Differential regulation of germinal center genes, BCL6 and SWAP-70, during the course of MAIDS.
Germinal centers (GC) are the sites of antigen-driven B cell switch recombination, V(D)J gene hypermutation, and selection to generate high-afinity CD38+ memory B cells. A marked expansion of GC associated with hypergammaglobulinemia followed by complete disruption of normal splenic architecture and a striking drop in immunoglobulin levels are prominent features of the murine retrovirus-induced immunodeficiency syndrome, MAIDS. B cell lymphomas are frequent in long-term infected mice. Normal GC formation is critically dependent on a number of genes including the transcription factor, Bcl6. Deregulated expression of BCL6 protein has been implicated in the development of human and mouse B cell lymphomas. Another nuclear protein, SWAP-70, has been identified as a subunit of the protein complex, SWAP, that recombines switch regions in vitro. To develop a fuller understanding of B cell biology in MAIDS, we examined the characteristics of BCL6, SWAP-70, CD38, and peanut agglutinin (PNA)-staining cells during the course of the disease. The levels of both nuclear proteins increased rapidly until 6-8 weeks after infection. During this time frame, BCL6 was expressed at highest levels in the usually rare CD4+ Thyl- T cell subset as well as in B cells. At later times. BCL6 levels dropped to undetectable levels while SWAP-70 levels continued to increase. Changes in the levels of either protein could not be ascribed to transcriptional regulation. PNA-reactive cells decreased in concert with BCL6 while CD38 staining increased with SWAP-70. These results demonstrate that progression of MAIDS results in the massive accumulation of B cells with the morphology of secretory cells that behave like post-GC cells for expression of BCL6 and CD38, and for PNA-staining but with abnormally high-level expression of SWAP-70.
Qi
C F
CF
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0760, USA. cqi@atlas.niaid.nih.gov
Jessberger
R
R
Torrey
T A
TA
Taddesse-Heath
L
L
Ohta
Y
Y
Morse
H C
HC
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005812:Genes, Switch; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D016183:Murine Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D009244:NAD+ Nucleosidase / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D011995:Recombination, Genetic; D014157:Transcription Factors / Q000235:genetics*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D017931:DNA Primers; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C491873:SWAP70 protein, human; C113365:Swap70 protein, mouse; D014157:Transcription Factors; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1