Role of BH3-only protein Bim in autoimmune and degenerative diseases

Background

Apoptosis is the physiological process used by an organism to eliminate cells that are no longer needed, have been damaged or are dangerous. Defects in the control of apoptosis have been implicated as a cause or a contributing factor in a variety of diseases. Proteins of the Bcl-2 family are major regulators of this process.

We have previously shown that Bim is required for certain apoptotic responses, for hematopoietic cell homeostasis and as a barrier against autoimmune disease.

Objectives

We study Bim-deficient mice in order to understand the role of Bim in homeostasis and to evaluate its role in the ontogeny of certain autoimmune and degenerative diseases.

Methods

We intercrossed Bim-deficient mice with mouse strains used as models for such diseases, namely bcl-2-KO, PKD1-KO, IL7R-KO and Lurcher mice, and analysed double mutants.

Results

We have shown that Bim is essential for the development of tolerance to self-antigens [1]. Using six different model systems, we have demonstrated that, during development in the thymus, Bim plays a major role in the elimination of the T lymphocytes that bear a T-cell receptor (TCR)/CD3 complex that engages self-antigens (negative selection). Thus, Bim appears essential for apoptosis of autoreactive T lymphocytes and B lymphocytes in central as well as peripheral tolerance.

By intercrossing mice with mutations in bcl-2 and bim, we have generated mice lacking both genes and shown that all the deficiencies caused by the absence of Bcl-2 (runting, polycystic kidneys, lymphopenia, hair greying) could be efficiently rescued by the concomitant absence of Bim [2]. This result demonstrates that BH3-only proteins can be involved in the induction of certain degenerative diseases.

By contrast, removal of Bim does not prevent the degeneration of cerebellar Purkinje cells and granular neurons in Lurcher mice.

We are currently investigating the consequences of the loss of Bim in PKD1-deficient and IL7R-deficient mice.

Conclusions

Our results indicate that BH3-only proteins may be at the origin of certain autoimmune and degenerative diseases, and may be targets of interest for the research of new drugs against such diseases.