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Selective IgM deficiency is commonly found in Bloom's syndrome (BS). We reported that membrane-bound mu (micron(s)) mRNA was well transcribed but secreted mu (microseconds) mRNA was not, although there was no mutation or deletion in the sequence including the microseconds C-terminal coding sequence in the patients with BS. Furthermore, we have shown previously, preferential damage to IgM production by ultraviolet (UV) irradiation of the cells of the patient. In the study described here, mutation in the sequence which is upstream of the 5' end of the microseconds C-terminal coding sequence was induced by UV irradiation in the lymphoblastoid cell line (LCL) of BS patient. These results suggest that abnormal repair of DNA damage is present in this LCL, and that preferential damage to IgM production by UV irradiation in this LCL may be due to the abnormal repair of DNA damage.

In most patients with Bloom's syndrome (BS), selective IgM deficiency is commonly found. We examined proliferative responses by incorporation of [3H]-thymidine and the production of immunoglobulin after ultraviolet B (UVB) irradiation in the cells of two patients with BS. With regard to the proliferative responses in peripheral blood mononuclear cells (PBMC) cultured with pokeweed mitogen (PWM), the patients' PBMC were more sensitive to UVB irradiation than controls. Although the effect of UVB irradiation in lymphoblastoid cell lines (LCL) after 0 days of culture showed no difference between one patient and controls, the patient's LCL were more sensitive to UVB than the controls after 3 and 7 days of culture. These results suggest that the proliferative responses of the patient's LCL recovered later than those of controls. IgM production was the most sensitive to UVB in the patients' PBMC and LCL. IgG and IgA production in the patients' PBMC and LCL showed the same sensitivity as controls. From our results, it is suspected that the preferential damage to IgM production by UVB is connected with the selective IgM deficiency of BS.

We report a case of common variable immunodeficiency (CVI) that shows low levels of IgG and IgA, but a normal quantitative or qualitative level of IgM. T-cell functions were not disturbed. Increased numbers of surface IgM (sIgM) and sIgD, sIgM and sIgG, sIgM and sIgA double-bearing B cells were observed as compared with a control. No IgG and IgA induction upon stimulation with Staphylococcus aureus Cowan I (SAC) and recombinant interleukin-2 (rIL-2), or pokeweed mitogen (PWM) and rIL-4 or rIL-6 was observed, although there was proliferation. Although mu mRNA was expressed as much as in a healthy control, transcription of gamma mRNA and alpha mRNA was very low. Furthermore, no enhanced effects of gamma mRNA and alpha mRNA were recognized upon stimulation with rIL-4 and rIL-6. These results suggest that the patient's B cells might be defective at the switching process from mu, mu and delta, mu and gamma to gamma or mu and alpha to alpha.

Serum IgM concentrations were low although serum IgG and IgA concentrations were normal in both our patients with Bloom's syndrome. Although the percentages of surface IgM-bearing cells were not reduced, the numbers of IgM-secreting cells were markedly reduced. The membrane-bound mu (microns) and secreted mu (microseconds) mRNAs are produced from transcripts of a single immunoglobulin mu gene by alternative RNA processing pathways. The control of microseconds mRNA synthesis depends on the addition of poly(A) to microseconds C-terminal segment. In both patients, mu mRNA was well detected but microseconds C-terminal mRNA was scarcely detected, suggesting that microns mRNA was well transcribed but microseconds mRNA was not. There was, at least, no mutation or deletion in the microseconds C-terminal coding sequence, the RNA splice site (GG/TAAAC) at the 5' end of microseconds C-terminal segment and the AATAAA poly(A) signal sequence in both patients. Our results suggest that selective IgM deficiency in Bloom's syndrome is due to an abnormality in the maturation of surface IgM-bearing B cells into IgM-secreting cells and a failure of microseconds mRNA synthesis. Moreover, reduced microseconds mRNA synthesis may be due to the defect on developmental regulation of the site at which poly(A) is added to transcripts of the mu gene.

The immune state was evaluated over a 10-year period in two individuals with Bloom's syndrome. In both patients, serum concentrations of IgM were markedly low. Mildly decreased serum concentrations of IgG and IgA increased significantly with age, whereas the IgM levels remained low. From assessments of B-cell and T-cell functions in pokeweed mitogen-induced immunoglobulin production, the IgM deficiencies were thought to result from B-cell dysfunction. T-cell function appeared intact. Moreover, although the percentages of surface IgM-bearing cells were not reduced, the numbers of IgM-secreting cells were reduced. These findings suggest that the IgM deficiency is due to an abnormality in the maturation of surface IgM-bearing B cells into IgM-secreting cells.