Diagnostics and therapy of Epstein-Barr virus in autoimmune disorders

Abstract

Data consistent with autoimmune disease being caused by Epstein-Barr virus are shown. Based on this evidence, an effective vaccine would prevent the autoimmune disease in those vaccinated, modified or administered so that the vaccine is not itself capable of inducing autoimmune disease. In the case of anti-Sm, structures to be avoided in an Epstein-Barr virus-derived vaccine have been identified. Differences have been identified in the immune responses to Epstein-Barr infection between individuals who develop a specific autoimmune disease and those who do not. These differences are used to distinguish those who are at greater risk for developing specific autoimmune diseases from those who are a lesser risk. Assuming Epstein-Barr virus causes autoimmune disease and that Epstein-Barr virus remains latent in the patient for life, reactivation of the virus from the latent state is important in generating or maintaining the autoimmune response that culminates in autoimmune disease. Cells infected with latent virus may also encourage autoimmunity. Based on the understanding that reactivation or latency are important to produce or sustain autoimmunity, then therapies directed against Epstein-Barr virus will also be effective therapies for the autoimmune manifestations of disease for which Epstein-Barr virus is responsible.

We claim:  
     
         1 . A vaccine for alleviating or preventing autoimmune disorders induced by infection with Epstein-Barr virus comprising 
 Epstein-Barr virus or a component thereof in a pharmaceutically acceptable carrier for administration of the virus or viral component in an amount and mode of administration effective to alleviate or prevent the autoimmune disorders.    
     
     
         2 . The vaccine of  claim 1  wherein one or more structures of the Epstein-Barr virus are removed or altered to decrease the potential that the vaccine will induce an autoimmune disorder.  
     
     
         3 . The vaccine of  claim 1  wherein the component of Epstein-Barr virus is selected from the group consisting of peptides or proteins expressed from recombinant DNA or RNA with sequence identity to Epstein-Barr virus, viral DNA or RNA, and carbohydrate components of the Epstein-Barr virus.  
     
     
         4 . The vaccine of  claim 1  wherein the Epstein-Barr virus comprises the nuclear antigen 1 protein not including a peptide sequence selected from the group consisting of PPPGRRP, GRGRGRGG and RGRGREK.  
     
     
         5 . The vaccine of  claim 1  in a pharmaceutical carrier for administration by injection.  
     
     
         6 . A diagnostic test comprising 
 reagents which can be used to detect levels of antibodies to Epstein-Barr virus, indicators of Epstein-Barr infection of cells, or levels of Epstein-Barr DNA or protein in a patient, and    control samples from individuals not at risk of developing an autoimmune disease, and    means for determining the differences in levels of a patient and control samples to distinguish individuals at higher risk of developing an autoimmune disease from those at lower risk of developing an autoimmune disease.    
     
     
         7 . The diagnostic test of  claim 6  wherein the reagents are used in assays based upon the relative presence of an antibody, cellular proliferation, molecular binding, cytokine production, skin reaction, or cell surface antigen.  
     
     
         8 . The diagnostic test of  claim 6  wherein the reagents are used to detect antibodies to peptides from Epstein-Barr virus selected from the group consisting of PPPGRRP, GRGRGRGG, RGRGREK, GAGAGAGAGAGAGAGAGAGAGAGA, GPQRRGGDNHGRGRGRGRGRGGGRPG, GGSGSGPRHRDGVRRPQKRP, RPQKRPSC, QKRPSCIGCKGTHGGTG, GTGAGAGARGRGG, SGGRGRGG, RGGSGGRRGRGR, RARGRGRGRGEKRPRS, SSSSGSPPRRPPPGR, RPPPGRRPFFHPVGEADYFEYHQEG, PDVPPGAI, PGAIEQGPA, GPSTGPRG, GQGDGGRRK, DGGRRKKGGWFGKHR, GKHRGQGGSN, GQGGSNPK, NPKFENIA, RSHVERTT, VFVYGGSKT, GSKTSLYNL, GMAPGPGP, PQPGPLRE, CNIRVTVC, RVTVCSFDDG, PPWFPPMVEG.  
     
     
         9 . The diagnostic test of  claim 8  comprising reagents for detection of antibodies to GAGAGAGAGAGAGAGAGAGAGAGA.  
     
     
         10 . The diagnostic test of  claim 6  for testing patients identified with or at risk of developing systemic lupus erythematosus comprising control samples from individuals with systemic lupus erythematosus.  
     
     
         11 . A method for preventing or alleviating autoimmune disorders induced by infection with Epstein-Barr virus comprising 
 vaccinating or administering to a individual at risk of developing, or who has been identified as having symptoms associated with, an autoimmune disorder induced by infection with Epstein-Barr virus,    Epstein-Barr virus or a component thereof in a pharmaceutically acceptable carrier for administration of the virus or viral component in an amount and mode of administration effective to alleviate or prevent the autoimmune disorders.    
     
     
         12 . The method of  claim 11  wherein one or more structures of the Epstein-Barr virus are removed or altered to decrease the potential that the vaccine will induce an autoimmune disorder.  
     
     
         13 . The method of  claim 11  wherein the component of Epstein-Barr virus is selected from the group consisting of peptides or proteins expressed from recombinant DNA or RNA with sequence identity to Epstein-Barr virus, viral DNA or RNA, and carbohydrate components of the Epstein-Barr virus.  
     
     
         14 . The method of  claim 11  wherein the Epstein-Barr virus comprises the nuclear antigen 1 protein not including a peptide sequence selected from the group consisting of PPPGRRP, GRGRGRGG and RGRGREK.  
     
     
         15 . The method of  claim 11  wherein the individual has symptoms of or is at risk of developing an autoimmune disorder selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, juvenile onset diabetes mellitus, Wegener's granulomatosis, inflammatory bowel disease, polymyositis, dermatomyositis, multiple endocrine failure, Schmidt's syndrome, autoimmune uveitis, Addison's disease, adrenalitis, primary biliary cirrhosis, Graves' disease, thyroiditis, Hashimoto's thyroiditis, autoimmune thyroid disease, pernicious anemia, lupoid hepatitis, demyelating diseases, multiple sclerosis, subacute cutaneous lupus erythematosus, hypoparathyroidism, Dressler's syndrome, myasthenia gravis, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, autoimmune hemolytic anemia, pemphigus vulgar is, pemphigus, bullous pemphigoid, dermatitis herpetiformis, alopecia areata, autoimmune cystitis, pemphigoid, scleroderma, progressive systemic sclerosis, CREST syndrome (calcinosis, Raynaud's esophageal dysmotility, sclerodactyly, and telangiectasia), adult onset diabetes mellitus (Type II diabetes), male or female autoimmune infertility, ankylosing spondylitis, ulcerative colitis, Crohn's disease, mixed connective tissue disease, polyarteritis nodosa, systemic necrotizing vasculitis, juvenile onset rheumatoid arthritis, glomerulonephritis, atopic dermatitis, atopic rhinitis, Goodpasture's syndrome, Chagas' disease, sarcoidosis, rheumatic fever, asthma, recurrent abortion, anti-phospholipid syndrome, farmer's lung, erythema multiforme, postcardotomy syndrome, Cushing's syndrome, autoimmune chronic active hepatitis, bird-fancier's lung, allergic encephalomyelitis, toxic necrodermal lysis, alopecia, Alport's syndrome, alveolitis, allergic alveolitis, fibrosing alveolitis, interstitial lung disease, erythema nodosum, pyoderma gangrenosum, transfusion reaction, chronic fatigue syndrome, fibromyalgia, Takayasu's arteritis, Kawasaki's disease, polymyalgia rheumatica, temporal arteritis, giant cell arteritis, Sampter's syndrome (triaditis also called, nasal polyps, eosinophilia, and asthma), Behcet's disease, Caplan's syndrome, dengue, encephalomyositis, endocarditis, myocarditis, endomyocardial fibrosis, endophthalmitis, erythema elevatum et diutinum, psoriasis, erythroblastosis fetalis, fascitis with eosinophilia, Shulman's syndrome, Felty's syndrome, filariasis, cyclitis, chronic cyclitis, heterochromic cyclitis, Fuch's cyclitis, IgA nephropathy, Henoch-Schonlein purpura, glomerulonephritis, gcardiomyopathy, post vaccination syndromes, Hodgkin's and non-Hodgkin's lymphoma, renal cell carcinoma, Eaton-Lambert syndrome, relapsing polychondritis.  
     
     
         14 . The method of  claim 9  wherein the vaccine is administered prior to infection with Epstein-Barr virus.  
     
     
         15 . The method of  claim 9  wherein the vaccine is administered to an individual who has or has previously had an infection with Epstein-Barr virus.  
     
     
         16 . The method of  claim 9  wherein the autoimmune disorder is systemic lupus erythematosus.  
     
     
         17 . A method for determining the liklihood that an individual has an autoimmune disorder induced by Epstein-Barr virus, or is at risk for developing such an autoimmune disorder, comprising 
 obtaining a sample from the individual to be tested,    mixing the sample with reagents which can be used to detect levels of antibodies to Epstein-Barr virus, indicators of Epstein-Barr infection of cells, or levels of Epstein-Barr DNA or protein in a patient,    analyzing the sample, and    comparing the analysis of the sample with results obtained with control samples from individuals not at risk of developing an autoimmune disease to determine if the differences in levels of the individual and control samples indicates the individual is at a higher risk of developing an autoimmune disease than controls who are at lower risk of developing an autoimmune disease.    
     
     
         18 . The method of  claim 17  wherein the reagents are used in assays based upon the relative presence of an antibody, cellular proliferation, molecular binding, cytokine production, skin reaction, or cell surface antigen.  
     
     
         19 . The method of  claim 17  wherein the reagents are used to detect antibodies to peptides from Epstein-Barr virus selected from the group consisting of PPPGRRP, GRGRGRGG, RGRGREK, GAGAGAGAGAGAGAGAGAGAGAGA, GPQRRGGDNHGRGRGRGRGRGGGRPG, GGSGSGPRHRDGVRRPQKRP, RPQKRPSC, QKRPSCIGCKGTHGGTG, GTGAGAGARGRGG, SGGRGRGG, RGGSGGRRGRGR, RARGRGRGRGEKRPRS, SSSSGSPPRRPPPGR, RPPPGRRPFFHPVGEADYFEYHQEG, PDVPPGAI, PGAIEQGPA, GPSTGPRG, GQGDGGRRK, DGGRRKKGGWFGKHR, GKHRGQGGSN, GQGGSNPK, NPKFENIA, RSHVERTT, VFVYGGSKT, GSKTSLYNL, GMAPGPGP, PQPGPLRE, CNIRVTVC, RVTVCSFDDG, PPWFPPMVEG.  
     
     
         20 . The method of  claim 17  wherein the individual is tested for the presence of antibodies to GAGAGAGAGAGAGAGAGAGAGAGA.  
     
     
         21 . A method for screening of therapeutics for prevention or alleviation of autoimmune disorders induced by infection with Epstein-Barr virus comprising 
 administering the therapeutic to be tested to an animal vaccinated with Epstein-Barr virus or a component thereof in an amount and mode of administration effective to induce an autoimmune response.    
     
     
         22 . The method of  claim 21  further comprising administering the therapeutic to an animal which does not develop an autoimmune response when vaccinated with the same composition effective in another strain of the animal, and determining the difference in response to the therapeutic.  
     
     
         23 . The method of  claim 22  wherein the animals are mice.  
     
     
         24 . A method for screening for genetic markers or risk factors for development of autoimmune disorders induced by infection with Epstein-Barr virus comprising comparing the responses of different strains of the same species of an animal vaccinated with Epstein-Barr virus or a component thereof in an amount and mode of administration effective to induce an autoimmune response in at least one of the strains and comparing the differences in the genetics of the different strains to identify potential genetic markers or risk factors.