Scientific Report 2007

Molecular and Experimental Medicine

Division of Rheumatology Research

Autoimmunity Induced by Xenobiotics

K.M. Pollard, D. Cauvi, P. Hultman*

* Linköping University, Linköping, Sweden

We focus on mechanisms involved in the initiation of autoimmunity and how the interplay between genetics and the environment influences the expression of systemic autoimmune diseases.

Role of Decay-Accelerating Factor in Systemic Autoimmunity

Decay-accelerating factor (DAF/CD55) is one of the complement regulatory proteins that protect host cells from damage by autologous complement. Deficiency in DAF1 can exacerbate development of various autoimmune diseases, and this effect may occur because the factor limits T-cell hyperresponsiveness. Some research has suggested that the lack of DAF1 aggravates murine autoimmune disease in a complement-dependent manner, but other results have shown that activation of human T cells by DAF can be complement independent. The contribution of the interaction between DAF1 and complement to lymphocyte activation, cytokine expression, and antibody production in mice that are not DAF1 deficient remains to be determined.

In mercury-induced autoimmunity in mice, we found that an accumulation of CD44^high DAF1^low CD4⁺ T cells is associated with the development of autoimmunity. In recent studies, we used cobra venom factor to show that complement depletion does not affect the accumulation of activated CD4⁺ T cells, elevation of splenic IL-4 expression, or production of autoantibodies in this model. In addition, neither the accumulation of CD44^high DAF1^low CD4⁺ T cells nor the downregulation of DAF1 expression on CD4⁺ T cells was influenced by a lack of complement. These observations indicate that reduction of DAF1 on CD4⁺ T cells does not enhance the contribution of complement to T-cell activation and autoantibody production during development of autoimmunity.

Gold-induced Autoimmune and Immunostimulatory Responses in Mice

Natrium aurothiomaleate (GSTM) is a useful drug in patients with rheumatism, but many patients treated with GSTM experience a variety of immune-mediated adverse effects. We used a mouse model to study the effects of GSTM on the immune system, including induction of systemic autoimmunity. Mice were given weekly intramuscular injections of GSTM or equimolar amounts of sodium thiomaleate (controls). The effects of treatment on lymphocyte subpopulations were determined by using flow cytometry. Humoral autoimmunity was measured by using indirect immunofluorescence and immunoblotting, and deposition of immunoglobulin and C3 was used to assess immunopathologic changes.

We found that GSTM stimulated the immune system, causing strain-dependent lymphoproliferation and autoimmunity, including an MHC-restricted autoantibody response against the nucleolar protein fibrillarin. The drug did not cause deposition of immunoglobulin G in the glomeruli or vessel walls, but it did have a strong B cell–stimulating effect, including both type 1 and type 2 T helper cell–dependent isotypes. All of these autoimmune and immunostimulatory responses depended on the MHC genotype, suggesting a strong genetic link for the major adverse immune reactions associated with GSTM treatment.

Publications

Cauvi, D.M., Cauvi, G., Pollard, K.M. Reduced expression of decay-accelerating factor 1 in CD4⁺ T cells in murine systemic autoimmune disease. Arthritis Rheum. 56:1934, 2007.

Havarinasab, S., Johansson, U., Pollard, K.M., Hultman, P. Gold causes genetically determined autoimmune and immunostimulatory responses in mice. Clin. Exp. Immunol., in press.

Pollard, K.M., Hultman, P. Fibrillarin autoantibodies. In: Textbook of Autoantibodies. Shoenfeld, Y., Gershwin, M.E., Meroni, P.-L. (Eds.). Elsevier, Philadelphia, 2007, p. 317.