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Pediatric Clinics of North America Oct 2019The most common primary immune deficiencies are those of the humoral immune system, and most of these present in childhood. The severity of these disorders ranges from... (Review)
Review
The most common primary immune deficiencies are those of the humoral immune system, and most of these present in childhood. The severity of these disorders ranges from transient deficiencies to deficiencies that are associated with a complete loss of ability to make adequate or functional antibodies, and have infectious as well as noninfectious complications. This article reviews, in a case-based discussion, the most common of the humoral immune deficiencies; their presentations, diagnoses, treatments; and, when known, the genetic defects.
Topics: Agammaglobulinemia; Antibody Formation; Child; Child, Preschool; Humans; Immunity, Humoral; Immunoglobulins; Immunologic Deficiency Syndromes; Infant; Infant, Newborn
PubMed: 31466679
DOI: 10.1016/j.pcl.2019.06.010 -
International Journal of Molecular... Aug 2020A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response... (Review)
Review
A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future.
Topics: Adaptive Immunity; Animals; Antibody Formation; Clinical Trials as Topic; Hepacivirus; Humans; T-Lymphocytes; Viral Vaccines
PubMed: 32781731
DOI: 10.3390/ijms21165644 -
Current Opinion in Organ Transplantation Aug 2014Human leukocyte antigen (HLA) antibodies are now recognized as being specific for epitopes which can be defined structurally with amino acid differences between HLA... (Review)
Review
PURPOSE OF REVIEW
Human leukocyte antigen (HLA) antibodies are now recognized as being specific for epitopes which can be defined structurally with amino acid differences between HLA alleles. This article addresses two general perspectives of HLA epitopes namely antigenicity, that is their reactivity with antibody and immunogenicity, that is their ability of eliciting an antibody response.
RECENT FINDINGS
Single-antigen bead assays have shown that HLA antibodies recognize epitopes that are equivalent to eplets or corresponding to eplets paired with other residue configurations. There is now a website-based Registry of Antibody-Defined HLA Epitopes (http://www.epregistry.com.br). Residue differences within eplet-defined structural epitopes may also explain technique-dependent variations in antibody reactivity determined in Ig-binding, C1q-binding and lymphocytotoxicity assays.HLA antibody responses correlate with the numbers of eplets on mismatched HLA antigens, and the recently proposed nonself-self paradigm of epitope immunogenicity may explain the production of epitope-specific antibodies.
SUMMARY
These findings support the usefulness of HLA matching at the epitope level, including the identification of acceptable mismatches for sensitized patients and permissible mismatching for nonsensitized patients aimed to reduce HLA antibody responses.
Topics: Animals; Antibodies; Antibody Formation; Antibody Specificity; Epitopes; HLA Antigens; Histocompatibility Testing; Humans
PubMed: 25010064
DOI: 10.1097/MOT.0000000000000100 -
European Journal of Pharmaceutics and... Dec 2019Both Gram-positive and Gram-negative bacteria can release nano-sized lipid bilayered structures, known as membrane vesicles (MVs). These MVs play an important role in... (Review)
Review
Both Gram-positive and Gram-negative bacteria can release nano-sized lipid bilayered structures, known as membrane vesicles (MVs). These MVs play an important role in bacterial survival by orchestrating interactions between bacteria and between bacteria and host. The major constituents of MVs are proteins, lipids and nucleic acids. Due to the immunogenicity of the membrane lipids and/or proteins of the MVs, in combination with adjuvant danger signals and the repeating patterns on the nanosized surface, MVs can effectively stimulate the innate and adaptive immune system. Since they are non-replicating, they are safer than attenuated vaccines. In addition, by genetic engineering of the donor cells, further improvements to their safety profile, immunogenicity and yield can be achieved. To date, one MV-based vaccine against Neisseria meningitidis (N. meningitidis) serogroup B was approved. Other (engineered) MVs in the pipeline study are mostly in the preclinical phase.
Topics: Adaptive Immunity; Adjuvants, Immunologic; Animals; Antibody Formation; Bacteria; Bacterial Proteins; Humans; Lipid Bilayers; Membrane Lipids; Membranes; Vaccines
PubMed: 31560955
DOI: 10.1016/j.ejpb.2019.09.021 -
Frontiers in Immunology 2020The continuous development of molecular biology and protein engineering technologies enables the expansion of the breadth and complexity of protein therapeutics for... (Review)
Review
The continuous development of molecular biology and protein engineering technologies enables the expansion of the breadth and complexity of protein therapeutics for administration. However, the immunogenicity and associated development of antibodies against therapeutics are a major restriction factor for their usage. The B cell follicular and particularly germinal center areas in secondary lymphoid organs are the anatomical sites where the development of antibody responses against pathogens and immunogens takes place. A growing body of data has revealed the importance of the orchestrated function of highly differentiated adaptive immunity cells, including follicular helper CD4 T cells and germinal center B cells, for the optimal generation of these antibody responses. Understanding the cellular and molecular mechanisms mediating the antibody responses against therapeutics could lead to novel strategies to reduce their immunogenicity and increase their efficacy.
Topics: Animals; Antibody Formation; Antigens; B-Lymphocytes; Drug Therapy; Germinal Center; Humans; Immunity, Humoral; Lymph Nodes; Mice
PubMed: 32477334
DOI: 10.3389/fimmu.2020.00791 -
Expert Review of Clinical Immunology Jun 2018Antibodies or fusion proteins termed biologics allow the targeted therapy of diseases. Many of these agents have proven superior efficacy and safety to conventional... (Review)
Review
Antibodies or fusion proteins termed biologics allow the targeted therapy of diseases. Many of these agents have proven superior efficacy and safety to conventional therapies, and subsequently revolutionized the management of numerous chronic diseases. Repetitive administration of these protein-based therapeutics to immunocompetent patients elicit immune responses in the form of Anti Drug Antibodies (ADAs), which in turn impact their pharmacological properties and may trigger adverse events. Areas covered: Structural characteristics determining the immunogenicity of biologics are reviewed along with strategies to minimize it. Next, the different types of treatment-emerging ADAs, their potential clinical implications, and assays to detect them are addressed. Emphasis is put on the review of data on the immunogenicity of different types of biologics across numerous indications. Finally, practical considerations are discussed on how to manage patients with issues around the immunogenicity of their biologic treatment. Expert commentary: Immunogenicity is a clinically relevant criterion when selecting a biologic. Besides intrinsic properties of the agent (namely its structure), its respective mode of action, dosing regimen, comedication, and the indication treated must be considered. ADA detection assays need to be standardized to improve comparability of available data and to allow clinical decision-making.
Topics: Antibody Formation; Biological Factors; Humans
PubMed: 29683362
DOI: 10.1080/1744666X.2018.1468753 -
Current Opinion in Organ Transplantation Oct 2022In antibody-mediated allograft rejection, donor-reactive antibodies cause transplant injury in part via complement activation. New mechanistic insights indicate... (Review)
Review
PURPOSE OF REVIEW
In antibody-mediated allograft rejection, donor-reactive antibodies cause transplant injury in part via complement activation. New mechanistic insights indicate complement also modulates development of humoral immune responses. Herein we review recent data that describes how complement affects antibody formation and we discuss therapeutic implications.
RECENT FINDINGS
Extravasating T cells interacting with integrins express and activate intracellular complement that drives immune-metabolic adaptations vital for CD4 + helper cells. Marginal zone B cells can acquire intact major histocompatibility complexes from dendritic cells via complement-dependent trogocytosis for presentation to T cells. Activated B cells in germinal centers receive co-stimulatory signals from T-helper cells. These germinal center B cells undergo coordinate shifts in surface complement regulator expression that permit complement receptor signaling on the germinal center B cells required for affinity maturation. The positively selected, high-affinity B cells can differentiate into plasma cells that produce donor-HLA-reactive antibodies capable of ligating endothelial, among other, graft cells. Subsequent sublytic complement attack can stimulate endothelial cells to activate CD4 + and CD8 + T cells, promoting cellular and humoral rejection. Newly developed complement inhibitors are being tested to prevent/treat transplant rejection.
SUMMARY
The complement system influences T-cell, B-cell and endothelial-cell activation, and thereby contributes allograft injury. Emerging therapeutic strategies targeting complement activation have the potential to prevent or abrogate transplant injury and improve transplant outcomes.
Topics: Antibody Formation; Complement System Proteins; Endothelial Cells; Graft Rejection; Humans; Isoantibodies
PubMed: 35857345
DOI: 10.1097/MOT.0000000000001002 -
Trends in Immunology Sep 2015Activation-induced cytidine deaminase (AID) mediates cytosine deamination and underlies two central processes in antibody diversification: somatic hypermutation and... (Review)
Review
Activation-induced cytidine deaminase (AID) mediates cytosine deamination and underlies two central processes in antibody diversification: somatic hypermutation and class-switch recombination. AID deamination is not exclusive to immunoglobulin loci; it can instigate DNA lesions in non-immunoglobulin genes and thus stringent checks are in place to constrain and restrict its activity. Recent findings have provided new insights into the mechanisms that target AID activity to specific genomic regions, revealing an involvement for noncoding RNAs associated with polymerase pausing and with enhancer transcription as well as genomic architecture. We review these findings and integrate them into a model for multilevel regulation of AID expression and targeting in immunoglobulin and non-immunoglobulin loci. Within this framework we discuss gaps in understanding, and outline important areas of further research.
Topics: Animals; Antibody Formation; Cytidine Deaminase; Gene Expression Regulation; Genetic Loci; Humans; Immunoglobulin Class Switching; Immunoglobulins; Protein Binding; Protein Interaction Domains and Motifs; Transcription Factors
PubMed: 26254147
DOI: 10.1016/j.it.2015.07.003 -
Cold Spring Harbor Protocols Oct 2021Ascitic fluid (also called ascites) is an intraperitoneal fluid extracted from mice that have developed a peritoneal tumor. For antibody production, the tumor is induced...
Ascitic fluid (also called ascites) is an intraperitoneal fluid extracted from mice that have developed a peritoneal tumor. For antibody production, the tumor is induced by injecting hybridoma cells into the peritoneum, which serves as a growth chamber for the cells. The hybridoma cells grow to high densities and continue to secrete the antibody of interest, thus creating a high-titered solution of antibodies for collection. A single mouse may yield as much as 10 mL of ascitic fluid or as little as 1 mL per batch. Antibody concentrations will typically be between 1 and 10 mg/mL. The most common problem encountered in storing ascites is contamination of these solutions with bacteria or fungi. This can be prevented by the addition of sodium azide.
Topics: Animals; Antibody Formation; Ascites; Ascitic Fluid; Hybridomas; Mice; Peritoneum
PubMed: 34599077
DOI: 10.1101/pdb.prot103309 -
Molecular Immunology Oct 2014Antibodies, forming immune complexes with their specific antigen, can cause complete suppression or several 100-fold enhancement of the antibody response. Immune... (Review)
Review
Antibodies, forming immune complexes with their specific antigen, can cause complete suppression or several 100-fold enhancement of the antibody response. Immune complexes containing IgG and IgM may activate complement and in such situations also complement components will be part of the immune complex. Here, we review experimental data on how antibodies via the complement system upregulate specific antibody responses. Current data suggest that murine IgG1, IgG2a, and IgG2b upregulate antibody responses primarily via Fc-receptors and not via complement. In contrast, IgM and IgG3 act via complement and require the presence of complement receptors 1 and 2 (CR1/2) expressed on both B cells and follicular dendritic cells. Complement plays a crucial role for antibody responses not only to antigen complexed to antibodies, but also to antigen administered alone. Lack of C1q, but not of Factor B or MBL, severely impairs antibody responses suggesting involvement of the classical pathway. In spite of this, normal antibody responses are found in mice lacking several activators of the classical pathway (complement activating natural IgM, serum amyloid P component (SAP), specific intracellular adhesion molecule-grabbing non-integrin R1 (SIGN-R1) or C-reactive protein. Possible explanations to these observations will be discussed.
Topics: Animals; Antibodies; Antibody Formation; Antigens; Complement System Proteins; Humans; Immunoglobulin M
PubMed: 25001046
DOI: 10.1016/j.molimm.2014.06.010