TIBS 18 - APRIL 1993 119-125 9 Bairoch, A. and Boeckmann, B. (1992) Nucleic Acids Res. 20, 2019-2022 10 Hollingshead, S. K., Rschetti, V. A. and Scott, J. R. (1986) J. BioL Chem. 261, 1677-1686 11 Frithz, E., H6den, L-O. and Lindahl, C. (1989) MoL MicrobioL 3,1111-1119 12 Gomi, H. et aL (1990) J. Immunol. 144, 4046-4052 13 Heath, D. G. and Cleary, P. P. (1989) Proc. Natl Acad. ScL USA 86, 4741-4745 14 Torigoe, H. et aL (1990) Biochemistry 29, 8787-8793 15 Uan, L-Y. et al. (1991) Biochemistry 30, 5335-5340
AUTOIMMUNE DISEASES constitute a major medical problem which encompass a spectrum of conditions, some common (e.g. rheumatoid arthritis), some rare (e.g. primary biliary cirrhosis, PBC), some highly targeted (e.g. autoimmune thyroiditis) and some systemic (e.g. systemic lupus erythematosus). Despite this variety they have in common a breakdown in tolerance, whereby the immune system attacks self (see glossary). They are frequently characterized by the presence of autoantibodies against specific self proteins. Some diseases, such as multiple sclerosis and insulin-dependent diabetes, have been subject to massive research effort, but no clear disease mechanism has been established for these, or any other autoimmune disease. This article outlines an hypothesis for such a mechanism.
Role of class II human leucocyte antigens (HLA) The cell-surface heterodimeric molecules encoded within the MHC are central to immune responses. In humans these are termed HLA molecules (for human leucocyte antigen). The function of HLA molecules is to display peptides, derived from intracellular enzymatic processing of self and foreign proteins, to the antigen receptors of T lymphocytes (for reviews see Refs 1, 2). HLA molecules are broadly classified based P. Butler and A. K. Burroughs are at the Hepato-biliary and Liver Transplantation Unit, Royal Free Hospital and School of Medicine, Pond Street, Hampstead, London, UK
NW32QG.M. J. E. Sternbergis at the BiomolecularModellingLaboratory,Imperial CancerResearchFund,POBox123, 44 Lincoln'sInn Fields,London,UK WC2A3PX. B. Baum and B. Davies are at the Schoolof Life BasicMedicaland Health Sciences,King'sCollege,CampdenHill Road, London,UKW8 7AH.
16 O'Toole, P., Stenberg, L., Rissler, M. and Lindahl, G. (1992) Prec. Nat/Acad. Sci. USA 89,
8661-8665 17 Gierasch, L. M. (1989) Biochemistry28, 923-930 18 McLachlan,A. D. (1987) Cold Spring Harbor Syrup. Quant. Biol. 52, 411-420 19 Jeffreys, A. J. (1987) in Genetic Engineering
(Williams, R., ed.), Vol. 2, pp. 1-48, Academic Press 20 Dayhoff, M. 0., Barker, W. C. and Hunt, L. H. (1983) Methods Enzymol. 91, 524-545 21 Shuttleworth, H. L. et aL (1987) Gene 58, 283-295 22 Stone, G. C. et al. (1989) J./mmunol. 143, 565-570
23 Heath, D. G., Boyle, M. D. P. and Clean/, P. P. ~1990) MoL Microbiol. 4, 2071-2079 24 Derrick, J. P. and Wigley, D. B. (1992) Nature
359, 752-754 25 Feng, D-F. and DoolitUe, R. F. (1987) J. Mol. BioL 48, 443-453 26 Devereux, J., Haeberli, P. and Smithies, O. (1984) Nucleic Acids Res. 12, 387-395 27 Rschetti, V. A., Pancholi, V. and Schneewind, O. (1990) MoL MicrobioL 4, 1603-1605 28 Needleman, S. B. and Wunsch, C. D. (1970) J. MoL BioL 48, 443-453 29 Barton, G. J. and Steinberg, M. J. E. (1987) J. MoL BioL 198, 327-337 30 Hein, J. (1990) Methods Enzymol. 183, 626-645
Autoimmune disease and molecular mimic,ry:,,an hypothesis
Helper T lymphocytes are normally only stimulated to initiate an immune reaction through the recognition of peptides bound to class II major histocompatibility complex (MHC) molecules. Class II MHC molecules are constitutively expressed on antigen-presenting cells which play a critical role in the initiation of immune responses. In disease states, however, other cells often express class II MHC molecules inappropriately. This article suggests an hypothesis for the pathogenesis of autoimmune diseases based on molecular mimicry. The mimicry described is between microbial or viral peptides presented by antigen-presenting cells and self peptides presented inappropriately on a target tissue. This leads to helper T cells, stimulated by peptides derived from infectious organisms, initiating an autoimmune attack on the target tissue.
on their structure, locus within the MHC, and phenotype of the corresponding acceptor T cell. Of particular interest to us are the class II HLA molecules normally expressed only on antigenpresenting cells such as macrophages and B lymphocytes, but which may also be 'inappropriately' expressed on other cell types, e.g. under the influence of interferon 7. These molecules are alSheterodimers which, during assembly and export to the surface of these cells, pass through compartments of the endocytic pathway where they pick up peptides usually arising from the enzymatic processing of endocytosed proteins. Thus, peptides associated with class II HLA molecules are derived largely from a variety of recycled membrane proteins (cell-surface receptors and other HLA molecules), the invariant
(or I') chain (a chaperone for class II HLA molecules which is cleaved off in the endosomes) and proteins of extracellular origin, including endocytosed foreign proteins ~. These peptides are then specifically presented at the cell surface to T cells expressing the CD4 marker. By contrast to class II antigens, class I HLA are found on all nucleated cells (with the probable exception of cells of the central nervous system) and present peptides derived from proteins synthesized in the cell, including foreign ones arising from viral infection. Foreign peptides presented on class I antigens are recognized by cytotoxic, CD8 T cells. T cells that might respond to selfpeptides presented by HLA molecules are normally eliminated or silenced dur-
© 1993, Elsevier Science Publishers, (UK) 0968-0004/93/$06.00
TIBS 18 - APRIL 1 9 9 3
ing their development. This is the basis of self-tolerance, a condition that is breached in autoimmune disease. The molecular mechanism(s) underlying tolerance are still largely obscure, and it seems, for example, that tolerance for peptides presented by class ! HLA is achieved in a variety of ways. lmmunoglobulin-synthesizing cells, B lymphocytes, initially interact with their specific antigen via surface-bound immunoglobulin, and then present fragments of it to CD4 T cells. The function of most CD4 T cells is to provide signals to such activated B cells, in the form of lymphokines, to promote their differentiation into antibody-secreting plasma cells 7. Most B cells have an absolute requirement for such 'help' such that we all safely possess B cells capable of producing autoreactive antibodies, but which are prevented from doing so by mechanisms of tolerance at the helper T cell level. HLA molecules are remarkably polymorphic: an individual may inherit between 6 and 12 allelic variants selected from a gene pool consisting of several dozen alleles. These alleles differ from each other in the topography of their peptide binding site, which is visualized as a deep cleft. Class I HLA usually accommodate peptides of around 9 amino acids in their clefts e-l°, whereas the peptides accommodated by Class II molecules are more heterogeneous in size, usually 13-18 residues ~,u. While the variety of different peptlde sequences that can be accommodated by the cleft may run into thousands, there exists selectivity in binding. Peptides associated with each allele possess common 'anchor' residues that interact with subsites (or 'pockets') located within the cleft. Hence, the ability of an individual to respond to a particular antigen is determined in part by the HLA molecules expressed. For reasons that have never been explained satisfactorily, many autoimmune diseases are much more prevalent in individuals expressing particular HLA alleles. The most striking association is the class I allele HLA-B27 with ankylosing spondylitis, a chronic inflammatory disease primarily affecting the axial skeleton and especially the sacroitiac joints. There are similar associations with the expression of certain class II alleles found at the HI.A-DR locus; notably DR4 and Dw4 with rheumatoid arthritis, and DR3/DR4 heterozygosity with insulin-dependent diabetes. Polymorphism in these latter
Glossary /~tlgen processing. Enzymaticdegradation of antigen into peptides prior to complexingwith MHC molecules and presentation of the peptides to the antigen receptors of T lymphocytes.
Autolmmunedisease. Pathologyarising from breakdownof tolerance. B lymphocytes. Lymphocytes that secrete immunoglobulin (antibody). B cells endocytose antigen via surface immunoglobulin, process it into peptides and transport these to the cell surface within class II MHC molecules for presentation to CD4 helper T lymphocytes. B cells become activated during antigen processing and are thus receptive to the stimulatory cytokines produced by helper T cells. CD4. An accessory molecule found on helper T lymphocytes. CD4 binds to class II MHC molecules on B lymphocytesor other antigen-presentingcells and enhances antigen-specific interactions between the cells. CDS. An accessory molecule found on cytotoxic T lyrnphocytes. CD8 binds to class I MHC molecules on target cells and enhances antigen-specific interactions between the cells. Cytotoxlc T lymphocytes. A subset of T lymphocytes (usually CD8 positive) that kill vitally infected or neoplastic cells of the body. Epitope. The part of an antigen recognized by an antigen receptor. Receptors on B lymphocytes are immunoglobulins,which recognize epitopes that are areas on tho antigen surface. T-cell receptors recognizeepitopesthat are processed antigenfragments (peptides)presented by MHC molecules on other cells. Helper T lymphocytes.A subset of T lymphocytes(usually CD4 positive); some release cytokines that stimulate antibody production by activated B lymphocytes. MHC molecules.Polymorphiccell-surfacemoleculesthat present antigenic peptidesto T tymphocytes; encoded within the cluster of genes called the major histocompatibiUtycomplex (MHC). In humans they are known as human leucocyte antigen (HLA) molecules. Tolerance. A state of immunological unresponsiveness that prevents the immune system from mounting damaging responses against self-antigens; maintained by deletion, suppression or paralysis of potentially autoreactive lymphocytes.
alleles is in the -chain; the a-chain of all DR alleles is the same. In order to interact with a universe of different antigenic peptides, the T-cell recepto~r repertoire is correspondingly very large. Indeed, each receptor, the product of random recombination of separate gene elements, is unique and clonally distributed. The ligand for each receptor ~s conventionally understood to be a sp,eciflc peptide-HLA molecular complex (Fig. 1). However, there are increasing numbers of examples to suggest that some T cells may 'cross-react' with unrelated peptides. Whether or not there is cross-reactivity, the consequences of a T-cell receptor interaction with a peptide--HLA ligand is activation. Helper T cells release lympholdnes which initiate the cascade of an immune response, including antibody production from activated B cells that also recognize the same antigen, and the activation of cytotoxic CD8 T cells.
Molecular mimicry and PBC Primary biliary cirrhosis (PBC), is a rare, often fatal disease, mainly affecting middle-aged women, which involves a gradual, progressive obliteration of the intrahepatic bile ducts. A fascinating feature is the presence of high and persistent titres of antimitochondrial antibodies (see below). Against the back-
ground summarized above, we have recently put forward an hypothesis to explain the pathogenesis of PBC~2 and now wish to extend it to other autoimmune diseases. The hypothesis for PBC is based upon a striking similarity that we have identified between two peptide sequences. One of these (F_,AQGALANIAVDKANLE) is an invariant sequence in the a-chain of the human MHC class ll antigen, HLA DR. Significantly, a fragment, identical to the human peptide, derived from the a-chain of the corresponding and highly homologous mouse class ll MHC antigen, is a self peptide presented by two other mouse class II antigens, I-Ab (Ref. 3) and I-Ad (Ref. 6). The other sequence (EAEQSLITVEGDKASME) is in the lipoyl domain of the E2 subunit of the pyruvate dehydrogenase complex (PDC) of E. coil Homologous E2s are found in a number of microbial and mitochondrial oxoacid dehydrogenase complexes and each may be a target antigen for the polyclonal antimitochondrial antibodies that are characteristic of PBC*. The major autoantigen of this set is mitochondrial PDC-E2, whose immunodomi*For a comprehensive review of the occurrence, specificities and significance of antimitochondrial antibodies see: Baum, H. in Current Topics in Bioenergetics (Vo/17) (Lee, C. P., ed.), Academic Press(in press). 141
TIBS 18 - APRIL 1993
possible that such class 11 molecules might also present, under some circumstances, the mimicking peptides arising from intracellular processing of self E2s. The response would be somewhat analogous to the graft-versus-host reaction that occurs when ,) donor T cells initiate an immune reaction against host cells presenting antigens that are foreign to the donor animal. In this respect the process would be comparable to an animal model of PBC which is an experimentally induced graft-versus-host reaction in (B6 × bml2) FI mice receiving CD4-positive T cells from B6 donor mice19. Cross-reactive Rgum 1 helper T cells are thus proSchematic representation of the specific interaction of posed to initiate an autoa peptide with a class II HLA molecule and co-recogimmune cascade. Such a nition of the HLA-peptide complex by a T-lymphocyte reaction could, inter alia, clo.e bearing a specific antigen receptor. Accessory give rise to autoantibodies molecules involved in this interaction have been omitagainst self antigens. ted for clarity. In PBC, autoantibodies against the E2s of the nant epitope is in the corresponding mitochondrial oxo-acid dehydrogenase llpoyl domain, around the amino acid complexes would be produced owing to residues DKAIs. We have also pointed their possession of HLA-blnding pepout I~ that a partially similar sequence tides mimicking those of the infecting that includes DKA is found in muscle organism. The spectrum of autoglycogen phosphorylase, and sulphite antibodies thus arising could be nonoxldase. Autoantibodles (designated re- overlapping, although all of the correspectively M9 and M4) against these sponding B-cell clones might be driven enzymes are also characteristic of by a common set of helper T cells. PBCi4,1s.
MHC class !1 molecules are inappropriately expressed on bile duct epithelial cells in PBCle, and the disease is frequently associated with recurrent urinary tract infection 17. Furthermore, patients with such infections but normal liver function frequently exhibit low titres of antibody against both mitochondrial and microbial E2sla. in the light of these findings, we have proposed that the EAEQSLITVEGDKASME peptide of microbial E2 (or a close homologue) is presented by MHC class II on antigen-presenting cells. T-helper cells stimulated by this peptide might then, through a process of molecular mimicry between the respective peptides, initiate an autoimmune response against any tissue 'inappropriately' expressing, on MHC class II, the self peptide derived from HLA-DRa. It is also
Generalization of the mimicryhypothesis
I! expression, a predisposition, in terms of the DRa fragment being preferentially presented, and a 'priming' by a chronic bacterial infection. Also, it should be borne in mind that PBC is not exclusively a liver disease. Other secretory ducts are affected, and there are frequently other immunological derangements'. Instead, our hypothesis focuses on a general concept of mimicry between a motif on an environmental immunogen and a corresponding sequence presented as a self peptide by an MHC molecule on any target tissue. Thus the model is not intended to be limited to mimicry with the HLA-DRa motif that we have discussed. In particular, we believe that it will be fruitful to explore possible mimicry with the invariant (T) chain of HLA class If, a specific peptide of which has been shown to be a major self-antigen presented by class !! molecules in three separate studies 3,4,~. Nevertheless, the potential significance of the model may be assessed by consideration of the nature of other proteins bearing the DRa motif.
Other proteinsbearingthe DRa motif A more general structure of the DRa motif, which matches the DRa and E. coil E2 sequences and allows for conservative substitutions at positions 1, 6 and 11, can be defined as: [EDKRH]Xc [AIVL]X~[GAILV]DKAX2E,where [ ] includes a set of allowed residues. A protein motif search program PROMOT~ was used to identify proteins with matching sequences. Using this program to search the OWL data base of 44702 protein sequences, and even allowing one mismatch at positions 1, 6, 11 or 17, only about 75 other proteins (or protein families) were found to meet this criterion. (Note that the deftnition chosen was too stringent to select the iipoyl domains of many members of the highly conserved family of E2 peptides.) Among this very limited set of proteins (see Table 1) are only seven human proteins:
Although the present hypothesis focuses for the first time on specific motifs known to be associated both with autoantigens and peptides presented by HLA; but otherwise it is not entirely novel. Molecular mimicry of various kinds has frequently been adduced as a possible basis for autoimmune disease 7,2°-2s. Moreover, the hypothesis does not attempt to explain (1) The asialoglycoprotein receptor in detail the precise set of conditions (hepatic lectin HI); which is the that determine the breaking of toler'liver-specific protein' known to be ance, although there indeed is now evian autoantigen in chronic active dence that infection can lead to the hepatitis 2s. Class 11HLAare inapprobreaking of tolerance to self antigens 2e. priately expressed on hepatocytes The question of tissue specificity of the in that disease; and the autoantidisease is also not dealt with explicitly. body is also frequently associated with PBC29,3°. It might be that in PBC this arises from a particular co-incidence of a triggering (2) The insulin receptor, antibodies to event (e.g. inflammation) leading to class which are found in diabetes.
TIBS 18 - APRIL 1 9 9 3
(3) Glutandc acid decarboxylase (GAD), identified as the 64 kDa autoantigen associated with the onset of Type I diabetes mellitus31. (4) The mitochondriai matrix protein P1, corresponding to the P60 lymphocyte protein and to the heat shock protein, hsp65. This is inappropriately expressed on bile ducts in both PBC and primary sclerosing cholangitis 32, but such cell-surface expression of hsp is not confined to liver disease; it has been detected in other autoimmune diseases 33,34 and can be induced by viral infection 3s. (5) Human vimentin. (6) The DNA binding and high-mobilitygroup protein HMG I. (7) The DNAbinding factor GRFI.
Table I. Some proteins bearingthe 'HLA-DRa' motif, speculated as underlyingsome autolmmune processes Self T-cell epltope Putative
HLA DRe (human)
Asialoglycoprotein receptor (human)
Insulin receptor (human)
Glutamic acid decarboxylase (human) 430 D K H Y D L S Y D T G D K A L Q C Hsp65 (human)
358 K D D A M L L K G K G D K A Q I E
High-mobility group protein HMG1 (human)
PDC E2 II (E. coh)
E L R R Q V D Q L T N DKA
S Q E
132 E A E Q S T. I T V E G D K A S M ~-
environmental Hsp70 (Trypanosoma brucei) 176 :. P T A A A Z A Y G T. D K A D E G
FcrV protein(Streptococcus) 326 D L g A K T. D E A N A D K A K T. :. RtbAprotein(Salmonella 57 V I V N A A A H T A V D K A E S E typhimurium) Pedplasmicprotein 144 P E D K V I A K A A A D K A A A E (Treponemapallidum) Protein HHLF1 181 E V D P AA D P T L GDKA G H P (Cytomegalovirus) 709 G I R K V L F L D G X D K A Q D E Pol (HIV1) 158 K N S P T L C Q K F V D K A I L T Pol (MMTV)
The occurrence of hsp65 in the list is interesting since there is extensive evolutionary conservation of the structure of hsp, and mimicry between hsps of pathogens, self hsps and self proteins bearing common epitopes has been speculated as the basis of many autoimmune diseases from ulcerative colitis, Sequences were identified from the database according to the first algorithm defined in the text. systemic lupus erythematosus and Letters in heavy type are residues which are identical or are conservative substitutions (as defined rheumatoid arthritis, to experimentally in our search) to corresponding ones in HLA-DRa. induced adjuvant arthritis and autoimmune diabetes 22-2s. For example, it has been reported that hsp65 serologically E2s, sulfite oxidase (the M4 antigen of cross-reacts with GAD In connection Significance of Identified mimicries In order to assess the significance of PBC) and 11 other human proteins. with Type I diabetes in man3~. Exogenous hsps are known to be such a high proportion (four out of These included two heat shock proteins major targets of human immune re- seven) of the human proteins that bear (hsp60/65 and hsp70), cytochrome sponses to pathogens, and antibodies the defined motif being of relevance to P450 II BI, [~enolase and the insulin and T cells against these have been autolmmune disease, we repeated the receptor. Other species of cytochrome detected not only in bacterial infection, sequence search but with the sequence P450 are known autoantigens 37, and but also in infection with protozoan DKA at positions 12-14 being replaced enolase is an autoantigen in autoimparasites, it is therefore also of interest by AKD. Only three human proteins mune vasculitis 38. that our algorithm has also identified as were identified, none of which is a potential immunogens hspT0 from a known autoantigen. As a further test we Implications of the hypothesis Apart from such comparative searches, schistosome and from Trypanosoma searched a more scrambled motif but
bacter, Clostridium, Myxococcus, Pseudomonas, Salmonella, Streptococcus and Treponema as well as human para-
still with the same set of defined residues as in the original motif. The reason for scrambling rather than searching a completely random sequence as a control is that any bias relating to the frequency of occurrence of the various
influenza virus, cytomegalovirus and human immunodeficiency virus (I-lPO. In the last case, the protein is Pol, the reverse transcriptase characteristic of retroviruses, and it is interesting that whilst the corresponding peptide of Pol of the mouse mammary tumour virus (MMTV) is also in the set selected by the algorithm, the only identities between the two peptides are those defining their common similarity to the DRa peptide.
amino acids is thereby avoided. This search selected nine sets of human sequences, only one of which, the heat shock protein hspT0, is of any obvious relevance to autoimmunity. As a further test, we redefined the motif with a shorter sequence to match more closely the sequence of the E2 of human PDC, rather than that of E. coli.: [AIVL][AIVL][EOKR][AIVL]SXGDKAX[AIVL]. A search of this sequence selected, in addition to DRo~and a set of other
brucei. Other potential environmental immunogens are proteins from Campylo-
there is no obvious way of assessing the significance of the sets of sequence matches that we have identified since most proteins must be considered as potential autoantigens, although fewer than 100 have been identified as such.
Nevertheless, the basic hypothesis does appear tenable and we draw attention to how infection with an appropriate pathogen could stimulate helper T cells that might subsequently, through molecular mimicry, initiate a 'pseudo graft-versus-host' attack on cells expressing class II HLA presenting the DR(~ fragment. These could, for example, be islet cells responding to an independent environmental challenge. An outcome might then be, again 143
TIBS 18 - A F R I L 1 9 9 3 through molecular mimicry, the stimulation of the production of antibodies against islet glutamic acid decarboxylase as markers of the onset of Type I diabetes. Similarly the immune response to the Pol peptide presented on some HW-infected T cells, could lead, through an analogous mechanism, to a generalized autoimmune cascade involving all T cells presenting the mimicking self-epitope. An even more striking similarity than the one between corresponding motifs on Pol and DRy, is that between HLA-DR[~ (residues 142-151) and gpl20 HIV (residues 254-263) 39. if the DR[~ decapeptide were shown to be a self peptide presented by class 11 antigens, then a similar, but even stronger argument would apply.
H~ association with specific disease As mentioned earlier, particular HLA types may be associated with specific diseases. Interestingly, it has recently been shown that a major self peptide presented by HI.A-DR may be derived from a class ! HLA antigen 4. Our hypothesis would suggest that mimicry with specific class I peptides (as well as peptides from class !i antigens) might account for such associations. This is already the basis of an analogous hypothesis for the strong association of HLA-B27 (a class ! antigen) with ankyiosing spondylitis, in relation to infection with Klebsiella zl, Of relevance in this connection is the fact that the peptide EQKRAA, found in the class il antigens HLA DR4/Dw4 and HLA DR9 (both associated with rheumatoid arthritis), is found in only one non-MHC protein in the database, glycoprotein B of human herpes virus 4 (Epstein-Barr virus). This virus has been speculated to be associated with the pathogenesis of rheumatoid arthritis. However, it remains to be tested whether EQKRAAcontaining peptides can be presented by HLA antigens,
Conclusion These, admittedly very speculative, examples encourage us to believe that our hypothesis may indeed have a general bearing on the pathogenesis of autoimmune disease. These ideas now need to be vigorously and rigorously tested. For example, cloned T helper cells can be used to identify stimulatory peptides which could then be matched with those in infectious organisms, or with self peptides. The peptides in the class II HLA cleft in autoimmune target tissues can be isolated, their sequences
identified, and lymphocyte responses explored. If the hypothesis withstands such tests, then it would open up exciting prospects for the prevention and/or treatment of autoimmune diseases and even for the initiation of autoimmune attack on any tumour that expresses, or can be made to express, class I! HLA presenting a characteristic self peptide.
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