PubMed · 68880
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O Lees. Immunoperoxidase method B lymphocyte recognition.. https://doi.org/10.1016/0014-2964(77)90079-2
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Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) and primary effusion lymphoma (PEL) are derived from germinal center (GC) and post-GC B cells, respectively. Neither express many of the B cell genes or surface markers typically expressed by other GC-derived B cell lymphomas or normal B cells. This loss of B cell gene expression is not due to a lack of essential transcription factors, as studies have shown that the ectopic expression of missing transcription factors failed to reactivate endogenous target genes. These results implicate epigenetic mechanisms extinguishing B cell gene expression. Silenced endogenous B cell genes representing a surface receptor, B29 (Igbeta, CD79b), a signaling molecule, TCL1, and a transcription factor, Bob1 (OCA-B, OBF-1), were reactivated by 5-aza-2'-deoxycytidine, indicating that gene silencing in HRS and PEL cells is due to DNA methylation. Genomic bisulfite sequencing corroborated this prediction and revealed three distinct patterns of methylation for the silenced B29 and TCL1 promoters. These distinct patterns consisted of 5' promoter CpG methylation alone, 5' and 3' promoter CpG methylation sparing sites in the central cores, and complete CpG methylation throughout the promoter regions. The silenced Bob1 promoter showed one pattern of dense CpG methylation at essentially all sites. These consistent patterns predict that, although gene silencing in many HRS and PEL cells mimics appropriate gene silencing, in some cases of complete CpG methylation throughout entire promoters both the activation and targeting of methylation is abnormal.
The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI). One of the four individuals with CVID had a single nucleotide insertion in the other TNFRSF13B allele. None of these mutations were present in 50 healthy subjects. TNFRSF13B mutations cosegregated with the phenotype of CVID or IgAD in family members of four index individuals that we studied. B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching. These results suggest that TACI mutations can result in CVID and IgAD.
A major focus of tumor immunology is to reveal the potential role and capacity of immunocompetent cells found in different solid tumor tissues. The most abundant infiltrating cells (TIL), the T lymphocytes have been investigated in details concerning T-cell receptor usage and specificity. However, B cells have hardly been investigated in this respect, although high cellular B-cell infiltration has been correlated with improved patients' survival in some breast carcinomas. This led to our objectives to study variable region gene usage of the tumor-infiltrating B cells in different breast carcinoma types. By defining the immunoglobulin repertoire of the tumor-infiltrating B lymphocytes in the most common invasive ductal carcinoma (IDC) of the breast we compared it to the rare medullary breast carcinoma (MBC). After phenotyping infiltrating ductal carcinomas, B cells were obtained from tumor tissue by microdissection technique. Numerous rearranged TIL-B immunoglobulin heavy chain V genes (VH) were amplified, cloned, sequenced, and comparatively analyzed. Some characteristics were found for both breast carcinoma types. The immunoglobulins produced by TIL-B in ductal carcinoma are highly matured and oligoclonal. We conclude that Ig variable region gene usage reveals similar and distinguishable characteristics of TIL-B immunoglobulin repertoires, which are representative of the nature of the immune responses in invasive ductal and medullary breast carcinomas.