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. 2014;2014:239358.
doi: 10.1155/2014/239358. Epub 2014 May 4.

Elements of the B Cell Signalosome Are Differentially Affected by Mercury Intoxication

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Free PMC article

Elements of the B Cell Signalosome Are Differentially Affected by Mercury Intoxication

Randall F Gill et al. Autoimmune Dis. .
Free PMC article

Abstract

It has been suggested that environmental exposures to mercury contribute to autoimmune disease. Disruption of BCR signaling is associated with failure of central tolerance and autoimmunity, and we have previously shown that low levels of Hg(2+) interfere with BCR signaling. In this report we have employed multiparametric phosphoflow cytometry, as well as a novel generalization of the Overton algorithm from one- to two-dimensional unimodal distributions to simultaneously monitor the effect of low level Hg(2+) intoxication on activation of ERK and several upstream elements of the BCR signaling pathway in WEHI-231 B cells. We have found that, after exposure to low levels of Hg(2+), only about a third of the cells are sensitive to the metal. For those cells which are sensitive, we confirm our earlier work that activation of ERK is attenuated but now report that Hg(2+) has little upstream effect on the Btk tyrosine kinase. On the other hand, we find that signaling upstream through the Syk tyrosine kinase is actually augmented, as is upstream activation of the B cell signalosome scaffolding protein BLNK.

Figures

Figure 1
Figure 1
Time course of pERK in WEHI-231 B cells after stimulation of the BCR with anti-mu as determined with phosphoflow cytometry. (a) Histograms at various times for pERK (green, light hue) and isotype control (red, dark hue). (b) Change in MFI (as calculated from the histograms in (a) as a function of time after BCR stimulation.
Figure 2
Figure 2
Change in pERK at 5 minutes after stimulation as a function of concentration of anti-mu used to stimulate the BCR.
Figure 3
Figure 3
Effect of Hg+2 and anti-mu (12.5 μg/mL) as a function of time after addition of (a) pERK and (b) pSyk.
Figure 4
Figure 4
Effect of Hg+2 on stimulation of elements of the BCR signal transduction pathway after stimulation of the BCR with anti-mu (12.5 μg/mL). In Figure 4 the y-axis represents differences in MFI between (BCR stimulated cells treated or not with Hg2+) and control cells which have neither been treated with Hg nor stimulated via the BCR. The x-axis represents time after stimulation of the BCR. (a) pERK versus time, (b) pSyk versus time, (c) pBtk versus time, (d) pBLNK versus time, (e) pERK versus pSyk versus time in the absence of Hg+2, and (f) pERK versus pSyk in the presence of Hg+2.
Figure 5
Figure 5
Two-dimensional histogram representation of pSyk versus pERK after stimulation of BCR with anti-mu (12.5 μg/mL). (a) Control cells at 0 minutes after stimulation of the BCR; (b) 5 minutes after stimulation of the BCR; (c) five minutes after BCR stimulation in Hg+2 intoxicated cells; (d) “Overton” subtraction of (c) from (b).

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