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Life Science Alliance Mar 2022Antibody secreting cells (ASCs) circulate after vaccination and infection and migrate to the BM where a subset known as long-lived plasma cells (LLPCs) persists and...
Antibody secreting cells (ASCs) circulate after vaccination and infection and migrate to the BM where a subset known as long-lived plasma cells (LLPCs) persists and secrete antibodies for a lifetime. The mechanisms by which circulating ASCs become LLPCs are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared with BM LLPCs. Compared with blood ASCs, BM LLPCs have decreased nucleus/cytoplasm ratio but increased endoplasmic reticulum and numbers of mitochondria. LLPCs up-regulate pro-survival genes , , and while simultaneously down-regulating pro-apoptotic genes , , and Consistent with reduced gene expression, the pro-apoptotic gene loci are less accessible in LLPCs. Of the pro-survival genes, only is concordant in gene up-regulation and loci accessibility. Using a novel in vitro human BM mimetic, we show that blood ASCs undergo similar morphological and molecular changes that resemble ex vivo BM LLPCs. Overall, our study demonstrates that early-minted blood ASCs in the BM microniche must undergo morphological, transcriptional, and epigenetic changes to mature into apoptotic-resistant LLPCs.
Topics: Adolescent; Adult; Antibody Formation; Apoptosis; Biomarkers; Cell Survival; Epigenesis, Genetic; Female; Gene Expression Regulation; Genetic Heterogeneity; Genomic Imprinting; Histocytochemistry; Humans; Immunophenotyping; Male; Middle Aged; Plasma Cells; Time Factors; Young Adult
PubMed: 34952892
DOI: 10.26508/lsa.202101285 -
Nature Communications Oct 2021Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection,...
Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection, however large-scale representative studies are limited. Here we estimated antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as 'non-responders' not developing anti-spike antibodies, who were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
Topics: Adult; Aged; Antibodies, Viral; Antibody Formation; Bayes Theorem; COVID-19; Female; Humans; Immunoglobulin G; Male; Middle Aged; SARS-CoV-2
PubMed: 34716320
DOI: 10.1038/s41467-021-26479-2 -
Annals of Surgery Aug 1991An intriguing and increasingly understood facet of immune responses is the ability of a recipient to destroy a foreign tissue or organ graft. The phenomenon of acute... (Review)
Review
An intriguing and increasingly understood facet of immune responses is the ability of a recipient to destroy a foreign tissue or organ graft. The phenomenon of acute rejection of an allograft involves a series of complex and inter-related cellular and humoral events, culminating in graft death. Some of the current thinking surrounding this phenomenon is reviewed.
Topics: Animals; Antibody Formation; Graft Rejection; Humans; Immunity, Cellular; Lymphocytes; Transplantation, Homologous
PubMed: 1867525
DOI: 10.1097/00000658-199108000-00002 -
American Journal of Transplantation :... Jun 2003According to the humoral theory of transplantation, antibodies cause allograft rejection. Publications are cited showing that antibodies: (1). cause hyperacute kidney... (Review)
Review
According to the humoral theory of transplantation, antibodies cause allograft rejection. Publications are cited showing that antibodies: (1). cause hyperacute kidney rejection, (2). lead to C4d deposits associated with early kidney graft failures, (3). are a good indicator of presensitization leading to early acute rejections, (4). were present in 96% of 826 patients who rejected a kidney graft, (5). are associated with chronic rejection in 33 studies of kidney, heart, lung and liver grafts, and (6). in three studies, appeared in the circulation BEFORE evidence of bronchiolitis obliterans in lung transplants, and BEFORE kidney rejection. In addition, a prospective cooperative study of 1629 patients in 24 centers demonstrated that antibodies foretold subsequent failures after a follow-up period of 6 months (p = 0.05). The specificity of antibodies detected in the serum of rejecting patients were often not donor specific, presumably because they were absorbed by the rejecting organ. If the humoral theory is accepted, even provisionally, transplanted patients who have antibodies could be treated with immunosuppression until the antibodies disappear to determine whether chronic rejection can be blocked. If successful, in patients who do not have antibodies, immunosuppression could be reduced until antibodies appear.
Topics: Antibody Formation; Graft Rejection; HLA Antigens; Humans; Kidney Transplantation; Organ Transplantation
PubMed: 12780557
DOI: 10.1034/j.1600-6143.2003.00135.x -
Molecular Therapy : the Journal of the... Feb 2010Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid...
Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) has been effective in most patients with Pompe disease, but efficacy was reduced by high-titer antibody responses. Immunomodulatory gene therapy with a low dose adeno-associated virus (AAV) vector (2 x 10(10) particles) containing a liver-specific regulatory cassette significantly lowered immunoglobin G (IgG), IgG1, and IgE antibodies to GAA in Pompe disease mice, when compared with mock-treated mice (P < 0.05). AAV-LSPhGAApA had the same effect on GAA-antibody production whether it was given prior to, following, or simultaneously with the initial GAA injection. Mice given AAV-LSPhGAApA had significantly less decrease in body temperature (P < 0.001) and lower anaphylactic scores (P < 0.01) following the GAA challenge. Mouse mast cell protease-1 (MMCP-1) followed the pattern associated with hypersensitivity reactions (P < 0.05). Regulatory T cells (Treg) were demonstrated to play a role in the tolerance induced by gene therapy as depletion of Treg led to an increase in GAA-specific IgG (P < 0.001). Treg depleted mice were challenged with GAA and had significantly stronger allergic reactions than mice given gene therapy without subsequent Treg depletion (temperature: P < 0.01; symptoms: P < 0.05). Ubiquitous GAA expression failed to prevent antibody formation. Thus, immunomodulatory gene therapy could provide adjunctive therapy in lysosomal storage disorders treated by enzyme replacement.
Topics: Animals; Antibody Formation; Cell Line; Dependovirus; Enzyme Replacement Therapy; Enzyme-Linked Immunosorbent Assay; Genetic Therapy; Glycogen Storage Disease Type II; Humans; Mice; Mice, Inbred C57BL; alpha-Glucosidases
PubMed: 19690517
DOI: 10.1038/mt.2009.195 -
Eye (London, England) Sep 2019
Topics: Adaptive Immunity; Antibody Formation; Biological Products; Biological Therapy; Eye Diseases; Humans; Immune Privilege; Ophthalmology
PubMed: 30967643
DOI: 10.1038/s41433-019-0434-y -
Science Advances Apr 2020Activation-induced cytidine deaminase (AID) mediates immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM), critical processes for...
Activation-induced cytidine deaminase (AID) mediates immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM), critical processes for maturation of the antibody response. Epigenetic factors, such as histone deacetylases (HDACs), would underpin B cell differentiation stage-specific AID expression. Here, we showed that NAD-dependent class III HDAC sirtuin 1 (Sirt1) is highly expressed in resting B cells and down-regulated by stimuli inducing AID. B cell Sirt1 down-regulation, deprivation of NAD cofactor, or genetic Sirt1 deletion reduced deacetylation of promoter histones, Dnmt1, and nuclear factor-κB (NF-κB) p65 and increased AID expression. This promoted class-switched and hypermutated T-dependent and T-independent antibody responses or led to generation of autoantibodies. Genetic Sirt1 overexpression, Sirt1 boost by NAD, or allosteric Sirt1 enhancement by SRT1720 repressed AID expression and CSR/SHM. By deacetylating histone and nonhistone proteins (Dnmt1 and NF-κB p65), Sirt1 transduces metabolic cues into epigenetic changes to play an important B cell-intrinsic role in modulating antibody and autoantibody responses.
Topics: Animals; Antibody Formation; B-Lymphocytes; Biomarkers; Chromosomal Proteins, Non-Histone; Cytidine Deaminase; DNA Methylation; Epigenesis, Genetic; Humans; Immunophenotyping; Mice; Promoter Regions, Genetic; Sirtuin 1; T-Lymphocytes
PubMed: 32270032
DOI: 10.1126/sciadv.aay2793 -
Diabetes, Obesity & Metabolism Jul 2016We examined insulin antibody formation in patients with type 1 (T1D) or type 2 diabetes (T2D) treated with once-daily insulin degludec (IDeg) or insulin glargine (IGlar)... (Comparative Study)
Comparative Study
We examined insulin antibody formation in patients with type 1 (T1D) or type 2 diabetes (T2D) treated with once-daily insulin degludec (IDeg) or insulin glargine (IGlar) to evaluate the impact of antibody formation on efficacy and safety. Insulin antibodies were measured using subtraction radioimmunoassays in six phase IIIa clinical trials using IDeg (n = 2250) and IGlar (n = 1184). Spearman's correlation coefficient was used to evaluate associations between cross-reacting antibodies and change from baseline glycated haemoglobin (HbA1c) and insulin dose. IDeg- and IGlar-specific antibodies remained low [<1% bound/total radioactivity (B/T)] and with low levels of antibodies cross-reacting with human insulin in patients with T1D (<20% B/T) and T2D (<6% B/T). Spearman's correlation coefficients between insulin antibody levels and change in HbA1c or insulin dose were low in both treatment groups. No clinically meaningful differences in adverse event (AE) rates were observed in patients with >10% B/T or without an absolute increase in antibodies cross-reacting with human insulin. IDeg treatment resulted in few immunogenic responses in patients with T1D and T2D; antibody formation was not associated with change in HbA1c, insulin dose or rates of AEs.
Topics: Antibody Formation; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunity, Cellular; Insulin Antibodies; Insulin, Long-Acting; Randomized Controlled Trials as Topic
PubMed: 26663320
DOI: 10.1111/dom.12621 -
EMBO Molecular Medicine Mar 2018Human memory B cells and plasma cells represent a rich source of antibodies that have been selected in response to human pathogens. In the last decade, different methods...
Human memory B cells and plasma cells represent a rich source of antibodies that have been selected in response to human pathogens. In the last decade, different methods have been developed to interrogate the human memory repertoire and isolate monoclonal antibodies. I will discuss how a target-agnostic approach based on high-throughput screening of antibodies produced by cultured B cells and plasma cells has not only provided potent and broadly neutralizing antibodies against a range of pathogens, but has also advanced our understanding of basic aspects of the immune response, from host-pathogen interaction to the role of somatic mutations in affinity maturation and in the diversification of the antibody response. Most surprisingly, this approach has also revealed a new mechanism of diversification based on templated insertion of non-Ig DNA into antibody genes that we discovered in the context of the immune response to malaria infection.
Topics: Antibodies, Neutralizing; Antibody Formation; Humans; Mutation; Orthomyxoviridae; Polymorphism, Genetic; Receptors, Cell Surface; Vaccination
PubMed: 29363490
DOI: 10.15252/emmm.201808879 -
Philosophical Transactions of the Royal... Jun 2015Vaccines have revolutionized modern public health. The effectiveness of some vaccines is limited by the variation in response observed between individuals and across... (Review)
Review
Vaccines have revolutionized modern public health. The effectiveness of some vaccines is limited by the variation in response observed between individuals and across populations. There is compelling evidence that a significant proportion of this variability can be attributed to human genetic variation, especially for those vaccines administered in early life. Identifying and understanding the determinants of this variation could have a far-reaching influence upon future methods of vaccine design and deployment. In this review, we summarize the genetic studies that have been undertaken attempting to identify the genetic determinants of response heterogeneity for the vaccines against hepatitis B, measles and rubella. We offer a critical appraisal of these studies and make a series of suggestions about how modern genetic techniques, including genome-wide association studies, could be used to characterize the genetic architecture of vaccine response heterogeneity. We conclude by suggesting how the findings from such studies could be translated to improve vaccine effectiveness and target vaccination in a more cost-effective manner.
Topics: Antibody Formation; Communicable Diseases; Genetic Variation; Genome-Wide Association Study; Humans; Vaccines
PubMed: 25964463
DOI: 10.1098/rstb.2014.0341