Disease relevance of Germinal Center

• The AIDS disease of CD4C/HIV transgenic mice shows impaired germinal centers and autoantibodies and develops in the absence of IFN-gamma and IL-6 [1].
• Through this mechanism, BCL6 may facilitate the proliferative expansion of germinal centers during the normal immune response and, when deregulated, the pathological expansion of B cell lymphomas [2].
• CD77 is also a marker for germinal center B lymphocytes and Burkitt's lymphoma cells [3].
• Contrary to the expected outcome, mice deficient for both FasL and TNF had a substantially milder gld phenotype with regard to mortality, lymphoaccumulation, germinal center formation, and hypergammaglobulinemia [4].
• Together, these results indicate that patients with active lupus nephritis exhibit abnormalities in the peripheral B cell compartment that are consistent with intensive germinal center activity, are driven via CD154-CD40 interactions, and may reflect or contribute to the propensity of these patients to produce autoantibodies [5].

High impact information on Germinal Center

• MTA3 is expressed in the same pattern in germinal centers as BCL-6 [6].
• By sequencing V kappa Ox1 L-chains characteristic of phOx-specific antibodies, we show that somatic mutations accumulate in germinal center B cells and that a mutation conferring high affinity binding is found with increasing frequency [7].
• We have compared the diversification of the antigen-specific repertoire of B cells, both from within and from outside the germinal centers, during the murine response to 2-phenyloxazolone (phOx) [7].
• In mice injected with high-affinity turkey lysozyme, Cr2null B cells responded by follicular retention; however, they could not survive within germinal centers [8].
• Abundant RAG1 and RAG2 protein and messenger RNA was detected in the activated B cells that populate murine splenic and Peyer's patch germinal centers [9].

Chemical compound and disease context of Germinal Center

• As predicted, they are highly susceptible to challenge with an infectious agent (Candida albicans), are resistant to the lethality of minute doses of lipopolysaccharide (LPS) following D-galactosamine treatment, have a deficiency in granuloma development, and do not form germinal centers after immunization [10].
• Mice bearing a disrupted C3 locus (C3-/-) have an impaired Ab response to T-dependent Ags (bacteriophage phiX 174 and nuclear protein-keyhole limpet hemocyanin) characterized by a reduction in number and size of germinal centers and impaired retention of Ag by follicular dendritic cells [11].
• Transmembrane adaptor protein PAG, also known as Csk-binding protein (Cbp), which binds and activates the cytoplasmic tyrosine kinase Csk, the major negative regulator of Src-family kinases, was found to be expressed in germinal centers of lymphoid follicles as well as in follicular, but not mantle cell lymphomas [12].

Biological context of Germinal Center

• BCL-6 encodes a POZ/zinc finger transcriptional repressor that is required for germinal center formation and may influence apoptosis [13].
• Since Bcl-3 is required for germinal center formation, these results suggest functional similarities with the unrelated Bcl-6 oncoprotein in suppressing potential p53-dependent cell cycle arrest and apoptosis in response to somatic hypermutation and class switch recombination [14].
• In immunized mice with mutations in CD19 Y482 and Y513, early germinal center B cells appeared normal in phenotype and number, but maturation in the germinal center was defective [15].
• These results demonstrate that B7-mediated signaling plays a critical role in germinal center formation and immunoglobulin class switching in vivo [16].
• FLICE-inhibitory protein is a key regulator of germinal center B cell apoptosis [17].

Anatomical context of Germinal Center

• Additionally, spleens from Bcl-3(-/-) mice are abnormal and void of germinal centers [18].
• We generated LTbeta-deficient mice and found them to lack Peyer's patches, peripheral lymph nodes, splenic germinal centers, and follicular dendritic cells [19].
• Furthermore, C4BP colocalized with B cells in the germinal centers of human tonsils [20].
• Transgenic and CD40(-/-) mice were bred so that only the transgenic CD40 molecule is expressed in B cells, macrophages, and dendritic cells. mCD40-LMP1tg mice had normal lymphocyte subsets, and immunization elicited an antibody response featuring normal isotype switching, affinity maturation, and germinal center (GC) formation [21].
• Arrest of B lymphocyte terminal differentiation by CD40 signaling: mechanism for lack of antibody-secreting cells in germinal centers [22].

Associations of Germinal Center with chemical compounds

• In mice deficient in either lymphotoxin-alpha (LT-alpha) or the type I tumor necrosis factor (TNF) receptor, but not the type II TNF receptor, germinal centers failed to develop in peripheral lymphoid organs [23].
• Life and death in germinal centers (redux) [24].
• The serine/threonine kinase HPK1 is a member of the germinal center kinase (GCK) family that has been implicated in the regulation of MAP kinase pathways [25].
• In addition, germinal center cells isolated from C3-deficient mice produced a similar defect in isotype production [26].
• The presence of germinal centers was associated with decreased androgen levels [27].

Gene context of Germinal Center

• The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation [28].
• Mice deficient in both B7-1 and B7-2 failed to generate antigen-specific IgG1 and IgG2a responses and lacked germinal centers when immunized by a number of routes and even in the presence of complete Freund's adjuvant [16].
• Therefore, Bcl6 and germinal center formation are essential for somatic hypermutation, and generation of memory B cells can occur independently of germinal center formation, somatic hypermutation, and Ig class switching [29].
• BCL6 encodes a transcription factor that represses genes necessary for the terminal differentiation of lymphocytes within germinal centers, and the misregulated expression of this factor is strongly implicated in several types of B cell lymphoma [30].
• In conclusion, whereas normal splenic microarchitecture and isotype switch might require the LT beta receptor, differentiation of FDC network, development of germinal centers, and full IgG response depend on signaling via TNFR1 [31].

Analytical, diagnostic and therapeutic context of Germinal Center

• In situ hybridization of secondary follicles for BLC showed high expression in mantle zones and low expression in germinal centers [32].
• Immunohistochemistry of another blinded set of samples demonstrated expression of phosphorylated p38MAPK in 6/6 DLBCLs and 1/5 FLs, but not in benign germinal centers [33].
• The ligation of CD40 on B lymphocytes by CD40 ligand, transiently expressed on activated Th cells, provides a key activation signal required for the germinal center B cell response [34].
• Furthermore, the germinal center reaction in the primary xid immune response was diminished and the frequency of NP-specific memory B cells prior to secondary immunization was reduced 10-fold [35].
• By ligation-mediated PCR, we studied IgV DSBs that occurred in mature germinal center B cells in response to nitrophenyl-chicken gamma-globulin in a RAG1-independent, Ag-dependent, and IgV-selective manner [36].

References