louis pasteur 's epochal germ theory of disease   triggered the fastest advance of medicine ever . the great host of infectious diseases , with their aetiology at last discovered , was soon substantially conquered . additionally , freed of inevitable wound infection , modern surgery was made possible , led by lister . in stark contrast to coombs and gell 's classification of harmful immune responses   was preautoimmunity , antediluvian , based on the misapprehension that paul ehrlich 's  horror autotoxicus , ehrlich   wrote that  possible failure of the internal regulation  of immune processes might be  the explanation of many disease phenomena . the independent demonstration of autoimmunity in four different laboratories [ 59 ] made coombs and gell 's classification obviously wrong , yet it lingered on for decades   as an inhibition to clarity of thought . table 1 shows a valid classification   based on awareness of autoimmunity and awareness that allergy is a defect of immune defence against worms and other parasites , being caused by the occurrence of b lymphocyte clones that secrete ige antibodies with specificity for nonparasitic foreign antigens . autoimmune diseases are caused by defects of immune specificity , which is determined by the amino acid sequence of the variable regions of the receptors for antigen on b and t lymphocytes , not by cytokines nor dendritic cells . niels jerne won the nobel prize for his epochal realization that antibodies are not formed on a template of antigen but are preformed , in myriad diversity , awaiting contact with an antigen that fits , the selection theory . macfarlane burnet realised that it is not antibodies that are selected but the cells that make them and that these cells are lymphocytes , whose unit of specificity is the lymphocyte clone , a subset of lymphocytes with identical receptors for antigen , hence , burnet 's clonal selection theory   of acquired immunity , today in general acceptance . however , widely neglected is burnet 's equally important forbidden clone theory , postulating that autoimmune disease is caused by somatic mutation in lymphocytes multiplying in response to a microbial antigenic stimulus . in 1838 , robert graves , in dublin , identified the syndrome of tachycardia , goitre , weight loss and exophthalmos , which bears his name as graves ' disease .   in 1933 , charles harington isolated thyroxine , the first hormone to be chemically isolated , and found the molecule to contain iodine atoms , explaining the cause of endemic goitre , which is due to deficiency of dietary iodine . in 1956 , adams and purves [ 17 , 18 ] in dunedin , using radioactive iodine for a bioassay of thyroid - stimulating hormone in baby guinea pigs , discovered a long - acting thyroid stimulator ( lats ) . this proved to be an autoantibody that causes thyrotoxicosis   by accidentally reacting with the thyroid gland receptor for thyroid - stimulating hormone from the pituitary gland , the conductor of the endocrine orchestra . affinity chromatography of thyroid - stimulating autoantibodies from individual patients shows that they contain only one of two possible antibody light chain types , k or  , but never both . therefore , these autoantibodies originate from single b lymphocytes in which a v gene has mutated . furthermore , the variation from patient to patient of reactivity with the slightly differing tsh receptors of various nonhuman animals shows the random element in the somatic mutations forming the thyroidstimulating autoantibodies . in 1971 allison et al .   postulated that lack of suppressor t cells causes the autoimmune diseases . in 1975 nachigal et al .   proposed that on meeting antigen , mature t cells become helpers and immature t cells become suppressors . knight and adams   disproved claims that lack of suppressor t cells causes autoimmune disease in the new zealand mice . in 1999 shevack , in paul 's fundamental immunology , reported that the autoimmune diseases are not caused by lack of suppressor t cells . in 2010 adams   has postulated that the pericyte loss is the cause of the vascular collapse of diabetic retinopathy . furthermore , adams proposes that the pericytes are destroyed by forbidden clones of cytotoxic t cells , antigenically related to those that cause type l diabetes by destroying the pancreatic islet  cells that make insulin . this seems to be an example of cross - tissue t cell autoimmunity , analogous to the cross - tissue b cell autoimmunity of graves ' disease , where thyroid cells and orbital fat cells can both be targets , causing thyrotoxicosis and exophthalmos . therapeutically , this new understanding suggests that ineffective  tight glycaemic control  should be replaced by immunosuppression with low - dose prednisone for treatment of diabetic retinopathy . the main reason is for defence against the explosive speed of replication of infecting viruses . in influenza virus infection , for example , each virus - infected cell bursts open after 18 hours to release about a thousand virions , each of which infects a new cell , which in turn produces another thousand virions and so on , with death of the patient in 3 or 4 days . they found that peptides , from a virus infecting a cell , are extruded to the cell surface on a histocompatibility antigen molecule . there , the viral peptide is available for reaction with the antigen receptor of a cytotoxic t - cell clone , if one with complementary antigen specificity exists . this was first explained in the lancet in 1987 , which shows that the mhc presentation is necessitated by the explosive speed of virus replication . this huge number of virions would swamp the cytotoxic t cells , muffling their antigen receptors and so preventing them from destroying the virus factories that the infected cells become . it follows that to prevent virus infections from being universally lethal , the defending cytotoxic t - cell clones must be reactive with the conjoint mhc - virus antigen on the surface of the infected cells , rather than reactive with the free virions . the forbidden clone theory , postulating somatic mutations in lymphocytes as the cause of the autoimmune diseases , does not explain the familial aggregation , which indicates involvement of germline genes . when the immunoglobulin v ( variable region ) genes , coding for the antigen specificity of lymphocyte clones were discovered , they seemed likely to be germline genes that influence the risks of autoimmune diseases . however , the discovery that the autoimmune disease lupus nephritis occurs in f l hybrids of two inbred strains of mice , but not in either parental strain , afforded an opportunity to analyse the parental contributions to this autoimmune disease . in dunedin , bielschowsky 's nzb bl inbred strain of mice had been found to develop autoimmune haemolytic anaemia , spontaneously . to study the genetics , howie and helyer crossed nzb mice with the normal nzw strain and found that the f l hybrids spontaneously develop lupus nephritis . backcross studies showed involvement of three genes in the lupus nephritis , one from the nzb strain and two from the nzw strain . linkage studies showed none were the expected v genes , one being in the mhc and two being in the neighbourhood of minor histocompatibility antigen genes . combining the fields of transplantation genetics and autoimmunity , adams and knight produced the h gene theory , which states that histocompatibility antigens , major , minor , and hy , delete nascent lymphocyte clones with complementary antigen receptors and so dictate the immune repertoire , altering the risks of autoimmune diseases . additionally , germ - line v genes , which provide the initial immune repertoire , influence the risk of autoimmune disease . necessary for the h gene theory is explanation of how histocompatibility antigens , by deleting complementary clones , can add to the immune repertoire . it was postulated that microbes bear multiple antigens and that a high - affinity clone for one antigen will preempt reactivity by lower - affinity clones for other antigens on the same microbe . hence , histocompatibility antigens , by deleting certain clones , can cause others to be added to the immune repertoire and developed by somatic mutation , an alternative clonal development concept [ 11 , 25 , 36 ] .   as described below , ebringer and his colleagues , in the course of discovering the microbial triggers of rheumatoid arthritis and ankylosing spondylitis , have confirmed the h gene theory , by finding that these bacterial triggers have two antigens , one resembling the predisposing histocompatibility antigen and one resembling the autoantigen attacked . working on graves ' disease , knight   realized that schizophrenia has many similar aetiological features . accordingly , he postulated that forbidden clones of b lymphocytes develop by somatic mutation and make autoantibodies that act on neuronal cell receptors to affect the function of the brain limbic system . knight proposed that : the familial aggregation is due to h genes and v genes , and the wait for v gene mutation explains the 50% discordance of monozygous twins and the juvenile grace gap ( relative absence in children ) . kety ' s adoptive studies , remission and relapse , the rheumatoid arthritis / schizophrenia discordance . strong confirmation comes from harrison and owen 's   discovery of predisposition by mhc and b - cell light chain v genes , which are immune response genes . in the light of the forbidden clone and h gene theories , the genetics of autoimmune disease changes from mystery to elegant simplicity . the key is the random element imposed on the genesis of an autoimmune disease by the need for unlucky somatic mutations in lymphocyte v genes . table 2 shows that autoimmune disease provides a fourth category to go with dominant , recessive , and sex - linked diseases in mckusick 's catalogue of mendelian inheritance in man . rheumatic carditis and streptococcibefore the advent of penicillin , rheumatic fever with lesions of the heart and joints was a frequent autoimmune complication of infections by -haemolytic streptococci of lancefield group a. this was because of an antigenic similarity between components of the streptococcus and heart tissue , found by kaplan and meyeserian . today , with such infections therapeutically aborted by penecillin , rheumatic heart disease , once common , has virtually disappeared . 
  before the advent of penicillin , rheumatic fever with lesions of the heart and joints was a frequent autoimmune complication of infections by -haemolytic streptococci of lancefield group a. this was because of an antigenic similarity between components of the streptococcus and heart tissue , found by kaplan and meyeserian . today , with such infections therapeutically aborted by penecillin , rheumatic heart disease , once common , has virtually disappeared . reactive arthritisthis has been observed after enteric infection with shigella , salmonella , yersinia , and campylobacter and genital infection with neisseria gonorrhea . this has been observed after enteric infection with shigella , salmonella , yersinia , and campylobacter and genital infection with neisseria gonorrhea . rheumatoid arthritis ( ra ) and proteus mirabilis multiple studies over three decades have found high titres of antibodies against this bacterium in a total of 1,375 ra patients , but not in other diseases or healthy controls , in studies by independent groups in 15 different countries . there is evidence that the upper urinary tract is the main source of proteus infection in ra . multiple studies over three decades have found high titres of antibodies against this bacterium in a total of 1,375 ra patients , but not in other diseases or healthy controls , in studies by independent groups in 15 different countries . there is evidence that the upper urinary tract is the main source of proteus infection in ra . 
 ankylosing spondylitis ( as ) and klebsiella in worldwide studies involving 1330 as patients and 1191 healthy controls , the as patients showed significantly increased antibody titres to klebsiella there is evidence that the gut is the main site of klebsiella infection in as . 
  in worldwide studies involving 1330 as patients and 1191 healthy controls , the as patients showed there is evidence that the gut is the main site of klebsiella infection in as . schizophrenia and virus infectionacute schizophrenia has been observed to follow upper respiratory tract virus infections , and g. knight et al . have assembled much evidence indicating that schizophrenia is an autoimmune disease caused by autoantibodies that react with neuronal receptors influencing the limbic system . seeking antigenic triggers and their corresponding autoantigen , with excellent technology at the nih , laing et al . immunized rabbits with neurotropic strains of influenza virus , inducing autoantibodies to a brain - specific 37  kda protein . this needs further exploration , as does the whole field of psychotic aetiology , until the presumptive forbidden clones have been demonstrated with the clarity obtained for graves ' disease and myasthenia gravis . acute schizophrenia has been observed to follow upper respiratory tract virus infections , and g. knight et al . have assembled much evidence indicating that schizophrenia is an autoimmune disease caused by autoantibodies that react with neuronal receptors influencing the limbic system . seeking antigenic triggers and their corresponding autoantigen , with excellent technology at the nih , laing et al . immunized rabbits with neurotropic strains of influenza virus , inducing autoantibodies to a brain - specific 37  kda protein . this needs further exploration , as does the whole field of psychotic aetiology , until the presumptive forbidden clones have been demonstrated with the clarity obtained for graves ' disease and myasthenia gravis . details of the development of the methods used for successful determination of the amino acid sequences of antigens on the autoimmune disease - triggering bacteria , proteus mirabilis and klebsiella pneumoniae , are recorded in the book rheumatoid arthritis and proteus by ebringer . this research provides experimental confirmation , at the molecular level , of the h gene theory of the inheritance of the autoimmune diseases , described above , in confirming the speculated presence of multiple antigens on triggering bacteria and alternative clonal development causing the autoimmune disease . figure 1 shows space - filling models of the amino acid sequences of the histocompatibility antigen , hla - dr1/4 , and the proteus mirabilis haemolysin antigen . this means the immune tolerance imposed by the histocompatibility antigen will extend to this proteus antigen , preventing immune reaction with it . figure 2 shows space - filling models of the amino acid sequences of the proteus mirabilis urease antigen and type 11 collagen , an autoantigen attacked in rheumatoid arthritis . the urease antigen is completely different from hla - dr1/4 , so it will not be protected from immune reaction , being free to stimulate development of a forbidden clone reacting with the closely similar type 11 collagen molecule , an autoantigen attacked in rheumatoid arthritis . figure 3 shows space - filling models of the amino acid sequences of the histocompatibility antigen , hla - b27 , and two antigenic peptides on the bacterium klebsiella pneumoniae . the klebsiella nitrogenase antigen closely resembles hla - b27 , so it will be covered by the tolerance induced by hla - b27 , but the bacterium pullanase peptide is different and able to stimulate development of a forbidden clone , attacking the spine causing ankylosing spondylitisn . it is now apparent that , in the present state of knowledge , there are 4 laws of autoimmunity , as detailed in table 3 . recognition of the universality of microbial triggers is a major advance as it shows that all autoimmune diseases are potentially preventable by vaccinations against their microbial triggers . a new zealand example occurred in 1938 and was reported in the press and observed by adams , trapped in a boarding school at masterton . an epidemic of leg paralyses occurred in christchurch and spread progressively north , from town to town , to picton , wellington , featherstone , then carterton , the town next to masterton , engendering great fear . then , the boy in the bed next to adams complained of a stiff neck , was taken away , and reported to have polio . these events make it probable that the leg paralyses of poliomyelitis were a rare autoimmune complication of virtually universal virus infection , the paralyses probably caused by forbidden clones of cytotoxic t cells which attacked anterior horn neurons , hence the name ,  acute anterior poliomyelitis  . the salk ( killed ) and sabin ( attenuated ) polio vaccines have both been brilliantly successful in preventing the polio leg paralyses . this exemplifies how autoimmune diseases in general can be prevented by finding and vaccinating against their microbial triggers . ebringer has succeeded in this with rheumatoid arthritis and ankylosing spondalitis , he has pioneered this new field of medical research , developing a whole new technology which needs to be copied in other diseases , especially schizophrenia . systematic studies of other autoimmune diseases , with collaboration between clinicians and microbiologists , are needed . the american association of microbiologists would be an ideal organization for providing this urgently needed knowledge . some disease associations are cross - tissue autoimmunity , for example the proptosis of graves ' disease , caused by variants of the thyroid - stimulating autoantibodies that react with receptors on orbital fat cells   and diabetic retinopathy , probably caused by destruction of retinal pericytes by antigenic variants of the t - cell forbidden clones that destroy the pancreatic islet  cells to cause type 1 diabetes . immunotherapy , by radiological or chemical immune ablation with immune reconstitution by autologous bone marrow cells , pioneered by farge et al . , can be used to save the lives of patients with dangerous autoimmune diseases , such as systemic scleroderma . selective destruction of forbidden clones could be achieved by isolating their autoantigen ( such as the tsh receptor of graves ' disease ) and attaching it to a cytotoxic moiety , such as bungarotoxin or iodine ( emitting short - range beta particles ) , then administering the molecular complex intravenously to destroy the pathogenic clones of plasma cells . prevention is better than cure , so finding and countering antigenic triggers of autoimmune diseases is the ideal . it shows how the diseases can be prevented by finding and vaccinating against the triggers . ebringer has led the way by discovering two major triggers and developing the technology for finding others .