Dissociation of severe lupus-like disease from polyclonal B cell activation and IL 2 deficiency in C3H-lpr/lpr mice.

The lymphoproliferation characteristic of all strains of mice homozygous for the gene lpr results from the expansion of an unusual subset of cells that express reduced levels of Ly-1 and Thy-1 antigens and high levels of Ly-5(B220), an antigen that is normally only detected on cells of the B lineage. In the present study, C3H-lpr mice were studied to determine when this population of cells first appears in lymph node (LN) and spleen and whether its appearance relates to the development of B cell activation and deficiencies in interleukin 2 (IL 2) production. The results showed that Ly-5(B220)+, sIg- cells were first detected in LN at 4 wk of age; thereafter their numbers increased exponentially until at 16 wk of age they represented more than 80% of LN cells. Two subpopulations of Ly-5(B220)+, sIg- cells were present in LN; one Ly-1+, Thy-1+ and the other Ly-1+, Thy-1-. Ly-5(B220)+, sIg- cells were not detected in C3H-lpr spleen until 6 to 10 wks after their appearance in LN, and their proportions never reached those in LN. Polyclonal B cell activation in C3H-lpr spleens was not observed until Ly-5(B220)+, sIg- cells were present, suggesting that this population may play a role in B cell stimulation. IL 2 production by C3H-lpr spleen and LN cells was normal up to 6 wk of age and was significantly impaired thereafter, with LN being more severely affected than spleen. The IL 2 defect could be significantly repaired by the addition of PMA to the cultures. Although defective IL 2 production coincided with the appearance of Ly-5(B220)+, sIg- cells in LN, it preceded the appearance of these cells in spleen. In spite of the impaired ability to produce IL 2 in vitro, CTL responses to alloantigens were normal. Although C3H-lpr mice share many of the lymphoid abnormalities observed in MRL-lpr mice, they do not develop severe, early-onset SLE-like disease characteristic of the latter strain. This suggests that factors other than defective IL 2 production and polyclonal B cell activation are required for the development of fulminant autoimmune disease.