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Lyme Borreliosis
Chapter 22
Lyme Borreliosis H.-I. Huppertz1,2 and H.J. Girschick3,4 1
Prof.-Hess-Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany, 2Universita¨tskinderklinik Go¨ttingen, Go¨ttingen, Germany, 3Universita¨tskinderklinik Wu¨rzburg, Wu¨rzburg, Germany, 4 Klinik fu¨r Kinder- und Jugendmedizin, Vivantes Netzwerk fu¨r Gesundheit GmbH, Klinikum im Friedrichshain, Berlin, Germany
INTRODUCTION Lyme disease or Lyme borreliosis (LB) is an infectious multisystem disease. LB is caused by Borrelia burgdorferi, a spirochete. Borrelia burgdorferi organisms can be subdivided into several genotypes, which have been associated with different though overlapping clinical syndromes. LB is transmitted by the vector Ixodes ricinus, a hard tick that is prevalent in many areas of the temperate northern zones including most of Europe and parts of the United States. In some parts of Europe and the United States LB may be among the most frequent infectious diseases with an incidence of 111 per 100,000 or more [1]. Up to 90% of patients with LB have erythema migrans, a mild reddening of the skin at the site of the tick bite that will disappear without intervention after a few days to weeks. The infection can affect the nervous system, joints, heart, eyes, and other organs. Clinical manifestations are classified as early or late. Early manifestations occur a few days to several weeks after infection, while late manifestations occur months to years after infection [2]. Early manifestations are self-limiting and do not cause lasting damage. However, late manifestations may become chronic and lead to organ damage. Clinical manifestations differ in adults and children: in children radiculitis is rare while lymphocytic meningitis with or without cranial nerve palsy is more frequent. Acrodermatitis chronica atrophicans, chronic central nervous system disease, and heart involvement are very rare in children. Arthritis, called Lyme arthritis (LA), is the most frequent late manifestation in children. It is often episodic, but may become chronic and up to 10%
Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00022-0 © 2016 Elsevier B.V. All rights reserved.
465
466
Pediatrics in Systemic Autoimmune Diseases
of cases are resistant to antibiotic treatment [3]. Risk factors are female gender, age above 10, and treatment with systemic or intraarticular steroids prior to initiation of antibiotic treatment. LB, and in particular LA, has attracted special interest by clinicians and researchers since arthritis due to infection with B. burgdorferi can become chronic. Chronic arthritis following infection with B. burgdorferi has been attributed to several factors including persistent infection or antigenic stimulation, immunopathological reactions to components of B. burgdorferi, and autoimmunity.
PERSISTENT INFECTION At the time of early manifestations, the presence of B. burgdorferi can be verified by isolation of the spirochete or by polymerase chain reaction (PCR) of borrelial genomic and/or plasmid-derived sequences, but this often proves impractical. In otherwise healthy patients with acrodermatitis chronica atrophicans B. burgdorferi could be grown from affected skin up to 10 years after the beginning of the disease showing the remarkable capability of the spirochete to persist in the human body in the presence of an apparently well-functioning immune system. In contrast, B. burgdorferi is rarely isolated from synovial fluid or tissue in patients with LA or from cerebrospinal fluid in patients with late neuroborreliosis. B. burgdorferi may persist in vitro in synovial cells [20]. However PCR may be positive. The spirochete has been demonstrated in synovial tissue, by staining with silver salts or monoclonal antibodies [4]. Interestingly, B. burgdorferi is found in a very low density and it is not clear if these are viable spirochetes or remnants difficult to degrade.
IMMUNOPATHOLOGICAL REACTIONS Borrelia burgdorferi may modulate the immune system. In patients with acrodermatitis chronica atrophicans decreased expression of the major histocompatibility complex (MHC) has been observed on Langerhans cells in contact with B. burgdorferi [5]. Infection may increase or decrease the expression of adhesion molecules on a variety of cell types [6 8]. Borrelia burgdorferi-specific CD4-positive T cells can be isolated from peripheral blood or synovial fluid of patients with LA [9] and the response increases with prolonged disease. The lymphokines secreted by these cells have typical Th1 characteristics [10]. CD8-positive B. burgdorferi-specific T cells have been isolated from children with LA after resolution of arthritis suggesting a regulatory deficiency may contribute to the development of chronic arthritis [11]. Borrelia burgdorferi does not produce toxins and does not harbor lipopolysaccharides, but it contains a variety of lipoproteins that may influence the development of arthritis [12].
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AUTOIMMUNITY Patients with persistent LA have been shown to express MHC class II molecules associated with rheumatoid arthritis (RA), including HLA-DRB1 0401 and 0101 [13]. These patients showed high titers of antibodies against the outer surface protein A (OspA), which is a plasmid-encoded virulence factor located in the outer envelope of the spirochete [14]. After phagocytosis borrelial antigens can be presented by MHC II molecules to T cells [15]. It was shown that the T-cell antigen LFA-1 can stimulate OspA-specific T cells from patients with treatment-resistant LA [16]. Thus LFA-1 might serve as cross-reactive autoantigen by way of molecular mimicry in which initially an immune response is mounted against OspA; then the immune response also affects LFA-1, which leads to the stimulation of the T cells; and finally, the immune response may persist even in the absence of OspA and is directed against LFA-1. However, although conclusive, this hypothesis has not been confirmed subsequently. In an animal model, B-cell tolerance was broken following chronic infection with B. burgdorferi. The immune complexes induced synergistic signaling between B-cell receptor, Toll-like receptors, and T-helper cell [17]. Thus autoimmune reactions and not just molecular mimicry between bacterial and host antigens contribute to the chronic arthritis of LB [18].
CONCLUSIONS LA is an intriguing disease: it is infectious, but the rate of response to antibiotic treatment of about 90% is inferior to that found in other bacterial diseases. LA may also be considered a rheumatic disease, but with a very favorable outcome: there are few or no other rheumatic diseases that remit in 90% of patients after one or two short courses of antibiotics. Moreover, the other 10% of patients have a good chance to reach remission a few months or years later after appropriate antirheumatic treatment including intraarticular steroids and/or methotrexate. Although several theories have been proposed, the mechanisms of the pathogenesis of antibiotic refractory LA remains unknown. In addition, the hope to find clues for understanding the pathogenesis of RA or juvenile idiopathic arthritis (JIA) by better understanding the pathogenesis of LA have not come true so far. Much more research is necessary to achieve that goal. However, at present LA is not a research priority and very little knowledge could be added during the past few years. In contrast alternative medicine is using LB as a platform for attempts called “antiscience” to improve unexplained symptoms usually amenable to multimodal treatment including psychotherapy [19]. However, a better understanding of the pathogenesis of treatment-refractory LA might not only help patients with LA to be treated more effectively. It might also increase our understanding of RA and JIA
468
Pediatrics in Systemic Autoimmune Diseases
and thereby it might be possible to outline new options for treatment or even prevention that should counter the causative disease process rather than just suppress the inflammatory response as actual pharmacological treatment options do.
KEY POINTS G
G
G
Lyme arthritis is the most frequent bacterial infection associated with arthritis. Chronic Lyme arthritis may be a human model of chronic inflammatory joint disease with a known etiology. Clarification of its pathogenesis may provide clues to the pathogenesis of other chronic inflammatory joint diseases including rheumatoid arthritis and juvenile idiopathic arthritis.
REFERENCES [1] Huppertz HI, Bo¨hme M, Standaert SM, Karch H, Plotkin SA. Incidence of Lyme borreliosis in the Wu¨rzburg area of Germany. Eur J Clin Microbiol Infect Dis 1999;18:697 703. [2] Huppertz HI, Zemel L, Dressler F. Lyme disease. In: Petty RE, Laxer RM, et al., editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2015. p. 551 62. [3] Bentas W, Karch H, Huppertz HI. Lyme arthritis in children and adolescents:outcome 12 months after initiation of antibiotic therapy. J Rheumatol 2000;27:2025 30. [4] Priem S, Burmester GR, Kamradt T, et al. Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy. Ann Rheum Dis 1998;57:118 21. [5] Silberer M, Koszik F, Stingl G, Aberer E. Downregulation of class II molecules on epidermal Langerhans cells in Lyme borreliosis. Br J Dermatol 2000;143:786 94. [6] Sellati TJ, Burns MJ, Ficazzola MA, Furie MB. Borrelia burgdorferi upregulates expression of adhesion molecules on endothelial cells and promotes transendothelial migration of neutrophils in vitro. Infect Immun 1995;63:4439 47. [7] Singh SK, Baar V, Morbach H, Girschick HJ. Expression of ICAM-1, ICAM-2,NCAM-1 and VCAM-1 by synovial cells exposed to Borrelia burgdorferi in vitro. Rheumatol Int 2005;24:1 10. [8] Girschick HJ, Meister S, Karch H, Huppertz HI. Borrelia burgdorferi downregulates ICAM-1 on human synovial cells in vitro. Cell Adhes Commun 1999;7:73 83. [9] Huppertz HI, Mo¨sbauer S, Busch DH, Karch H. Lymphoproliferative responses to Borrelia burgdorferi in the diagnosis of Lyme arthritis in children and adolescents. Eur J Pediatr 1996;155:297 302. [10] Yssel H, Shanafelt MC, Soderberg C, Schneider PV, Angola J, Pelty G. Borrelia burgdorferi activates a T helper type 1-like cell subset in Lyme arthritris. J Exp Med 1991; 174:593 601. [11] Busch DH, Jassoy C, Brinckmann U, Girschick HJ, Huppertz HI. Detection of Borrelia burgdorferi-specific CD8+ cytotoxic T cells in patients with Lyme arthritis. J Immunol 1996;157:3534 41.
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[12] Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopolypeptides induce the production of IL-17 in T helper cells. J Immunol 2000;165:6107 15. [13] Steere AC, Baxter-Lowe LA. Association of chronic, treatment resistant Lyme arthritis with rheumatoid arthriris alleles. Arthritis Rheum 1998;41:S81. [14] Kalish RA, Leong JM, Steere AC. Early and late antibody responses to full length and truncated constructs of outer surface protein A of Borrelia burgdorferi in Lyme disease. Infect Immun 1995;63:2228 35. [15] Filgueiria L, Nestle FO, Rittig M, Joller HI, Groscurth P. Human dendritic cells phagocytose and process Borrelia burgdorferi. J Immunol 1996;157:2998 3005. [16] Trollmo C, Meyer AL, Steere AC, Hafler DA, Huber BT. Molecular mimicry in Lyme arthritis demonstrated at the single cell level: LFA-1 alpha is a partial agonist for outer surface protein A-reactive T cells. J Immunol 2001;166:5286 91. [17] Soulas P, Woods A, Jaulhac B, Knapp AM, Pasquali JL, Martin T, et al. Autoantigen, innate immunity, and T cells cooperate to break B cell tolerance during bacterial infection. J Clin Invest 2005;115:2257 67. [18] Kamradt T, Volkmer-Engert R. Cross-reactivity of T lymphocytes in infection and autoimmunity. Mol Divers 2004;8:271 80. [19] Huppertz HI, Bartmann P, Heininger U, Fingerle V, Kinet M, et al. Rational diagnostic strategies for Lyme borreliosis in children and adolescents: recommendations by the committee for infectious diseases and vaccinations of the German Academy for Pediatrics and Adolescent Health. Eur J Pediatr 2012;171:1619 24. [20] Girschick HJ, Huppertz HI, Ru¨ssmann H, Krenn V, Karch H. Intracellular persistence of Borrelia burgdorferi in human synovial cells. Rheumatol Int 1996;16:125 32.
Lyme Borreliosis H.-I. Huppertz1,2 and H.J. Girschick3,4 1
Prof.-Hess-Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany, 2Universita¨tskinderklinik Go¨ttingen, Go¨ttingen, Germany, 3Universita¨tskinderklinik Wu¨rzburg, Wu¨rzburg, Germany, 4 Klinik fu¨r Kinder- und Jugendmedizin, Vivantes Netzwerk fu¨r Gesundheit GmbH, Klinikum im Friedrichshain, Berlin, Germany
INTRODUCTION Lyme disease or Lyme borreliosis (LB) is an infectious multisystem disease. LB is caused by Borrelia burgdorferi, a spirochete. Borrelia burgdorferi organisms can be subdivided into several genotypes, which have been associated with different though overlapping clinical syndromes. LB is transmitted by the vector Ixodes ricinus, a hard tick that is prevalent in many areas of the temperate northern zones including most of Europe and parts of the United States. In some parts of Europe and the United States LB may be among the most frequent infectious diseases with an incidence of 111 per 100,000 or more [1]. Up to 90% of patients with LB have erythema migrans, a mild reddening of the skin at the site of the tick bite that will disappear without intervention after a few days to weeks. The infection can affect the nervous system, joints, heart, eyes, and other organs. Clinical manifestations are classified as early or late. Early manifestations occur a few days to several weeks after infection, while late manifestations occur months to years after infection [2]. Early manifestations are self-limiting and do not cause lasting damage. However, late manifestations may become chronic and lead to organ damage. Clinical manifestations differ in adults and children: in children radiculitis is rare while lymphocytic meningitis with or without cranial nerve palsy is more frequent. Acrodermatitis chronica atrophicans, chronic central nervous system disease, and heart involvement are very rare in children. Arthritis, called Lyme arthritis (LA), is the most frequent late manifestation in children. It is often episodic, but may become chronic and up to 10%
Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00022-0 © 2016 Elsevier B.V. All rights reserved.
465
466
Pediatrics in Systemic Autoimmune Diseases
of cases are resistant to antibiotic treatment [3]. Risk factors are female gender, age above 10, and treatment with systemic or intraarticular steroids prior to initiation of antibiotic treatment. LB, and in particular LA, has attracted special interest by clinicians and researchers since arthritis due to infection with B. burgdorferi can become chronic. Chronic arthritis following infection with B. burgdorferi has been attributed to several factors including persistent infection or antigenic stimulation, immunopathological reactions to components of B. burgdorferi, and autoimmunity.
PERSISTENT INFECTION At the time of early manifestations, the presence of B. burgdorferi can be verified by isolation of the spirochete or by polymerase chain reaction (PCR) of borrelial genomic and/or plasmid-derived sequences, but this often proves impractical. In otherwise healthy patients with acrodermatitis chronica atrophicans B. burgdorferi could be grown from affected skin up to 10 years after the beginning of the disease showing the remarkable capability of the spirochete to persist in the human body in the presence of an apparently well-functioning immune system. In contrast, B. burgdorferi is rarely isolated from synovial fluid or tissue in patients with LA or from cerebrospinal fluid in patients with late neuroborreliosis. B. burgdorferi may persist in vitro in synovial cells [20]. However PCR may be positive. The spirochete has been demonstrated in synovial tissue, by staining with silver salts or monoclonal antibodies [4]. Interestingly, B. burgdorferi is found in a very low density and it is not clear if these are viable spirochetes or remnants difficult to degrade.
IMMUNOPATHOLOGICAL REACTIONS Borrelia burgdorferi may modulate the immune system. In patients with acrodermatitis chronica atrophicans decreased expression of the major histocompatibility complex (MHC) has been observed on Langerhans cells in contact with B. burgdorferi [5]. Infection may increase or decrease the expression of adhesion molecules on a variety of cell types [6 8]. Borrelia burgdorferi-specific CD4-positive T cells can be isolated from peripheral blood or synovial fluid of patients with LA [9] and the response increases with prolonged disease. The lymphokines secreted by these cells have typical Th1 characteristics [10]. CD8-positive B. burgdorferi-specific T cells have been isolated from children with LA after resolution of arthritis suggesting a regulatory deficiency may contribute to the development of chronic arthritis [11]. Borrelia burgdorferi does not produce toxins and does not harbor lipopolysaccharides, but it contains a variety of lipoproteins that may influence the development of arthritis [12].
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AUTOIMMUNITY Patients with persistent LA have been shown to express MHC class II molecules associated with rheumatoid arthritis (RA), including HLA-DRB1 0401 and 0101 [13]. These patients showed high titers of antibodies against the outer surface protein A (OspA), which is a plasmid-encoded virulence factor located in the outer envelope of the spirochete [14]. After phagocytosis borrelial antigens can be presented by MHC II molecules to T cells [15]. It was shown that the T-cell antigen LFA-1 can stimulate OspA-specific T cells from patients with treatment-resistant LA [16]. Thus LFA-1 might serve as cross-reactive autoantigen by way of molecular mimicry in which initially an immune response is mounted against OspA; then the immune response also affects LFA-1, which leads to the stimulation of the T cells; and finally, the immune response may persist even in the absence of OspA and is directed against LFA-1. However, although conclusive, this hypothesis has not been confirmed subsequently. In an animal model, B-cell tolerance was broken following chronic infection with B. burgdorferi. The immune complexes induced synergistic signaling between B-cell receptor, Toll-like receptors, and T-helper cell [17]. Thus autoimmune reactions and not just molecular mimicry between bacterial and host antigens contribute to the chronic arthritis of LB [18].
CONCLUSIONS LA is an intriguing disease: it is infectious, but the rate of response to antibiotic treatment of about 90% is inferior to that found in other bacterial diseases. LA may also be considered a rheumatic disease, but with a very favorable outcome: there are few or no other rheumatic diseases that remit in 90% of patients after one or two short courses of antibiotics. Moreover, the other 10% of patients have a good chance to reach remission a few months or years later after appropriate antirheumatic treatment including intraarticular steroids and/or methotrexate. Although several theories have been proposed, the mechanisms of the pathogenesis of antibiotic refractory LA remains unknown. In addition, the hope to find clues for understanding the pathogenesis of RA or juvenile idiopathic arthritis (JIA) by better understanding the pathogenesis of LA have not come true so far. Much more research is necessary to achieve that goal. However, at present LA is not a research priority and very little knowledge could be added during the past few years. In contrast alternative medicine is using LB as a platform for attempts called “antiscience” to improve unexplained symptoms usually amenable to multimodal treatment including psychotherapy [19]. However, a better understanding of the pathogenesis of treatment-refractory LA might not only help patients with LA to be treated more effectively. It might also increase our understanding of RA and JIA
468
Pediatrics in Systemic Autoimmune Diseases
and thereby it might be possible to outline new options for treatment or even prevention that should counter the causative disease process rather than just suppress the inflammatory response as actual pharmacological treatment options do.
KEY POINTS G
G
G
Lyme arthritis is the most frequent bacterial infection associated with arthritis. Chronic Lyme arthritis may be a human model of chronic inflammatory joint disease with a known etiology. Clarification of its pathogenesis may provide clues to the pathogenesis of other chronic inflammatory joint diseases including rheumatoid arthritis and juvenile idiopathic arthritis.
REFERENCES [1] Huppertz HI, Bo¨hme M, Standaert SM, Karch H, Plotkin SA. Incidence of Lyme borreliosis in the Wu¨rzburg area of Germany. Eur J Clin Microbiol Infect Dis 1999;18:697 703. [2] Huppertz HI, Zemel L, Dressler F. Lyme disease. In: Petty RE, Laxer RM, et al., editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2015. p. 551 62. [3] Bentas W, Karch H, Huppertz HI. Lyme arthritis in children and adolescents:outcome 12 months after initiation of antibiotic therapy. J Rheumatol 2000;27:2025 30. [4] Priem S, Burmester GR, Kamradt T, et al. Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy. Ann Rheum Dis 1998;57:118 21. [5] Silberer M, Koszik F, Stingl G, Aberer E. Downregulation of class II molecules on epidermal Langerhans cells in Lyme borreliosis. Br J Dermatol 2000;143:786 94. [6] Sellati TJ, Burns MJ, Ficazzola MA, Furie MB. Borrelia burgdorferi upregulates expression of adhesion molecules on endothelial cells and promotes transendothelial migration of neutrophils in vitro. Infect Immun 1995;63:4439 47. [7] Singh SK, Baar V, Morbach H, Girschick HJ. Expression of ICAM-1, ICAM-2,NCAM-1 and VCAM-1 by synovial cells exposed to Borrelia burgdorferi in vitro. Rheumatol Int 2005;24:1 10. [8] Girschick HJ, Meister S, Karch H, Huppertz HI. Borrelia burgdorferi downregulates ICAM-1 on human synovial cells in vitro. Cell Adhes Commun 1999;7:73 83. [9] Huppertz HI, Mo¨sbauer S, Busch DH, Karch H. Lymphoproliferative responses to Borrelia burgdorferi in the diagnosis of Lyme arthritis in children and adolescents. Eur J Pediatr 1996;155:297 302. [10] Yssel H, Shanafelt MC, Soderberg C, Schneider PV, Angola J, Pelty G. Borrelia burgdorferi activates a T helper type 1-like cell subset in Lyme arthritris. J Exp Med 1991; 174:593 601. [11] Busch DH, Jassoy C, Brinckmann U, Girschick HJ, Huppertz HI. Detection of Borrelia burgdorferi-specific CD8+ cytotoxic T cells in patients with Lyme arthritis. J Immunol 1996;157:3534 41.
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[12] Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopolypeptides induce the production of IL-17 in T helper cells. J Immunol 2000;165:6107 15. [13] Steere AC, Baxter-Lowe LA. Association of chronic, treatment resistant Lyme arthritis with rheumatoid arthriris alleles. Arthritis Rheum 1998;41:S81. [14] Kalish RA, Leong JM, Steere AC. Early and late antibody responses to full length and truncated constructs of outer surface protein A of Borrelia burgdorferi in Lyme disease. Infect Immun 1995;63:2228 35. [15] Filgueiria L, Nestle FO, Rittig M, Joller HI, Groscurth P. Human dendritic cells phagocytose and process Borrelia burgdorferi. J Immunol 1996;157:2998 3005. [16] Trollmo C, Meyer AL, Steere AC, Hafler DA, Huber BT. Molecular mimicry in Lyme arthritis demonstrated at the single cell level: LFA-1 alpha is a partial agonist for outer surface protein A-reactive T cells. J Immunol 2001;166:5286 91. [17] Soulas P, Woods A, Jaulhac B, Knapp AM, Pasquali JL, Martin T, et al. Autoantigen, innate immunity, and T cells cooperate to break B cell tolerance during bacterial infection. J Clin Invest 2005;115:2257 67. [18] Kamradt T, Volkmer-Engert R. Cross-reactivity of T lymphocytes in infection and autoimmunity. Mol Divers 2004;8:271 80. [19] Huppertz HI, Bartmann P, Heininger U, Fingerle V, Kinet M, et al. Rational diagnostic strategies for Lyme borreliosis in children and adolescents: recommendations by the committee for infectious diseases and vaccinations of the German Academy for Pediatrics and Adolescent Health. Eur J Pediatr 2012;171:1619 24. [20] Girschick HJ, Huppertz HI, Ru¨ssmann H, Krenn V, Karch H. Intracellular persistence of Borrelia burgdorferi in human synovial cells. Rheumatol Int 1996;16:125 32.