Receptor editing is a major B cell tolerance mechanism that operates by secondary Ig gene rearrangements to change the specificity of autoreactive developing B cells. In the 3-83Igi mouse model, receptor editing operates in every autoreactive anti-H-2Kb B cell, providing a novel receptor without additional cell loss. Despite the efficiency of receptor editing in generating nonautoreactive Ag receptors, we show in this study that this process does not inactivate the autoantibody-encoding gene(s) in every autoreactive B cell. In fact, receptor editing can generate allelically and isotypically included B cells that simultaneously express the original autoreactive and a novel nonautoreactive Ag receptors. Such dual Ab-expressing B cells differentiate into transitional and mature B cells retaining the expression of the autoantibody despite the high avidity interaction between the autoantibody and the self-Ag in this system. Moreover, we find that these high avidity autoreactive B cells retain the autoreactive Ag receptor within the cell as a consequence of autoantigen engagement and through a Src family kinase-dependent process. Finally, anti-H-2Kb IgM autoantibodies are found in the sera of older 3-83Igi mice, indicating that dual Ab-expressing autoreactive B cells are potentially functional and capable of differentiating into IgM autoantibody-secreting plasma cells under certain circumstances. These results demonstrate that autoreactive B cells reacting with ubiquitous membrane bound autoantigens can bypass mechanisms of central tolerance by coexpressing nonautoreactive Abs. These dual Ab-expressing autoreactive B cells conceal their autoantibodies within the cell manifesting a superficially tolerant phenotype that can be partially overcome to secrete IgM autoantibodies.

B cells and autoimmunity: cells of the immune system have the capacity to recognize/neutralize a myriad array of disease-causing pathogens, while simultaneously minimizing damage to self tissue. Obvious breakdowns in this ability to distinguish between self and non-self are evident in multiple forms of autoimmune disease, where B and T cells mount damaging attacks on cells and organs. B cells may directly damage tissue by producing pathogenic antibodies that bind self antigen, fix complement or form immune complexes. Recent evidence also suggests B cells indirectly induce autoimmunity by concentrating low avidity self antigen through the B cell receptor and presenting self-peptides to autoreactive T cells. B cells may also initiate autoimmunity when provided sufficient help from autoreactive T cells that have escaped deletion in the thymus. Here, we will review the role of anergy in maintenance of tolerance and how alterations in the normal balance of positive and negative signals may contribute to the development of autoimmune disease in mouse models and humans.

The use of selenium in stainless steels and the importance of selenium in biological materials and processes have been discussed in the literature (1-6). However, the separation and determination of selenium in these materials by conventional chemical methods can be difficult, tedious, and, if care is not exercised, subject to inaccuracies due to volatilization (1, 4-10). Neutron activation analysis techniques also have been used for the determination of selenium (2, 5). Generally, the production of 120-day 78Se, 17.4-second 77™Se, and 18.6-minute 81sSe has been used for the analysis (2). However, with selective dry distillation techniques, standard radiochemical procedures are not required and quantitative recovery is possible. The radiochemistry of selenium has been discussed by Leddicotte (11) and DeVoe (12).In the method reported here, the selenium-containing sample and a standard are irradiated by either thermal neutrons or by 14-MeV neutrons. The selenium is then separated by a dry distillation technique and is determined by counting the gamma rays of 121-day 75Se or 57-minute 81"'Se. This method also permits the qualitative identification of selenium by the appearance of the metal in the dry distillation collection tube. The various known neutron reactions which can occur are given elsewhere (13-15). EXPERIMENTAL Apparatus and Reagents. The counting system included a 3-X 3-inch Nal(Tl) crystal, with associated electronics, connected to a Technical Measurements Corp. 400-channel analyzer.Thermal neutron irradiations of samples were performed in the Sandia Reactor Facility (SRF) in a position which had