immunoglobulin M（IgM） Antibody Overview
Immunoglobulins serve as key detection molecules in the immune system. Of the five major classes of immunoglobulins, the immunoglobulin M (IgM) antibody characterized by the µ heavy chain, is the largest. It is generated as a B cell membrane bound monomer and a secreted pentamer. IgM is the first immunoglobulin developed during human fetal development at 20 weeks. Unlike IgG antibody which provides passive immunity to the fetus, IgM antibody is restricted from crossing the placenta due to its size. It is also the first antibody to respond during infection. IgM antibody earned the title of the "natural antibody" as it can bind to specific antigens without prior immunization. This ability to react, despite naïve immune status, is likely due its avidity and polyreactivity. An IgM antibody can also be generated in response to infection; termed "immune IgM antibody," they are produced around one week and persist in serum for 5-8 days. While IgG antibody has been the dominant class of immunoglobulin utilized in research and therapeutic applications, attention is turning to other classes such as IgM antibodies which have their own distinct features and corresponding strengths. See comparison table below.
Figure 1: IgM pentamer and IgG monomer structures shown above.
|Feature||IgM Antibody||IgG Antibody|
|Size||970 kDa||150 kDa|
(monomeric as B-cell receptor)
|Location||Lymph and Blood||Blood, Lymph, Can Cross Placenta|
During infection, innate or “natural immunity” is provided by poly-reactive IgM antibody made by (B1a) B cells. IgM antibody acts to quickly recognize and initiate an immune response by directly neutralizing pathogens or clearing novel antigens. The three components of the IgM antibody-mediated immune response are activation of complement (C1qR and Fcα/µR), recruitment of phagocytic cells, and opsonization. Current research suggests that B1b B cells which make IgM antibodies may provide memory to certain pathogens and support T-cell independent immune responses. IgM antibody also acts as an educator of the immune system by transporting antigens to lymph tissues where memory is induced.
The rare disease of selective IgG deficiency highlights IgM antibody’s critical role in defense against infection. Clinically low IgM antibody levels, from undetectable to 20-40 mg/dL, result in persistent, recurrent infections. This is contrasted with healthy individuals who normally demonstrate an acute, 5-8 day, increase in IgM antibody concentrations following infection. However, selective IgM antibody deficiency can also be found in patients that are otherwise asymptomatic, suggesting a compensatory response exists.
Within the immune system, two hypothetical mechanisms suggest serum IgM antibodies may play a regulatory role, increasing or decreasing B-cell signaling via membrane bound IgM/antigen interaction. If antigen is disproportionately bound to pentameric IgM antibody relative to isomeric membrane bound IgM antibody, signaling to the membrane receptors would be decreased. This signal decrease would lead to shrinkage of the B cell population. However, should the pentameric IgM complex with many monomeric membrane bound IgM, this bridging of pentamer and monomer via antigen could induce positive signaling for B-cells survival. IgM therefore may act to control B-cell populations.
IgM antibody not only mediates the response to immunological challenges, but also participates in homeostatic functions of healthy tissue. As cells naturally turn over, IgM antibody clears apoptotic debris and induces marginal zone B-cell release of IL-10, an anti-inflammatory cytokine. In this way IgM antibody serves as a mediator of inflammation. Apoptotic cells release many self-antigens. IgM antibody clearance prevents self-antigen concentrations which could induce an immune response. IgM antibody also binds to misfolded proteins and altered cells, clearing them via dendritic cells, B cells, and macrophages. This functional “waste disposal” hypothesis also extends to atherosclerotic plaques. IgM antibody may bind to plaques via oxidized LDL interaction, marking them for clearance, and effecting vascular remodeling.
The IgM class of antibodies recognizes a large variety of pathogenic antigens and is highly active in cytotoxic and cytolytic reactions due to its superior activation of the complement system. IgM antibody has applications in Antibody Drug Discovery. Just a few reasons why IgM antibody can be an attractive therapeutic are listed below.
Recent advancements have made IgM antibody amenable to manipulation that allows further tuning of its effector function to meet the above therapeutic needs. There are several requirements for IgM antibodies to be considered as a potential standard platform, including in vitro optimization, recombinant production, and purification. IgM antibody variable chains have been manipulated using phage display technology in vitro to optimize IgM therapeutic antibody candidates. Their recombinant yields in cell culture have been improved and methods for purification have been optimized. Based on these advances an IgM therapeutics platform can be built.
As opposed to all other forms of immunoglobulins, IgM antibody not does not bind well to protein A or protein G for purification. It is also adversely affected by traditional elution techniques. IgM antibody stability and narrow solubility range proved confounding for purification techniques until recently. IgM antibody size serves well for size exclusion purification, but is speed-limiting at larger volumes. The advancement in purification of IgM monoclonal antibodies relies on the fact that they typically have a high charge, allowing them to be purified by ion exchange. Hydroxyapatite, a naturally occurring mineral, binds IgM antibodies under physiological pH conditions offering another means of separation.
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