Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of...
Reexamination Certificate
1994-09-27
2001-06-19
Allen, Marianne P. (Department: 1631)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
C435S320100, C435S252300, C536S023100, C536S023700
Reexamination Certificate
active
06248583
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a chromosomally-encoded membrane protein or polypeptide of
Borrelia burgdorferi.
BACKGROUND OF THE INVENTION
Lyme disease is a multisystem, tick-borne disease produced by
B. burgdorferi
. “Lyme Disease,” United States, 1991-1992, MMWR 42:345-348 (1993). It is characterized by recurrent systemic and local manifestations involving the skin, heart, nervous system and joints. Lyme disease has three clinical stages. Steere, A. C., “Lyme Disease,”
N. Engl. J. Med.,
321:586-596 (1989). Stage I lasts approximately four weeks, and includes skin rashes such as erythema chronicum and general influenza-like systemic symptoms. An asymptomatic period is followed by Stage II, characterized by musculoskeletal, nervous and cardiac system involvement. Arthritis is the major manifestation of Stage III. The clinical manifestations of Lyme disease are probably due to a mixture of infection by tissue-invasive
B. burgdorferi
, specific host immune responses to
B. burgdorferi
antigens, and autoimmune reactions triggered by
B. burgdorferi
antigens. Steere, A. C., “Lyme Disease,”
N. Engl. J. Med.,
321:586-596 (1989); Duffy, J. “Lyme Disease,”
Infect. Dis. Clin. N. Am.,
1:511-527 (1987); Marcus, L. C., et al., “Fatal Pancarditis In A Patient With Coexistent Lyme Disease and Babesiosis. Demonstration Of Spirochetes In The Myocardium,”
Ann. Inter. Med.,
103:374-376 (1986).
The role of infection by
B. burgdorferi
in the pathogenesis of Lyme disease is suggested by the presence of
B. burgdorferi
in tissues (Marcus, L. C., et al., “Fatal Pancarditis In A Patient With Coexistent Lyme Disease and Babesiosis. Demonstration Of Spirochetes In The Myocardium,”
Ann. Inter. Med.,
103:374-376 (1986); Syndman, D. R., et al., “
Borrelia Burgdorferi
In Joint Fluid In Chronic Lyme Arthritis,”
Ann. Inter. Med.,
104:798-800 (1986)), the strong anti-
B. burgdorferi
cellular and humoral response in Lyme disease patients (Szczepanski, A., et al., “Lyme Borreliosis: Host Responses to
Borrellia burgdorferi,” Microbiol. Rev.,
55:21-34-22 (1991); Rahn, D. W., “Lyme Disease: Clinical Manifestations, Diagnosis, and Treatment,”
Sem. Arthritis Rheum.,
20:201-218 (1991)), the effectiveness of antibiotic treatment in forestalling clinical manifestations of Stages I, II and III (Steere, A. C., et al., “Successful Parenteral Penicillin Therapy of Established Lyme Arthritis,”
N. Engl. J. Med.,
308:733-740 (1985); Steere, A. C., et al., “Treatment Of The Early Manifestations of Lyme Disease,”
Ann. Inter. Med.,
99:22-26 (1983)). Infection with
B. burgdorferi
is not the entire story in Lyme disease pathogenesis. However, processes associated with hypersensitivity and autoimmunity also appear to play an important role in at least some of the chronic manifestations of Lyme disease. Evidence for this includes treatment failure of antibiotics in half of patients with arthritis (Steere, A. C., et al., “Successful Parenteral Penicillin Therapy of Established Lyme Arthritis,”
N. Engl. J. Med.,
308:733-740 (1985); Steere, A. C., et al., “Treatment Of The Early Manifestations of Lyme Disease,”
Ann. Inter. Med.,
99:22-26 (1983)), the presence of anti-
B. burgdorferi
immune complexes in synovial fluid in the absence of demonstrable organisms (Steere, A. C., et al., “Chronic Lyme Arthritis: Clinical and Immunogenetic Differentiation Form Rheumatoid Arthritis,”
Ann. Inter. Med.,
90:896-901 (1979)), heavy infiltration of the synovia of affected joints with T lymphocytes (Yssel, H., et al., “
Borrelia Borgdorferi
Activates a T Helper Type 1-Like T Cell Subset In Lyme Arthritis,”
J. Exp. Med.,
174:593-601 (1991); Steere, A. C., et al., “Elevated Levels Of Collagenase And Prostaglandin E2 From Synovium Associated With Erosion Of Cartilage And Bone In A Patient With Chronic Lyme Arthritis,”
Arthritis Rheum,
23:591-599 (1983)), histological similarities of Lyme disease arthritis and rheumatoid arthritis (Yssel, H., et al., “
Borrelia Borgdorferi
Activates a T Helper Type 1-Like T Cell Subset In Lyme Arthritis,”
J. Exp. Med.,
174:593-601 (1991); Steere, A. C., et al., “Elevated Levels Of Collagenase And Prostaglandin E2 From Synovium Associated With Erosion Of Cartilage And Bone In A Patient With Chronic Lyme Arthritis,”
Arthritis Rheum,
23:591-599 (1983)), and cross-reactivity of
B. burgdorferi
antigens with human tissue (Fikrig, E., et al., “Serologic Response To The
Borrelia Burgdorferi
Flagellin Demonstrates An Epitope Common To A Neuroblastoma Cell Line,”
Proc. Natl. Acad. Sci. USA,
90:183-187 (1993)).
B. burgdorferi
can also directly stimulate production of cytokines such as interleukins-1, 2, and 6, interferons, and tumor necrosis factor from normal, uninfected lymphoid cells, synovial cells and rat glioma cells. Miller, L. C., et al., “Balance Of Synovial Fluid IL-1&bgr; and IL-1 Receptor Antagonist And Recovery From Lyme Arthritis,”
Lancet,
341:146-148 (1993); Habicht, G. S., et al., “Cytokines And The Pathogenesis Of Neuroborreliosis:
Borrelia Burgdorferi
Induces Glioma Cells To Secrete Interleukin-6,”
J. Infect. Dis.,
164:568-574 (1991). This could be important for Lyme disease pathogenesis since interleukin-1 can itself stimulate the production of collagenase and prostaglandin E2 by synovial cells and fibroblasts. Steere, A. C., et al., “Elevated Levels Of Collagenase And Prostaglandin E2 From Synovium Associated with Erosion Of Cartilage And Bone In A Patient With Chronic Lyme Arthritis,”
Arthritis Rheum,
23:591-599 (1983). The occurrence of hypersensitivity and autoimmunity in Lyme disease underscores the need to exclude
B. burgdorferi
antigens able to trigger these phenomena from any proposed Lyme disease vaccine.
B. burgdorferi
are taxonomically and antigenically complex.
B. burgdorferi sensu lato
consists of at least three genospecies (I, II, III), defined on the basis of genomic and antigenic similarities, and includes other non-classifiable strains (see Table I, below). Branton, G., et al., “Delineation of
Borrelia Burgdorferi Sensu Stricto, Borrelia Garinii
Sp. Nov., And Group VS461 Associated With Lyme Borreliosis,”
Int. J. Syst. Bacteriol,
42:378-383 (1992); Canica, M. M., et al., “Monoclonal Antibodies For Identification Of
Borrelia Afzelii
Sp. Nov. Associated With Late Cutaneous Manifestations Of Lyme Borreliosis,”
Scand. J. Infect. Dis.,
25:441-448 (1993); Belfaiza, J., et al., “Genomic Fingerprinting of
Borrelia Burgdorferi Sensu Lato
By Pulse-Field Gel Electrophoresis,”
J. Clin. Microbiol.,
31:2873-2877 (1993).
B. burgdorferi sensu strictu
consists only of genospecies I. Branton, G., et al., “Delineation of
Borrelia Burgdorferi Sensu Stricto, Borrelia Garinii
Sp. Nov., And Group VS461 Associated With Lyme Borreliosis,”
Int. J. Syst. Bacteriol,
42:378-383 (1992); Canica, M. M., et al., “Monoclonal Antibodies For Identification Of
Borrelia Afzelii
Sp. Nov. Associated With Late Cutaneous Manifestations Of Lyme Borreliosis,”
Scand. J. Infect. Dis.,
25:441-448 (1993); Belfaiza, J., et al., “Genomic Fingerprinting of
Borrelia Burgdorferi Sensu Lato
By Pulse-Field Gel Electrophoresis,”
J. Clin. Microbiol.,
31:2873-2877 (1993). In addition to antigenic variability between strains ((Szczepanski, A., et al., “Lyme Borreliosis: Host Responses To
Borrelia Burgdorferi,” Microbiol. Rev.,
55:21-34-22 (1991); Barbour, A. G., “Biological And Social Determinants Of The Lyme Disease Problem,”
Infect. Agents Dis.,
1:50-61 (1992)), a given strain may show antigenic variations in different hosts, after exposure to host defenses in a single host, and/or after repeated laboratory passages (Barbour, A. G., et al., “Biology Of Borrelia Species,”
Microbiol. Rev.,
50:381-400 (1986)). The antigenic complexity of
B. burgdorferi
has in turn complicated development of vaccines and diagnostic assays for Lyme disease.
The surface of
B. burgdorferi
, the bacterial structure that interacts with the mammalian immune system, is composed of a layer of carbohydrates covering an outer sheath or cell membrane. Ba
Aron Lieselotte
Cabello Felipe
Godfrey Henry P.
Schwartz Ira
Allen Marianne P.
New York Medical College
Nixon & Peabody LLP
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