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Lymphoproliferative Responses to Borrelia burgdorferi in Patients With Erythema Migrans, Acrodermatitis Chronica Atrophicans, Lymphadenosis Benigna Cutis, and Morphea

Lymphoproliferative Responses to Borrelia burgdorferi in Patients With Erythema Migrans,... Abstract Background and Design: Specific humoral and cell-mediated immune responses play an important role in the pathogenesis of Lyme borreliosis. Several previous studies demonstrated that a specific cellular immune response to Borrelia burgdorferi can occur independently of a diagnostic humoral response. Little is known about T-cell reactivities against B burgdorferi in early and late cutaneous manifestations of Lyme borreliosis. We studied the lymphoproliferative response of peripheral blood mononuclear cells to B burgdorferi antigen from 99 patients (25 with erythema migrans, 16 with acrodermatitis chronica atrophicans, 13 with lymphadenosis benigna cutis, and 45 with localized scleroderma) and 21 control subjects. The results are expressed as a stimulation index (SI) (mean count per minute of triplicate cultures with stimulant divided by mean count per minute without stimulant). The serum samples from all patients and control subjects were tested for antibodies to B burgdorferi by indirect immunofluorescence assay. Results: The 21 healthy seronegative controls had an SI of 3.3±2.0 (mean±SD). Compared with that of control subjects, the SIs were significantly elevated in patients with erythema migrans (9.8±9.1), acrodermatitis chronica atrophicans (11.8±8.2), and lymphadenosisbenigna cutis (7.2±6.2). The 45 patients with localized scleroderma had elevated proliferative responses, with an SI of 6.5±7.3, but these responses did not significantly differ from those of controls. Elevated titers of antibodies to B burgdorferi were present in six (24%) of 25 patients with erythema migrans, five (38%) of 13 patients with lymphadenosis benigna cutis, and 13 (29%) of 45 patients with localized scleroderma. All 16 patients with acrodermatitis chronica atrophicans had markedly elevated antibody titers. Conclusions: Our findings show that a significant lymphoproliferative response to B burgdorferi occurs in the majority of patients with cutaneous manifestations of Lyme borreliosis. The lymphocyte proliferation assay may be of diagnostic value in patients in whom Lyme borreliosis is strongly clinically suspected and who have nondiagnostic levels of antibodies against B burgdorferi.(Arch Dermatol. 1995;131:673-677) References 1. Asbrink E, Hovmark A. Cutaneous manifestations in Ixodes-borne Borrelia spirochetosis . Int J Dermatol. 1987;26:215-223.Crossref 2. Malane MS, Grant-Kels JM, Feder HM, Luger SW. Diagnosis of Lyme disease based on dermatologic manifestations . Ann Intern Med. 1991;114:490-498.Crossref 3. Asbrink E, Olsson I, Hovmark A. Clinical manifestations of erythema chronicum migrans Afzelius in Sweden: a study on 231 patients . Zentralbl Bakteriol Mikrobiol Hyg A. 1986;263:229-236. 4. Asbrink E, Olsson I. Clinical manifestations of erythema chronicum migrans Afzelius in 161 patients . Acta Derm Venereol (Stockh). 1985;65:43-52. 5. Hovmark A, Asbrink E, Olsson I. The spirochetal etiology of lymphadenosis benigna cutis solitaria . Acta Derm Venereol (Stockh). 1986;66:479-484. 6. Abele DC, Anders KH. The many faces and phases of borreliosis, I: Lyme disease . J Am Acad Dermatol. 1990;23:167-186.Crossref 7. Abele DC, Anders KH. The many faces and phases of borreliosis, II . J Am Acad Dermatol. 1990;23:401-410.Crossref 8. Asbrink E, Hovmark A. Lyme borreliosis: aspects of tick-borne Borrelia burgdorferiinfection from a dermatologic viewpoint . Semin Dermatol. 1990;9:277-291. 9. Strle F, Pleterski-Rigler D, Stanek G, Pejovnik-Pustinek A, Ruzic E, Cimperman J. Solitary borrelial lymphocytoma: report of 36 cases . Infection. 1992;20:201-206.Crossref 10. Asbrink E, Hovmark A, Olsson I. Clinical manifestations of acrodermatitis chronica atrophicans in 50 Swedish patients . Zentralbl Bakteriol Mikrobiol Hyg A. 1986; 263:253-261. 11. Aberer E, Stanek G, Ertl M, et al. Evidence for spirochetal origin of circumscribed scleroderma (morphea) . Acta Derm Venereol (Stockh). 1987;67:225-231. 12. Aberer E, Neumann R, Stanek G. Is localized scleroderma a Borrelia infection? Lancet. 1985;2:278.Crossref 13. Buechner SA, Winkelmann RK, Lautenschlager S, Gilli L, Rufli T. Localized scleroderma associated with Borrelia burgdorferi infection: clinical, histologic, and immunohistochemical observations . J Am Acad Dermatol. 1993;29:190-196.Crossref 14. Aberer E, Klade H, Stanek G, Gebhart W. Borrelia burgdorferi and different types of morphea . Dermatologica. 1991;182:145-154.Crossref 15. Schempp C, Bocklage H, Lange R, Kölmel HW, Orfanos CE, Gollnick H. Further evidence for Borrelia burgdorferi infection in morphea and lichen sclerosus et atrophicus confirmed by DNA amplification . J Invest Dermatol. 1993; 100:717-720.Crossref 16. Sigal LH. Immunopathogenesis of Lyme borreliosis . Clin Dermatol. 1993;11: 415-422.Crossref 17. Hansen K. Laboratory diagnostic methods in Lyme borreliosis . Clin Dermatol. 1993;11:407-414.Crossref 18. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease: dissociation of specific Tand B-lymphocyte responses to Borrelia burgdorferi . N Engl J Med. 1988;319:1441-1446.Crossref 19. Dattwyler RJ, Thomas JA, Benach JL, Golightly MG. Cellular Immune response in Lyme disease: the response to mitogens, live Borrelia burgdorferi, NK cell function and lymphocyte subsets . Zentralbl Bakteriol Mikrobiol Hyg A. 1986;263:151-159. 20. Dressler F, Yoshinari NH, Steere AC. The T-cell proliferative assay in the diagnosis of Lyme disease . Ann Intern Med. 1991;115:533-539.Crossref 21. Krause A, Burmester GR, Rensing A, et al. Cellular immune reactivity to recombinant OspA and flagellin from Borrelia burgdorferi in patients with Lyme borreliosis: complexity of humoral and cellular immune responses . J Clin Invest. 1992;90:1077-1084.Crossref 22. Sigal LH, Steere AC, Freeman DH, Dwyer JM. Proliferative responses of mononuclear cells in Lyme disease: reactivity to Borrelia burgdorferi antigens is greater in joint fluid than in blood . Arthritis Rheum. 1986;29:761-769.Crossref 23. Krause A, Brade V, Schoerner C, Solbach W, Kalden JR, Burmester GR. T-cell proliferation induced by Borrelia burgdorferi in patients with Lyme borreliosis . Arthritis Rheum. 1991;34:393-402.Crossref 24. Zoschke DC, Skemp AA, Defosse DL. Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease . Ann Intern Med. 1991;114:285-289.Crossref 25. Asbrink E, Hederstedt B, Hovmark A. The spirochetal etiology of erythema chronicum migrans Afzelius . Acta Derm Venereol (Stockh). 1984;64:291-295. 26. Weir DM. Handbook of Experimental Immunology . 3rd ed. Boston, Mass: Blackwell Scientific Publications Inc; 1978. 27. Sigal LH, Moffat CM, Steere AC, Dwyer JM. Cellular immune findings in Lyme disease . J Biol Med. 1984;57:595-598. 28. Miller LC, Isa S, Vannier E, Georgilis K, Steere AC, Dinarello CA. Live Borrelia burgdorferi preferentially activate interleukin-1 beta gene expression and protein synthesis over the interleukin-1 receptor antagonist . J Clin Invest. 1992; 90:906-912.Crossref 29. Büchner SA, Rufli T. Erythema chronicum migrans: evidence for cellular immune reaction in the skin lesion . Dermatologica. 1987;174:144-149.Crossref 30. Steere AC, Duray PH, Butcher EC. Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis: comparison with rheumatoid synovium and tonsillar lymphoid tissue . Arthritis Rheum. 1988;31:487-495.Crossref 31. Baranton G, Postic D, Saint-Girons I, et al. Delineation of Borrelia burgdorferi sensu stricto, Borrelia garinii sp. nov., and group VS461 associated with Lyme borreliosis . Int J Syst Bacteriol. 1992;42:378-383.Crossref 32. van Dam AP, Kuiper H, Vos K, et al. Different genospecies of Borrelia burgdorferi are associated with distinct clinical manifestations of Lyme borreliosis . Clin Infect Dis. 1993;17:708-717.Crossref 33. Assous MV, Postic D, Paul G, Nivot P, Baranton G. Western blot analysis of sera from Lyme borreliosis patients according to the genomic species of the Borrelia strains used as antigens . Eur J Clin Microbiol Infect Dis. 1993;12: 261-268.Crossref 34. Sigal LH, Steere AC, Dwyer JM. In vivo and in vitro B-cell hyperactivity in Lyme disease . J Rheumatol. 1988;15:648-654. 35. Pachner AR, Steere AC, Sigal LH, et al. Antigen-specific proliferation of CSF lymphocytes in Lyme disease . Neurology. 1985;35:1642-1645.Crossref 36. Buechner SA, Rufli T, Erb P. Acrodermatitis chronica atrophicans: a chronic T-cell—mediated immune reaction against Borrelia burgdorferi? clinical, histologic, and immunohistochemical study of five cases . J Am Acad Dermatol. 1993;28:399-405.Crossref 37. Yssel H, Shanafelt MC, Soderberg C, Schneider PV, Anzola J, Peltz G. Borrelia burgdorferi activates a T-helper type 1—like T-cell subset in Lyme arthritis . J Exp Med. 1991;174:593-601.Crossref 38. Plörer A, Sepp N, Schmutzhard E, et al. Effects of adequate versus inadequate treatment of cutaneous manifestations of Lyme borreliosis on the incidence of late complications and late serologic status . J Invest Dermatol. 1993;100:103-109.Crossref 39. Breier F, Klade H, Aberer E. T-cell responses to Borrelia burgdorferi in circumscribed scleroderma . Arch Dermatol Res. 1992;284:21-22. 40. Büchner SA, Lautenschlager S, Itin P, Erb P, Rufli T. Lymphocyte proliferative response to Borrelia burgdorferi: new diagnostic test in borreliosis . Dermatologica. 1991;183:298-299. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

Lymphoproliferative Responses to Borrelia burgdorferi in Patients With Erythema Migrans, Acrodermatitis Chronica Atrophicans, Lymphadenosis Benigna Cutis, and Morphea

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Publisher
American Medical Association
Copyright
Copyright © 1995 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archderm.1995.01690180047008
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Abstract

Abstract Background and Design: Specific humoral and cell-mediated immune responses play an important role in the pathogenesis of Lyme borreliosis. Several previous studies demonstrated that a specific cellular immune response to Borrelia burgdorferi can occur independently of a diagnostic humoral response. Little is known about T-cell reactivities against B burgdorferi in early and late cutaneous manifestations of Lyme borreliosis. We studied the lymphoproliferative response of peripheral blood mononuclear cells to B burgdorferi antigen from 99 patients (25 with erythema migrans, 16 with acrodermatitis chronica atrophicans, 13 with lymphadenosis benigna cutis, and 45 with localized scleroderma) and 21 control subjects. The results are expressed as a stimulation index (SI) (mean count per minute of triplicate cultures with stimulant divided by mean count per minute without stimulant). The serum samples from all patients and control subjects were tested for antibodies to B burgdorferi by indirect immunofluorescence assay. Results: The 21 healthy seronegative controls had an SI of 3.3±2.0 (mean±SD). Compared with that of control subjects, the SIs were significantly elevated in patients with erythema migrans (9.8±9.1), acrodermatitis chronica atrophicans (11.8±8.2), and lymphadenosisbenigna cutis (7.2±6.2). The 45 patients with localized scleroderma had elevated proliferative responses, with an SI of 6.5±7.3, but these responses did not significantly differ from those of controls. Elevated titers of antibodies to B burgdorferi were present in six (24%) of 25 patients with erythema migrans, five (38%) of 13 patients with lymphadenosis benigna cutis, and 13 (29%) of 45 patients with localized scleroderma. All 16 patients with acrodermatitis chronica atrophicans had markedly elevated antibody titers. Conclusions: Our findings show that a significant lymphoproliferative response to B burgdorferi occurs in the majority of patients with cutaneous manifestations of Lyme borreliosis. The lymphocyte proliferation assay may be of diagnostic value in patients in whom Lyme borreliosis is strongly clinically suspected and who have nondiagnostic levels of antibodies against B burgdorferi.(Arch Dermatol. 1995;131:673-677) References 1. Asbrink E, Hovmark A. Cutaneous manifestations in Ixodes-borne Borrelia spirochetosis . Int J Dermatol. 1987;26:215-223.Crossref 2. Malane MS, Grant-Kels JM, Feder HM, Luger SW. Diagnosis of Lyme disease based on dermatologic manifestations . Ann Intern Med. 1991;114:490-498.Crossref 3. Asbrink E, Olsson I, Hovmark A. Clinical manifestations of erythema chronicum migrans Afzelius in Sweden: a study on 231 patients . Zentralbl Bakteriol Mikrobiol Hyg A. 1986;263:229-236. 4. Asbrink E, Olsson I. Clinical manifestations of erythema chronicum migrans Afzelius in 161 patients . Acta Derm Venereol (Stockh). 1985;65:43-52. 5. Hovmark A, Asbrink E, Olsson I. The spirochetal etiology of lymphadenosis benigna cutis solitaria . Acta Derm Venereol (Stockh). 1986;66:479-484. 6. Abele DC, Anders KH. The many faces and phases of borreliosis, I: Lyme disease . J Am Acad Dermatol. 1990;23:167-186.Crossref 7. Abele DC, Anders KH. The many faces and phases of borreliosis, II . J Am Acad Dermatol. 1990;23:401-410.Crossref 8. Asbrink E, Hovmark A. Lyme borreliosis: aspects of tick-borne Borrelia burgdorferiinfection from a dermatologic viewpoint . Semin Dermatol. 1990;9:277-291. 9. Strle F, Pleterski-Rigler D, Stanek G, Pejovnik-Pustinek A, Ruzic E, Cimperman J. Solitary borrelial lymphocytoma: report of 36 cases . Infection. 1992;20:201-206.Crossref 10. Asbrink E, Hovmark A, Olsson I. Clinical manifestations of acrodermatitis chronica atrophicans in 50 Swedish patients . Zentralbl Bakteriol Mikrobiol Hyg A. 1986; 263:253-261. 11. Aberer E, Stanek G, Ertl M, et al. Evidence for spirochetal origin of circumscribed scleroderma (morphea) . Acta Derm Venereol (Stockh). 1987;67:225-231. 12. Aberer E, Neumann R, Stanek G. Is localized scleroderma a Borrelia infection? Lancet. 1985;2:278.Crossref 13. Buechner SA, Winkelmann RK, Lautenschlager S, Gilli L, Rufli T. Localized scleroderma associated with Borrelia burgdorferi infection: clinical, histologic, and immunohistochemical observations . J Am Acad Dermatol. 1993;29:190-196.Crossref 14. Aberer E, Klade H, Stanek G, Gebhart W. Borrelia burgdorferi and different types of morphea . Dermatologica. 1991;182:145-154.Crossref 15. Schempp C, Bocklage H, Lange R, Kölmel HW, Orfanos CE, Gollnick H. Further evidence for Borrelia burgdorferi infection in morphea and lichen sclerosus et atrophicus confirmed by DNA amplification . J Invest Dermatol. 1993; 100:717-720.Crossref 16. Sigal LH. Immunopathogenesis of Lyme borreliosis . Clin Dermatol. 1993;11: 415-422.Crossref 17. Hansen K. Laboratory diagnostic methods in Lyme borreliosis . Clin Dermatol. 1993;11:407-414.Crossref 18. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease: dissociation of specific Tand B-lymphocyte responses to Borrelia burgdorferi . N Engl J Med. 1988;319:1441-1446.Crossref 19. Dattwyler RJ, Thomas JA, Benach JL, Golightly MG. Cellular Immune response in Lyme disease: the response to mitogens, live Borrelia burgdorferi, NK cell function and lymphocyte subsets . Zentralbl Bakteriol Mikrobiol Hyg A. 1986;263:151-159. 20. Dressler F, Yoshinari NH, Steere AC. The T-cell proliferative assay in the diagnosis of Lyme disease . Ann Intern Med. 1991;115:533-539.Crossref 21. Krause A, Burmester GR, Rensing A, et al. Cellular immune reactivity to recombinant OspA and flagellin from Borrelia burgdorferi in patients with Lyme borreliosis: complexity of humoral and cellular immune responses . J Clin Invest. 1992;90:1077-1084.Crossref 22. Sigal LH, Steere AC, Freeman DH, Dwyer JM. Proliferative responses of mononuclear cells in Lyme disease: reactivity to Borrelia burgdorferi antigens is greater in joint fluid than in blood . Arthritis Rheum. 1986;29:761-769.Crossref 23. Krause A, Brade V, Schoerner C, Solbach W, Kalden JR, Burmester GR. T-cell proliferation induced by Borrelia burgdorferi in patients with Lyme borreliosis . Arthritis Rheum. 1991;34:393-402.Crossref 24. Zoschke DC, Skemp AA, Defosse DL. Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease . Ann Intern Med. 1991;114:285-289.Crossref 25. Asbrink E, Hederstedt B, Hovmark A. The spirochetal etiology of erythema chronicum migrans Afzelius . Acta Derm Venereol (Stockh). 1984;64:291-295. 26. Weir DM. Handbook of Experimental Immunology . 3rd ed. Boston, Mass: Blackwell Scientific Publications Inc; 1978. 27. Sigal LH, Moffat CM, Steere AC, Dwyer JM. Cellular immune findings in Lyme disease . J Biol Med. 1984;57:595-598. 28. Miller LC, Isa S, Vannier E, Georgilis K, Steere AC, Dinarello CA. Live Borrelia burgdorferi preferentially activate interleukin-1 beta gene expression and protein synthesis over the interleukin-1 receptor antagonist . J Clin Invest. 1992; 90:906-912.Crossref 29. Büchner SA, Rufli T. Erythema chronicum migrans: evidence for cellular immune reaction in the skin lesion . Dermatologica. 1987;174:144-149.Crossref 30. Steere AC, Duray PH, Butcher EC. Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis: comparison with rheumatoid synovium and tonsillar lymphoid tissue . Arthritis Rheum. 1988;31:487-495.Crossref 31. Baranton G, Postic D, Saint-Girons I, et al. Delineation of Borrelia burgdorferi sensu stricto, Borrelia garinii sp. nov., and group VS461 associated with Lyme borreliosis . Int J Syst Bacteriol. 1992;42:378-383.Crossref 32. van Dam AP, Kuiper H, Vos K, et al. Different genospecies of Borrelia burgdorferi are associated with distinct clinical manifestations of Lyme borreliosis . Clin Infect Dis. 1993;17:708-717.Crossref 33. Assous MV, Postic D, Paul G, Nivot P, Baranton G. Western blot analysis of sera from Lyme borreliosis patients according to the genomic species of the Borrelia strains used as antigens . Eur J Clin Microbiol Infect Dis. 1993;12: 261-268.Crossref 34. Sigal LH, Steere AC, Dwyer JM. In vivo and in vitro B-cell hyperactivity in Lyme disease . J Rheumatol. 1988;15:648-654. 35. Pachner AR, Steere AC, Sigal LH, et al. Antigen-specific proliferation of CSF lymphocytes in Lyme disease . Neurology. 1985;35:1642-1645.Crossref 36. Buechner SA, Rufli T, Erb P. Acrodermatitis chronica atrophicans: a chronic T-cell—mediated immune reaction against Borrelia burgdorferi? clinical, histologic, and immunohistochemical study of five cases . J Am Acad Dermatol. 1993;28:399-405.Crossref 37. Yssel H, Shanafelt MC, Soderberg C, Schneider PV, Anzola J, Peltz G. Borrelia burgdorferi activates a T-helper type 1—like T-cell subset in Lyme arthritis . J Exp Med. 1991;174:593-601.Crossref 38. Plörer A, Sepp N, Schmutzhard E, et al. Effects of adequate versus inadequate treatment of cutaneous manifestations of Lyme borreliosis on the incidence of late complications and late serologic status . J Invest Dermatol. 1993;100:103-109.Crossref 39. Breier F, Klade H, Aberer E. T-cell responses to Borrelia burgdorferi in circumscribed scleroderma . Arch Dermatol Res. 1992;284:21-22. 40. Büchner SA, Lautenschlager S, Itin P, Erb P, Rufli T. Lymphocyte proliferative response to Borrelia burgdorferi: new diagnostic test in borreliosis . Dermatologica. 1991;183:298-299.

Journal

Archives of DermatologyAmerican Medical Association

Published: Jun 1, 1995

References