Identification of a novel retrovirus associated with primary...

Details Identification of a novel retrovirus associated with primary... Identification of a novel retrovirus associated with primary...

2000-06-01

2002-10-22

Park, Hankyel T. (Department: 1648)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving virus or bacteriophage

C536S023720

Reexamination Certificate

active

06468737

ABSTRACT:

1. INTRODUCTION
The present invention relates first, to the identification of a novel human retrovirus and the novel nucleotide sequences encoding a retroviral long terminal repeat and reverse transcriptase nucleotides associated with the existence of primary biliary cirrhosis (PBC), and other immune disorders such as Sjögren's syndrome, scleroderma, systemic lupus erythematosus (SLE), autoimmune thyroiditis and various other connective tissue disorders, in addition to lymphoma and breast cancer. The present invention further relates to methods for using the PBC retroviral nucleotides for the detection of PBC, Sjögren's syndrome, scleroderma, SLE, autoimmune thyroiditis and various other connective tissue disorders in patient samples. The present invention also relates to methods for using and targeting the PBC retroviral long terminal repeat and reverse transcriptase nucleotides in gene therapy protocols for the treatment of PBC, Sjögren's syndrome, scleroderma, SLE, autoimmune thyroiditis and various other connective tissue disorders in patients in need of such treatment. The present invention also relates to methods of treating or inhibiting PBC retroviral infection with antiviral agents, such as cytokines, inhibitors of reverse transcriptase, inhibitors of viral capping, and inhibitors of viral protease. The present invention further relates to diagnostic protocols and kits for the detection of PBC, Sjögren's syndrome, scleroderma, SLE, autoimmune thyroiditis and various other connective tissue disorders in tissue samples.
2. BACKGROUND OF THE INVENTION
Primary Biliary Cirrhosis and Autoimmunity
Primary biliary cirrhosis (PBC) is a progressive pluriglandular disease affecting the liver, pancreas, salivary and lachrymal glands (Neuberger, 1997, Lancet 850:875-79; Epstein et al., 1980, Lancet 1:1166-68). The hepatic disease is characterized by a florid bile duct lesion with lymphocytic infiltration and granulomatous destruction of 30 to 80 &mgr;m sized interlobular bile ducts (Rubin et al., 1965, Am. J. Pathol. 46:387-407). There is no curative therapy, apart from liver transplantation, and patients usually develop cirrhosis (Neuberger et al., 1997, Lancet 250:875-879). It is estimated to account for approximately 2% of patients dying from cirrhosis in Europe and 10% of patients that requiring orthotopic liver transplantation in North America (Neuberger et al., 1997, Lancet 250:875-879).
PBC is considered an archetypal autoimmune disease because patients have anti-mitochondrial antibodies (AMA) and can also present with other autoimmune disorders such as Sjögren's syndrome, scleroderma, systemic lupus erythematosus (SLE), autoimmune thyroiditis, and various other connective tissue disorders (Neuberger et al., 1997, Lancet 250:875-879). The clinical overlap with Sjögren's syndrome is particularly marked, as tests for xerophthalmia and xerostomia are positive in 70% to 100% of PBC patients (Alarcon-Segovia et al., 1973, Ann. Intern. Med. 79:31). In addition, patients with PBC have an increased incidence of urinary tract infection (Burroughs et al., 1984, Gut 25:133-7) and a 4 fold increased risk of breast cancer (Wolke et al., 1984, Am. J. Med. 76:1075).
The autoimmune phenomena associated with PBC have been well characterized. Over 95% of PBC patients have antibodies that bind and inhibit the dihydrolipoamide acetyltransferase enzymatic function of the E2 subunit of the pyruvate dehydrogenase complex (PDC) (Gershwin et al., 1992, Molecular biology of the 2-oxo-acid dehydrogenase complexes and anti-microbial antibodies. Philadelphia W. B. Saunders) These AMA have a higher affinity to the dehydrogenase E2 enzymes of mammals as compared to invertebrates and react to the E2 sub-units of other highly conserved inner membrane mitochondrial proteins of the oxoglutarate dehydrogenase complex, and branched chain 2-oxoacid dehydrogenase complex, and also the E1&agr; and E1&bgr; sub-units of PDC. For patients with liver disease, reactivity to the E2 mitochondrial enzymes is specific to PBC but these AMA have been observed in individuals with Sjögren's syndrome and SLE as well (Van-de-Water et al., 1989, New Eng. J. Med. 320: 1377-80). The reason why PBC patients have an antigen driven immune response to human PDC-E2 may be partially explained by the findings of immunohistochemical studies. Using monoclonal and combinatorial AMA, PDC-E2 or antigens resembling PDC-E2 have been observed on the surface of cultured PBC biliary epithelium cells (Joplin et al., 1992, Lancet 339: 93-94), biliary epithelium and lymph node macrophages in PBC patient's tissues (Joplin et al., 1991, Hepatology 14: 442-447, Van-de-Water et al., 1993, J. Clin. Invest. 91: 2654-64), and salivary glands of patients with PBC and Sjögrens syndrome (Tsuneyama et al., 1994, Hepatology 20: 893-898). In essence, the tissues affected by the pluriglandular disease process are the same as those with the abnormal distribution of PDC-E2 antigens on epithelial cell surface.
The disease has been observed in all races and predominantly affects women (Neuberger, 1997, Lancet 350: 875-879). To date, non-HLA genetic factors predisposing to PBC have not been identified but a positive family history provides the greatest risk of developing disease (Sherlock et al., 1993, Primary biliary cirrhosis: definition and epidemiological features. Kluwer Academic Publishers, Doredrecht/Boston/London, pp. 341-49). There are well documented cases of clustering in families and one report documented a 2.4% familial prevalence (Sherlock et al., 1993, Primary biliary cirrhosis: definition and epidemiological features. Kluwer Academic Publishers, Doredrecht/Boston/London. 341-49 pp). No HLA class I alleles are associated with PBC but other immunogenetic factors appear to play an important role.
There are limited data to suggest an infectious etiology of PBC. The spread of disease has been documented in unrelated care providers and has also been associated with a particular water supply in Sheffield, England which was reconfirmed with a follow-up study 10 year later (Sherlock et al., 1993, Primary biliary cirrhosis: definition and epidemiological features. Kluwer Academic Publishers, Doredrecht/Boston/London. pp. 341-49, Trigger 1980, Br. Med. J. 281: 772-5). Although the data are subject to debate, the specific anti-mitochondrial antibodies associated with PBC have been detected in related and non-related family members (Sherlock et al., 1993, Primary biliary cirrhosis: definition and epidemiological features. Kluwer Academic Publishers, Doredrecht/Boston/London, 341-49). Further evidence for an infectious etiology of PBC is suggested by the observation of recurrent disease in the hepatic allograft of approximately 15% of PBC patients undergoing orthotopic liver transplantation. This evidence includes the observation of granulomatous destruction of bile ducts after liver transplantation, the continued presence of serum AMA in the majority of PBC patients (Trigger, 1980, Br. Med. J. 281: 772-5), and immunohistochemical evidence of PDH-E2 on biliary epithelial cell surface in the allograft (Neuberger et al., 1982, N. Eng. J. Med. 306: 1-4).
The epidemiology of PBC does not suggest a simple infectious disease pattern. If an infectious etiology is entertained, it is probable that infection only causes PBC in predisposed individuals due to the modulating effects of genetic, hormonal, and environmental factors. This may partially explain why PBC patients develop AMA and liver disease while other family members develop merely develop serum AMA reactivity without PBC. Many investigators have postulated that either mycobacteria, or enterobacterial R-forms are etiologically related to PBC as they have the highly conserved dehydrogenase enzymes which possibly induce autoimmunity by the mechanism of microbial molecular mimicry with host proteins (O'Donohue et al., 1994, J. Hepatol. 21: 887-889; Stemerowicz et al., 1988, Lancet 1: 1166-1170). Others have made the claim that recurrent bacterial urinary tract infections may

Affiliated with

Also associated with

Rating

Identification of a novel retrovirus associated with primary... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Identification of a novel retrovirus associated with primary..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Identification of a novel retrovirus associated with primary... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2979540