IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism

Abstract

Antibodies are well-known protein mediators of immunity. IgM is the primordial member and the neglected sibling of the later-evolved and more proficient IgG in regard to their therapeutic and diagnostic use. Serendipitously, however, we found a paradox: While murine IgM antibodies specific for guanosine triphosphate (GTP) were able to recognize native guanylyl antigens found in primate or rat muscle tissues by immunofluorescence assays (which mimicked the auto-antibodies from autoimmune patients to skeletal or smooth muscle), the murine and human IgG counterparts failed. The results were replicated in cell-free direct binding assays using small latex microspheres decorated densely with GTP. The IgG antibodies could bind, however, if GTP was presented more spaciously on larger particles or as a univalent hapten. Accordingly, oligomerization of GTP (30-mer) destroyed the binding of the IgG antibodies but enhanced that of the IgMs in inhibition ELISA. We reason that, contrary to current belief, IgM does not bind in a lock-and-key manner like IgG. We hypothesize that whereas the intact and rigid antigen-binding site of IgG hinders the antibody from docking with antigens that are obstructed, in IgM, the two component polypeptides of the antigen-binding site can dissociate from each other and navigate individually through obstacles like the ancestral single-polypeptide antibodies found in sharks and camelids, both components eventually re-grouping around the antigen. We further speculate that polyreactive IgMs, which enigmatically bind to more than one type of antigen, use the same modus operandi. These findings call for a re-look at the clinical potential of IgM antibodies particularly in specific areas of cancer therapy, tissue pathology and vaccine design, where IgG antibodies have failed due to target inaccessibility.

Anti-JMH alloantibody in inherited JMH-negative patients leads to immunogenic destruction of JMH-positive RBCs

“…By day 21 post-transfusion, the type of deposited immunoglobulin gradually switched from primarily IgM to IgG. In addition to the engagement of specific antibodies, deposition of complement C3 was detected on day 5 posttransfusion and the fixation of complement C3 on the surface of JMH-positive RBCs, then gradually decreased over time, which might be related to the transformation from IgM to IgG in the later stage [75,76]. The most obvious example of this phenomenon is that only one IgM antibody can initiate the deposition of complement through C1q, while two IgG molecules initiate the deposition of complement [56,77,78].…”

Preparation, Characterization and Diagnostic Valuation of Two Novel Anti-HPV16 E7 Oncoprotein Monoclonal Antibodies

“…The reasons for the successful analysis of the pairing are as follows: (1) The IgM mAb 79A11 of the paired mAbs was derived from the spleen cells of an immunized mouse, and the IgG2a mAb of the paired mAb was also derived from the same immunized mouse lymph node cells, which confirmed that the two mAbs are directed against two different epitopes in the same antigen HPV16 E7-HIS fusion oncoprotein. (2) Although the affinity of IgG and an antigen is stronger than IgM, as a pentamer, an IgM can bind to 10 antigens and can access cryptic antigens denied to IgG [33]. IgM was used as a capture antibody in the double-antibody sandwich ELISA with less steric hindrance, which was more suitable for capturing antigens [34].…”

“…The high-risk human papillomavirus (HPV) integrating the cervix is a direct cause of cervical precancerous lesions and cervical cancer [1]. HPV 16 and 18 account for > 70% of cervical cancers and HPV 31,33,35,45,52, and 58 account for an additional 20% [2,3]. The prevalence of HPV infection in the cervix among women is 42.7% in the USA [4] and 17.7% in China [5].…”

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“…This only required high-affinity surface binding, subsequently slowing down VSG surface recycling, leading to motility arrest and rapid cell death. As such, while IgGs might have a higher binding affinity as compared to IgMs, the latter have an improved binding avidity due to their decavalent binding pattern and unique epitope recognition [104]. While VSG-antibody interaction modeling shows that when one IgG 'VH/VL arm' binds to VSG one homodimer, the other 'arm' can bind to any of 18 other VSG homodimers on the parasite surface [105], this number is increased to 9 IgM 'arms' being able to bind any of 61 other VSG homodimers, tremendously increasing avidity [106].…”