• Animal cells and systems
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• v.12 no.3
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• pp.127-136
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• 2008

Caspase-11 has been known as a dual regulator of cytokine maturation and apoptosis. Although the role of caspase-11 under pathological conditions has been well documented, its physiological role has not been studied much. In the present study, we investigated a possible physiological function of caspase-11 during immune response. In the absence of caspase-11, immunized spleen displayed increased cellularity and abnormal germinal center structure with disrupted microarchitecture. The rate of cell proliferation and apoptosis in the immunized spleen was not changed in the caspase-11-deficient mice. Furthermore, the caspase-11-deficient peritoneal macrophages showed normal phagocytotic activity. However, caspase-11-/-splenocytes and macrophages showed defective migrating capacity. The dysregulation of cell migration did not seem to be mediated by caspase-3, interleukin-$1{\alpha}$ or interleukin-$1{\beta}$ which acts downstream of caspase-11. These results suggest that a direct regulation of immune cell migration by caspase-11 is critical for the formation of germinal center microarchitecture during immune response. However, humoral immunity in the caspase-11-deficient mice was normal, suggesting the formation of germinal center structure is not essential for the affinity maturation of the antibodies.

• Korean Journal of Veterinary Research
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• v.1 no.1
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• pp.54-60
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• 1961

For the purpose of investigating seasonal changes of germinal centers of splenic lymph nodules and of blood lymphocytes of ducks, the spleens of 8 ducks from a flock were observed histologically every season; 2 cases in spring (March and April), 2 in summer (July and August), 2 in autumn (October and November) and 2 in winter (December and January). Blood cells of 8 ducks from the same flock also were counted during the summer (from July to August) and autumn (from October to November) The results obtained were summarized as follows: 1. There were seasonal changes in the germinal centers of lymph nodules, that is, the germinal centers were formed in spring and disappeared in autumn. In summer these were at the stage of transition from formation in spring to disappearance in autumn. In winter, on tile other hand. the process was reversed from the stage of disappearance in autumn to the stage of formation in spring. 2. The germinal center of splenic lymph nodule was encapsulated with a fibrous capsule which disappeared concommitantly with its germinal center. 3. The percentage and absolute value of lymphocytes in autumn were higher than those in summer, the fact that seemed to be not in agreement with Flemming's view that the lymphocytic clear germinal center may be functionally at the stage of lymphocyte formation, but in agreement with Maximow's view that the large lymphocytic clear germinal center is functionally at the stage of resting and medium-sized lymphocytic germinal center may be functionally at the stage of lympocyte formatiom.

• BMB Reports
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• v.29 no.2
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• pp.127-132
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• 1996

Germinal centers (GCs) are formed in peripheral lymphoid tissues in response to protein antigens. In order to see if immunoglobulin isotype switching takes place in GC B-cells, we isolated GC B-cells (PNA positive cells) from mouse popliteal lymph nodes by a flow cytometer after the staining of lymph node cells with PNA-FITC and anti-B220-PE, and determined the expression of ${\gamma}1$ germline transcript and ${\gamma}1$ mRNA by RT-PCR. ${\gamma}1$ germline transcript and ${\gamma}1$ mRNA were amplified specifically in cDNAs from hybridoma expressing IgG1 or splenocytes stimulated LPS plus IL-4. Germinal center B-cells formed in popliteal lymph nodes of mice immunized with chicken ovalbumin were isolated 7 days after immunization. We sorted GC B-cells five times. Immunoglobulin ${\gamma}1$ germline transcripts were expressed in germinal center B-cells in three out of five sorts whereas two out of five sorts did not express ${\gamma}1$ germline transcripts in GC B-cells. The contents of GC B-cells ranged from 5 to 7% of total lymph node cells in most flow cytometric analyses but those of two sorted cells which did not express ${\gamma}1$ germline transcripts were out of normal range. These results imply that isotype switching of immunoglobulins may take place in GCs.

• Hanyang Medical Reviews
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• v.33 no.1
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• pp.10-16
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• 2013

Follicular helper T cells (Tfh) play a significant role in providing T cell help to B cells during the germinal center reaction, where somatic hypermutation, affinity maturation, isotype class switching, and the differentiation of memory B cells and long-lived plasma cells occur. Antigen-specific T cells with IL-6 and IL-21 upregulate CXCR5, which is required for the migration of T cells into B cell follicles, where these T cells mature into Tfh. The surface markers including PD-1, ICOS, and CD40L play a significant role in providing T cell help to B cells. The upregulation of transcription factor Bcl-6 induces the expression of CXCR5, which is an important factor for Tfh differentiation, by inhibiting the expression of other lineage-specific transcription factors such as T-bet, GATA3, and RORγt. Surprisingly, recent evidence suggests that CD4 T cells already committed to Th1, Th2, and Th17 cells obtain flexibility in their differentiation programs by downregulating T-bet, GATA3, and RORγt, upregulating Bcl-6 and thus convert into Tfh. Limiting the numbers of Tfh within germinal centers is important in the regulation of the autoantibody production that is central to autoimmune diseases. Recently, it was revealed that the germinal center reaction and the size of the Tfh population are also regulated by thymus-derived follicular regulatory T cells (Tfr) expressing CXCR5 and Foxp3. Dysregulation of Tfh appears to be a pathogenic cause of autoimmune disease suggesting that tight regulation of Tfh and germinal center reaction by Tfr is essential for maintaining immune tolerance. Therefore, the balance between Tfh and Tfr appears to be a critical peripheral tolerance mechanism that can inhibit autoimmune disorders.

• Biomolecules & Therapeutics
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• v.24 no.3
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• pp.244-251
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• 2016

Understanding the developmental mechanisms of humoral immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by providing IL-21 and ICOS costimulation to activated B cells. However, the regulation of Tfh cell responses against intranasal antigens remains unclear. Here, we found that the generation of Tfh cells and germinal center B cells in the bronchial lymph node against intranasal proteinase antigens was independent of $TGF-{\beta}$. In contrast, administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE specific for the intranasal antigens. Cotransfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate that T cell-intrinsic STAT3 is required for the generation of Tfh cells to intranasal antigens and that targeting STAT3 might be an effective approach to ameliorate antibody-mediated pathology in the lung.

• Molecules and Cells
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• v.38 no.3
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• pp.195-201
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• 2015

Antibodies are powerful defense tools against pathogens but may cause autoimmune diseases when erroneously directed toward self-antigens. Thus, antibody producing cells are carefully selected, refined, and expanded in a highly regulated microenvironment (germinal center) in the peripheral lymphoid organs. A subset of T cells termed T follicular helper cells (Tfh) play a central role in instructing B cells to form a repertoire of antibody producing cells that provide life-long supply of high affinity, pathogenspecific antibodies. Therefore, understanding how Tfh cells arise and how they facilitate B cell selection and differentiation during germinal center reaction is critical to improve vaccines and better treat autoimmune diseases. In this review, I will summarise recent findings on molecular and cellular mechanisms underlying Tfh generation and function with an emphasis on T cell costimulation.

• Journal of Korean Neurosurgical Society
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• v.56 no.4
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• pp.334-337
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• 2014

Objective : The purpose of this study is to identify the risk factors associated with the development of germinal matrix-intraventricular hemorrhage (GM-IVH) and the relationship of the severity of disease and prematurity. Methods : A total of 168 premature neonates whose birth weight ${\leq}1500g$ or gestational age ${\leq}34$ weeks were examined by cranial ultrasound (CUS) for detection of GM-IVH among the babies admitted between January 2011 and December 2012 in our medical center neonatal intensive care unit. The babies were divided into two groups : GM-IVH and non-IVH. Clinical presentations, precipitating factors of the patients and maternal factors were analyzed. Results : In univariate analysis, gestational age, birth weight, delivery method, presence of premature rupture of membrane (PROM) and level of sodium and glucose were statistically meaningful factors (p<0.05). But only two factors, gestational age and presence of patent ductus arteriosus (PDA) were statistically meaningful in multivariate logistic regression (p<0.05). Delivery method [normal vaginal delivery (NVD) to Caeserean section] was borderline significant (p<0.10). Conclusion : Presence of PDA and gestational age were the important risk factors associated with development of GM-IVH.

• BMB Reports
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• v.39 no.5
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• pp.586-594
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• 2006

Germinal centers (GCs) have been identified as site at which the somatic mutation of immunoglobulins occurs. However, somatic mutations in immunoglobulins have also been observed in animals that normally do not harbor germinal centers. This clearly indicates that somatic mutations can occur in the absence of germinal centers. We therefore attempted to determine whether or not GCs exist in TNFR1-deficient mice, and are essential for the somatic mutation of immunoglobulins, using (4-hydroxy-3-nitropheny)acetyl-ovalbumin (NP-OVA). Both wild-type and TNFR1-deficient mice were immunized with NPOVA, and then examined with regard to the existence of GCs. No typical B-cell follicles were detected in the TNFR1-deficient mice. Cell proliferation was detected throughout all splenic tissue types, and no in vivo immune-complex retention was observed in the TNFR1-deficient mice. All of these data strongly suggest that no GCs were formed in the TNFR1-deficient mice. Although TNFR1-deficient mice are unable to form GCs, serological analyses indicated that affinity maturation had been achieved in both the wild-type and TNFR1-deficient mice. We therefore isolated and sequenced several DNA clones from wild-type and the TNFR1-deficient mice. Eight out of 12 wild-type clones, and 11 out of 14 clones of the TNFR-1-deficient mice contained mutations at the CDR1 site. Thus, the wild-type and TNFR1-deficient mice were not extremely different with regard to types and rates of somatic mutation. Also, high-affinity antibodies were detected in both types of mice. Collectively, our data appear to show that affinity maturation may occur in TNFR1-deficient mice, which completely lack GCs.

• IMMUNE NETWORK
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• v.3 no.3
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• pp.176-181
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• 2003

Background: The molecular basis of follicular dendritic cells (FDC)-germinal center (GC) B cell interaction is largely unknown, although this cellular interaction is thought to be important for the whole process of GC B cell differentiation. Methods: Using FDC-like cells, HK, and highly purified GC B cells, we attempted to identify the molecules that play critical roles in the interactions between FDC and B cells. GC B cells were co-cultured with HK cells and soluble CD154 in the presence or absence of various function-blocking monoclonal antibodies to examine their effect on GC B cell binding to HK cells and B cell proliferation. Results: Anti-CD11a and anti-CD54 antibodies inhibited GC B cell binding to HK cells while anti-CD49d and anti-CD106 antibodies did not. GC B cell proliferation was not impaired by the disruption of GC B cell-HK cell adherence. Conclusion: Our results suggest that CD11a/CD18-CD54 interactions play an important roles in the initial binding of GC B cells to FDC and diffusible growth factors from FDC may be responsible the massive proliferation of GC B cells.

• IMMUNE NETWORK
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• v.14 no.5
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• pp.227-236
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• 2014

Understanding germinal center reactions is crucial not only for the design of effective vaccines against infectious agents and malignant cells but also for the development of therapeutic intervention for the treatment of antibody-mediated immune disorders. Recent advances in this field have revealed specialized subsets of T cells necessary for the control of B cell responses in the follicle. These cells include follicular regulatory T cells and Qa-1-restricted cluster of differentiation $(CD)8^+$ regulatory T cells. In this review, we discuss the current knowledge related to the role of regulatory T cells in the B cell follicle.