Genetics of childhood disorders: XXVIII. Autoimmunity, part I.

855 The immune system fights infection by recognizing and destroying invading pathogens. To do this effectively, it must distinguish between proteins that are foreign and those that are not. Once this skill is acquired, the immune system is able to recognize foreign antigens and initiate an immunological response against them while ignoring proteins that are not foreign. Occasionally the immune system malfunctions and attempts to destroy self-proteins, mistaking them as foreign. This phenomenon is known as autoimmunity. Autoimmune diseases comprise a group of more than 75 chronic and disabling illnesses that can target almost any of the body’s tissues. It has been suggested that a subset of neuropsychiatric disorders result from autoimmune processes. The next several columns will review how the immune system normally functions and what happens when it malfunctions in autoimmune reactions. The importance of this area lies in the recent hypothesis that vulnerable individuals may develop several psychiatric disorders including Tourette’s syndrome and obsessive-compulsive disorder through an autoimmune process. It is important for us as clinicians to understand this phenomenon and how it might arise as well as the controversies that exist in the current debate. The immune system can be divided into two distinct arms: the innate and the adaptive systems. Innate immunity is the more primitive component and is found in many organisms. It refers to systems that are already in place and that do not require any further modifications to operate. Skin is a good example of innate immunity. Another is the ability of phagocytic lymphocytes to recognize certain proteins such as bacterial lipopolysaccharide molecules and to engulf organisms that have these proteins on their surfaces. Over the millennia pathogens have been evolving mechanisms to evade detection while mammalian immune systems have been evolving more sophisticated means of destroying them. Adaptive immunity is a more recently evolved immune mechanism. It differs from the innate mechanisms by having the capacity to recognize millions of different antigens associated with specific proteins, thereby generating a more specific immune response. In addition, an adaptive immune response takes several days to develop, in contrast to the innate response, which is always present and therefore immediate (Fig. 1). Finally, once an adaptive response is mounted against a specific antigen, a memory of that antigen is maintained throughout the life of the organism, making possible a more rapid response to subsequent infections. Three cells are critical for the adaptive response: B cells, T cells, and antigen-presenting cells (APCs). B cells are the lymphocytes that produce antibodies: the proteins—also called immunoglobulins—that bind to foreign antigens. Their production is one of the important early steps in signaling the detection of a foreign protein. T cells are divided into two types based on the expression of specific receptors on their cell surfaces. T cells with CD8 receptors are called killer T cells. These cells are responsible for the destruction of cells that are infected with pathogens. T cells with CD4 receptors on their surfaces are called helper T cells. These cells provide signals to antibody-producing B cells and instruct them to make antibodies. The third cell type critical to the adaptive immune response, the APCs, present antigens either to T cells or to B cells within the lymphoid tissues, thus informing them of an ongoing infection. When viruses or other foreign pathogens are engulfed by an APC, the proteins that make up the organisms are digested into small peptides of only 10 to 15 amino acids in length. These smaller peptides are bound to specific proteins, members of the major histocompatability complex class of proteins (MHC I or MHC II). Once the peptide associates with the MHC proteins, the resulting immune complexes are transported to the surface of the APCs. The presentation of these protein-peptide complexes on the cell surface activates a small subset of T cells and B cells that are programmed to recognize the foreign peptide. In general there are two types of infection, each of which requires a different immune response: cell-mediated and humoral immunity. Killer or cytotoxic T cells become activated in cellmediated immunity. These lymphocytes seek out infected cells and target them for destruction. In humoral immunity, B cells become activated through T helper cell stimulation. The B cells secrete specific antibodies directed against the antigens, and these antibodies initiate their own sequence of immune events to combat the foreign proteins. Cell-mediated immunity is exemplified by the mammalian response to viral infections. Viruses specialize in getting inside the host’s cells and using the host cell’s genetic material to replicate. There is not much that can be done to save a cell once it has been infected with a virus. The immune strategy that has evolved is simply to destroy the infected cells. APCs also become infected with the viruses that cause the more wideGenetics of Childhood Disorders: XXVIII. Autoimmunity, Part I