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Molecular Mimicry

The concept that molecular mimicry is an important factor in autoimmune disease was first published in 1985 and since that time substantial evidence has accumulated such that it has become the favoured mechanism for causing many autoimmune diseases including MS.

The concept is deceiving simple but entails a lot of understanding of the workings of the immune system. Basically molecular mimicry means that part of a molecule of a given protein closely resembles a part of another totally different protein. Proteins are made up of strings of amino acids and in molecular mimicry one series amino acids(eg~10) in one protein is very similar to a string of ten amino acids in another protein. Given that there are 20 different amino acids it is a rather rare occurrence to find such mimicking arrangements but many examples have been demonstrated.

The main types of proteins which came into play in autoimmune disease are:

  1. self proteins which are part of the human body.An example of this would be myelin basic protein which is the most common protein in myelin;
  2. proteins of infectious agents such as viruses and bacteria;
  3. food proteins.For example over 400 different proteins occur in cow's milk and most have over 150 amino acids.

To understand how molecular mimicry works in the induction of autoimmunity one must understand the basic mechanisms of an immune response to a foreign invader in the body. The immune system recognizes a part of the protein portion of the invader. It does this with T cells which have receptors which bind to short segments(~10 amino acids) of a foreign protein. It is helped in this task by so called antigen presenting cells such as macrophages. A macrophage will engulf a foreign invader(eg a bacteria or food particle) and break it down into fragments. A special molecule in the macrophage then carries a protein fragment(peptide) to the surface of the cell and "presents" it to the millions of circulating T cells. A T cell which has a matching receptor locks onto the presented protein fragment. The T cell then becomes activated and stimulates other portions of the immune system to begin an immune response against all proteins which contain a similar looking amino acid string. The details of what constitutes a similar looking string are beyond this summary but suffice to say it has been found that a variety of  similar, yet somewhat different strings, can be recognized by the same T cell.

Thus, it is easy to understand how molecular mimicry can trigger an autoimmune reaction. If the protein fragment from a foreign invader which is presented to the T cell closely resembles part of a self protein then the activated immune system will not only attack all foreign invaders which have the same string of amino acids but will also attack a very similar  string in a self protein. It has been shown that parts of proteins in various foods and infectious agents resemble parts of various self proteins. Sometimes a three way mimicry occurs with a protein fragment from a food closely resembling that of an infectious agent which in turn closely resembles part of a self protein. In Celiac disease part of the gliadin molecule (found in various grains such as wheat and rye), part of adenovirus 12 and part of a gut protein all closely resemble each other and the result of such mimicry is an immune attack on the gut when food containing gliadin protein  is eaten. A similar three way mimicry occurs between a cell wall protein in grains and legumes, part of the Epstein Barr virus and part of the collagen in joints. This leads to rheumatoid arthritis in genetically susceptible people. For type 1 diabetes parts of milk proteins and viral proteins mimic proteins in the insulin-producing beta cells of the pancreas.

For MS it has been established that numerous viruses and bacteria have amino acid strings which mimic parts of proteins in the myelin proteins of the central nervous system. Undoubtedly food proteins also contain such mimicking protein fragments and thus two and three way mimicry is a ready explanation for why the immune system attacks myelin and causes MS.

An important part of molecular mimicry is what exact string of amino acids is presented to the immune system because that will determine if part of a self protein is also mimicked or not. That is why MS and other autoimmune diseases are strongly dependent on genetic makeup and why only a small percentage of the population contracts these diseases. Most people do not have genes which result in mimicking peptides being presented to their immune system. A person's genes will also determine which self protein is mimicked and thus what specific autoimmune disease that person gets. People, who have genes such that a myelin protein is mimicked by a presented foreign protein fragment, will experience an immune attack on their myelin which eventually leads to clinical symptoms and a diagnosis of MS. Those who present collagen-mimicking fragments get rheumatoid arthritis.

Currently most researchers are concentrating on infectious agents as the main drivers of molecular mimicry despite the strong evidence that food proteins also supply appropriate mimics. In fact it is likely that food proteins are the main mimics in some cases because the geographical distribution of diseases such as MS and type 1 diabetes closely follows differences in dietary habits rather than differences in infectious agents. Of course it has been established that food proteins are the driver of Celiac disease, one of the few autoimmune diseases for which the cause is known.

In summary, molecular mimicry is currently the best  explanation for why the immune system attacks self tissue in some people. When all is said and done it just comes down to a case of mistaken identity in which the immune system in genetically susceptible people mistakes part of the body for a foreign invader. Below are some medline abstracts on the concept of molecular mimicry.


Medline Abstracts

Molecular mimicry and immune-mediated diseases.

FASEB J 1998 Oct;12(13):1255-65

Oldstone MB

Viral Immunobiology Laboratory, Division of Virology, The Scripps Research Institute, Department of Neuropharmacology, La
Jolla, California 92037, USA. mbaobo@scripps.edu

Molecular mimicry has been proposed as a pathogenetic mechanism for autoimmune disease, as well as a probe useful in uncovering its etiologic agents. The hypothesis is based in part on the abundant epidemiological, clinical, and experimental evidence of an association of infectious agents with autoimmune disease and observed cross-reactivity of immune reagents with host 'self' antigens and microbial determinants. For our purpose, molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either the molecules' linear amino acid sequences or their conformational fits may be shared, even though their origins are as separate as, for example, a virus and a normal host self determinant. An immune response against the determinant shared by the host and virus can evoke a tissue-specific immune response that is presumably capable of eliciting cell and tissue destruction. The probable mechanism is generation of cytotoxic cross-reactive effector lymphocytes or antibodies that recognize specific determinants on target cells. The induction of cross-reactivity does not require a replicating agent, and immune-mediated injury can occur after the immunogen has been removed a hit-and-run event. Hence, the viral or microbial infection that initiates the autoimmune phenomenon may not be present by the time overt disease develops. By a complementary mechanism, the microbe can induce cellular injury and release self antigens, which generate immune responses that cross-react with additional but genetically distinct self antigens. In both scenarios, analysis of the T cells or antibodies specifically engaged in the autoimmune response and disease provides a fingerprint for uncovering the initiating infectious agent.


Evidence for monoclonal expansion of synovial T cells bearing V alpha 2.1/V beta 5.5 gene segments and recognizing a synthetic peptide that shares homology with a number of putative autoantigens.

Immunology 1995 Oct;86(2):168-75

Ostenstad B, Dybwad A, Lea T, Forre O, Vinje O, Sioud M

Institute of Immunology and Rheumatology, University of Oslo, Norway.

A peptide of 15 amino acids derived from the cereal glycine-rich cell wall protein (GRP), sharing a significant homology with Epstein-Barr virus nuclear antigen-1 (EBNA-1), fibrillar and procollagen, stimulated synovial fluid (SF) T cells from juvenile (JRA) and adult (RA) rheumatoid arthritis patients. An over expression of the V alpha 2 gene family was found in the SF from patients who responded significantly to the peptide. To investigate in more detail the SF T-cell responses to the GRP peptide, we established peptide-specific T-cell lines and clones from a DR8+ positive JRA patient with pauciarticular form. The T-cell clones were phenotyped as T-cell receptor (TCR)alpha beta+/CD4+ and their clonality was investigated by polymerase chain reaction (PCR) and flow cytometric analysis. TCR sequences from different clones demonstrated that the clones were identical and used the V alpha 2. 1/J alpha 6 combined with V beta 5. 5/J beta 2. 7 gene segments. Interestingly, direct sequencing of the V alpha 2 family PCR product obtained from cDNA prepared from freshly isolated SF mononuclear cells identified the same TCR sequence as that used by the clones, suggesting the monoclonality of SF CD4+ T cells bearing V alpha 2. 1/J alpha 6 gene products. The present data suggest a recruitment and expansion of a SF T-cell subpopulation, and also support the hypothesis that autoimmune diseases can be triggered by protein epitopes with crucial amino acids homologous to self-proteins.


Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein.

Cell 1995 Mar 10;80(5):695-705

Wucherpfennig KW, Strominger JL

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138.

Structural similarity between viral T cell epitopes and self-peptides could lead to the induction of an autoaggressive T cell response. Based on the structural requirements for both MHC class II binding and TCR recognition of an immunodominant myelin basic protein (MBP) peptide, criteria for a data base search were developed in which the degeneracy of amino acid side chains required for MHC class II binding and the conservation of those required for T cell activation were considered. A panel of 129 peptides that matched the molecular mimicry motif was tested on seven MBP-specific T cell clones from multiple sclerosis patients. Seven viral and one bacterial peptide efficiently activated three of these clones. Only one peptide could have been identified as a molecular mimic by sequence alignment. The observation that a single T cell receptor can recognize quite distinct but structurally related peptides from multiple pathogens has important implications for understanding the pathogenesis of autoimmunity.


T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-2: potential for mimicry with rotavirus and other environmental agents.

Mol Med 1998 Apr;4(4):231-9

Honeyman MC, Stone NL, Harrison LC

Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
honeyman@wehi.edu.au

The tyrosine phosphatase IA-2 is a molecular target of pancreatic islet autoimmunity in type 1 diabetes. T-cell epitope peptides in autoantigens have potential diagnostic and therapeutic applications, and they may hold clues to environmental agents with similar sequences that could trigger or exacerbate autoimmune disease. We identified 13 epitope peptides in IA-2 by measuring peripheral blood T-cell proliferation to 68 overlapping, synthetic peptides encompassing the intracytoplasmic domain of IA-2 in six at-risk type 1 diabetes relatives selected for HLA susceptibility haplotypes. The dominant epitope, VIVMLTPLVEDGVKQC (aa 805-820), which elicited the highest T-cell responses in all at-risk relatives, has 56% identity and 100% similarity over 9 amino acids (aa) with a sequence in VP7, a major immunogenic protein of human rotavirus. Both peptides bind to HLA-DR4(*0401) and are deduced to present identical aa to the T-cell receptor. The contiguous sequence of VP7 has 75% identity and 92% similarity over 12 aa with a known T-cell epitope in glutamic acid decarboxylase (GAD), another autoantigen in type 1 diabetes. This dominant IA-2 epitope peptide also has 75-45% identity and 88-64% similarity over 8-14 aa to sequences in Dengue, cytomegalovirus, measles, hepatitis C, and canine distemper viruses, and the bacterium Haemophilus influenzae. Three other IA-2 epitope peptides are 71-100% similar over 7-12 aa to herpes, rhino-, hanta- and flaviviruses. Two others are 80-82% similar over 10-11 aa to sequences in milk, wheat, and bean proteins. Further studies should now be carried out to directly test the hypothesis that T-cell activation by rotavirus and possibly other viruses, and dietary proteins, could trigger or exacerbate beta-cell autoimmunity through molecular mimicry with IA-2 and (for rotavirus) GAD.

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