Somatic hypermutation in the absence of DNA-dependent protein kinase catalytic subunit (DNA-PK(cs)) or recombination-activating gene (RAG)1 activity.

Somatic hypermutation and isotype switch recombination occur in germinal center B cells, are linked to transcription, and are similarly affected by deficiency in MutS homologue (MSH)2. Class-switch recombination is abrogated by disruption of genes encoding components of the catalytic subunit of DNA-dependent protein kinase (DNA-PK(cs))/Ku complex and likely involves nonhomologous end joining (NHEJ). That somatic hypermutation might also be associated with end joining is suggested by its association with the creation of deletions, duplications, and sites accessible to terminal transferase. However, a requirement for NHEJ in the mutation process has not been demonstrated. Here we show that somatic mutation in mice deficient in NHEJ can be tested by introduction of rearranged immunoglobulin and T cell receptor transgenes: the transgene combination not only permits reconstitution of peripheral lymphoid compartments but also allows formation of germinal centers, despite the wholly monoclonal nature of the lymphocyte antigen receptors in these animals. Using this strategy, we confirm that somatic hypermutation like class-switching can occur in the absence of recombination-activating gene (RAG)1 but show that the two processes differ in that hypermutation can proceed essentially unaffected by deficiency in DNA-PK(cs) activity.

The remote prognosis of eclamptic women. Sixth periodic report.

All but three of the 270 women surviving eclampsia at the Margaret Hague Maternity Hospital in the period 1931 through 1951 were traced to 1973-74. Seventy-six have died and 13 were not re-examined. In white women having eclampsia in the first pregnancy carried to viability the remote mortality rate is not increased over that in unselected women; in white women having eclampsia as mulitparas and in all black women the remote mortality rate is from 2 to 5 times the expected numbers. Primiparous eclamptic women are not different from women matched for age, in several epidemiologic studies, in the prevalence of hypertension or in the frequency distributions of systolic and diastolic blood pressures. There is, however, a considerable increase in the prevalence of hypertension among women having had eclampsia as multiparas and that has accounted for their increased remote death rates. The prevalence of diabetes, developing many years after eclampsia is 2.5 times the expected rate in primiparous and about 4 times the expected rate among multiparous eclamptic women. Eclampsia neither is a sign of latent essential hypertension nor causes hypertension. Hypertensive pregnancies following eclampsia indicate the probabilty of later chronic hypertension, but do not cause it.