In vivo administration of HgCl2 causes autoimmune manifestations in susceptible rats and mice. We have previously shown that mercury is a unique molecule that can primarily activate murine T lymphocytes to transformation and proliferation in vitro. To test whether a specific TCR repertoire predisposes the autoimmune development induced by HgCl2 and our hypothesis that mercury may function as a superantigen, we examined the TCR V beta repertoire in HgCl2-stimulated T cells from the responder BALB/c or SJL mice and the non-responder DBA/2 mice. We found a selective activation of T cells bearing a certain set of TCR B beta chains in response to HgCl2, e.g. V beta 6, V beta 8, V beta 10 and V beta 14 in the BALB/c strain. Moreover, depletion of V beta 8+ T cells, a family predominantly expanded in the BALB/c strain upon HgCl2 stimulation, profoundly inhibited the response to HgCl2 in this strain. An alternative selection of V beta segments, involving V beta 6, V beta 7 and V beta 14, was observed in the SJL strain in which the V beta 8 family is genetically deleted. Mechanism(s) whereby mercury modulates the immune system under a stringent genetic control and a possible therapeutic regime against mercury-induced autoimmune disease by administration of antibody specific to the TCR V beta region are discussed.

The clonal immunoglobulin molecule, idiotype (ID), expressed on the surface of B-cell malignancies can function as a tumor-specific antigen. BiovaxID is a patient-specific therapeutic cancer vaccine composed of the tumor idiotype conjugated to a carrier protein, keyhole limpet hemocyanin (KLH). In a Phase II clinical trial, administration of ID-KLH vaccine together with granulocyte-macrophage colony-stimulating factor to follicular lymphoma patients in complete remission induced tumor-specific cellular and humoral immunity and molecular remissions, and was associated with prolonged disease-free survival. A randomized, double-blind, Phase III clinical trial is ongoing to definitively determine the clinical benefit of BiovaxID plus granulocyte-macrophage colony-stimulating factor vaccination in patients with follicular lymphoma.

It is unclear how HgCl2 causes autoimmune disorders in genetically predisposed rodents. We investigated the cytokine profile induced by HgCl2 in vitro, and found a high frequency of IL-2-secreting cells in splenocytes from susceptible A.SW and BALB/c mice, whereas the frequency was low in cells from resistant DBA/2 mice. More IL-2-secreting cells were induced in splenocytes from the high responder A.SW mice than in cells from the intermediate responder BALB/c mice. Unexpectedly, a similar level of IL-4 production was induced in splenocytes from BALB/c and DBA/2 mice. IL-4 production was high in unstimulated cells from A.SW mice and was further increased by HgCl2. IFN-gamma-secreting cells were detectable in splenocytes from all three strains after activation by HgCl2. The highest frequency of IL-10-secreting cells was found in splenocytes from A.SW mice after activation, whereas the frequency was lower in cells from BALB/c mice, followed by cells from DBA/2 mice. We showed that neutralizing anti-IL-2 antibody profoundly inhibited the in vitro response to HgCl2. In contrast, antibodies against IL-4, IFN-gamma and IL-10 did not significantly affect the response of splenocytes from either A.SW or DBA/2 mice. The addition of IL-2 into cultures enhanced the proliferative response to HgCl2 in splenocytes from DBA/2 mice to a level comparable with that in cells from BALB/c mice. We found no evidence for the suggestion that HgCl2 induces a Th1/Th2 imbalance in resistant/susceptible strains. We conclude that IL-2 may be a limiting factor precluding lymphocytes from resistant mice from responding to HgCl2.

A synthetic peptide corresponding to residues 65–79 of the α helix of the α-chain of the class II HLA molecule DQA03011 (DQ 65–79) inhibits the proliferation of human T lymphocytes in an allele nonrestricted manner. By using microarray technology, we found that expression of 29 genes was increased or decreased in a human CTL cell line after treatment with DQ 65–79. This study focuses on one of these genes, IκB-α, whose expression is increased by DQ 65–79. IκB proteins, including IκB-α and IκB-β, are increased in T cells treated with DQ 65–79. Nuclear translocation of the NF-κB subunits p65 and p50 is decreased in T cells after treatment with DQ 65–79, while elevated levels of p65 and p50 are present in cytosol. DQ 65–79 inhibits the degradation of IκB-α mRNA and inhibits the activity of IκB kinase. These findings indicate that the DQ 65–79 peptide increases the level of IκB proteins, thereby preventing nuclear translocation of the transcription factor, NF-κB, and inhibiting T cell proliferation.

Injections of HgCl2 lead to autoimmune manifestations in genetically predisposed rats and mice. In this study, the authors examined the responsiveness of T subsets from different mouse strains to HgCl2 by tracing their expression of the very early activation antigen CD69. The authors found increased expression of the CD69 antigen on CD4+ T cells from the responder A.SW and BALB/c mice, but not on CD4+ T cells from the non-responder DBA/2 mice, indicating an activation of T helper cells in the responder strains. However, the CD69 antigen was induced on CD8+ T cells from all strains irrespective whether they were susceptible or resistant to mercury-induced autoimmunity. Since CD8+ T cells have been described as mediating immunosuppression and as being responsible for the resistance to autoimmune induction by mercury, the authors tested whether CD8+ T cells inhibited the activation of CD4+ T cells by HgCl2 in the non-responder strains. However, there was no evidence for a suppressive role of CD8+ T cells from the DBA/2 mice in the response to HgCl2. The findings indicate that T helper cells play a central role in the immunological effects of HgCl2 and unresponsiveness of T helper cells in the nonresponder strains is not due to CD8(+)-mediated immunosuppression.