Lähettäjä: Soijuv Lähetetty: 23.9.2004 10:40
Bb kykenee estämään immuunijärjestelmän tuhoamisyritykset seuraavan tutkimuksen mukaan:
Infection and Immunity, October 2004, p. 5759-5767, Vol. 72, No. 10
0019-9567/04/$08.00+0 DOI: 10.1128/IAI.72.10.5759-5767.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Borrelia burgdorferi Changes Its Surface Antigenic Expression in Response to Host Immune Responses
Fang Ting Liang,1 Jun Yan,1 M. Lamine Mbow,2 Steven L. Sviat,3 Robert D. Gilmore,3 Mark Mamula,1 and Erol Fikrig1*
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut,1 Centocor, Inc., Malvern, Pennsylvania,2 Bacterial Zoonoses Branch, Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado3
Received 7 May 2004/ Returned for modification 17 June 2004/ Accepted 25 June 2004
The Lyme disease spirochete, Borrelia burgdorferi, causes persistent mammalian infection despite the development of vigorous immune responses against the pathogen. To examine spirochetal phenotypes that dominate in the hostile immune environment, the mRNA transcripts of four prototypic surface lipoproteins, decorin-binding protein A (DbpA), outer surface protein C (OspC), BBF01, and VlsE, were analyzed by quantitative reverse transcription-PCR under various immune conditions.
We demonstrate that B. burgdorferi changes its surface antigenic expression in response to immune attack. dbpA expression was unchanged while the spirochetes decreased ospC expression by 446 times and increased BBF01 and vlsE expression up to 20 and 32 times, respectively, under the influence of immune pressure generated in immunocompetent mice during infection. This change in antigenic expression could be induced by passively immunizing infected severe combined immunodeficiency mice with specific Borrelia antisera or OspC antibody and appears to allow B. burgdorferi to resist immune attack.
BORRELIABAKTEERI VAIKEA TUHOTA!
Valvojat: Jatta1001, Borrelioosiyhdistys, Bb
Lähettäjä: Sar_Ani Lähetetty: 23.9.2004 11:04
Cost-effective-Steere:n viimeisin julkaisu:
http://www.jci.org/cgi/content/full/113/8/1093
Mielenkiintoinen vasta-aineiden osalta, mutta ihmettelen hänen uskoaan ihmisen yliluonnolliseen immuunijärjestelmään ! (käy lukemassa koko artikkeli)
J. Clin. Invest. 113:1093-1101 (2004). doi:10.1172/JCI200421681.
Copyright ©2004 by the American Society for Clinical Investigation
Review Series
The emergence of Lyme disease
Allen C. Steere1, Jenifer Coburn2 and Lisa Glickstein1
1Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Address correspondence to: Allen C. Steere, Massachusetts General Hospital, 55 Fruit Street, CNY 149/8301, Boston, Massachusetts 02114, USA. Phone: (617) 726-1527; Fax: (617) 726-1544; E-mail: asteere@partners.org.
Disseminated infection
Within days to weeks after disease onset, B. burgdorferi often disseminates widely. During this period, the spirochete has been recovered from blood and cerebrospinal fluid (S7, S36, S37), and it has been seen in small numbers in specimens of myocardium, retina, muscle, bone, spleen, liver, meninges, and brain (45).
Possible clinical manifestations include secondary annular skin lesions, acute lymphocytic meningitis, cranial neuropathy, radiculoneuritis, atrioventricular nodal block, migratory musculoskeletal pain in joints, bursae, tendon, muscle, or bone, and, rarely, eye manifestations (reviewed in ref. 4). Less often, spirochetal dissemination is asymptomatic.
To disseminate, B. burgdorferi binds certain host proteins and adheres to integrins, proteoglycans, or glycoproteins on host cells or tissue matrices.
As in the tick, spreading of the spirochete through tissue matrices may be facilitated by the binding of plasminogen and its activators to the surface of the organism (24).
A 47-kDa spirochetal protein (BBK32) binds fibronectin, an ECM protein (46).
The sequences of OspC vary considerably among strains, and only a few sequences are associated with disseminated infection (47), probably because they bind as-yet unidentified host structures.
A 66-kDa outer-surface protein of the spirochete binds the fibrinogen receptor (IIbß3) and the vitronectin receptor (vß3) (48 ), which may allow the organism to establish an initial foothold and disseminate in the vasculature.
A 26-kDa Borrelia glycosaminoglycan-binding (GAG-binding) protein, Bgp, binds to the GAG side chains of heparan sulfate on endothelial cells, and to both heparan sulfate and dermatan sulfate on neuronal cells (49, 50).
Finally, spirochetal decorin-binding proteins A and B (DbpA and DbpB) bind decorin, a proteoglycan that associates with collagen (51). This may explain the alignment of spirochetes with collagen fibrils in the ECM of the heart, nervous system, or joints (45).
Despite an active immune response, B. burgdorferi may survive during dissemination by changing or minimizing antigenic expression of surface proteins and by inhibiting certain critical host immune responses.
Two linear plasmids (lp?s) seem to be essential, including lp25, which encodes a nicotinamidase (52), and lp28-1, which encodes the VlsE lipoprotein (53), the protein that undergoes antigenic variation.
In addition, the spirochete has a number of families of highly homologous, differentially expressed lipoproteins, including the OspE/F paralogs, which further contribute to antigenic diversity (54).
B. burgdorferi may downregulate lipoproteins because of host immune pressure (54, 55). For example, in a mouse model, the development of antibody to OspC, a prominent early response, induces downregulation of OspC; and therefore, this antibody response does not completely clear the infection (56).
Finally, B. afzelii and, to a lesser degree, B. burgdorferi have complement regulator?acquiring surface proteins that bind complement factor H and factor H?like protein 1 (57).
These complement factors inactivate C3b, which protects the organism from complement-mediated killing (57, S38?S41). In contrast, B. garinii is efficiently killed by complement (S42).
As shown definitively in mouse models, both innate and adaptive immune responses are required for optimal control of disseminated infection (Figure 3).
B. burgdorferi lipoproteins, which are B cell mitogens (S39), stimulate adaptive T cell?independent B cell responses (58, S43, S44). For example, antibody responses to OspC kill spirochetes (59).
In addition, humoral immune responses to nonlipidated spirochetal proteins, which are more likely to be T cell?dependent, aid in spirochetal killing (60, 61).
The primary role of B. burgdorferi?specific Th1 cells is to prime these T cell?dependent B cell responses (62). The combination of these responses leads to the production of antibodies against many components of the organism (63, 64), which promote spirochetal killing by complement fixation and opsonization (S45).
Within several weeks to months, these antibody responses, in conjunction with innate immune mechanisms, control widely disseminated infection even without antibiotic treatment, and generalized symptoms resolve.
Persistent infection
After weeks of disseminated infection, the Lyme disease agents may still survive in localized niches for several years. By this time, systemic symptoms are minimal or absent altogether. Although each of the three pathogenic species may spread to the joints, nervous system, or other skin sites, they seem to vary in the frequency of dissemination to these sites and in their ability to persist there.
B. burgdorferi, the sole cause of the infection in the US, seems to be the most arthritogenic. Months after the onset of illness, about 60% of untreated patients with this infection experience intermittent attacks of arthritis, primarily of the large joints, especially the knee (65).
As shown in a mouse model, neutrophil extravasation into the infected joint is a key initial step in the development of joint inflammation (66). In the human infection, CD4+ Th cells are of the proinflammatory Th1 subset (S46, S47), and B. burgdorferi?specific CD8+ T cells are found as well (S48).
Within the joint, B. burgdorferi?specific T cells may aid in the regulation of these inflammatory responses (S49, S50). Compared with other inbred strains of mice, C57BL/6 mice are protected from severe arthritis by IL-6 and IL-10, despite large numbers of spirochetes in the joint (67, 68). It is unknown, however, whether certain human patients control joint inflammation in this way.
Patients with Lyme arthritis have very high antibody responses to many spirochetal proteins, suggestive of hyperimmunization due to recurrent waves of spirochetal growth (63, 64).
Even without antibiotic treatment, the number of patients who continue to have attacks of arthritis decreases by about 10?20% each year, and few patients have had attacks for longer than 5 years (65). Thus, these immune mechanisms seem to succeed eventually in eradicating B. burgdorferi from the joint.
In Europe and Asia, B. afzelii may persist in the skin for decades, resulting in acrodermatitis chronica atrophicans, a skin condition that occurs primarily on sun-exposed surfaces of distal extremities in elderly women (S51).
Compared with EM lesions, infiltrates of T cells and macrophages in acrodermatitis lesions had a restricted cytokine profile, lacking IFN- production (37).
Consistent with this finding, ultraviolet B irradiation of B. burgdorferi?infected C3H mice decreased the Th1 response (69). Thus, spirochetal persistence in acrodermatitis skin lesions may involve both spirochetal factors and an ineffective local immune response.
B. garinii, which is also found only in Europe and Asia, appears to be the most neurotropic of the three Borrelia species. It may cause an exceptionally wide range of neurologic abnormalities (70), including borrelial encephalomyelitis (S52), a multiple sclerosis?like illness.
In the US, a rare, late neurologic syndrome has been described, called Lyme encephalopathy or polyneuropathy, which is manifested primarily by subtle cognitive disturbances, spinal radicular pain, or distal paresthesias (71, S53). With each of these three late neurologic complications, the possible duration of spirochetal persistence and the pathogenetic mechanisms are unknown.
Cost-effective-Steere:n viimeisin julkaisu:
http://www.jci.org/cgi/content/full/113/8/1093
Mielenkiintoinen vasta-aineiden osalta, mutta ihmettelen hänen uskoaan ihmisen yliluonnolliseen immuunijärjestelmään ! (käy lukemassa koko artikkeli)
J. Clin. Invest. 113:1093-1101 (2004). doi:10.1172/JCI200421681.
Copyright ©2004 by the American Society for Clinical Investigation
Review Series
The emergence of Lyme disease
Allen C. Steere1, Jenifer Coburn2 and Lisa Glickstein1
1Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Address correspondence to: Allen C. Steere, Massachusetts General Hospital, 55 Fruit Street, CNY 149/8301, Boston, Massachusetts 02114, USA. Phone: (617) 726-1527; Fax: (617) 726-1544; E-mail: asteere@partners.org.
Disseminated infection
Within days to weeks after disease onset, B. burgdorferi often disseminates widely. During this period, the spirochete has been recovered from blood and cerebrospinal fluid (S7, S36, S37), and it has been seen in small numbers in specimens of myocardium, retina, muscle, bone, spleen, liver, meninges, and brain (45).
Possible clinical manifestations include secondary annular skin lesions, acute lymphocytic meningitis, cranial neuropathy, radiculoneuritis, atrioventricular nodal block, migratory musculoskeletal pain in joints, bursae, tendon, muscle, or bone, and, rarely, eye manifestations (reviewed in ref. 4). Less often, spirochetal dissemination is asymptomatic.
To disseminate, B. burgdorferi binds certain host proteins and adheres to integrins, proteoglycans, or glycoproteins on host cells or tissue matrices.
As in the tick, spreading of the spirochete through tissue matrices may be facilitated by the binding of plasminogen and its activators to the surface of the organism (24).
A 47-kDa spirochetal protein (BBK32) binds fibronectin, an ECM protein (46).
The sequences of OspC vary considerably among strains, and only a few sequences are associated with disseminated infection (47), probably because they bind as-yet unidentified host structures.
A 66-kDa outer-surface protein of the spirochete binds the fibrinogen receptor (IIbß3) and the vitronectin receptor (vß3) (48 ), which may allow the organism to establish an initial foothold and disseminate in the vasculature.
A 26-kDa Borrelia glycosaminoglycan-binding (GAG-binding) protein, Bgp, binds to the GAG side chains of heparan sulfate on endothelial cells, and to both heparan sulfate and dermatan sulfate on neuronal cells (49, 50).
Finally, spirochetal decorin-binding proteins A and B (DbpA and DbpB) bind decorin, a proteoglycan that associates with collagen (51). This may explain the alignment of spirochetes with collagen fibrils in the ECM of the heart, nervous system, or joints (45).
Despite an active immune response, B. burgdorferi may survive during dissemination by changing or minimizing antigenic expression of surface proteins and by inhibiting certain critical host immune responses.
Two linear plasmids (lp?s) seem to be essential, including lp25, which encodes a nicotinamidase (52), and lp28-1, which encodes the VlsE lipoprotein (53), the protein that undergoes antigenic variation.
In addition, the spirochete has a number of families of highly homologous, differentially expressed lipoproteins, including the OspE/F paralogs, which further contribute to antigenic diversity (54).
B. burgdorferi may downregulate lipoproteins because of host immune pressure (54, 55). For example, in a mouse model, the development of antibody to OspC, a prominent early response, induces downregulation of OspC; and therefore, this antibody response does not completely clear the infection (56).
Finally, B. afzelii and, to a lesser degree, B. burgdorferi have complement regulator?acquiring surface proteins that bind complement factor H and factor H?like protein 1 (57).
These complement factors inactivate C3b, which protects the organism from complement-mediated killing (57, S38?S41). In contrast, B. garinii is efficiently killed by complement (S42).
As shown definitively in mouse models, both innate and adaptive immune responses are required for optimal control of disseminated infection (Figure 3).
B. burgdorferi lipoproteins, which are B cell mitogens (S39), stimulate adaptive T cell?independent B cell responses (58, S43, S44). For example, antibody responses to OspC kill spirochetes (59).
In addition, humoral immune responses to nonlipidated spirochetal proteins, which are more likely to be T cell?dependent, aid in spirochetal killing (60, 61).
The primary role of B. burgdorferi?specific Th1 cells is to prime these T cell?dependent B cell responses (62). The combination of these responses leads to the production of antibodies against many components of the organism (63, 64), which promote spirochetal killing by complement fixation and opsonization (S45).
Within several weeks to months, these antibody responses, in conjunction with innate immune mechanisms, control widely disseminated infection even without antibiotic treatment, and generalized symptoms resolve.
Persistent infection
After weeks of disseminated infection, the Lyme disease agents may still survive in localized niches for several years. By this time, systemic symptoms are minimal or absent altogether. Although each of the three pathogenic species may spread to the joints, nervous system, or other skin sites, they seem to vary in the frequency of dissemination to these sites and in their ability to persist there.
B. burgdorferi, the sole cause of the infection in the US, seems to be the most arthritogenic. Months after the onset of illness, about 60% of untreated patients with this infection experience intermittent attacks of arthritis, primarily of the large joints, especially the knee (65).
As shown in a mouse model, neutrophil extravasation into the infected joint is a key initial step in the development of joint inflammation (66). In the human infection, CD4+ Th cells are of the proinflammatory Th1 subset (S46, S47), and B. burgdorferi?specific CD8+ T cells are found as well (S48).
Within the joint, B. burgdorferi?specific T cells may aid in the regulation of these inflammatory responses (S49, S50). Compared with other inbred strains of mice, C57BL/6 mice are protected from severe arthritis by IL-6 and IL-10, despite large numbers of spirochetes in the joint (67, 68). It is unknown, however, whether certain human patients control joint inflammation in this way.
Patients with Lyme arthritis have very high antibody responses to many spirochetal proteins, suggestive of hyperimmunization due to recurrent waves of spirochetal growth (63, 64).
Even without antibiotic treatment, the number of patients who continue to have attacks of arthritis decreases by about 10?20% each year, and few patients have had attacks for longer than 5 years (65). Thus, these immune mechanisms seem to succeed eventually in eradicating B. burgdorferi from the joint.
In Europe and Asia, B. afzelii may persist in the skin for decades, resulting in acrodermatitis chronica atrophicans, a skin condition that occurs primarily on sun-exposed surfaces of distal extremities in elderly women (S51).
Compared with EM lesions, infiltrates of T cells and macrophages in acrodermatitis lesions had a restricted cytokine profile, lacking IFN- production (37).
Consistent with this finding, ultraviolet B irradiation of B. burgdorferi?infected C3H mice decreased the Th1 response (69). Thus, spirochetal persistence in acrodermatitis skin lesions may involve both spirochetal factors and an ineffective local immune response.
B. garinii, which is also found only in Europe and Asia, appears to be the most neurotropic of the three Borrelia species. It may cause an exceptionally wide range of neurologic abnormalities (70), including borrelial encephalomyelitis (S52), a multiple sclerosis?like illness.
In the US, a rare, late neurologic syndrome has been described, called Lyme encephalopathy or polyneuropathy, which is manifested primarily by subtle cognitive disturbances, spinal radicular pain, or distal paresthesias (71, S53). With each of these three late neurologic complications, the possible duration of spirochetal persistence and the pathogenetic mechanisms are unknown.