which carries out effector functions. Two hands to hold the target, one base to call for help.

Figure: Variable and Constant regions of Immunoglobulins

This antigen-binding region of an immunoglobulin is formed by the 100-110 amino acids located in the amino-terminal regions of corresponding heavy and light chains. These amino acids vary greatly among antibodies of different specificity. These segments of the variable sequence are called V regions: VL in light chains and VH in heavy chains.

Complementarity-determining regions (CDRs)

Within the variable regions of heavy chains and light chains, sequence variations are mostly concentrated in three discrete regions, known as hypervariable regions. Hypervariable regions form the antigen-binding site of the antibody molecule. As these regions are complementary to the structure of the epitope, they are also known as complementarity determining regions (CDRs).

Because the CDRs are where the antibody actually contacts the epitope, they are the most variable part of the whole molecule, and they are what monoclonal antibody drugs are engineered to control.

Constant regions

The remainder of both the L and H chain contain regions of amino acid sequences which show very little variation among immunoglobulins and is called the constant region, CL on the light chain and CH on the heavy chain. Heavy chain constant regions are also the site for carbohydrate attachment.

This region of an immunoglobulin, known as Fc fragment, does not have antigen-binding activity but is involved in most of the effector functions.

Figure: Schematic diagram of Immunoglobulin

There are five basic sequence patterns that correspond to five different heavy-chain constants (C) regions γ, α, μ, ε, and δ. Each of these five different heavy chains is called an isotype. The heavy chains of a given antibody molecule determine the class of that antibody: IgG (γ), IgA (α), IgM (μ), IgE (ε), and IgD (δ).

Figure: Constant regions determine immunoglobulin class

Light chains have only one constant region whereas heavy chains have many constant regions CH1, CH2, CH3, and sometimes CH4. IgM and IgE have four heavy chain constant regions with approximately 440 amino acids but the remaining immunoglobulins (IgG, IgA, IgD) have only three heavy chain constant regions with approximately 330 amino acids.

Hinge regions

The γ, α, and δ heavy chains contain an extended proline-rich peptide sequence between the CH1 and CH2 domains known as the hinge region. Hinge regions give segmental flexibility to IgG, IgA, and IgD classes of antibodies as a result Fab can form different angles with each other while capturing the antigen. Although μ and ε heavy chains lack a hinge region, they have an additional domain of 110 amino acids that have hinge-like features.

Immunoglobulin classes

There are 5 classes of immunoglobulins IgG, IgA, IgM, IgE, and IgD as determined by the presence of unique amino acid sequences in the heavy chain constant regions. The basic structural properties of these immunoglobulin classes are discussed here briefly.

Figure: General structure of five major classes of immunoglobulins (antibodies)(Image source: Kuby Immunology)

The five classes at a glance

The five antibody classes differ only in their heavy chain constant region, and that single difference gives each class its own shape, location, and job.

A memory anchor for the order of abundance in serum: G, A, M, E, D, from most to least (IgG is by far the most abundant; IgD and IgE are the least). The full structure and clinical detail of each class is covered in its own article, linked below.

Immunoglobulin G (IgG)

The IgG molecule consists of two γ heavy chains and two κ or two λ light chains. There are four human IgG subclasses, distinguished by differences in γ -chain sequence and numbered according to their decreasing average serum concentrations: IgG1, IgG2, IgG3, and IgG4.

The full structure, properties, and clinical significance of IgG are covered in a separate article on IgG antibodies.

Immunoglobulin A (IgA)

The IgA molecule consists of two α heavy chains and two κ or two λ light chains. The molecular formula of IgA is (α2κ2)n or (α2λ2)n, where n =1, 2, 3 or 4.

IgA exists primarily as a monomer in serum but in external secretions, it (secretory IgA) is present as a dimer or tetramer linked by a J-chain polypeptide.

The full structure, properties, and clinical significance of IgA class are covered in a separate article on IgA antibodies.

Immunoglobulin M (IgM)

The IgM molecule consists of two μ heavy chains and two κ or two λ light chains. IgM has an “additional” heavy chain constant domain and the absence of a hinge region in the μ-chain. The molecular formula of IgM is (μ2κ2)n or (μ2λ2)n, where n =1 or 5.

IgM has two forms; monomeric IgM (membrane-bound on B cells) and pentameric IgM (secreted by plasma cells). In pentameric IgM, five monomer units are held together by disulfide bonds that link their carboxyl-terminal heavy chain domains (Cμ4/Cμ4) and their (Cμ3/Cμ3) domains held together by an Fc-linked polypeptide called the J (joining) chain.

The full structure, properties, and clinical significance of IgM are covered in a separate article on IgM antibodies.

Immunoglobulin E (IgE)

The IgE molecule consists of two ε heavy chains and two κ or two λ light chains. IgE has an “additional” heavy chain constant domain and the absence of a hinge region in the ε-chain.

Immunoglobulin E (IgE) is well known for its role in mediating immediate hypersensitivity reactions and defense against parasites. The full structure, properties, and clinical role of IgE are covered in a separate article on IgE antibodies.

Immunoglobulin D (IgD)

The IgD molecule consists of two δ heavy chains and two κ or two λ light chains. IgD is typically coexpressed with IgM on the surface of mature B cells.

IgD is present in very low amounts in serum, and its main known role is as a receptor on the surface of mature naive B cells, where it is co-expressed with IgM. Its function in serum remains poorly understood.

How to remember

The design in one line: variable grabs, constant acts. The variable region (Fab tips) binds the target; the constant region (Fc stem) determines class and function.

Five classes, five Greek letters: G-γ, A-α, M-μ, E-ε, D-δ. The heavy chain's Greek letter names the class. Match the letter to remember which heavy chain builds which class.

Abundance order: "GAMED." IgG > IgA > IgM > IgE > IgD in serum, roughly most to least. (IgE and IgD are trace.)

Which classes have a hinge: G, A, D (the three-domain classes). IgM and IgE lack a hinge but have an extra fourth constant domain instead. Hinge OR extra domain, not both.

Big classes are polymers: IgM is a pentamer, secretory IgA is a dimer. Both use a J chain to link their units. The big ones travel in bundles.

Key exam facts in one table

Where students get confused

"The whole antibody is variable." No. Only the tips (the variable regions of the Fab arms) differ between antibodies. The rest, the constant region, is shared by all antibodies of the same class. Variable to recognize, constant to act.

"The light chain determines the antibody class." No. The heavy chain constant region determines the class. Light chains are only kappa or lambda and do not define the class.

"All antibodies have a hinge region." No. Only IgG, IgA, and IgD have a true hinge. IgM and IgE lack a hinge but have an extra fourth constant domain that gives similar flexibility.

"IgM is always a big pentamer." Not always. Secreted IgM is a pentamer, but membrane-bound IgM on the B-cell surface is a monomer. The form depends on where it is.

"There are five classes, so there are five different light chains too." No. There are five heavy chains (one per class) but only two light-chain types (kappa and lambda), and any class can use either. The five classes come from the heavy chain alone.

References and further readings

• Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 10th ed. Elsevier; 2022.
• Punt J, Stranford SA, Jones PP, Owen JA. Kuby Immunology. 8th ed. W.H. Freeman; 2019.
• Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitt's Essential Immunology. 13th ed. Wiley-Blackwell; 2017.