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Nature Oct 2019B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR), and the diverse range...
B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR), and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.
Topics: Adult; Aged; Clone Cells; Humans; Immune System Diseases; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Isotypes; Middle Aged; Receptors, Antigen, B-Cell; Young Adult
PubMed: 31554970
DOI: 10.1038/s41586-019-1595-3 -
Developmental and Comparative Immunology Feb 2021Cartilaginous fishes, comprising the chimeras, sharks, skates, and rays, split from the common ancestor with other jawed vertebrates approx. 450 million years ago. Being... (Review)
Review
Cartilaginous fishes, comprising the chimeras, sharks, skates, and rays, split from the common ancestor with other jawed vertebrates approx. 450 million years ago. Being the oldest extant taxonomic group to possess an immunoglobulin (Ig)-based adaptive immune system, examination of this group has taught us much about the evolution of adaptive immunity, as well as the conserved and taxon-specific characteristics of Igs. Significant progress has been made analyzing sequences from numerous genomic and transcriptomic data sets. These findings have been supported by additional functional studies characterizing the Igs and humoral response of sharks and their relatives. This review will summarize what we have learned about the genomic organization, protein structure, and in vivo function of these Ig isotypes in cartilaginous fishes and highlight the areas where our knowledge is still lacking.
Topics: Adaptive Immunity; Animals; Datasets as Topic; Elasmobranchii; Fish Proteins; Gene Expression Profiling; Immunoglobulin Isotypes
PubMed: 32979434
DOI: 10.1016/j.dci.2020.103873 -
Clinical and Experimental Immunology Mar 2021The clinical application of monoclonal antibodies (mAbs) has revolutionized the field of cancer therapy, as it has enabled the successful treatment of previously... (Review)
Review
The clinical application of monoclonal antibodies (mAbs) has revolutionized the field of cancer therapy, as it has enabled the successful treatment of previously untreatable types of cancer. Different mechanisms play a role in the anti-tumour effect of mAbs. These include blocking of tumour-specific growth factor receptors or of immune modulatory molecules as well as complement and cell-mediated tumour cell lysis. Thus, for many mAbs, Fc-mediated effector functions critically contribute to the efficacy of treatment. As immunoglobulin (Ig) isotypes differ in their ability to bind to Fc receptors on immune cells as well as in their ability to activate complement, they differ in the immune responses they activate. Therefore, the choice of antibody isotype for therapeutic mAbs is dictated by its intended mechanism of action. Considering that clinical efficacy of many mAbs is currently achieved only in subsets of patients, optimal isotype selection and Fc optimization during antibody development may represent an important step towards improved patient outcome. Here, we discuss the current knowledge of the therapeutic effector functions of different isotypes and Fc-engineering strategies to improve mAbs application.
Topics: Antibodies, Monoclonal; Cytotoxicity, Immunologic; Humans; Immunoglobulin A; Immunoglobulin D; Immunoglobulin E; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Neoplasms
PubMed: 33155272
DOI: 10.1111/cei.13545 -
MBio Apr 2021causes the severe diarrheal disease cholera. Clinical disease and current oral cholera vaccines generate antibody responses associated with protection. Immunity is...
causes the severe diarrheal disease cholera. Clinical disease and current oral cholera vaccines generate antibody responses associated with protection. Immunity is thought to be largely mediated by lipopolysaccharide (LPS)-specific antibodies, primarily targeting the O-antigen. However, the properties and protective mechanism of functionally relevant antibodies have not been well defined. We previously reported on the early B cell response to cholera in a cohort of Bangladeshi patients, from which we characterized a panel of human monoclonal antibodies (MAbs) isolated from acutely induced plasmablasts. All antibodies in that previous study were expressed in an IgG1 backbone irrespective of their original isotype. To clearly determine the impact of affinity, immunoglobulin isotype and subclass on the functional properties of these MAbs, we re-engineered a subset of low- and high-affinity antibodies in different isotype and subclass immunoglobulin backbones and characterized the impact of these changes on binding, vibriocidal, agglutination, and motility inhibition activity. While the high-affinity antibodies bound similarly to O-antigen, irrespective of isotype, the low-affinity antibodies displayed significant avidity differences. Interestingly, despite exhibiting lower binding properties, variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies, suggesting that how the MAb binds to the O-antigen may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition. Immunity to the severe diarrheal disease cholera is largely mediated by lipopolysaccharide (LPS)-specific antibodies. However, the properties and protective mechanisms of functionally relevant antibodies have not been well defined. Here, we have engineered low and high-affinity LPS-specific antibodies in different immunoglobulin backbones in order to assess the impact of affinity, immunoglobulin isotype, and subclass on binding, vibriocidal, agglutination, and motility inhibition functional properties. Importantly, we found that affinity did not directly dictate functional potency since variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies. This suggests that how the antibody binds sterically may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition.
Topics: Antibodies, Bacterial; Antibodies, Monoclonal; Binding Sites, Antibody; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; O Antigens; Vibrio cholerae O1
PubMed: 33879588
DOI: 10.1128/mBio.03679-20 -
Advances in Immunology 2019Class switch recombination (CSR) generates isotype-switched antibodies with distinct effector functions essential for mediating effective humoral immunity. CSR is... (Review)
Review
Class switch recombination (CSR) generates isotype-switched antibodies with distinct effector functions essential for mediating effective humoral immunity. CSR is catalyzed by activation-induced deaminase (AID) that initiates DNA lesions in the evolutionarily conserved switch (S) regions at the immunoglobulin heavy chain (Igh) locus. AID-initiated DNA lesions are subsequently converted into DNA double stranded breaks (DSBs) in the S regions of Igh locus, repaired by non-homologous end-joining to effect CSR in mammalian B lymphocytes. While molecular mechanisms of CSR are well characterized, it remains less well understood how upstream signaling pathways regulate AID expression and CSR. B lymphocytes express multiple receptors including the B cell antigen receptor (BCR) and co-receptors (e.g., CD40). These receptors may share common signaling pathways or may use distinct signaling elements to regulate CSR. Here, we discuss how signals emanating from different receptors positively or negatively regulate AID expression and CSR.
Topics: Animals; B-Cell Activation Factor Receptor; B-Lymphocytes; Cytidine Deaminase; DNA Breaks, Double-Stranded; Humans; Immunity, Humoral; Immunoglobulin Class Switching; Immunoglobulin Heavy Chains; Immunoglobulin Isotypes; Mice; Receptors, Antigen, B-Cell; Recombination, Genetic; Signal Transduction; Toll-Like Receptors; Transmembrane Activator and CAML Interactor Protein
PubMed: 30904131
DOI: 10.1016/bs.ai.2019.01.001 -
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 -
Biomolecules Nov 2014Although lymphocyte-like cells secreting somatically-recombining receptors have been identified in the jawless fishes (hagfish and lamprey), the cartilaginous fishes... (Review)
Review
Although lymphocyte-like cells secreting somatically-recombining receptors have been identified in the jawless fishes (hagfish and lamprey), the cartilaginous fishes (sharks, skates, rays and chimaera) are the most phylogenetically distant group relative to mammals in which bona fide immunoglobulins (Igs) have been found. Studies of the antibodies and humoral immune responses of cartilaginous fishes and other cold-blooded vertebrates (bony fishes, amphibians and reptiles) are not only revealing information about the emergence and roles of the different Ig heavy and light chain isotypes, but also the evolution of specialised adaptive features such as isotype switching, somatic hypermutation and affinity maturation. It is becoming increasingly apparent that while the adaptive immune response in these vertebrate lineages arose a long time ago, it is most definitely not primitive and has evolved to become complex and sophisticated. This review will summarise what is currently known about the immunoglobulins of cold-blooded vertebrates and highlight the differences, and commonalities, between these and more "conventional" mammalian species.
Topics: Adaptive Immunity; Amphibian Proteins; Amphibians; Animals; Evolution, Molecular; Fishes; Immunoglobulin Isotypes; Immunoglobulins; Phylogeny; Reptiles; Vertebrates
PubMed: 25427250
DOI: 10.3390/biom4041045 -
Viruses Feb 2023Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these...
Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL/6 male and female mice. We focused on IgG2b, an isotype that lends to virus control and that has been previously shown to be elevated in murine females compared to males. Improvements in IgG2b serum levels, and/or IgG2b ratios with other non-IgM isotypes, were observed when: (i) wildtype (WT) female mice were compared to estrogen receptor knockout mice (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all higher in WT mice), (ii) unmanipulated female mice were compared to ovariectomized mice (IgG2b/IgA was higher in unmanipulated animals), (iii) female mice were supplemented with estrogen in the context of an inflammatory insult (IgG2b and IgG2b/IgG3 were improved by estrogen supplementation), and (iv) male mice were supplemented with testosterone, a hormone that can convert to estrogen in vivo (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all improved by supplementation). We next examined data from three sets of previously described male and female human blood samples. In each case, there were higher IgG2 levels, and/or ratios of IgG2 with non-IgM isotypes, in human females compared to males. The effects of sex and sex hormones in the mouse and human studies were subtle, but frequent, suggesting that sex hormones represent only a fraction of the factors that influence isotype patterns. Examination of the gene loci suggested that upregulation of murine IgG2b or human IgG2 could be mediated by estrogen receptor binding to estrogen response elements and cytosine-adenine (CA) repeats upstream of respective Cγ genes. Given that murine IgG2b and human IgG2 lend to virus control, the isotype biases in females may be sufficient to improve outcomes following vaccination or infection. Future attention to sex hormone levels, and consequent immunoglobulin isotype patterns, in clinical trials are encouraged to support the optimization of vaccine and drug products for male and female hosts.
Topics: Humans; Female; Male; Animals; Mice; Mice, Inbred C57BL; Testosterone; Receptors, Estrogen; Sex Characteristics; COVID-19; SARS-CoV-2; Immunoglobulin G; Estrogens; Mice, Knockout; Immunoglobulin A
PubMed: 36851695
DOI: 10.3390/v15020482 -
Toxins Jun 2012Antibody therapy remains the only effective treatment for toxin-mediated diseases. The development of hybridoma technology has allowed the isolation of monoclonal... (Review)
Review
Antibody therapy remains the only effective treatment for toxin-mediated diseases. The development of hybridoma technology has allowed the isolation of monoclonal antibodies (mAbs) with high specificity and defined properties, and numerous mAbs have been purified and characterized for their protective efficacy against different toxins. This review summarizes the mAb studies for 6 toxins--Shiga toxin, pertussis toxin, anthrax toxin, ricin toxin, botulinum toxin, and Staphylococcal enterotoxin B (SEB)--and analyzes the prevalence of mAb functions and their isotypes. Here we show that most toxin-binding mAbs resulted from immunization are non-protective and that mAbs with potential therapeutic use are preferably characterized. Various common practices and caveats of protection studies are discussed, with the goal of providing insights for the design of future research on antibody-toxin interactions.
Topics: Animals; Antibodies, Monoclonal; Humans; Immunoglobulin Isotypes; Toxins, Biological
PubMed: 22822456
DOI: 10.3390/toxins4060430 -
Blood Mar 2016Monoclonal antibody (mAb) therapeutics are revolutionizing cancer treatment; however, not all tumors respond, and agent optimization is essential to improve outcome. It... (Review)
Review
Monoclonal antibody (mAb) therapeutics are revolutionizing cancer treatment; however, not all tumors respond, and agent optimization is essential to improve outcome. It has become clear over recent years that isotype choice is vital to therapeutic success with agents that work through different mechanisms, direct tumor targeting, agonistic receptor engagement, or receptor-ligand blockade, having contrasting requirements. Here we summarize how isotype dictates mAb activity and discuss ways in which this information can be used for the development of enhanced therapeutics.
Topics: Antibodies, Monoclonal; Humans; Immunoglobulin Isotypes; Immunologic Factors; Models, Biological; Receptors, IgG; Vaccines
PubMed: 26764357
DOI: 10.1182/blood-2015-09-625343