autoimmune diseases are complex immune - mediated diseases that involve both genetic and environmental factors in their pathogenesis . infectious microorganisms have long been suggested to trigger an immune response to autoantigens by providing stimuli for the breakdown of self - tolerance and also by generating cross - reactive t cells and antibodies via molecular mimicry . molecular mimicry is a mechanism that has a proposed role in many autoimmune diseases such as acute rheumatic fever , rheumatoid arthritis , guillain - barr syndrome , multiple sclerosis , type 1 diabetes mellitus , and lyme arthritis . in autoimmune diseases , the concept of molecular mimicry has often been used to describe similar structures shared by molecules from dissimilar proteins , as illustrated by the -helical coiled - coil streptococcal m protein and cardiac myosin in rheumatic fever . however , some proteins such as heat shock proteins are evolutionally highly conserved from prokaryotes to eukaryotes . in this review , we explore the potential role of the evolutionary conserved bacterial proteins in the production of autoantibodies with focus on granulomatosis with polyangiitis ( gpa ) and rheumatoid arthritis ( ra ) . gpa ( wegener 's ) is a type of anca - associated vasculitis that affects small- and medium - sized vessels in many organs . its clinical symptoms include fever , fatigue , weight loss , nasal discharge , sinusitis , cough , dyspnea , hematuria , and proteinuria . pathologically , gpa is characterized by multi - focal granulomatous inflammation with central necrosis and necrotizing vasculitis . in addition , the presence of an anca in serum is used as a diagnostic marker . there are two types of ancas , i.e. , directed against either proteinase 3 ( pr3-anca ) or myeloperoxidase ( mpo - anca ) . the anca antigen specificity of gpa in european patients is predominantly pr3 , whereas that in japanese patients is predominantly mpo . the pathogenesis of necrotizing vasculitis is understood to involve infiltration of neutrophils into vessel walls and their subsequent activation . anca is known to mediate the activation of neutrophils and degranulation via crosslinking of the fc receptor and antigens expressed on the membrane . however , what causes the production of anca and granulomatous inflammation , is not known . chronic nasal carriage of staphylococcus aureus is increased in gpa patients compared to healthy subjects ( 63% vs. 25% ) , and the carriage of s. aureus increases the risk of relapse by 7.16 fold ( 9 ) . furthermore , the addition of trimethoprim / sulfamethoxazole to maintenance treatment reduced the relapses by 60% ( 10 ) . although the underlying mechanisms for the increased relapse by s. aureus is not clear , potential roles in polyclonal activation of b cells , priming of neutrophils , and induction of anti - idiotypic antibodies to pr3-anca have been suggested ( 6 ) . reported a new anca directed against lysosomal membrane glycoprotein 2 ( lamp-2 ) as a specific marker for focal necrotizing glomerulonephritis and showed that the autoantibodies to lamp-2 can be induced by immunization with fimh , a bacterial fimbrial adhesin of gram - negative bacteria ( 11 ) . the eight amino acids of one lamp-2 epitope ( p41 - 49 ) recognized by autoantibodies have a strong homology with the fimh of several common gram - negative species , suggesting molecular mimicry between the two proteins . we previously demonstrated that the membrane bound pr3 on neutrophils acts as a receptor for non - opsonic phagocytosis of bacteria and that the neutralization of pr3 with anca reduces both binding and phagocytosis of bacteria ( 12 ) . it raised the possibility that anca may be induced by some pathogens possessing a pr3-homologous protein to avoid host immunity . when the bacterial protein database was searched using the pr3 protein sequence as a query , hundreds of bacterial proteases with 28% to 36% identity were indeed found . among the bacteria containing pr3-homologous proteases , only vibrio cholerae , v. vulnificus , v. parahaemolyticus , and saccharomonospora viridis the spores of s. viridis , a gram - negative bacterium frequently found in hot compost and hay , can be readily dispersed in air . prolonged exposure to those spores can cause farmer 's lung , bagassosis , and humidifier fever that manifest symptoms such as fever , malaise , cough , and dyspnea similar to gpa ( 13 ) . granulomas are usually formed in an attempt to segregate foreign substances that are resistant to phagocytic clearance . if s. viridis induces anca production via molecular mimicry , the anca would inhibit phagocytosis of s. viridis . furthermore , if s. viridis survives after phagocytosis , infection with s. viridis may also contribute to the formation of granulomatous inflammation . already proposed evolutionarily conserved antigens as stimuli to cause breakdown of tolerance and reported well - conserved bacterial orthologs for pyruvate dehydrogenase complex e2 , glutamic acid decarboxylase , histidyl - trna synthetase , and enolase among seven major autoantigens examined ( 14 ) . therefore , we further explored the possibility that evolutionarily conserved bacterial proteins are involved in autoantibody production in ra , the most common systemic autoimmune disease . ra is characterized by the presence of diverse autoantibodies in serum and synovial fluid . rheumatoid factor ( rf ) is the first autoantibody described in ra , which is directed against the fc portion of igg , a major serum component ( 15 ) . the anti - citrullinated protein antibodies are a group of autoantibodies that recognize citrulline - containing peptides / proteins as common antigenic epitopes ( 16 ) . other antigens characterized as targets of autoantibodies in ra include type ii collagen ( cii ) , binding immunoglobulin protein ( bip ) , glucose-6-phosphate isomerase ( g6pi ) , -enolase , and heterogeneous nuclear ribonuclear protein ( hnrnp ) a2 ( 17 ) . homology search with the sequence of human immunoglobulin gamma-1 heavy chain constant region did not retrieve any bacterial proteins . when the ch2 and ch3 domains , the antigenic epitopes of rf , were searched separately , however , several bacterial proteins such as the cell wall binding repeat 2 family protein and cell surface protein of clostridium difficile were found to share 46% similarities with the ch2 over 76% of the domain . ra patients often contain high titers of anti - cii antibodies in sera and synovial fluids ( 19 ) . because cii is exclusively expressed in the cartilage , autoantibodies against cii induce joint destruction . surprisingly , a large number of bacterial species contain collagen triple helix repeat family proteins that share a high degree of identity ( 32~47% ) and homology ( 36~52% ) with human cii . among those , important human pathogens such as clostridium difficile and bacillus cereus ( 20,21 ) and a member of normal gut flora c. beijerinckii ( 22 ) bip ( also known as 78 kda glucose - regulated protein or heat shock 70 kda protein 5 ) , is a stress protein located in the endoplasmic reticulum . therefore , cellular and humoral immune responses initiated by microbial stress proteins may target cross - reactive self proteins , resulting in autoimmunity ( 24 ) . among the hundreds of bacterial species that contain a bip - homologous stress protein dnak , human pathogens such as bartonella spp . in addition to the pathogenic bacteria , a number of bacteria in the human oral flora such as prevotella spp . and atopobium parvulum contained the bip - homologous dnak . selective examples of bacterial dnak listed in table iii have 49~54% identities and 67~70% similarities with the human bip over 92% of the entire protein . glucose-6-phosphate isomerase ( g6pi ) is a ubiquitously expressed glycolytic enzyme that is also highly conserved through evolution . selected bacterial g6pis for several human - associated species present even higher identities ( 65~68% ) and similarities ( 78~80% ) than those observed in the stress protein bip ( table iv ) . the human - associated bacteria include both commensals and pathogens that colonize the respiratory tract , urinary tract , or gastrointestinal tract . given the high degree of similarity between the human and bacterial g6pis shown in table iv , it can be speculated that a large body of human - associated bacteria , including those in the normal flora , may share significant homology ( greater than 30% ) in their g6pis with the human protein . k / bxn mice spontaneously develop autoantibodies to g6pi and autoimmune arthritis ( 25 ) . the serum autoantibody titer and autoimmune arthritis in the k / bxn mice are significantly attenuated under germ - free conditions , which are reinstated by the introduction of a single gut - residing species , asegmented filamentous bacteria ( 26 ) . a homology search revealed that the g6pi of the segmented filamentous bacteria candidatus arthromitus sp . sfb - mouse - japan has 40% homology with a mouse g6pi , supporting the role of this bacterium in anti - g6pi antibody production . it is also expressed on the surface of stimulated leukocytes , and then serves as a plasminogen - binding receptor , which assists in inflammatory cell invasion ( 27 ) . the similar usage of enolase and plasminogen for the invasion of host tissue has been demonstrated by several pathogens ( 28 ) . interestingly , members of the normal flora in the oral cavity and gut express the enolase that shares a high degree of identity ( 51~55% ) and similarity ( 68~72% ) with the human -enolase ( table v ) . the enolases of several important human pathogens such as treponema denticola , turicella otitidis , clostridium botulinum , bacillus cereus , and neisseria meningitidis also have high degrees of homology with the human -enolase . the hnrnp a2 is an abundant rna - binding protein that is predominantly expressed inside the nucleus and involved in pre - mrna splicing , mrna transport , and translation ( 29 ) . although bacteria do not make mrna , a homology search using the hnrnp a2 retrieved 61 bacterial proteins that share 27~49% identities and 51~73% similarities with the first rna recognition motif ( rrm ) superfamily domain of hnrnp a2 . indeed , all retrieved bacterial proteins were rna - binding proteins . among them , variovorax paradoxus is a member of the human oral flora , and acidovorax avenae and delftia acidovorans are involved in catheter - related infection ( table vi ) . it is remarkable that most of the pathogenic bacteria listed in table ii~v have been reported to develop reactive arthritis , septic arthritis , or rheumatic symptoms ( 30 - 38 ) . accumulating evidence suggests that not only infectious but also indigenous microorganisms may be involved in the initiation and perpetuation of ra ( 39 ) . increased epithelial permeability , loss of immune tolerance , and trafficking of both microbial components and activated immune cells to the joints have been suggested as underlying mechanisms for the involvement of the indigenous bacteria ( 39 ) . we explored seven autoantigens for the presence of evolutionary conserved counterparts in the bacterial protein database . of the seven autoantigens , pr3 , cii , bip , g6pi , -enolase , and hnrnp a2 have well conserved bacterial orthologs . although there are no bacterial orthologs for human immunoglobulin gamma-1 heavy chain constant region , proteins with an immunoglobulin superfamily domain are found in bacteria . the wide distribution of the highly conserved dnak , g6pi , or enolase among the members of the normal flora and common infectious microorganisms rather raises the question on how cross - reactive autoantibodies are not produced during the immune response to these bacteria in most healthy people . understanding the mechanisms that deselect auto - reactive b cell clones during the germinal center reaction to homologous foreign antigens may provide a novel strategy to treat autoimmune diseases .
molecular mimicry is an attractive mechanism for triggering autoimmunity . in this review 
 , we explore the potential role of evolutionary conserved bacterial proteins in the production of autoantibodies with focus on granulomatosis with polyangiitis ( gpa ) and rheumatoid arthritis ( ra ) . 
 seven autoantigens characterized in gpa and ra were blasted against a bacterial protein database . 
 of the seven autoantigens , proteinase 3 , type ii collagen , binding immunoglobulin protein , glucose-6-phosphate isomerase , -enolase , and heterogeneous nuclear ribonuclear protein have well - conserved bacterial orthologs . 
 importantly , those bacterial orthologs are also found in human - associated bacteria . 
 the wide distribution of the highly conserved stress proteins or enzymes among the members of the normal flora and common infectious microorganisms raises a new question on how cross - reactive autoantibodies are not produced during the immune response to these bacteria in most healthy people . 
 understanding the mechanisms that deselect auto - reactive b cell clones during the germinal center reaction to homologous foreign antigens may provide a novel strategy to treat autoimmune diseases .