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Molecular Mimicry in Autoimmune Disease 448 Arch Dis Child 1998;79:448–451 Arch Dis Child: first published as 10.1136/adc.79.5.448 on 1 November 1998. Downloaded from CURRENT TOPIC Molecular mimicry in autoimmune disease Susan Leech α Chain The origins of autoimmune disease are multi- factorial. Environmental factors and a genetic Bone β marrow 2 Microglobulin predisposition result in tissue injury caused by Processed autoreactive T cells or antibodies. Usually a antigen single organ or individual cell type is aVected in the absence of gross abnormalities of the t Primitive T cell immune system. Autoimmune diseases tend to Thymus have long, asymptomatic prodromal periods and the initiating events leading to loss of Cell self tolerance occur long before the disease Positive selection becomes clinically manifest. This makes the Selects T cells that can bind to initiating factors harder to identify and they MHC. Removes cells that cannot be Figure 1 MHC class I: remain largely unknown in humans. HLA A, HLA B, HLA recognised C—for example, HLA B27. Several diVerent pathological processes have Expressed on the surface of the potential to break tolerance and cause Negative selection virtually all cells except autoimmune disease. Antigenic similarity be- Removes strongly self reactive mature erythrocytes and tween pathogenic organisms or foreign pro- T cells trophoblast cells. Presents 99% antigen (processed peptides) teins and self proteins (molecular mimicry) is Apoptosis to CD8 T cells. Comprises one of them. an á polypeptide chain and The major histocompatibility complex â2 microglobulin (invariant). (MHC) is a collection of genes on chromo- 1% some 6 that codes for the human leucocyte T cell receptor CD3 Processed antigens (HLA). These are glycoproteins CD4 or CD8 antigen expressed on the surface of cells that bind short α chain peptides, degraded or generated by the cell, T Mature T cell http://adc.bmj.com/ β Chain and present them to T lymphocytes (figs 1 and 2). The term “molecular mimicry” was used in the 1970s to explain persistent viral infections. Figure 3 T cell development and thymic education. Antigen It was suggested that the MHC and viruses presenting encoded similar peptide sequences, which cell allowed the host to regard an infecting virus as develop a T cell receptor (containing CD3) on “self” and forego an immune response. More the cell surface along with an accessory recently, it has been used as a hypothesis to molecule; either CD4 or CD8. The primitive T on September 27, 2021 by guest. Protected copyright. Figure 2 MHC class II: cells undergo both positive selection, which explain autoimmune disease.1 Several patho- HLA DP,HLA DQ, HLA selects cells able to interact usefully with DR—for example, HLA gens share antigenic determinants with host peptide presented by MHC, and negative DR3. Constitutively proteins. Often, these are used to gain entry expressed on the surface of selection, which deletes cells that are strongly into the cell; rhinovirus binds to an adhesion macrophages, monocytes, reactive with self or are unable to interact with dendritic cells, and B molecule, ICAM-1, on epithelial cells,2 and presented peptide antigens. Positive and nega- lymphocytes. Presents human immunodeficiency virus (HIV) binds antigen (processed peptides) tive selection occur using MHC present on to CD4,3 and enters the cell using a chemokine to CD4 T cells. Comprises cells within the thymus; it is postulated that an á and â polypeptide receptor. Most infections result in a specific much of the peptide presented by this MHC is chain. immune response against the infecting organ- derived from MHC itself.4 The process of ism. Cross reactivity may occur between the thymic selection eliminates 99% of precursor clones of T and B lymphocytes generated cells, which undergo apoptosis (programmed against an infecting agent and a host protein cell death), leaving only 1% to reach the sequence (immunological crossreactivity). periphery. The T cell receptor repertoire This “hit and run” mechanism could be generated allows a certain degree of self Department of Child induced to persist long after the pathogen has reactivity in return for a reasonably compre- Health, King’s College disappeared, by the presence of autoantigens hensive coverage of foreign antigens. School of Medicine driving the immune response. and Dentistry, If a foreign peptide (such as a virus) resem- Bessemer Road, bles these MHC derived peptides, it has the London SE5 9PJ, UK How does molecular mimicry occur? potential to activate such T cells. If a self anti- S Leech During T cell development, primitive cells gen is also structurally similar, exposure to the Correspondence to: leave the bone marrow and enter the thymus foreign peptide results in these activated T cells Dr Leech. (fig 3). During the subsequent three weeks they becoming autoreactive. Molecular mimicry in autoimmune disease 449 Arch Dis Child: first published as 10.1136/adc.79.5.448 on 1 November 1998. Downloaded from 3 Autoimmune tant. Early work suggested an association of the 1 Positive selection disease MHC class I molecules, HLA B8 and HLA in the thymus B15, with diabetes. Later, stronger associations were found with the class II molecules HLA Attacks DR3 and HLA DR4. The class II associations MHC derived were assumed to be a result of the B8−DR3 and peptide − expressed on Self/target antigen B15 DR4 linkage disequilibrium (that is, that MHC in thymic 1 Self reactive 3 (for example, on these alleles appear together on the same chro- epithelium T cell pancreas or mosome more often than their single gene fre- small bowel) quencies suggest). The DR3−DR4 heterozy- gote had a greater risk and HLA DR2 was protective. Identical twins have a relatively low (45%) concordance rate for IDDM. There is strong evidence for an environmental trigger 2 such as coxsackie virus, rubella, and Myco- plasma pneumoniae. Diabetes occurs in up to 2 Upregulation 7 Pathogen 20% of patients following congenital rubella. by or Three way molecular mimicry exists between a food peptide of carboxypeptidase H (an enzyme Foreign antigen expressed within islet cell granules and an β autoantigen) and a peptide of the â chain of (for example, casein, coxsackie B4, adenovirus 12) HLA DQ, which is processed and presented by Figure 4 Three way molecular mimicry. HLA DR4,8 and peptides of coxsackie virus “Three way molecular mimicry” is thus said coat protein. Another sequence in the â chain to exist between peptide sequences of three of HLA DQ resembles the islet cell autoantigen diVerent origins: jun B (a nuclear transcription factor against (1) the MHC, which is critically involved in which T cell autoreactivity has been 9 thymic T cell selection demonstrated), and the islet cell antigen, ICA 10 (2) foreign antigens (such as bacteria, viruses, 512, has similarities with peptides in human or food), which upregulate antigen presen- herpesvirus 1 (herpes simplex virus 1) and 4 tation and provide co-stimulation (Epstein-Barr virus). (3) self or target antigens, which are recog- nised by self reactive T cells (fig 4). COXSACKIE VIRUS Identification of the mechanism of molecu- In the 1970s, epidemiological studies sug- lar mimicry fuses the influences of genetics and gested an association between diabetes and the environment into a single pathogenic proc- viral infections. Several studies demonstrated ess and is a powerful hypothesis in diseases raised titres of both IgM and IgG antibodies to where both can be shown, epidemiologically, to coxsackie virus and later to coxsackie B4 in newly diagnosed type 1 diabetics. Initially, the have an influence. http://adc.bmj.com/ association of coxsackie virus was thought to be a result of its tropism for â cells,11 which might Ankylosing spondylitis cause damage to these cells and initiate For example, in diseases with a genetic predis- autoimmunity. More recently, autoimmune position, the contribution of environmental reactivity of T cells to the â cell enzyme factors to the pathogenesis can be estimated by glutamic acid decarboxylase (GAD; an enzyme the incidence of the disease in identical twins. that catalyses glutamic acid to ã aminobutyric The drop in concordance from 100% is an acid (GABA)) has been shown to be important on September 27, 2021 by guest. Protected copyright. index of the size of the influence of environ- in the pathogenesis of diabetes.12 The major mental factors. Ninety five per cent of patients peptide determinant of GAD recognised by with ankylosing spondylitis carry the HLA B27 patients with diabetes has a significant se- allele compared with 7% of the general quence similarity to a 15 amino acid sequence population. Fifty per cent discordance in within the P2-C protein of coxsackie B virus. monozygotic twins implies a significant envi- Antibodies to the P2-C protein cross react with ronmental factor. It was suggested that this GAD 65 and vice versa, suggesting that might be a result of mimicry between HLA molecular mimicry might be responsible for B27 and a microorganism. Several microbial the disease.13 agents (klebsiella, yersinia, and shigella) were Finland has one of the highest incidences of epidemiologically associated with the disease. diabetes in the world (0.6%). In 1995, as part In 1979, cross reactivity between HLA B27 of Akerblom and Tuomilehto’s childhood positive lymphocytes and a klebsiella antigen 5 diabetes in Finland study group, a prospective was reported. The association has now been study suggested antenatal exposure to cox- linked to the presence of an amino acid sackie enterovirus increased the risk of diabetes sequence, QTDRED (table 1), in the nitroge- in the child (particularly if onset was before 3 nase protein of klebsiella and in HLA B27 14 Table 1 Abbreviations 6 years of age). Serologically verified enterovi- used for amino acids (amino acids 72–77). rus infections were twice as common in siblings who developed clinical diabetes compared with Q Glutamine T Threonine Insulin dependent diabetes siblings who remained non-diabetic, several D Aspartic acid In humans the HLA associations of insulin years before diagnosis.
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