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Frontiers in Immunology 2019The germinal center reaction is an important target for modulating antibody responses. Antibody production from germinal centers is regulated by a negative feedback...
The germinal center reaction is an important target for modulating antibody responses. Antibody production from germinal centers is regulated by a negative feedback mechanism termed antibody feedback. By imposing antibody feedback, germinal centers can interact and regulate the output of other germinal centers. Using an agent-based model of the germinal center reaction, we studied the impact of antibody feedback on kinetics and efficiency of a germinal center. Our simulations predict that high feedback of antibodies from germinal centers reduces the production of plasma cells and subsequently the efficiency of the germinal center reaction by promoting earlier termination. Affinity maturation is only weakly improved by increased antibody feedback and ultimately interrupted because of premature termination of the reaction. The model predicts that the asynchronous onset and changes in number of germinal centers could alter the efficiency of antibody response due to changes in feedback by soluble antibodies. Consequently, late initialized germinal centers have a compromised output due to higher antibody feedback from the germinal centers formed earlier. The results demonstrate potential effects of germinal center intercommunication and highlight the importance of understanding germinal center interactions for optimizing the antibody response, in particular, in the elderly and in the context of vaccination.
Topics: Animals; Antibody Formation; Feedback, Physiological; Germinal Center; Humans; Models, Immunological
PubMed: 31555300
DOI: 10.3389/fimmu.2019.02116 -
Cancer Control : Journal of the Moffitt... 2000The prime function of the immune system is to protect the entire organism from a variety of insults and illnesses, including the development of cancer. The question of... (Review)
Review
BACKGROUND
The prime function of the immune system is to protect the entire organism from a variety of insults and illnesses, including the development of cancer. The question of how age-related declines in immune function contribute to an increasing incidence of malignancies continues to be a focus of discussion and speculation.
METHODS
The recent literature from the National Library of Medicine database (1990 through the present) was searched for articles using the medical subject headings (MeSH terms) of aging, immunity, cancer, senescence, and apoptosis. Bibliographies of articles retrieved were also scanned.
RESULTS
Data from in vitro and in vivo animal and human studies demonstrate clear age-related alterations in both the cellular and humoral components of the immune system, but there is little evidence supporting direct causal links between immune senescence and most malignancies.
CONCLUSIONS
Senescent decline in immune surveillance leads to the accumulation of cellular and DNA mutations that could be a significant factor in the development of malignancy and programmed cell death or apoptosis observed in the elderly.
Topics: Aged; Aging; Animals; Antibody Formation; Female; Humans; Immunity, Cellular; Male; Neoplasms; Prognosis; Risk Assessment; Survival Analysis
PubMed: 11088060
DOI: 10.1177/107327480000700603 -
Applied Biochemistry and Biotechnology Feb 2013Currently, mammalian cell technology has become the focus of biopharmaceutical production, with strict regulatory scrutiny of the techniques employed. Major concerns...
Currently, mammalian cell technology has become the focus of biopharmaceutical production, with strict regulatory scrutiny of the techniques employed. Major concerns about the presence of animal-derived components in the culture media led to the development of serum-free (SF) culture processes. However, cell adaptation to SF conditions is still a major challenge and limiting step of process development. Thus, this study aims to assess the impact of SF adaptation on monoclonal antibody (mAb) production, identify the most critical steps of cell adaptation to the SF EX-CELL medium, and create basic process guidelines. The success of SF adaptation was dependent on critical steps that included accentuated cell sensitivity to common culture procedures (centrifugation, trypsinization), initial cell concentration, time given at each step of serum reduction, and, most importantly, medium supplements used to support adaptation. Indeed, only one of the five supplement combinations assessed (rhinsulin, ammonium metavanadate, nickel chloride, and stannous chloride) succeeded for the Chinese hamster ovary-K1 cell line used. This work also revealed that the chemically defined EX-CELL medium benefits mAb production in comparison with the general purpose Dulbecco's Modified Eagle's Medium, but the complete removal of serum attenuates these positive effects.
Topics: Animals; Antibodies, Monoclonal; Antibody Formation; CHO Cells; Cricetinae; Cryopreservation; Culture Media, Serum-Free
PubMed: 23306891
DOI: 10.1007/s12010-012-0068-z -
International Immunology Mar 2019Nuclear hormone receptors including the estrogen receptor (ERα) and the retinoic acid receptor regulate a plethora of biological functions including reproduction,...
Nuclear hormone receptors including the estrogen receptor (ERα) and the retinoic acid receptor regulate a plethora of biological functions including reproduction, circulation and immunity. To understand how estrogen and other nuclear hormones influence antibody production, we characterized total serum antibody isotypes in female and male mice of C57BL/6J, BALB/cJ and C3H/HeJ mouse strains. Antibody levels were higher in females compared to males in all strains and there was a female preference for IgG2b production. Sex-biased patterns were influenced by vitamin levels, and by antigen specificity toward influenza virus or pneumococcus antigens. To help explain sex biases, we examined the direct effects of estrogen on immunoglobulin heavy chain sterile transcript production among purified, lipopolysaccharide-stimulated B cells. Supplemental estrogen in B-cell cultures significantly increased immunoglobulin heavy chain sterile transcripts. Chromatin immunoprecipitation analyses of activated B cells identified significant ERα binding to estrogen response elements (EREs) centered within enhancer elements of the immunoglobulin heavy chain locus, including the Eµ enhancer and hypersensitive site 1,2 (HS1,2) in the 3' regulatory region. The ERE in HS1,2 was conserved across animal species, and in humans marked a site of polymorphism associated with the estrogen-augmented autoimmune disease, lupus. Taken together, the results highlight: (i) the important targets of ERα in regulatory regions of the immunoglobulin heavy chain locus that influence antibody production, and (ii) the complexity of mechanisms by which estrogen instructs sex-biased antibody production profiles.
Topics: Animals; Antibody Formation; Binding Sites; Enhancer Elements, Genetic; Immunoglobulin Heavy Chains; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Receptors, Estrogen; Response Elements; Sex Characteristics
PubMed: 30407507
DOI: 10.1093/intimm/dxy074 -
Medecine Sciences : M/S Dec 2019Monoclonal antibodies have revolutionized the treatment of many diseases, but their clinical effectiveness remains limited in some cases. Associations of antibodies... (Review)
Review
Monoclonal antibodies have revolutionized the treatment of many diseases, but their clinical effectiveness remains limited in some cases. Associations of antibodies binding to the same target (homo-combination) or to several different targets (hetero-combination), thereby mimicking a polyclonal humoral immune response, have demonstrated a therapeutic improvement in pre-clinical and clinical trials, mainly in the field of oncology and infectious diseases. The combinations increase the efficacy of the biological responses and override resistance mechanisms observed with antibody monotherapy. The most common method of formulating and administering antibody combinations is a separate formulation, with sequential injection of each antibody as individual drug substance. Alternatively, combined formulations are developed where the separately-produced antibodies are mixed before administration or produced simultaneously by a single cell line, or a mixture of cell lines as a polyclonal master cell bank. The regulation, the toxicity and the injection sequence of these oligoclonal antibody-based mixtures remain points to be clarified and optimized for a better therapeutic effect.
Topics: Animals; Antibodies, Monoclonal; Antibody Formation; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Communicable Diseases; Drug Combinations; Humans; Immunity, Humoral; Immunotherapy; Molecular Mimicry; Neoplasms; Oligoclonal Bands
PubMed: 31903921
DOI: 10.1051/medsci/2019216 -
Immunology Feb 1967A study was carried out on the function of macrophages in inducing antibody production to Shigella antigen, and on the effect of X-irradiation on the `immunogenic'...
A study was carried out on the function of macrophages in inducing antibody production to Shigella antigen, and on the effect of X-irradiation on the `immunogenic' function of macrophages. Peritoneal macrophages, which had been incubated with Shigella and then injected into mice exposed to 550 r, triggered the formation of agglutinating antibody in animals which did not respond to the injection of the antigen alone. The antibody formed was not produced by `contaminating' lymphocytes of the peritoneal exudate, since: (a) lymph node cells at doses higher than those of the macrophage inocula did not produce antibody when treated and injected under similar conditions, and (b) lymphocyte-free macrophage populations, obtained by culturing cells of peritoneal exudates, triggered the production of antibody when injected in to X-irradiated recipients after interaction with the antigen. Macrophages from irradiated donors incubated with Shigella were incapable of inducing antibody formation in X-irradiated mice. Animals exposed to higher doses of irradiation (900 r) did not produce antibody following injection of macrophage—antigen complexes. It was, therefore, concluded that macrophages from normal animals elicited the production of antibody by the lymphoid cells of the irradiated recipients.
Topics: Animals; Antibody Formation; Culture Techniques; Female; Lymphocytes; Macrophages; Mice; Radiation Injuries, Experimental; Shigella
PubMed: 6020122
DOI: No ID Found -
The Journal of Experimental Medicine Mar 2014Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found...
Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found in RA patients; they interact with cartilage in vivo and are often highly pathogenic in the mouse. Autoreactivity to CII is directed to multiple epitopes and conserved between mice and humans. We have previously mapped the antibody response to CII in a heterogeneous stock cohort of mice, with a strong association with the IgH locus. We positioned the genetic polymorphisms and determined the structural requirements controlling antibody recognition of one of the major CII epitopes. Polymorphisms at positions S31R and W33T of the associated variable heavy chain (VH) allele were identified and confirmed by gene sequencing. The Fab fragment binding the J1 epitope was crystallized, and site-directed mutagenesis confirmed the importance of those two variants for antigen recognition. Back mutation to germline sequence provided evidence for a preexisting recognition of the J1 epitope. These data demonstrate a genetic association of epitope-specific antibody responses with specific VH alleles, and it highlights the importance of germline-encoded antibodies in the pathogenesis of antibody-mediated autoimmune diseases.
Topics: Animals; Antibody Formation; Arthritis, Rheumatoid; Autoantibodies; Base Sequence; Collagen Type II; Crystallography; Epitopes; Humans; Immunoglobulin Heavy Chains; Mice; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Polymorphism, Genetic; Protein Conformation; Sequence Analysis, DNA; Surface Plasmon Resonance
PubMed: 24534192
DOI: 10.1084/jem.20130968 -
Annals of Medicine Dec 1995In reviewing the available evidence, the involvement of an immunological mechanism behind hypertension has been proposed. However, whether altered immunological function... (Review)
Review
In reviewing the available evidence, the involvement of an immunological mechanism behind hypertension has been proposed. However, whether altered immunological function is a primary factor in the pathogenesis of hypertension or secondary to tissue damage of vascular beds induced by hypertension is still poorly defined. A major difficulty has been the relative paucity of information about the nature of specific immune targets which initiate and perpetuate abnormal immune responses in hypertension. This article will discuss the status of understanding of the involvement of immunological factors in both clinical and experimental hypertension.
Topics: Antibody Formation; Autoimmunity; Disease Susceptibility; GTP-Binding Proteins; HLA Antigens; Humans; Hypertension; Immunity, Cellular
PubMed: 8652147
DOI: 10.3109/07853899509019254 -
The Journal of Experimental Medicine Jan 1967The present studies have shown that the influence of X-irradiation on the secondary antibody response in vitro is remarkably similar to its effect on the primary...
The present studies have shown that the influence of X-irradiation on the secondary antibody response in vitro is remarkably similar to its effect on the primary response in vivo. When sensitized tissue was first irradiated and then reexposed to antigen, the duration of the interval between irradiation and antigen addition determined the degree of inhibition of the secondary response obtained. A delay of 12 hr resulted in stronger inhibition than a delay of 6 hr, and an interval of 24 hr before reexposure to antigen caused complete suppression of antibody production to diphtheria toxoid and almost complete suppression when sheep RBC were used as the antigen. Induction of the secondary response in rabbit lymph node tissue in vitro followed by exposure to X-irradiation, revealed that immediate exposure to irradiation after antigen produced stronger inhibition of the subsequent response than irradiation on days 2-3. Irradiation on day 6 had no detectable effect. The effectiveness of the early radiation is probably due to prevention of the proliferation of the antibody-forming cells. BUDR was found to be effective at similar time periods as X-irradiation, whereas colchicine could still stop antibody formation when added late during the secondary response in vitro. It was noted that lymph nodes from some BSA-sensitized rabbits as late as 18 months after sensitization gave a response indistinguishable from a typical secondary response, even when not reexposed to antigen.
Topics: Animals; Antibody Formation; Bromodeoxyuridine; Colchicine; Culture Techniques; Diphtheria Toxoid; Lymph Nodes; Rabbits; Radiation Effects; Serum Albumin, Bovine; gamma-Globulins
PubMed: 4163360
DOI: 10.1084/jem.125.1.33 -
The Journal of Experimental Medicine Dec 1970Rabbits were immunized to two antigens and 18-55 days later exchange transfusion was performed using blood of rabbits immunized to one antigen only. By this means, serum...
Rabbits were immunized to two antigens and 18-55 days later exchange transfusion was performed using blood of rabbits immunized to one antigen only. By this means, serum antibody levels to one antigen were reduced 50-84% while maintaining serum antibody levels to the second antigen. After exchange, serum antibody levels of the removed antibody rose rapidly for 24-48 hr and then more slowly, reaching peak titers an average of 8 days later. The peak titer was 48-222% higher than the preexchange titer. The specificity of this rebound excluded as a cause nonspecific changes in Ig levels. Passive administration of antibody to a third antigen 4-7 days before the exchange indicated that re-equilibration of preformed antibody was not a major factor in the rebound. A change in the ratio of IgM to IgG antibodies as a cause of an increased neutralization titer in the postexchange sera was also excluded. It was therefore suggested that a change in the rate of antibody formation had occurred, although other changes in the quality of serum antibody were not excluded.
Topics: Animals; Antibodies; Antibody Formation; Antibody Specificity; Exchange Transfusion, Whole Blood; Immunity, Active; Immunity, Maternally-Acquired; Rabbits
PubMed: 5511573
DOI: 10.1084/jem.132.6.1279