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Annual Review of Biochemistry Jun 2019Antibodies are immunoglobulins that play essential roles in immune systems. All antibodies are glycoproteins that carry at least one or more conserved -linked... (Review)
Review
Antibodies are immunoglobulins that play essential roles in immune systems. All antibodies are glycoproteins that carry at least one or more conserved -linked oligosaccharides (-glycans) at the Fc domain. Many studies have demonstrated that both the presence and fine structures of the attached glycans can exert a profound impact on the biological functions and therapeutic efficacy of antibodies. However, antibodies usually exist as mixtures of heterogeneous glycoforms that are difficult to separate in pure glycoforms. Recent progress in glycoengineering has provided useful methods that enable production of glycan-defined and site-selectively modified antibodies for functional studies and for improved therapeutic efficacy. This review highlights major approaches in glycoengineering of antibodies with a focus on recent advances in three areas: glycoengineering through glycan biosynthetic pathway manipulation, glycoengineering through in vitro chemoenzymatic glycan remodeling, and glycoengineering of antibodies for site-specific antibody-drug conjugation.
Topics: Animals; Antibodies; Glycoproteins; Glycosylation; Humans; Protein Engineering
PubMed: 30917003
DOI: 10.1146/annurev-biochem-062917-012911 -
Frontiers in Immunology 2023Significant progress has been made in the elucidation of human antibody repertoires. Furthermore, non-canonical functions of antibodies have been identified that reach... (Review)
Review
Significant progress has been made in the elucidation of human antibody repertoires. Furthermore, non-canonical functions of antibodies have been identified that reach beyond classical functions linked to protection from pathogens. Polyclonal immunoglobulin preparations such as IVIG and SCIG represent the IgG repertoire of the donor population and will likely remain the cornerstone of antibody replacement therapy in immunodeficiencies. However, novel evidence suggests that pooled IgA might promote orthobiotic microbial colonization in gut dysbiosis linked to mucosal IgA immunodeficiency. Plasma-derived polyclonal IgG and IgA exhibit immunoregulatory effects by a diversity of different mechanisms, which have inspired the development of novel drugs. Here we highlight recent insights into IgG and IgA repertoires and discuss potential implications for polyclonal immunoglobulin therapy and inspired drugs.
Topics: Humans; Immunoglobulins, Intravenous; Immunoglobulin G; Antibody Diversity; Immunologic Deficiency Syndromes; Immunization, Passive; Immunoglobulin A
PubMed: 37063852
DOI: 10.3389/fimmu.2023.1166821 -
Seminars in Immunology May 2023The dynamic and complex community of microbes that colonizes the intestines is composed of bacteria, fungi, and viruses. At the mucosal surfaces, immunoglobulins play a... (Review)
Review
The dynamic and complex community of microbes that colonizes the intestines is composed of bacteria, fungi, and viruses. At the mucosal surfaces, immunoglobulins play a key role in protection against bacterial and fungal pathogens, and their toxins. Secretory immunoglobulin A (sIgA) is the most abundantly produced antibody at the mucosal surfaces, while Immunoglobulin G (IgG) isotypes play a critical role in systemic protection. IgA and IgG antibodies with reactivity to commensal fungi play an important role in shaping the mycobiota and host antifungal immunity. In this article, we review the latest evidence that establishes a connection between commensal fungi and B cell-mediated antifungal immunity as an additional layer of protection against fungal infections and inflammation.
Topics: Humans; Antifungal Agents; Immunoglobulin A, Secretory; Immunoglobulin G; Bacteria; Immunity, Mucosal; Immunoglobulins
PubMed: 37003056
DOI: 10.1016/j.smim.2023.101757 -
Clinical and Experimental Immunology Dec 2022The ability of B cells to generate antibodies and provide long-lived protective immunity is the cornerstone of vaccination and has contributed to the success of modern...
The ability of B cells to generate antibodies and provide long-lived protective immunity is the cornerstone of vaccination and has contributed to the success of modern medicine. The nine different antibody subclasses produced by humans have effector functions that differ according to antigen type and route of exposure. Expression of the appropriate isotype is critical for effective humoral immunity, and it is becoming clear that subclass specificity is to some extent reflected at the cellular level. Understanding the mechanisms that govern the induction, expansion, and maintenance of B cells expressing different antibody subclasses informs the strategic manipulation of responses to benefit human health. This article provides an overview of the mechanisms by which the different human antibody subclasses regulate immunity, presents an update on how antibody subclass expression is regulated at the cellular level and highlights key areas for future research.
Topics: Humans; Immunoglobulin Isotypes; B-Lymphocytes; Antibodies; Immunity, Humoral; Vaccination
PubMed: 36197112
DOI: 10.1093/cei/uxac091 -
Viruses Jul 2023Antibody-dependent enhancement (ADE) is a phenomenon where virus-specific antibodies paradoxically cause enhanced viral replication and/or excessive immune responses,... (Review)
Review
Antibody-dependent enhancement (ADE) is a phenomenon where virus-specific antibodies paradoxically cause enhanced viral replication and/or excessive immune responses, leading to infection exacerbation, tissue damage, and multiple organ failure. ADE has been observed in many viral infections and is supposed to complicate the course of COVID-19. However, the evidence is insufficient. Since no specific laboratory markers have been described, the prediction and confirmation of ADE are very challenging. The only possible predictor is the presence of already existing (after previous infection) antibodies that can bind to viral epitopes and promote the disease enhancement. At the same time, the virus-specific antibodies are also a part of immune response against a pathogen. These opposite effects of antibodies make ADE research controversial. The assignment of immunoglobulins to ADE-associated or virus neutralizing is based on their affinity, avidity, and content in blood. However, these criteria are not clearly defined. Another debatable issue (rather terminological, but no less important) is that in most publications about ADE, all immunoglobulins produced by the immune system against pathogens are qualified as pre-existing antibodies, thus ignoring the conventional use of this term for natural antibodies produced without any stimulation by pathogens. Anti-glycan antibodies (AGA) make up a significant part of the natural immunoglobulins pool, and there is some evidence of their antiviral effect, particularly in COVID-19. AGA have been shown to be involved in ADE in bacterial infections, but their role in the development of ADE in viral infections has not been studied. This review focuses on pros and cons for AGA as an ADE trigger. We also present the results of our pilot studies, suggesting that AGAs, which bind to complex epitopes (glycan plus something else in tight proximity), may be involved in the development of the ADE phenomenon.
Topics: Humans; SARS-CoV-2; COVID-19; Antibodies, Viral; Antibody-Dependent Enhancement; Antibodies, Neutralizing; Virus Diseases; Viruses; Epitopes
PubMed: 37515270
DOI: 10.3390/v15071584 -
JCI Insight Jul 2023Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no vaccines or therapeutics to prevent congenital HCMV (cCMV)...
Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence indicates that antibody Fc effector functions may be a previously underappreciated component of maternal immunity against HCMV. We recently reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of FcγRI/FcγRII were associated with protection against cCMV transmission, leading us to hypothesize that additional Fc-mediated antibody functions may be important. In this same cohort of HCMV-transmitting (n = 41) and nontransmitting (n = 40) mother-infant dyads, we report that higher maternal sera antibody-dependent cellular cytotoxicity (ADCC) activation is also associated with lower risk of cCMV transmission. We investigated the relationship between ADCC and IgG responses against 9 viral antigens and found that ADCC activation correlated most strongly with sera IgG binding to the HCMV immunoevasin protein UL16. Moreover, we determined that higher UL16-specific IgG binding and FcγRIII/CD16 engagement were associated with the greatest risk reduction in cCMV transmission. Our findings indicate that ADCC-activating antibodies against targets such as UL16 may represent an important protective maternal immune response against cCMV infection that can guide future HCMV correlates studies and vaccine or antibody-based therapeutic development.
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Antibody-Dependent Cell Cytotoxicity; Antibodies, Viral; Immunoglobulin Fc Fragments; Immunoglobulin G
PubMed: 37427588
DOI: 10.1172/jci.insight.167768 -
Frontiers in Immunology 2023Autoimmune nodopathies (AN) have been diagnosed in a subset of patients fulfilling criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who...
INTRODUCTION
Autoimmune nodopathies (AN) have been diagnosed in a subset of patients fulfilling criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who display no or poor response to intravenous immunoglobulins. Biomarkers of AN are autoantibodies, mainly IgG4, directed against the ternary paranodal complex composed by neurofascin-155, contactin-1 (CNTN1), and Contactin-associated-protein-1 (CASPR1) or against the nodal isoforms of neurofascin. IgG4 can undergo a Fab-arm exchange (FAE) which results in functionally monovalent antibody. This phenomenon differentially affects the pathogenicity of IgG4 depending on the target of autoantibodies. Here, we have evaluated this issue by examining the impact of valency on anti-CNTN1 IgG4 which induces paranodal destruction through a function blocking activity.
METHODS
Sera were obtained from 20 patients with AN associated with anti-CNTN1 antibodies. The proportion of monospecific/bispecific anti-CNTN1 antibodies was estimated in each patient by ELISA by examining the ability of serum antibodies to cross-link untagged CNTN1 with biotinylated CNTN1. To determine the impact of monovalency, anti-CNTN1 IgG4 were enzymatically digested into monovalent Fab and tested on cell aggregation assay. Also, intraneural injections were performed to determine whether monovalent Fab and native IgG4 may penetrate paranode, and antibody infiltration was monitored 1- and 3-days post injection.
RESULTS AND DISCUSSION
We found that the percentage of monospecific antibodies were lower than 5% in 14 out of 20 patients (70%), suggesting that IgG4 have undergone extensive FAE . The levels of monospecific antibodies correlated with the titers of anti-CNTN1 antibodies. However, no correlation was found with clinical severity, and patients with low or high percentage of monospecific antibodies similarly showed a severe phenotype. Native anti-CNTN1 IgG4 were shown to inhibit the interaction between cells expressing CNTN1/CASPR1 and cells expressing neurofascin-155 using an aggregation assay. Similarly, monovalent Fab significantly inhibited the interaction between CNTN1/CASPR1 and neurofascin-155. Intraneural injections of Fab and native anti-CNTN1 IgG4 indicated that both mono- and bivalent anti-CNTN1 IgG4 potently penetrated the paranodal regions and completely invaded this region by day 3. Altogether, these data indicate anti-CNTN1 IgG4 are mostly bispecific in patients, and that functionally monovalent anti-CNTN1 antibodies have the pathogenic potency to alter paranode.
Topics: Immunoglobulin G; Nerve Growth Factors; Contactin 1; Cell Adhesion Molecules; Autoantibodies; Antibodies, Bispecific
PubMed: 36999029
DOI: 10.3389/fimmu.2023.1021513 -
Seminars in Immunology Apr 2012Antibody mediated rejection is a significant clinical problem encountered in a subset of renal transplant recipients. This type of rejection has a variable pathogenesis... (Review)
Review
Antibody mediated rejection is a significant clinical problem encountered in a subset of renal transplant recipients. This type of rejection has a variable pathogenesis from the presence of donor specific antibodies with no overt disease to immediate hyperacute rejection and many variations between. Antibody mediated rejection is more common in human leukocyte antigen sensitized patients. In general, transplant graft survival after antibody mediated rejection is jeopardized, with less than 50% graft survival 5 years after this diagnosis. A variety of agents have been utilized singly and in combinations to treat antibody mediated rejection with differing results and significant research efforts are being placed on developing new targets for intervention. These same agents have been used in desensitization protocols with some success. In this review, we describe the biology of antibody mediated rejection, review the available agents to treat this form of rejection, and highlight areas of ongoing and future research into this difficult clinical problem.
Topics: Antibodies, Monoclonal; Clinical Trials as Topic; Desensitization, Immunologic; Graft Rejection; Humans; Immunoglobulins, Intravenous; Isoantibodies; Kidney Transplantation; Plasmapheresis; Treatment Outcome
PubMed: 21940179
DOI: 10.1016/j.smim.2011.08.015 -
Transplant International : Official... Jun 2012With the advent of novel therapies to directly intervene with B cell immunity and complement activation, antibody-mediated kidney allograft rejection (AMR) has come into... (Review)
Review
With the advent of novel therapies to directly intervene with B cell immunity and complement activation, antibody-mediated kidney allograft rejection (AMR) has come into the focus of transplant immunologists. Intravenous immunoglobulin, rituximab, bortezomib, and eculizumab have been used to treat patients with acute AMR, apart from the standard treatment of antibody removal with plasma exchange or immunoadsorption and steroid pulses. This article describes the experimental rationale and summarizes the still limited clinical experience with these novel therapies in the transplant setting. Results with the standard treatment for acute AMR, including intense plasmapheresis, intravenous immunoglobulins, and steroids are good with a graft survival of 80% at 18 months. In contrast, patients suffering from chronic AMR have significant irreversible damage in their grafts with substantially impaired graft survival. Thus, the authors propose a step-wise escalation of therapy in refractory cases of acute AMR and advocate an urgent need for controlled therapeutic trials for acute and chronic AMR not to inflict unnecessary harm on our patients by uncontrolled polypragmasy.
Topics: Acute Disease; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Boronic Acids; Bortezomib; Chronic Disease; Graft Rejection; Graft Survival; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosorbent Techniques; Isoantibodies; Kidney Transplantation; Plasma Exchange; Pyrazines; Rituximab; Splenectomy
PubMed: 22394269
DOI: 10.1111/j.1432-2277.2012.01453.x -
Journal of Clinical Pathology Jan 1960A serum which specifically agglutinated penicillin-coated erythrocytes is described. The active constituent had the charac eristics of an antibody. Its laboratory and...
A serum which specifically agglutinated penicillin-coated erythrocytes is described. The active constituent had the charac eristics of an antibody. Its laboratory and clinical significance is discussed.
Topics: Anti-Bacterial Agents; Antibodies; Humans; Immunoglobulins; Penicillins
PubMed: 13800855
DOI: 10.1136/jcp.13.1.51