IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism
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 guano...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.01820/full |
| _version_ | 1828859702745759744 |
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| author | Eric Chun Yiu Law Danny Tze Ming Leung Frankie Chi Hang Tam Frankie Chi Hang Tam Kitty Kit Ting Cheung Naomi Hua Yin Cheng Pak Leong Lim Pak Leong Lim |
| author_facet | Eric Chun Yiu Law Danny Tze Ming Leung Frankie Chi Hang Tam Frankie Chi Hang Tam Kitty Kit Ting Cheung Naomi Hua Yin Cheng Pak Leong Lim Pak Leong Lim |
| author_sort | Eric Chun Yiu Law |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T02:23:43Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T02:23:43Z |
| publishDate | 2019-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-12e4da23223a4cdfb4efefda72c385482022-12-22T00:02:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-08-011010.3389/fimmu.2019.01820468889IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding MechanismEric Chun Yiu Law0Danny Tze Ming Leung1Frankie Chi Hang Tam2Frankie Chi Hang Tam3Kitty Kit Ting Cheung4Naomi Hua Yin Cheng5Pak Leong Lim6Pak Leong Lim7Clinical Immunology Unit, The Chinese University of Hong Kong, Hong Kong, ChinaClinical Immunology Unit, The Chinese University of Hong Kong, Hong Kong, ChinaClinical Immunology Unit, The Chinese University of Hong Kong, Hong Kong, ChinaIgGENE, FoTan, Hong Kong, ChinaClinical Immunology Unit, The Chinese University of Hong Kong, Hong Kong, ChinaClinical Immunology Unit, The Chinese University of Hong Kong, Hong Kong, ChinaClinical Immunology Unit, The Chinese University of Hong Kong, Hong Kong, ChinaIgGENE, FoTan, Hong Kong, ChinaAntibodies 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.01820/fullIgMantibody specificityguanosine triphosphatelock-and-keyantigen-binding sitesteric hindrance |
| spellingShingle | Eric Chun Yiu Law Danny Tze Ming Leung Frankie Chi Hang Tam Frankie Chi Hang Tam Kitty Kit Ting Cheung Naomi Hua Yin Cheng Pak Leong Lim Pak Leong Lim IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism Frontiers in Immunology IgM antibody specificity guanosine triphosphate lock-and-key antigen-binding site steric hindrance |
| title | IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism |
| title_full | IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism |
| title_fullStr | IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism |
| title_full_unstemmed | IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism |
| title_short | IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism |
| title_sort | igm antibodies can access cryptic antigens denied to igg hypothesis on novel binding mechanism |
| topic | IgM antibody specificity guanosine triphosphate lock-and-key antigen-binding site steric hindrance |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.01820/full |
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