Immunoglobulin M (IgM Antibody) – Definition, Structure, Functions

Immunoglobulin M (IgM Antibody) is a type of antibody that is produced by plasma cells during early immune response. It is the first antibody formed when any foreign antigen enters into the body. It acts as an important first line defence of the immune system.

IgM is considered as the most ancient immunoglobulin of adaptive immunity. It is found mainly in the blood and lymph. It is also present on the surface of resting B-lymphocytes as a monomer form, where it acts as an antigen receptor.

The secreted form of IgM is usually pentameric in nature. It is made up of five antibody units joined together by a J-chain. Due to this pentameric structure, it has very large molecular weight, about more than 900 kDa.

Each IgM molecule has many antigen binding sites. One single unit may have low affinity for antigen, but the whole pentamer shows very high binding strength due to its multiple binding sites. This total binding strength is called avidity.

IgM is very effective in agglutination of antigens. It traps and clumps the pathogens together, especially encapsulated bacteria. This makes the pathogen easy to remove by immune cells.

Another important function of IgM is activation of classical complement pathway. A single bound pentameric IgM can activate complement strongly. This leads to inflammation, opsonization and destruction of invading microbes.

Because of its large size, IgM mainly remains inside the blood vessels. It cannot easily enter deep tissues. But in some condition it may be transported to mucosal surface, where it helps in local mucosal immunity.

Discovery and Historical Background of IgM

• IgM is recognized as the most ancient antibody of vertebrate adaptive immune system. It is believed to be originated about 500 million years ago with the appearance of jawed cartilaginous fishes.
• During human development, IgM is the first antibody that appears. It is also the first antibody secreted during primary immune response when antigen enters into the body.
• The name IgM comes from the word macroglobulin. The letter M was used because this antibody is very large in size and has high molecular weight than IgG.
• The structural study of IgM started mainly during the 1960s. At that time, researchers used negative staining electron microscopy to observe serum isolated IgM.
• In these early studies, IgM was found as a flat and five pointed star like molecule. This shape was due to the pentameric arrangement of five antibody units.
• Some diseases related with IgM also have important historical background. Jan Gösta Waldenström first described Waldenström Macroglobulinemia, where monoclonal IgM protein is secreted in high amount.
• Another important finding was selective IgM deficiency. It was first described by Hobbs et al. in 1967. In this condition, the level of IgM becomes very low but other immunoglobulins may remain normal.

Normal Serum Levels of IgM

Structure of IgM

• IgM is made up of a basic Y-shaped monomeric unit. This monomer has molecular weight about 180 to 190 kDa. It consists of two heavy chains and two light chains joined together by covalent bonds.
• Each light chain of IgM has one variable domain and one constant domain. These domains help in antigen binding and also maintain the antibody structure.
• The heavy chain of IgM is different from many other antibodies. It has one variable domain and four constant domains. It does not have a flexible hinge region.
• At the end of each heavy chain, there is an 18 amino acid tailpiece. This tailpiece contains a conserved cysteine residue. It is important for joining more than one monomer together.
• The secreted form of IgM is mainly pentameric in structure. It is found in blood as a large molecule with molecular weight more than 900 kDa.
• Pentameric IgM is formed by five monomeric units. So, it contains total 10 heavy chains, 10 light chains and 10 antigen binding sites. Due to these many binding sites, it can bind antigen very strongly.
• The five monomers of IgM are joined by a small protein called J-chain. The J-chain has about 15 kDa molecular weight. It joins the monomers by disulfide bonds.
• The J-chain caps the tailpiece region of the monomers. It helps to pack the central part of the molecule into a compact core. This makes the molecule slightly asymmetric in shape.
• The pentameric IgM looks like a hexagon with one missing part. This structure is not fully symmetrical because the J-chain occupies the position between the monomers.
• In absence of J-chain, IgM can form a hexameric structure. This form contains six monomer units. It is more symmetrical than pentameric IgM.
• The membrane bound form of IgM is present on mature resting B-cells. This form is always monomeric. It remains attached with the cell membrane.
• Membrane bound IgM works as B-cell receptor. It remains associated with signaling proteins called Igα and Igβ. These proteins help to transfer signal inside the B-cell after antigen binding.

Molecular Characteristics of IgM

• IgM is a large molecular antibody. The single monomeric unit of IgM has molecular weight about 180 to 190 kDa.
• The secreted polymeric form of IgM is very large in size. Its molecular weight is about 900 to 970 kDa.
• IgM is present in two main molecular forms. It is present as a monomer on the surface of B-cell and as a polymer when secreted in blood.
• Secreted IgM is mainly pentameric when it is joined with J-chain. In absence of J-chain, it may form a hexameric structure.
• Pentameric IgM has 10 antigen-binding sites. Due to these many binding sites, the total binding strength is very high. This is called avidity.
• IgM is a glycoprotein in nature. It contains carbohydrate portion also. About 12% of its total weight is made up of carbohydrates.
• In human blood serum, the mean concentration of IgM is about 1.5 mg/mL. It mainly remains inside blood circulation because of its large size.
• The serum half-life of IgM is about 5 to 10 days. After this time it is gradually removed from the bloodstream.
• The J-chain of IgM is a small acidic polypeptide. It has molecular weight about 15 kDa.
• The J-chain contains eight conserved cysteine residues. These residues help in linking and stabilizing the pentameric form of IgM.

Types of IgM

1. Membrane-bound IgM (mIgM)– It is the form of IgM present on the surface of mature resting B-lymphocytes. It is present as a single monomer unit and works as B-cell receptor (BCR) for antigen recognition.
2. Secreted pentameric IgM– It is the major form of IgM secreted by plasma cells into blood circulation. It is a large molecule made up of five monomer units joined together by J-chain protein.
3. Secreted hexameric IgM– It is a less common soluble form of IgM. It is made up of six monomer units and forms a complete symmetrical structure. This form is produced when J-chain is absent during assembly.
4. Secretory IgM (sIgM)– It is a special form of pentameric IgM found in mucosal secretions. It is transported through mucosal epithelial layer of respiratory tract and gastrointestinal tract.
5. Secretory Component (SC) bound IgM– In this form, IgM remains attached with Secretory Component (SC) protein. This protein protects the antibody from enzymatic digestion and also helps to anchor it in mucus layer.
6. Natural IgM– It is a functional type of IgM produced without previous exposure to any specific foreign pathogen. It is mainly secreted by B-1 cells and marginal zone B-cells.
7. Natural IgM function– It acts as a part of innate immune defence. It recognizes common microbial molecules such as polysaccharides and lipids and helps in early protection against infection.

Distribution of IgM in the Body

• Bloodstream (Vasculature)– Soluble IgM is mainly present in the blood circulation. Because of its large multimeric size, it does not easily pass out from the blood vessels into deep tissues. Thus it acts as major antibody for protection of blood and circulatory system from blood borne pathogens.
• Lymphatic system– Secreted IgM is also found in the lymph fluid. It moves with the lymph and helps in immune reaction against antigens present in the lymphatic system.
• Mucosal surfaces– Polymeric IgM is transported across mucosal epithelial layer of gastrointestinal tract and respiratory tract. Though IgA is the main antibody of these areas, secretory IgM also helps in neutralization of pathogens and protection of mucosal spaces.
• B-cell membranes– Monomeric IgM is attached on the surface of mature resting B-lymphocytes. It acts as antigen receptor of the B-cell. These B-cells are present or migrate through secondary lymphoid organs like spleen, lymph nodes, mucosal tissues and peritoneal cavity.

Synthesis and Production of IgM

• IgM is mainly synthesized and secreted by plasma cells. These plasma cells are developed from activated B-lymphocytes. Some special B-cells like marginal zone B-cells and fetal liver derived B-1 cells also produce natural IgM continuously without any previous exposure to pathogen.
• The genetic information for IgM heavy chain is present on chromosome 14. It is arranged by a random cutting and joining process known as V(D)J recombination. This recombination forms different antibody gene arrangement.
• The V(D)J recombination is catalyzed by RAG complex. This complex is made of RAG1 and RAG2 proteins. It works during the development of B-cells in the bone marrow.
• The diversity of IgM is increased by terminal deoxynucleotidyl transferase (TdT). This enzyme randomly adds extra nucleotides at the junctions between recombined gene segments. Thus large variety of antibody can be produced.
• In resting naive B-cells, alternative RNA processing produces membrane bound IgM and IgD receptors at the same time. After activation, alternative polyadenylation replaces the transmembrane anchor with a short hydrophilic tailpiece. This helps IgM to be released from the cell.
• During secretory pathway, individual IgM monomers are joined by disulfide bonds. When J-chain is incorporated, five monomers form pentameric IgM. When J-chain is absent, six monomers form hexameric IgM.
• The polymerization of IgM is checked inside the endoplasmic reticulum by ERp44 protein. It holds the misfolded and incomplete intermediates. So only fully assembled and correct IgM multimers are secreted from the cell.

Mechanism of IgM Production

• The production of IgM starts in bone marrow. Developing B cells use RAG complex. This complex has RAG1 and RAG2 proteins. It cuts and joins Variable (V), Diversity (D) and Joining (J) gene segments on chromosome 14. A special heavy chain gene is formed.
• Terminal deoxynucleotidyl transferase (TdT) enzyme adds extra nucleotides between the joined gene segments. This increases antibody variation. Different B cells can form different antigen binding sites.
• The newly formed heavy chain is checked at pre-BCR checkpoint. This checking is done by Bruton’s tyrosine kinase (BTK) signalling. If the heavy chain is useful then the cell goes for light chain formation.
• Light chain genes are then recombined. First kappa (κ) locus is tried. If it is not successful, then lambda (λ) locus is used. The light chain joins with heavy chain and functional IgM monomer is formed.
• The formed IgM is checked so that it does not react strongly with self antigen. Only proper and non-self reacting B cells are selected. This becomes mature naive B cell.
• In resting naive B cells, IgM and IgD are formed from same primary transcript by alternative RNA processing. These remain as membrane bound form on B cell surface.
• Membrane IgM and IgD are attached with signalling proteins. These proteins are Igα and Igβ. Together they act as B-cell receptor (BCR).
• When antigen binds with BCR, the B cell becomes activated. It changes into plasma cell. This step is important for secretion of IgM.
• In activated B cell, secretory switch takes place by alternative polyadenylation. The hydrophobic transmembrane anchor is removed from transcript. A short hydrophilic tailpiece is formed. So IgM can be secreted outside the cell.
• Inside endoplasmic reticulum (ER), five secreted IgM monomers come together. Their tailpieces pack with each other and form core like structure.
• Joining chain (J-chain) binds with this core. It forms disulfide bonds with heavy chains. It fixes the five IgM monomers into pentameric IgM.
• If J-chain is absent, then sixth IgM monomer may join in place of it. In this way, hexameric IgM is formed.
• ERp44 is a chaperone protein present in ER. It checks the polymerization of IgM. Misfolded or incomplete IgM remains inside the cell.
• Only fully formed and correctly assembled IgM polymer is released from plasma cell. It enters into blood stream as secreted IgM.

Functions of IgM

• IgM is the first antibody secreted during primary immune response. It appears early when a new pathogen enters into the body and gives first protection before other antibodies are produced.
• IgM traps and neutralizes pathogens by its large multimeric structure. It has high avidity, so it binds strongly with antigen and prevents the pathogen from attaching with host tissues.
• IgM is very effective against non-protein antigens like carbohydrates and lipids. It is also important against encapsulated bacteria, because these bacteria are difficult to engulf without antibody coating.
• IgM strongly activates the classical complement pathway. One bound pentameric IgM molecule can start complement cascade and this causes inflammation, opsonization and lysis of pathogen.
• IgM mainly protects the bloodstream. Due to its very large size, it does not enter deep tissues easily and remains mostly inside blood vessels. So it clears blood-borne pathogens from the circulation.
• IgM also helps in mucosal immunity. Pentameric IgM can pass across mucosal epithelial layers and it binds and neutralizes pathogens on surfaces like gut and respiratory tract.
• Membrane bound IgM acts as antigen receptor on mature naive B-cells. In this monomeric form, it recognizes foreign antigen and starts signal transduction which activates the B-cell.
• Natural IgM helps in immune homeostasis. It clears dead or apoptotic cells safely and reduces harmful inflammation, so it protects the body from autoimmune type reaction.
• Soluble IgM-Fc fragments may act as decoy molecule in blood. It binds complement proteins and helps to prevent unwanted complement dependent cytotoxicity, which may damage host tissues.

Immunological Significance of IgM

• IgM is the first antibody secreted during primary immune response. It appears when a new pathogen enters into the body. It acts as an early protective antibody and also forms a bridge between innate and adaptive immunity.
• IgM has high overall binding strength due to its multivalent structure. Though single antigen binding site may have low affinity, pentameric and hexameric IgM have 10 to 12 antigen binding sites. Thus it traps, neutralizes and agglutinates pathogens very effectively, mainly encapsulated bacteria having repeated surface antigens.
• IgM is a strong activator of classical complement pathway. After binding with antigen, IgM changes its structure into staple like form and exposes binding site for C1q protein. This starts complement cascade and causes inflammation, opsonization and destruction of invading microbes.
• IgM has important role in protection of blood circulation. Due to its large molecular size, it does not easily move out from blood vessels into deep tissues. So it mainly clears blood borne pathogens and protects the circulatory system.
• IgM also protects mucosal surface. Pentameric IgM can bind with polymeric immunoglobulin receptor (pIgR) and is transported across epithelial cell layer. It helps to neutralize and exclude pathogens from mucosal areas like gut and respiratory tract.
• Natural IgM is produced without previous exposure to a specific pathogen. It helps in safe clearance of dead or apoptotic cells from the body. It also gives immunomodulatory protection against damaging inflammation and autoimmune diseases.
• Membrane bound IgM acts as B-cell receptor (BCR) on mature naive B-cells. In this monomeric form it recognizes antigen and starts intracellular signaling pathway. This causes B-cell activation and clonal expansion.

Laboratory Detection and Measurement of IgM

• Serum measurement– Total IgM concentration can be directly measured from blood serum in medical laboratory. Normal adult level is usually about 37 to 286 mg/dl. This is used to check immune system, detect Selective IgM Deficiency where level may fall below 5 mg/dL in complete deficiency, and also to identify abnormal increase of IgM.
• Serology test– Specific IgM antibodies are detected to know recent exposure to a particular pathogen. As IgM is the first antibody produced in primary immune response, its presence usually indicates recent or early infection. In newborn baby, pathogen specific IgM is very important because maternal IgM cannot cross placenta, so it directly indicates infection exposure of the infant.
• ABO blood typing– IgM antibodies are used in ABO blood group detection due to their natural agglutinating property. Anti-A and anti-B isohemagglutinins cause clumping of incompatible red blood cells. Before transfusion, patient serum is mixed with donor blood cells to detect incompatible IgM mediated agglutination.
• Electrophoresis and immunofixation– Serum protein electrophoresis and immunofixation are used to detect abnormal single clone antibody production. These tests show M spike when monoclonal IgM is produced in excess. It is important in diagnosis of Waldenström macroglobulinemia and other B-cell malignancies.
• Isohemagglutinin titer– This test measures natural IgM isohemagglutinins produced against bacterial antigens present in the digestive system. If these antibody titers fall below 1:4, it may indicate an underlying antibody deficiency disorder.
• Rheumatoid factor assay– Rheumatoid factor (RF) test detects IgM autoantibody which binds with the Fc region of body’s own IgG antibody. Its detection is used as an important clinical marker for diagnosis of rheumatoid arthritis.
• Heterophile antibody test– This test detects heterophile IgM antibodies in serum. It is used for diagnosis of Epstein-Barr virus (EBV) infection.

Diseases Associated with Elevated IgM Levels

• Hyper-IgM syndromes (HIGM)– Hyper-IgM syndrome is a rare primary immunodeficiency disorder. In this disease, antibody class switching is defective. IgM is normal or increased. IgG, IgA and IgE are decreased. It is seen in CD40L, CD40, AID and UNG deficiencies.
• Waldenström macroglobulinemia (WM)– Waldenström macroglobulinemia is a rare blood cancer. It is a slow growing lymphoplasmacytic lymphoma. In this disease, malignant cells infiltrate the bone marrow. Large amount of monoclonal IgM protein is secreted.
• IgM MGUS– IgM monoclonal gammopathy of undetermined significance is a premalignant condition. It is mostly asymptomatic. In this condition monoclonal IgM is produced more. It may progress into Waldenström macroglobulinemia.
• Cold agglutinin disease (CAD)– Cold agglutinin disease is an autoimmune hemolytic anemia. It is caused mainly by IgM autoantibodies. These antibodies bind with red blood cells in cold temperature. Then destruction of red blood cells takes place.
• Activated PI3K delta syndrome– Activated PI3K delta syndrome is an inherited immunodeficiency disorder. In this disorder IgM level may be increased. IgG and IgA may be decreased or normal.
• Genetic and immune syndromes– Some genetic and immune syndromes show increased or normal IgM with other immune defects. These are constitutional mismatch repair deficiency, PMS2 deficiency, MSH6 deficiency, NEMO/IKBKG deficiency, Ataxia-telangiectasia and Nijmegen breakage syndrome.

Diseases Associated with Decreased IgM Levels

• Selective IgM deficiency (SIGMD)– Selective IgM deficiency is a rare primary immunodeficiency. In this condition serum IgM is very low or absent. Other immunoglobulins like IgG and IgA are normal. T-cells are also normal.
• X-linked agammaglobulinemia (XLA)– X-linked agammaglobulinemia is also known as Bruton agammaglobulinemia. It is a genetic defect. In this disease B-cell maturation is blocked. Due to this all antibody classes are absent or very low, including IgM.
• Common variable immunodeficiency (CVID)– Common variable immunodeficiency is an immunodeficiency disease. It is mostly seen in adolescence or adult stage. In this condition many immunoglobulin types are decreased. These are IgM, IgG and IgA.
• Wiskott-Aldrich syndrome– Wiskott-Aldrich syndrome is a primary immunodeficiency disorder. In this disorder circulating IgM level is low. But IgG and IgA may be high.
• Transient hypogammaglobulinemia of infancy– Transient hypogammaglobulinemia of infancy is a temporary condition of newborn and young infant. In this condition antibody production is delayed. So IgM and IgG becomes low. Later these levels gradually become normal.

Advantages of IgM

• High avidity– IgM has high total binding strength. It is due to pentameric or hexameric structure. It has 10 to 12 antigen binding sites. So even if single site has low affinity, whole IgM binds antigen strongly.
• Rapid defence– IgM is the first antibody secreted in primary immune response. It appears early after entry of foreign pathogen. Thus it gives immediate early protection to the body.
• Complement activation– IgM is a very strong activator of classical complement pathway. A single pentameric IgM attached with pathogen can start complement reaction. This causes inflammation and destruction of pathogen.
• Agglutination– IgM has large and multi armed structure. It can trap and clump many pathogens together. This agglutination is very useful against encapsulated bacteria.
• Non-protein antigen binding– IgM is effective against non-protein antigens. It can recognize and neutralize carbohydrates and lipids present on microbial surface.
• Dead cell clearance– Natural IgM helps in safe removal of dead or apoptotic cells. It maintains immune homeostasis. Soluble IgM fragments may also bind complement proteins and protect host tissues from inflammatory damage.
• Therapeutic value– IgM has high valency. So it is useful in modern therapeutic engineering. It can target low affinity tumor antigens and complex microbial glycans, where ordinary two armed IgG may not bind effectively.

Limitations of IgM

• Lower affinity– IgM has low binding affinity at single antigen binding site. It is mainly seen in primary immune response. Later antibodies like IgG bind antigen with more affinity.
• Poor tissue entry– Secreted IgM is very large in size. Due to this it cannot easily leave the blood vessel. It does not enter deep tissues like IgG, IgE or monomeric IgA.
• Less flexibility– IgM heavy chain has no flexible hinge region. So the molecule has less rotational movement. It is less flexible than IgG, IgA and IgD.
• Neutralization limit– IgM can neutralize pathogens. But it is not very effective like IgG and IgA. This is due to absence of hinge region and less flexibility of the molecule.
• Short half-life– IgM has short serum half life. It remains in blood for about 5 to 10 days. This is shorter than IgG, which remains about 21 to 24 days.
• Therapeutic difficulty– IgM is difficult to use in medicine as engineered antibody. It has complex multi chain structure. So manufacturing is difficult and batch to batch uniformity is not easy.
• Rapid clearance– Therapeutic IgM may be cleared fast by the liver. So it has shorter systemic half life than IgG therapy. Due to this higher dose or frequent dose may be needed.

Comparison of IgM with Other Immunoglobulins

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