T Cell Autoimmunity in Lupus

Lupus autoimmunity is the product of interactions of a vast array of self tissues, lymphopoetic cells, self antigens, and soluble macromolecules. Clearly, the immune system evolved to enhance the survival of the species, not for the generation of autoimmune syndromes. This has led the scientific community to seek specific immunologic defects or irregularities that may be responsible for this aberrant response. Unfortunately, no single overwhelming defect has been identified as a specific trigger in spite of the fact that lupus autoimmunity is not subtle in its expression. In the absence of obvious malfunctions of the immune system, is it possible that the immune system is functioning in a manner in which it was designed with the exception that the target of the response is self antigen, not a foreign pathogen? With few exceptions, the central features of immunity to foreign antigens are identical to those important in experimental models of lupus autoimmunity. For example, autoimmune-prone mice depleted of either B or T lymphocytes fail to exhibit the typical immunologic or pathologic outcomes of this disease (1–3). However, these mice also fail to respond to pathogens or conventional immunization with foreign protein as compared with unmanipulated mice (4). If all the components of immunity, or indeed autoimmunity, are in place, why are autoimmune diseases still an uncommon occurrence? This chapter examines the selection and activation of lymphocytes as they arise in the immune system with particular relevance to those forms of self antigen and costimulatory components that may impinge on the response to self antigens.