Molecular mimicry

Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the promiscuity of several peptide sequences which can be both foreign and self in nature, a single antibody or TCR (T cell receptor) can be activated by even a few crucial residues which stresses the importance of structural homology in the theory of molecular mimicry. Upon the activation of B or T cells, it is believed that these "peptide mimic" specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity).[1] Molecular mimicry is a phenomenon that has been just recently discovered as one of several ways in which autoimmunity can be evoked. A molecular mimicking event is, however, more than an epiphenomenon despite its low statistical probability of occurring and these events have serious implications in the onset of many human autoimmune disorders. In the past decade the study of autoimmunity, the failure to recognize self antigens as "self," has grown immensely. Autoimmunity is a result of a loss of immunological tolerance, the ability for an individual to discriminate between self and non-self. Growth in the field of autoimmunity has resulted in more and more frequent diagnosis of autoimmune diseases. Consequently, recent data show that autoimmune diseases affect approximately 1 in 31 people within the general population.[2] Growth has also led to a greater characterization of what autoimmunity is and how it can be studied and treated. With an increased amount of research, there has been tremendous growth in the study of the several different ways in which autoimmunity can occur, one of which is molecular mimicry. The mechanism by which pathogens have evolved, or obtained by chance, similar amino acid sequences or the homologous three-dimensional crystal structure of immunodominant epitopes remains a mystery. Tolerance is a fundamental property of the immune system. Tolerance involves non-self discrimination which is the ability of the normal immune system to recognize and respond to foreign antigens, but not self antigens. Autoimmunity is evoked when this tolerance to self antigen is broken.[3] Tolerance within an individual is normally evoked as a fetus. This is known as maternal-fetal tolerance where T cells expressing receptors specific for a particular antigen enters the circulation of the developing fetus via the placenta.[4] After pre-T cells leave the bone marrow where they are synthesized, they are moved to the thymus where the maturation of T cells occurs. It is here where the first wave of T cell tolerance arises. Within the thymus, pre-T cells will encounter various self and foreign antigens present in the thymus that enter the thymus from peripheral sites via the circulatory system. Within the thymus, pre-T cells undergo a selection process where they must be positively selected and should avoid negative selection. T cells that bind with low avidity to self-MHC receptors are positively selected for maturation, those that do not die by apoptosis. Cells that survive positive selection, but bind strongly to self-antigens are negatively selected also by active induction of apoptosis. This negative selection is known as clonal deletion, one of the mechanisms for T cell tolerance. Approximately 99 percent of pre-T cells within the thymus are negatively selected. Only approximately 1 percent are positively selected for maturity.