CD5+B Cell Lymphomas of Mice

Abstract

Spontaneous murine lymphomas commonly arise from CD5 B cells. They appear late in life and the frequency of their occurrence can be increased by transferring syngeneic lymphoid cells from old animals to young. Such transfer experiments show that although the lymphomas are not detected until late in life, the commitment to neoplasia is made much earlier and is followed by an indolent phase before the neoplastic phenotype becomes manifest. The repertoire of immunoglobulin (Ig) V genes expressed is not random, but certain VH genes appear repeatedly and, at least in some cases, are specifically associated with particular VK genes. This unbalanced repertoire is similar to that expressed by normal CD5 B cells of young adult mice, implying that the process of lymphomagenesis operates after the normal CD5 B cell repertoire has been established. Development of new CD5 B cells from pre-B cells only occurs before and shortly after birth; in the adult, the population is self sustaining and is not replenished from Ig negative precursors. The newly generated population of CD5 B cells present at birth more nearly approximates a random selection from the germ line genes. Skewing of the repertoire occurs during the first few weeks of post-natal life and results from antigen driven clonal selection by self antigens, predominantly type 2 thymus independent antigens. From 5-20% of normal adult CD5 B cells (and lymphomas) produce antibody reactive with phosphatidyl choline. Almost exclusively, these cells express VH11 or VH12 family genes in combination with specific VK genes and displaying severe constraints as to size and sequence of VDJ regions. These VH genes have not been seen expressed by conventional B cells. Neither do conventional B cells produce antibody of this specificity. In vivo, murine CD5 B cell lymphomas produce IgM; in vitro they can respond to differentiative signals and undergo isotype switching, with a marked predilection for IgA. Somatic mutation of assembled Ig genes has not been seen in these tumors and idiotype-loss variants have not been seen to result from anti-idiotype therapy.