IgM Antibodies: Structure, Properties, Functions, and Clinical Significance

Two facts make IgM one of the most useful antibodies in the clinic. First, it is always the first to appear: finding IgM against a pathogen tells a clinician the infection is recent or active, right now. Second, it cannot cross the placenta, which turns it into a test for the newborn: if a baby has IgM against an infection, the baby made it, which means the baby was infected in the womb. One antibody, two diagnostic uses, both flowing directly from its structure. This article covers that structure and the properties it produces.

Immunoglobulin M (IgM), the largest pentameric immunoglobulin, is a marker of recent primary infection for some diseases. IgM constitutes 5-10% of serum immunoglobulins in adults. IgM has a half-life of 5 days and can be produced in T independent manner.

The immature B cell, called a pre-B cell, expresses only mIgM; later in maturation, mIgD appears and is coexpressed with IgM on the surface of mature B cells before they have been activated by antigen. A memory B cell can express mIgM, mIgG, mIgA, or mIgE.

Structure

IgM is built on the standard antibody plan (two heavy and two light chains), covered in the article on immunoglobulin structure. What is distinctive about IgM is its heavy chain and how the molecule assembles, and that is the focus here.

Figure: Pentameric IgM

IgM has four heavy chain constant domains and the absence of a hinge region in the μ-chain. There are two forms of IgM;

• Monomeric IgM: Expressed as membrane-bound antibody on B cells.
• Pentameric IgM: Pentameric IgM is secreted by plasma cells. Five monomer subunits are arranged with their Fc regions in the center and ten antigen-binding sites on the periphery. The pentameric nature of IgM compensates relatively low affinity of IgM monomers and confers high overall avidity.

The monomers are held together by the interconnection formed in the Fc region by disulfide bonds and the J (joining) chain. J chain, which is added just before the secretion of pentamer helps in the polymerization of the monomers.

One structure, many properties

Almost everything IgM does follows from a single fact: it is a large pentamer with ten binding sites. Holding that in mind explains the whole property list.

1. Ten binding sites give it very high avidity, so it grips repetitive antigens (like bacterial surfaces) tightly even though each individual site binds weakly. This is why early, low-affinity IgM still works.
2. Ten binding sites make it the best agglutinin, clumping cells and pathogens far better than the two-armed IgG.
3. Five Fc regions in one molecule make it the best complement activator, because complement needs two Fc regions close together, and one pentamer already provides them.
4. Large size keeps it in the bloodstream, so IgM guards the blood against invasion, and IgM deficiency is linked to septicemia.

So rather than memorizing IgM's properties as a list, remember the pentamer: big, ten arms, five stems, stuck in the blood. Every property is one of those features in action.

Functions, and Clinical Significance of IgM

1. Congenital infection marker. IgM is the earliest immunoglobulin synthesized by the fetus, beginning at about 20 weeks of gestation. IgM can not cross the placenta.
   The presence of IgM in the fetus or newborn indicates intrauterine infection (The IgM must have been produced by the baby itself, as IgM cannot cross the placenta of pregnant women, placental transfer is ruled out) and its detection is useful in the diagnosis of congenital infections such as Toxoplasmosis, syphilis, rubella, cytomegalovirus infection and HIV infection.
2. First antibody in a response. IgM is the first immunoglobulin class produced in a primary response to an antigen. IgM antibodies are relatively short-lived, disappearing earlier than IgG. These early IgM antibodies have a low affinity as they are produced before B cells have undergone somatic hypermutation.
3. Marker of acute infection. The presence of specific IgM against a pathogen in the serum of patients indicates recent/acute infection and helps in disease diagnosis. IgM ELISA test can be performed to detect such antibodies in the serum of patients.
   In some pathogens such as cytomegalovirus, Mycoplasma pneumoniae, hepatitis A virus, Toxoplasma gondii, and Borrelia burgdorferi, IgM levels may persist beyond the acute stage (i.e., for months to years following infection), so cautious interpretation of IgM serology is required.
4. Best agglutinin. Pentameric IgM has 10 antigen-binding sites and 5 Fc portions held together by disulfide bridge bonds and J chains. IgM has the highest avidity of all immunoglobulins for antigens with multiple epitopes. Less IgM than IgG is required to neutralize viral infectivity. IgM is highly effective against viruses. IgM is a better agglutinin than other antibody isotypes. It takes 100 to 1000 times more molecules of IgG than IgM to achieve the same level of agglutination.
5. Best complement activator. IgM is more efficient than IgG in activating the classical pathway of complement. Complement activation requires two Fc regions in close proximity, and the pentameric nature of a single molecule of IgM fulfills this requirement.
6. B-cell receptor. Monomeric IgM is the major antibody receptor on the surface of B lymphocytes for antigen recognition.
7. Confined to blood. Because of its large size, IgM remains largely confined to the bloodstream (80%).  IgM does not diffuse well and therefore is found in very low concentrations in the intercellular tissue fluids.

IgM is believed to be responsible for protection against blood invasion by microorganisms. IgM deficiency is often associated with septicemias.

1. High Molecular Weight: Because of its high molecular weight (900,000- 1,000,000), it is often called macroglobulin and the ‘millionaire molecule’.
2. Presence of J chains: The presence of the J chain allows IgM to bind to receptors on secretory cells, which transport it across epithelial linings to enter the external secretions that bathe mucosal surfaces. Although IgA is the major isotype found in these secretions, IgM plays an important accessory role as a secretory immunoglobulin.

How to remember

IgM = the pentamer, and the pentamer explains everything. Big, ten binding sites, five Fc stems, stuck in the blood. Every property is one of those in action.

M for the First and Made-in-the-womb. IgM is the First antibody in a response (so it means recent infection), and it is the one Made by the fetus (it cannot cross the placenta, so a newborn's IgM means intrauterine infection).

Complement champion: five Fc in one molecule. Complement needs two Fc close together; a single IgM pentamer already has five. Best complement activator of all classes.

Best agglutinin: ten arms clump better than two. 100 to 1000 times more effective than IgG at agglutination.

The millionaire molecule. IgM's molecular weight is around 900,000 to 1,000,000, earning it the nicknames macroglobulin and "millionaire molecule."

Key exam facts

Where students get confused

"IgM has low avidity because its individual sites bind weakly." The opposite. Each site binds weakly (low affinity), but ten sites together give the highest avidity of any antibody. Affinity is per-site; avidity is total. IgM is the classic example of low affinity but high avidity.

"IgM appears late, after IgG." No. IgM is the first antibody in a response. IgG comes later. This is why IgM means recent or acute infection.

"A newborn's IgM came from the mother." No, and this is the key clinical point. IgM cannot cross the placenta. If a newborn has IgM against a pathogen, the baby made it, which means the baby was infected in the womb.

"IgM is a monomer like IgG." Secreted IgM is a pentamer. Only the membrane-bound form on B cells (the B-cell receptor) is a monomer. Same class, two forms.

"IgG is the best complement activator because it is most abundant." No. IgM is the best complement activator, because a single pentamer provides the two nearby Fc regions complement needs. IgG can activate complement but needs several molecules clustered together.

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.