scholarly journals Structure, Function, and Therapeutic Use of IgM Antibodies

Antibodies ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 53 ◽  
Author(s):  
Bruce A. Keyt ◽  
Ramesh Baliga ◽  
Angus M. Sinclair ◽  
Stephen F. Carroll ◽  
Marvin S. Peterson
Keyword(s):  
Structure Function ◽  
Therapeutic Potential ◽  
Immunoglobulin M ◽  
Antigen Binding ◽  
High Avidity ◽  
Protein Antigens ◽  
Immunoglobulin Receptor ◽  
Heavy Chains ◽  
Igm Antibodies ◽  
Binding Domains

Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) or 12 (hexamer) antigen binding domains consisting of paired µ heavy chains with four constant domains, each with a single variable domain, paired with a corresponding light chain. Although the antigen binding affinities of natural IgM antibodies are typically lower than IgG, their polyvalency allows for high avidity binding and efficient engagement of complement to induce complement-dependent cell lysis. The high avidity of IgM antibodies renders them particularly efficient at binding antigens present at low levels, and non-protein antigens, for example, carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a joining (J) chain that stabilizes the pentameric structure and enables binding to several receptors. One such receptor, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lung and gastrointestinal tract. Several naturally occurring IgM antibodies have been explored as therapeutics in clinical trials, and a new class of molecules, engineered IgM antibodies with enhanced binding and/or additional functional properties are being evaluated in humans. Here, we review the considerable progress that has been made regarding the understanding of biology, structure, function, manufacturing, and therapeutic potential of IgM antibodies since their discovery more than 80 years ago.

scholarly journals 3D Structures of IgA, IgM, and Components

2021 ◽  
Vol 22 (23) ◽  
pp. 12776
Author(s):  
Shunli Pan ◽  
Noriyoshi Manabe ◽  
Yoshiki Yamaguchi
Keyword(s):  
Structure Function ◽  
Structural Information ◽  
Immunoglobulin A ◽  
Structural Complexity ◽  
Secretory Component ◽  
Immunoglobulin M ◽  
Atomic Scale ◽  
3D Structures ◽  
Heavy Chains ◽  
Effective Option

Immunoglobulin G (IgG) is currently the most studied immunoglobin class and is frequently used in antibody therapeutics in which its beneficial effector functions are exploited. IgG is composed of two heavy chains and two light chains, forming the basic antibody monomeric unit. In contrast, immunoglobulin A (IgA) and immunoglobulin M (IgM) are usually assembled into dimers or pentamers with the contribution of joining (J)-chains, which bind to the secretory component (SC) of the polymeric Ig receptor (pIgR) and are transported to the mucosal surface. IgA and IgM play a pivotal role in various immune responses, especially in mucosal immunity. Due to their structural complexity, 3D structural study of these molecules at atomic scale has been slow. With the emergence of cryo-EM and X-ray crystallographic techniques and the growing interest in the structure-function relationships of IgA and IgM, atomic-scale structural information on IgA-Fc and IgM-Fc has been accumulating. Here, we examine the 3D structures of IgA and IgM, including the J-chain and SC. Disulfide bridging and N-glycosylation on these molecules are also summarized. With the increasing information of structure–function relationships, IgA- and IgM-based monoclonal antibodies will be an effective option in the therapeutic field.

scholarly journals Immunoglobulin-binding domains: Protein L from Peptostreptococcus magnus

2003 ◽  
Vol 31 (3) ◽  
pp. 716-718 ◽  
Author(s):  
N.G. Housden ◽  
S. Harrison ◽  
S.E. Roberts ◽  
J.A. Beckingham ◽  
M. Graille ◽  
...  
Keyword(s):  
Binding Sites ◽  
Protein A ◽  
Cell Wall Protein ◽  
Protein G ◽  
Protein L ◽  
Heavy Chains ◽  
Binding Domains ◽  
Peptostreptococcus Magnus ◽  
Immunoglobulin Binding

Protein L is a multidomain cell-wall protein isolated from Peptostreptococcus magnus. It belongs to a group of proteins that contain repeated domains that are able to bind to Igs without stimulating an immune response, the most characterized of this group being Protein A (Staphylococcus aureus) and Protein G (Streptococcus). Both of these proteins bind predominantly to the interface of CH2-CH3 heavy chains, while Protein L binds exclusively to the VL domain of the κ-chain. The function of these proteins in vivo is not clear but it is thought that they enable the bacteria to evade the host's immune system. Two binding sites for κ-chain on a single Ig-binding domain from Protein L have recently been reported and we give evidence that one site has a 25–55-fold higher affinity for κ-chain than the second site.

scholarly journals Evaluation of the TGS TA system for the detection of anti-Toxoplasma antibodies

2017 ◽  
Vol 32 (1) ◽  
Author(s):  
Olivia Arpino ◽  
Annalisa Cianflone ◽  
Maria Teresa Manco ◽  
Alessia Paganini ◽  
Massimo De Paschale ◽  
...  
Keyword(s):  
High Avidity ◽  
Past Infection ◽  
Recent Infection ◽  
Igm Antibodies ◽  
Igg Avidity ◽  
Avidity Test ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

<em>Background and aims.</em> The aim of the present study was to evaluate the new chemiluminescence TGS TA system of Technogenetics (Milan, Italy) for detecting anti-Toxoplasma IgG and IgM antibodies and IgG avidity. The TGS TA system was compared with our chemiluminescence routinely used system, LIAISON XL, supplied by Diasorin (Saluggia, Italy), for the detection of IgG and IgM antibodies. Only in positive IgM samples (retrospective study) and for the IgG avidity (if existent), TGS TA system was compared to an Enzyme Linked Fluorescent Assay (ELFA) test (VIDAS, BioMérieux, Marcy-l’Étoile, France). <br /><em>Materials and methods</em>. Three hundred and one sera samples, from women who came to our centre for the routine follow up pregnancy, were examined with the TGS TA system and divided in 3 groups according to IgG and IgM screening LIAISON XL tests: 106 were non-immune women (Group 1), 100 were pregnant with past infection (Group 2) and 95 were pregnant with positive or equivocal IgM (82 with positive IgG and 13 with negative IgG) (Group 3). <br /><em>Results</em>. The overall concordance of the IgG results between LIAISON XL and TGS TA was 99.3%: 100% in Group 1, 98% in Group 2 and 100% in Group 3. The overall concordance of the IgM results between LIAISON XL and TGS TA was 93.9%: 100% in Group 1, 94% in Group 2 and 82.8% in Group 3. In Group 3, the concordance between the results of the IgG avidity with the ELFA and TGS TA tests was 81.7%. Comparing the clinical diagnosis obtained with our protocol and that of the TGS TA system, the overall concordance was 92.7%: 100% in Group 1, 92.0% in Group 2 and 78.9% in Group 3. <br /><em>Conclusions</em>. The overall concordance of IgG antibodies is excellent for both protocols while for IgM antibodies is very high in the first group and lower in the third group, due to the presence of non-specific IgM subjects in this group. The TGS TA avidity test seems to predict ealier the maturation of the IgG compared to the ELFA test since many samples with low avidity with the ELFA were seen with moderate avidity with TGS TA and all those with borderline avidity with the ELFA were seen with high avidity with TGS TA. This system shows to be a valuable tool with overall good clinical correlation and able to clearly identify nonspecific subjects, those with a non-recent infection.

scholarly journals A Coreceptor-Mimetic Peptide Enhances the Potency of V3-Glycan Antibodies

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Ina Fetzer ◽  
Meredith E. Davis-Gardner ◽  
Matthew R. Gardner ◽  
Barnett Alfant ◽  
Jesse A. Weber ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Target Cells ◽  
Broadly Neutralizing Antibodies ◽  
Mimetic Peptide ◽  
Heavy Chains ◽  
Binding Domains ◽  
C Terminus ◽  
Gp120 Subunit ◽  
Hiv 1

ABSTRACTBroadly neutralizing antibodies (bNAbs) target five major epitopes on the HIV-1 envelope glycoprotein (Env). The most potent bNAbs have median half-maximal inhibitory concentration (IC50) values in the nanomolar range, and the broadest bNAbs neutralize up to 98% of HIV-1 strains. The engineered HIV-1 entry inhibitor eCD4-Ig has greater breadth than bNAbs and similar potency. eCD4-Ig is markedly more potent than CD4-Ig due to its C-terminal coreceptor-mimetic peptide. Here we investigated whether the coreceptor-mimetic peptide mim6 improved the potency of bNAbs with different epitopes. We observed that when mim6 was appended to the C terminus of the heavy chains of bNAbs, this sulfopeptide improved the potency of all classes of bNAbs against HIV-1 isolates that are sensitive to neutralization by the sulfopeptide alone. However, mim6 did not significantly enhance neutralization of other isolates when appended to most classes of bNAbs, with one exception. Specifically, mim6 improved the potency of bNAbs of the V3-glycan class, including PGT121, PGT122, PGT128, and 10-1074, by an average of 2-fold for all HIV-1 isolates assayed. Despite this difference, 10-1074 does not induce exposure of the coreceptor-binding site, and addition of mim6 to 10-1074 did not promote shedding of the gp120 subunit of Env. Mixtures of 10-1074 and an Fc domain fused to mim6 neutralized less efficiently than a 10-1074/mim6 fusion, indicating that mim6 enhances the avidity of this fusion. Our data show that mim6 can consistently improve the potency of V3-glycan antibodies and suggest that these antibodies bind in an orientation that facilitates mim6 association with Env.IMPORTANCEHIV-1 requires both the cellular receptor CD4 and a tyrosine-sulfated coreceptor to infect its target cells. CD4-Ig is a fusion of the HIV-1-binding domains of CD4 with an antibody Fc domain. Previous studies have demonstrated that the potency of CD4-Ig is markedly increased by appending a coreceptor-mimetic sulfopeptide to its C terminus. We investigated whether this coreceptor-mimetic peptide improves the potency of broadly neutralizing antibodies (bNAbs) targeting five major epitopes on the HIV-1 envelope glycoprotein (Env). We observed that inclusion of the sulfopeptide dramatically improved the potency of all bNAb classes against isolates with more-open Env structures, typically those that utilize the coreceptor CXCR4. In contrast, the sulfopeptide improved only V3-glycan antibodies when neutralizing primary isolates, on average by 2-fold. These studies improve the potency of one class of bNAbs, show that coreceptor-mimetic sulfopeptides enhance neutralization through distinct mechanisms, and provide insight for the design of novel multispecific entry inhibitors.

scholarly journals Increased Immunogenicity and Induction of Class Switching by Conjugation of Complement C3d to Pneumococcal Serotype 14 Capsular Polysaccharide

2001 ◽  
Vol 69 (5) ◽  
pp. 3031-3040 ◽  
Author(s):  
Samuel T. Test ◽  
Joyce Mitsuyoshi ◽  
Charles C. Connolly ◽  
Alexander H. Lucas
Keyword(s):  
Antibody Response ◽  
Capsular Polysaccharide ◽  
Immunoglobulin M ◽  
Complement C3 ◽  
Primary Immune Response ◽  
Protein Antigens ◽  
Adjuvant Effect ◽  
Primary Antibody Response ◽  
Dependent Protein ◽  
Encapsulated Bacteria

ABSTRACT Previous studies have demonstrated an adjuvant effect for the C3d fragment of complement C3 when coupled to T-dependent protein antigens. In this study, we examined the antibody response to covalent conjugates of C3d and a T-independent antigen, the capsular polysaccharide of serotype 14 Streptococcus pneumoniae (PPS14). We prepared a conjugate of mouse C3d and PPS14 and compared its immunogenicity with that of a conjugate of PPS14 and ovalbumin (OVA). When BALB/c mice were immunized with PPS14-C3d, there was a significant increase in serum anti-PPS14 concentrations compared with either native PPS14 or control PPS14-glycine conjugates. This was accompanied by a switch in anti-PPS14 from predominantly immunoglobulin M (IgM) to IgG1 by day 25 following primary immunization. Following secondary immunization with PPS14-C3d, there was a marked booster response and a further increase in the ratio of IgG1 to IgM anti-PPS14. Although the primary antibody response to the PPS14-OVA conjugate exceeded that induced by immunization with PPS14-C3d, serum anti-PPS14 concentrations after a second injection of PPS14-C3d were nearly identical to those induced by secondary immunization with PPS14-OVA. Experiments with athymic nude mice suggested that T cells were not required for the adjuvant effect of C3d on the primary immune response to PPS14 but were necessary for enhancement of the memory response after a second injection of PPS14-C3d. These studies show that the adjuvant effects of C3d extend to T-independent antigens as well as T-dependent antigens. As a means of harnessing the adjuvant potential of the innate immune system, C3d conjugates may prove useful as a component of vaccines against encapsulated bacteria.

Immunodiagnosis and molecular validation of Toxoplasma gondii infection among patients with end-stage renal disease undergoing haemodialysis

Parasitology ◽  
2019 ◽  
Vol 146 (13) ◽  
pp. 1683-1689 ◽  
Author(s):  
Zahra Arab-Mazar ◽  
Shirzad Fallahi ◽  
Davood Yadegarynia ◽  
Amirreza Javadi Mamaghani ◽  
Seyyed Javad Seyyed Tabaei ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Immunoglobulin M ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Controls ◽  
Blood Samples ◽  
Igm Antibodies ◽  
Stage Renal Disease ◽  
End Stage

AbstractInfection is a significant cause of morbidity and mortality in patients with chronic kidney disease, especially who were under dialysis due to their depressed immunity. Toxoplasma gondii is a ubiquitous parasite that causes severe manifestations in immunocompromised patients. This case-control study was conducted to the immunodiagnosis and molecular validation of T. gondii infection among patients with end-stage renal disease undergoing haemodialysis. The study population consisted of 260 haemodialysis patients and 259 healthy controls referred to the main dialysis centres of Tehran, Iran during 2016. Anti-T. gondii immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies were assessed using enzyme-linked immunosorbent assay. As well, the T. gondii genomic DNA in whole blood samples of IgM-positive patients and healthy controls was evaluated using GRA6-polymerase chain reaction (PCR) and SAG1-loop-mediated isothermal amplification (LAMP) assays. The anti-T. gondii IgG and IgM antibodies were detected in 175 (67.3%) and 18 (7%) of haemodialysis patients and 122 (47%) and 4 (1.5%) of controls, respectively. Two of the 18 blood samples from IgM-positive patients and none of the IgM-positive control subjects were positive by GRA6-PCR. Whereas, nine and two blood samples of IgM-positive patients and controls were positive for Toxoplasma DNA by a SAG1-LAMP technique respectively. The seropositivity of the Toxoplasma IgM antibody was significantly different between haemodialysis patients and healthy controls which was confirmed by PCR and LAMP. The higher prevalence of T. gondii infection in haemodialysis patients compared with the controls proposes that these patients can be a group at risk for toxoplasmosis and screening for toxoplasmosis before dialysis is necessary for the patients.

scholarly journals Antigen binding and idiotype analysis of antibodies obtained after electroporation of heavy and light chain genes encoding phosphocholine-specific antibodies: a model for T15-idiotype dominance.

1992 ◽  
Vol 176 (6) ◽  
pp. 1637-1643 ◽  
Author(s):  
J J Kenny ◽  
C M Moratz ◽  
G Guelde ◽  
C D O'Connell ◽  
J George ◽  
...  
Keyword(s):  
Immune Response ◽  
Amino Acid ◽  
B Cell ◽  
Molecular Model ◽  
Immunoglobulin M ◽  
Single Amino Acid ◽  
Primary Immune Response ◽  
Antigen Binding ◽  
Large Numbers ◽  
Genes Encoding

Antibodies bearing the T15 idiotype dominate the murine primary immune response to phosphocholine (PC). Analysis of antigen binding of antibodies derived from V1:DFL16.1:JH1 (VH1) germline and N region-derived variant heavy (H) chains and kappa 22, kappa 24, and kappa 8 light (L) chains demonstrates that the T15H:kappa 22L (T15) antibody binds PC at least 20-40 times better than other antibodies derived from alternate germline forms of the VH1 H chain and kappa 22, kappa 24, or kappa 8 L chains. To achieve affinities in the same range as the T15 antibody, kappa 24 and kappa 8 L chain-containing antibodies must have H chains derived from variant N region or somatically mutated VH1 genes. Single amino acid differences at the VD junction of the various germline and N region variant VH1 H chains dictate the L chain that can associate with the H chain to produce a PC-specific antibody. Several H:L combinations give rise to T15 or M167 idiotype-positive antibodies that lack specificity for PC, and single amino acid substitutions or insertions at the VH1:D junction result in the loss of T15 or M167 idiotopes. Based on these observations, our data support a molecular model involving both preferential gene rearrangement and antigen-driven B cell selection to explain T15 idiotype dominance in the immune response to PC. In the absence of N region diversification, large numbers of neonatal B cells bearing the T15H:kappa 22L surface immunoglobulin M (sIgM) receptors would be selected and expanded by autologous or environmental PC antigen into the long-lived peripheral B cell pool.

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