Self-reactive B Cells Are Not Eliminated or Inactivated by Autoantigen Expressed on Thyroid Epithelial Cells

The Journal of Experimental Medicine 1997, 186: 2005 ­ 2012

By Srinivas Akkaraju, Karen Canaan, and Christopher C. Goodnow

In autoimmune diseases such as myasthenia gravis and Graves' disease, autoantibodies target membrane bound antigens (ACh receptor, TSH receptor). The ability of normal individuals to develop autoimmunity to these antigens following immunization with adjuvant has suggested that immunization may reverse the normal processes of anergy or elimination. Alternatively, the B cells to these types of membrane bound antigens may not be eliminated by anergy or deletion.

To explore these possibilities further, the authors have constructed transgenic animals with thyroid specific, membrane bound hen egg lysozyme (mHEL). This model mimics the most common antibody-mediated autoimmune disease, Graves' disease, where antibodies target the thyroid TSH (thyroid stimulating hormone) receptor, activating the thyroid to cause a potentially life-threatening increase in heart rate, blood pressure, and metabolism.

When animals were immunized with HEL in solution, the control animals (no mHEL) mounted a normal immune response, whereas the transgenic mice did not. Thus, mHEL induced a state of anergy or deletion of pre-immune HEL B cells in these transgenic animals.

Re-immunization of both groups with HEL conjugated to chicken gamma globulin (a potent T cell immunogen), resulted in both groups producing high levels of IgG to HEL. Either the pre-immune B cells had not been permanently anergized, or the potent T cell help induced by chicken gamma globulin overcame the previous unresponsiveness.

They then constructed double transgenic animal groups that also express high levels of anti-HEL B cells. Unlike the single transgenic mice that has only made mHEL and did not make antibody when exposed to soluble HEL, these mice produced high levels of antibodies to HEL.

These studies suggest that mHEL was able to induce a weak state of anergy or partial anergy in pre-immune B cells to HEL that could be broken by a strong T cell stimulus. The studies also show that thyroid specific HEL could not systemically inactivate or eliminate the HEL specific B cells produced by the double transgenic. They imply that autoimmunity may begin when local defects occur in the normal process of T cell tolerance to self or when T cell tolerance breaks down due to a lack of generally available self-antigen, resulting in inappropriate T cell activation and signaling.