Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-03-29
2001-08-28
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C435S810000, C536S023200, C536S024310, C536S024330
Reexamination Certificate
active
06280941
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application various publications are referenced within parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.
1. The Field of the Invention
This invention relates to the medical arts. In particular, it relates to a method of detecting a genetic predisposition to systemic lupus erythematosus.
2. Discussion of the Related Art
Systemic lupus erythematosus (SLE), commonly known as lupus, is an autoimmune rheumatic disease characterized by deposition in tissues of autoantibodies and immune complexes leading to tissue injury (B. L. Kotzin,
Systemic lupus erythematosus
, Cell 85:303-06 [1996]). In contrast to autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus, SLE potentially involves multiple organ systems directly, and its clinical manifestations are diverse and variable. (Reviewed by B. L. Kotzin and J. R. O'Dell,
Systemic lupus erythematosus
, In:
Samler's Immunologic Diseases
, 5th ed., M. M. Frank et al., eds., Little Brown & Co., Boston, pp. 667-97 [1995]).
For example, some patients may demonstrate primarily skin rash and joint pain, show spontaneous remissions, and require little medication. At the other end of the spectrum are patients who demonstrate severe and progressive kidney involvement that requires therapy with high doses of steroids and cytotoxic drugs such as cyclophosphamide. (B. L. Kotzin [1996]). The serological hallmark of SLE, and the primary diagnostic test available until now, is elevated serum levels of IgG antibodies to constituents of the cell nucleus, such as double-stranded DNA (dsDNA), single-stranded DNA (ss-DNA), and chromatin. Among these autoantibodies, IgG anti-dsDNA antibodies play a major role in the development of lupus glomerulonephritis (GN). (B. H, Hahn and B. Tsao, Antibodies to DNA, In:
Dubois' Lupus Erythematosus
, 4th ed., D. J. Wallace and B. Hahn, eds., Lea and Febiger, Philadelphia, pp. 195-201 [1993]; Ohnishi et al., Comparison of pathogenic and nonpathogenic murine antibodies to DNA: Antigen binding ard structural characteristics, Int. Immunol. 6:817-30 [1994]). Glomerulonephritis is a serious condition in which the capillary walls of the kidney's blood purifying glomeruli become thickened by accretions on the epithelial side of glomerular basement membranes. The disease is often chronic and progressive and may lead to eventual renal failure.
Mechanisms by which autoantibodies are induced remain unclear. Chromatin and/or nucleosomes, released by apoptotic cells in SLE, may become autoantigens that induce autoimmune responses, including antibodies to dsDNA. (R. W. Burlingame et al., The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus, J. Clin. Invest. 94:184-92 [1994]; C. Mohan et al., Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus, J. Exp. Med. 177:1367-81 [1993]; D. A. Bell el al., Immunogenic DNA-relatedfactors. Nucleosomes spontaneously released from normal murine lymphoid cells stimulate prolferation and immunoglobulin synthesis of normal mouse lymphocytes, J. Cin. Invest. 85:1487-96 [1990
9
).
Cumulative studies suggest that interaction of multiple genes and environmental factors result in susceptibility to SLE, as is true for many multifactorial complex human diseases. (F. C. Arnett, Jr., The genetics of human lupus, In:
Dubois' Lupus Erythematosus
, 5th ed., D. J. Wallace and B. Hahn, eds., Williams and Wilkins, Baltimore, pp. 77-117 [1997]; T. J. Vyse and B. L. Kotzin, Genetic susceptibility to systemic lupus erythematosus, Ann. Rev. Immunol. 16:261-92 [1998]). Although SLE can occur at nearly any age, it primarily affects women of childbearing age; the female to male ratio is greatest (>8:1) for patients presenting between ages 15 to 50 years; incidence rates for patients and studies in certain animal models support a role for estrogens enhancing disease development, and androgens protecting against it. (B. L. Kotzin [1996]). Although rare among males, SLE may be linked in males with functional hypoandrogenism and a higher than normal estradiol/testosterone ratio. (J. F. Sequeira el al.,
Systemic lupus erythematosus
: sex hormones in male patients, Lupus 2(5):315-17 [1993]).
It appears that underlying genetic factors exert the greatest influence on autoantibody production and on predisposition to SLE, as studies of populations, segregation of disease in families, and twin concordance rates have consistently demonstrated. The prevalence of SLE in the general population is approximately 15-50 in 100,000. (M. D. Hochberg, The epidemiology of
systemic lupus erythematosus
, In:
Dubois' Lupus Erythematosus
, 5th ed., D. J. Wallace and B. Hahn, eds., Williams and Wilkins, Baltimore, pp. 49-65 [1997]). The relatively high incidence (10-16%) of more than one case in a family has suggested a genetic basis for SLE. The concordance rate of SLE in monozygotic twins (24%-57%) is approximately ten times higher than the rate in dizygotic twins (2-5%). (F. C. Amett, Jr. [1997]; M. D. Hochberg [1997]). Based on these epidemiological studies, the relative risk for siblings of SLE patients compared to the general population, As, is at least 40-fold. (See, N. Risch, Assessing the role of HLA-linked aid unlinked determinants of disease, Am. J. Hum. Genet. 40:1-14 [1987]).
The genetic basis for SLE in humans is complex, with an unknown but non-Mendelian mode of inheritance. This complexity has impeded the development of a reliable and predictive genetic test for SLE until the present invention.
Many investigators have reported that certain human MHC class II alleles (HLA-DR and/or DQ but not DP) and certain class III genes (C2, C4, TNF&agr; and HSP70-2 alleles) confer susceptibility to SLE in most ethnic groups studied. (F. C. Arnett, Jr., The genetics of human lupus, In:
Dubois' Lupus Erythematosus
, 5th ed., D. J. Wallace and B. Hahn, eds., Williams and Wilkins, Baltimore, pp. 77-117[1997]; T. J. Vyse and B. L. Kotzin, Genetic susceptibility to systemic lupus erythemalosus, Ann. Rev. Immunol. 16:261-92 [1998]). Among the other non-MHC genes that have been associated with SLE, evidence for homozygous deficiency of Clq predisposing to SLE is particularly compelling, including the observation that 90% of such individuals have SLE and Clq knockout mice display an SLE-ike phenotype. (M. Botto et al., Homozygous Clq deficiency causes glomerulonephritis associated with multiple apoptotic bodies, Nat. Genet. 19:56-59 [1998]; P. Bowness et al., Hereditary Clq deficiency and
systemic lupus erythematosus
, Quart. J. Med. 87:455-64 [1994]).
In addition, polymorphisms in many genes encoding molecules with relevant immunological functions have been studied most frequently by the case-control approach, including T-cell receptor &agr; and &bgr; chains, immunoglobulin allotypes, Fc&ggr;RIIa, FcgRIIIa, IL-6, IL-10, Bcl-2, mannose-binding protein (or lectin), as well as deletion of specific variable gene segments of immunoglobulin genes. (F. C. Arnett, Jr. [1997]; T. J. Vyse and B. L. Kotzin [1998], J. Wu et al., A novel polymorphism of Fc&ggr;RlilA, which alters function, associates with SLE phenotype, J. Invest. Med. 45:200A [1997]; R. Mehrian et al., Synergistic effect between IL-10 and Bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus, Arthritis Rheum. 41:596-602 [1998]). Mutations in nucleic acids encoding T cell receptor zeta chain have been linked to SLE in some patients. (K. Tsuzaka et al, Mutations in T cell receptor zeta chain mRNA of peripheral T cells from
systemic lupus erythematosus
patients, J. Autoimmun. 11 (5):381-85 &lsqb
Cantor Rita M.
Rotter Jerome I.
Tsao Betty P.
Cedars-Sinai Medical Center
Johannsen Diana
Jones W. Gary
Sidley Austin Brown & Wood
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