The Transcriptional Profile of Follicular Lymphoma Associated Regulatory T-Cells (Tregs) Is More Consistent with Tregs Having a Germinal Center Localization and the Ability to Suppress Follicular Helper T-Cells
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Abstract Cr2 −/− mice have an impairment in humoral immunity, as shown by the decrease in the Ab titers against T cell-dependent Ags and abnormalities in germinal center formation. Germinal centers are present, but they are decreased in size and number, indicating problems in their development. In this study, we investigated whether this abnormality in germinal center development is associated with problems in the establishment of optimal affinity maturation and the generation of memory B cells, processes closely related to the germinal center reaction. We immunized the Cr2−/− animals with different Ags with or without adjuvants. We showed that, when immunized without adjuvants, complement receptors are absolutely required for optimal affinity maturation. Although limited affinity maturation is elicited in the Cr2−/− Ab response, it is decreased as compared with normal animals. Memory B cell generation is also impaired. In the presence of adjuvants, germinal center development in the Cr2−/− mice is still abnormal, as demonstrated by their decreased size and number. Surprisingly, adjuvants establish optimal affinity maturation and partially restore the amount of Ab produced during the primary response and memory B cell generation. However, adjuvants cannot improve the ability of follicular dendritic cells to retain Ags in the form of immune complexes. These observations indicate that immunization with inflammatory Ags offset some of the immunological abnormalities found in the Cr2−/− mice and show that optimal affinity maturation in the Cr2−/− mice can be achieved in the absence of normal germinal centers.
Affinity maturation
Memory B cell
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Affinity maturation
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Follicular dendritic cells
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Summary Pathogen exposure elicits production of high‐affinity antibodies stimulated by T follicular helper (Tfh) cells in the germinal center reaction. Tfh cells provide both costimulation and stimulatory cytokines to B cells to facilitate affinity maturation, class switch recombination, and plasma cell differentiation within the germinal center. Under normal circumstances, the germinal center reaction results in antibodies that precisely target foreign pathogens while limiting autoimmunity and excessive inflammation. In order to have this degree of control, the immune system ensures Tfh‐mediated B‐cell help is regulated locally in the germinal center. The recently identified T follicular regulatory (Tfr) cell subset can migrate to the germinal center and inhibit Tfh‐mediated B‐cell activation and antibody production. Although many aspects of Tfr cell biology are still unclear, recent data have begun to delineate the specialized roles of Tfr cells in controlling the germinal center reaction. Here we discuss the current understanding of Tfr‐cell differentiation and function and how this knowledge is providing new insights into the dynamic regulation of germinal centers, and suggesting more efficacious vaccine strategies and ways to treat antibody‐mediated diseases.
Affinity maturation
Follicular dendritic cells
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Affinity maturation
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Abstract The humoral immune response requires germinal centers to produce high-affinity antigen-specific antibodies that counter pathogens. Numerous studies have provided a better understanding of how metabolic pathways regulate the development, activation and functions of immune cells. Germinal centers are transient, highly dynamic microanatomic structures that develop in lymphoid organs during a T-cell-dependent humoral immune response. Analysis of germinal centers provides an opportunity to understand how metabolic programs control the differentiation and function of highly specialized germinal center B cells and follicular helper CD4 + T cells. Targeting immunometabolism during the germinal center response may afford the possibility to improve vaccine design and to develop new therapies to alleviate autoimmunity. In this review, we discuss the major metabolic pathways that are used by germinal center B and T cells, as well as the plasma cells that they produce, all of which are influenced by the microenvironment of this unique structure of the adaptive immune system.
Follicular dendritic cells
Affinity maturation
Humoral immunity
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A B-lymphocyte that has been activated to be receptive to Epstein Barr virus and is found in the area of a lymph nodule containing aggregations of actively proliferating lymphocytes.
Center (category theory)
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Using enzyme Immuno-hlstochemlcal method with horseradish peroxidase (HRP), a study on the relation between localization of antigen and antibody, and development of germinal center in lymph node after primary and secondary stimulation was made. Blastic antibody forming cells and intercellular localization of the antibody were noticed in newly formed germinal centers of draining lymph nodes within 7 days after primary antigenic stimulation. With increase of circulating antibodies produced by the draining lymph nodes, it accumulated in ready made germinal centers of generalized non-draining lymph nodes. At the time of primary stimulation, the HRP antigen was never observed in solid follicles or newly formed germinal centers, and even in ready made germinal centers it became localized only transiently and was never retained. After secondary stimulation, the antigen accumulated quickly in the light zone of germinal centers, being trapped by the previously present antibody. Three days later, antibody forming cells began to be noticed in germinal centers as well as in medullae of non-draining lymph nodes where no antibody forming cells had been so far observed, and in medullae of draining lymph nodes they increased markedly. Passively injected anti-HRP antibody accumulated also in germinal centers of non-primed mice and successively injected antigen was easily trapped in these germinal centers. Passively injected soluble antigen-antibody-complexes were localized in germinal centers of non-primed mice. In both these cases, antibody forming cells appeared only in germinal centers and none in medullae. Blastic cells, proliferating in germinal center and producing 2-ME sensitive antibody were not considered to be directly related with antibody forming cells in the medulla of lymph node.
Horseradish peroxidase
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Abstract Recent findings imply that germinal center paucity in old mice, at least in part, results from a defect in the mechanisms responsible for the transport of antigens to lymphoid nodules (follicles) and the consequent impairment of the antigen retaining reticulum (ARR) of follicular dendritic cells (FDCs). The present objective was to observe the kinetics of lymph node germinal center development in old mice having antigen transport and ARR deficits. Germinal center development was monitored in popliteal (PLN) and axillary (AXLN) lymph nodes of 6–;8 wk and 23‐mo‐old horseradish peroxidase (HRP) immune C57BL/6 mice. Using the selective binding of germinal center B cells for peanut agglutinin (PNA), germinal centers were identified in serial vibratome sections following histochemical labeling with PNA‐peroxidase conjugates at times 0, 15 min, 1, 3, 5, and 10 days after footpad challenge with 8 μg HRP. To follow the fate of preexisting (environmental antigen‐induced) germinal centers and the development of de novo (HRP‐induced) germinal centers, it was essential to distinguish between these germinal centers. Accordingly, PNA positive germinal centers associated with HRP‐retaining (peroxidase positive) ARR were identified as de novo germinal centers and germinal centers not associated with a peroxidase positive ARR were classified as preexisting germinal centers. Kinetic analysis of PNA positive germinal centers showed the following: (1) Preexisting, environmentally‐induced germinal centers dissociated and disappeared by day 3 as indicated by a decline in their numbers after antigen injection; the process of germinal center dissociation remained unaffected by aging. (2) The latency of de novo germinal center appearance was approximately equal in duration (∼3 days) to the disappearance of preexisting germinal centers. (3) The number and size of de novo HRP‐induced germinal centers increased through the experimental period in young lymph nodes, but in old mice these parameters were depressed, resulting in a significant germinal center deficit. (4) The ratio of HRP‐retaining ARR to de novo induced germinal centers was 1:1 in young and responder old mice. This ratio was not affected by aging. This finding favored the concept that antigen retention in ARR is a requirement of germinal center development. The observations supported our hypothesis that germinal center development, at least in part, depends on a normal antigen transport by showing that in aged mice with defective antigen transport‐related ARR and iccosome deficits there is an impaired development of germinal centers.
Follicular dendritic cells
Horseradish peroxidase
Affinity maturation
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We discuss the origin of two classes of germinal centers that have been observed during humoral immune responses: Some germinal centers develop very well and give rise to a large number of high affinity antibody producing plasma cells. Other germinal center reaction are very weak and the output production is practically absent. We propose an explanation for this nearly all-or-none behavior of germinal center reactions: The affinity of the seeder B-cells to the antigen is the critical parameter that determines the fate of the germinal center reaction. This hypothesis is verified in the framework of a space-time simulation of germinal center reactions.
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