7 A and B), increasing concentrations of MK-5046 resulted TSA in increasing inhibition of the stimulation seen with a maximal effective concentration of peptide #1 (Fig. 7, A and B). Specifically, with hBRS-3 Balb 3T3 cells, MK-5046 caused a detectable inhibition of the maximally stimulated [3H]IP by peptide #1 at 1 nM, half-maximal inhibition at 13.76 �� 0.61 nM, and progressive inhibition with higher doses (Fig. 7A). In NCI-N417 (Fig. 7B), MK-5046 caused progressive inhibition with increasing concentrations >0.1 nM. Fig. 7. Increasing concentrations of MK-5046 (A and B) or Bantag-1 (C and D) alter the maximal [3H]IP generation stimulated by peptide #1 (1 ��M) (A and B) or by supramaximal MK-5046 (1 ��M) (C and D) in hBRS-3 Balb 3T3 and NCI-417 cells. The experimental …

These results demonstrate that the supramaximal inhibition caused by high concentrations of MK-5046 can also inhibit
Autoimmune diseases affect about 5% of the population and are often characterized by the production of autoantibodies directed against self-antigens (1). An important role for B cells in autoimmune diseases is demonstrated by the successful treatment of patients with RA, type 1 diabetes (T1D), MS, and other autoimmune syndromes with anti-CD20 monoclonal antibodies that eliminate B cells (2�C4). However, the underlying mechanisms that account for autoreactive B cells and autoantibody production in autoimmune diseases remain elusive. We previously established in healthy donors that most developing autoreactive B cells are removed at two discrete steps.

A central B cell tolerance checkpoint removes the vast majority of developing B cells that express polyreactive antibodies in the bone marrow (5). A peripheral B cell tolerance checkpoint further counterselects autoreactive new emigrant B cells before they enter the mature naive B cell compartment (5). In contrast, untreated active RA and SLE patients exhibit defective central and peripheral B cell tolerance checkpoints that result in the accumulation of self-reactive mature naive B cells in their blood (6, 7). However, it is unclear whether these early B cell tolerance defects precede the onset of autoimmunity or result from chronic ongoing inflammation processes. We recently reported that methotrexate or anti�CTNF-�� antiinflammatory treatments improved RA patients�� condition without resetting early B cell tolerance checkpoints, suggesting that they may be controlled by intrinsic Brefeldin_A genetic factors (8). Many susceptibility genes associated with autoimmune and inflammatory disease have recently been identified through genome-wide association studies (GWASs) (9). However, the mechanisms by which these gene variants contribute to the development of autoimmunity are unknown.