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 prevalence 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 just 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). 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. 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 prevalence 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 just 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). 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 System, the failure to recognize self antigens as 'self', has grown immensely. Autoimmunity is thought by many researchers to be a result of a loss of immunological tolerance, the ability for an individual to discriminate between self and non-self, though others are beginning to think that many autoimmune diseases are due to mutations governing programmed cell death, or to environmental products that injure target tissues, thus causing a release of immunostimulatory alarm signals,. 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. 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. Tolerance within an individual is normally evoked as a fetus. This is known as maternal-fetal tolerance where B cells expressing receptors specific for a particular antigen enter the circulation of the developing fetus via the placenta. After pre-B cells leave the bone marrow where they are synthesized, they are moved to the bone marrow where the maturation of B cells occurs. It is here where the first wave of B cell tolerance arises. Within the bone marrow, pre-B 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. B 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 B cell tolerance. Approximately 99 percent of pre-B cells within the thymus are negatively selected. Only approximately 1 percent are positively selected for maturity. However, there is only a limited repertoire of antigen that B cells can encounter within the thymus. B cell tolerance then must occur within the periphery after the induction of B cell tolerance within the thymus as a more diverse group of antigens can be encountered in peripheral tissues. This same positive and negative selection mechanism, but in peripheral tissues, is known as clonal anergy. The mechanism of clonal anergy is important to maintain tolerance to many autologous antigens. Active suppression is the other known mechanism of T cell tolerance. Active suppression involves the injection of large amounts of foreign antigen in the absence of an adjuvant which leads to a state of unresponsiveness. This unresponsive state is then transferred to a naïve recipient from the injected donor to induce a state of tolerance within the recipient. Tolerance is also produced in T cells. There are also various processes which lead to B cell tolerance. Just as in T cells, clonal deletion and clonal anergy can physically eliminate autoreactive B cell clones. Receptor editing is another mechanism for B cell tolerance. This involves the reactivation or maintenance of V(D)J recombination in the cell which leads to the expression of novel receptor specificity through V region gene rearrangements which will create variation in the heavy and light immunoglobulin (Ig) chains. Autoimmunity can thus be defined simply as exceptions to the tolerance 'rules.' By doing this, an immune response is generated against self-tissue and cells. These mechanisms are known by many to be intrinsic. However, there are pathogenic mechanisms for the generation of autoimmune disease. Pathogens can induce autoimmunity by polyclonal activation of B or T cells, or increased expression of major histocompatibility complex (MHC) class I or II molecules. There are several ways in which a pathogen can cause an autoimmune response. A pathogen may contain a protein that acts as a mitogen to encourage cell division, thus causing more B or T cell clones to be produced. Similarly, a pathogenic protein may act as a superantigen which causes rapid polyclonal activation of B or T cells. Pathogens can also cause the release of cytokines resulting in the activation of B or T cells, or they can alter macrophage function. Finally, pathogens may also expose B or T cells to cryptic determinants, which are self antigen determinants that have not been processed and presented sufficiently to tolerize the developing T cells in the thymus and are presented at the periphery where the infection occurs. Molecular mimicry has been characterized as recently as the 1970s as another mechanism by which a pathogen can generate autoimmunity. Molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either the linear amino acid sequence or the conformational fit of the immunodominant epitope may be shared between the pathogen and host. This is also known as 'cross-reactivity' between self antigen of the host and immunodominant epitopes of the pathogen. An autoimmune response is then generated against the epitope. Due to similar sequence homology in the epitope between the pathogen and the host, cells and tissues of the host associated with the protein are destroyed as a result of the autoimmune response. The prerequisite for molecular mimicry to occur is thus the sharing of the immunodominant epitope between the pathogen and the immunodominant self sequence that is generated by a cell or tissue. However, due to the amino acid variation between different proteins, molecular mimicry should not happen from a probability standpoint. Assuming five to six amino acid residues are used to induce a monoclonal antibody response, the probability of 20 amino acids occurring in six identical residues between two proteins is 1 in 206 or 1 in 64,000,000. However, there has been evidence shown and documented of many molecular mimicry events.