| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Tufts University School of Medicine and Sackler School of Biomedical Sciences, Department of Pathology, Boston, MA 02111;
New England Medical Center, Division of Rheumatology/Immunology, Tufts University School of Medicine, Boston, MA 02111
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In patients with Lyme disease, the immune response to Bb develops over a period of months, resulting in reactivity to an increasing array of spriochetal Ags (9). In approximately 70% of patients with Lyme arthritis, the final point of immune response expansion is the development of IgG Ab to outer-surface proteins A and B (OspA and OspB) of the spirochete (7). The onset of this response occurs near the beginning of prolonged episodes of arthritis (7). Patients with HLA-DR4 specificity often have T and B cell reactivity toward OspA, which has been associated with lack of response to antibiotic treatment (7). Thus, reactivity to OspA is a significant correlate of prolonged Lyme arthritis.
The subset of CD4+ T helper cells activated during an
infection determines the efficiency with which the host is able to
mount a protective immune response. This is achieved by the production
of characteristic cytokine profiles (10, 11, 12, 13, 14, 15, 16). Th1 cells, capable of
secreting IL-2, lymphotoxin, and IFN-
, elicit an inflammatory
response, thereby regulating antiviral responses and immunity to
intracellular pathogens (10, 11, 12, 13, 14, 15, 16). Alternatively, Th2 cells, which
produce IL-4, IL-5, IL-10, and IL-13, mediate humoral immunity, but
inhibit cell-mediated inflammatory responses (10, 11, 12, 13, 14, 15, 16). Therefore, the
type of Th cells induced in response to invasion by a particular
pathogen can have a significant effect on the host’s ability to
successfully combat the infection (10, 11, 12, 13, 14, 15).
Analysis of T cell subsets involved in the development of Lyme arthritis in mice reveals a picture reminiscent of murine Leishmania or human leprosy in which the Th response determines the severity of the disease (17, 18). BALB/c (H-2d) mice, which show only a mild arthritis when infected with Bb, develop a predominant Th2 response. In contrast, C3H/HeJ (H-2k) mice, which mount severe arthritis with Bb infection, have a dominant Th1 response (19, 20). When these T cell responses are reversed by administration of anti-cytokine blocking Abs, the severity of the arthritis is exacerbated or ameliorated in the respective mouse strains (19). Interestingly, the resistant and susceptible phenotypes appear to be MHC linked, as mice with an H-2d haplotype show minimal or no sign of arthritis any time during infection; mice with an H-2k haplotype develop severe arthritis, and mice with H-2b,r or s haplotypes demonstrate varying degrees of arthritis (21). A correlation with development of treatment-resistant chronic Lyme arthritis in human patients has been established with HLA-DR4 (5, 7), although the molecular basis of the susceptibility is not yet clear (22).
We have determined the Th phenotype in the synovial fluid of patients
with Lyme arthritis, as well as those with rheumatoid arthritis and
other forms of chronic inflammatory arthritis. In addition, we have
identified Ag-specificity of T cells in the synovial fluid of patients
representing the spectrum of Lyme arthritis. The novelty and power of
our analysis lies in the determination of the polyclonal T cell
response as an accurate representation of the repertoire present in the
patient at the time the sample was obtained. We have achieved this
unbiased picture by screening the total T cell population without in
vitro selection for individual clones that are able to proliferate.
This is particularly important, as it has been well established that
Th2 responses cannot be detected by proliferation assays in vitro.
Thus, we have designed an experimental approach that allows the
analysis of individual cells, both in terms of Ag-specificity and
lymphokine profile, while minimizing the number of patient cells
required to obtain the clearest answer to our objective. No such
investigations have been possible so far due to technical limitations.
Our results yield three points: 1) IFN--producing CD4+
cells dominate the T cell profile in the SF of patients with active
arthritis. Furthermore, the severity of active arthritis, as determined
by joint fluid effusion volume, directly correlates with the ratio of
Th1:Th2 cells in the SF. 2) Elevated Th2 responses inversely correlate
with severity of arthritis and duration of disease in Lyme arthritis
patients; and 3) IFN--producing T cells, which are Bb
Ag-specific, are localized to the SF only in patients with Lyme
arthritis. The identification of Ag-specific reactive Th1 cells in
synovial fluid is of particular importance with regard to patients with
treatment-resistant chronic Lyme arthritis, as such reactivity in the
absence of Bb suggests the possibility of an autoimmune
process.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We studied 10 patients with Lyme arthritis and 12 control patients with rheumatoid arthritis or other forms of chronic inflammatory arthritis. The Lyme arthritis patients represent the spectrum of disease severity and duration. All Lyme patients met the CDC case definition for diagnosis of Lyme Disease. They had arthritis affecting the knee and serologic reactivity with Bb by ELISA and Western blotting: two patients had a prior history of erythema migrans. Patients with other chronic inflammatory arthritides were seronegative for Bb. The 10 Lyme arthritis patients and 7 of the control patients were evaluated in the Lyme Disease Clinic at New England Medical Center (Boston, MA). The remaining 5 RA patients’ samples were a gift of Dr. S. Copper and Dr. R. Budd (Department of Medicine, University of Vermont Medical School, Burlington, VT). The protocol was approved by the Human Investigations Committee, and informed consent was obtained from each subject.
Duration of active arthritis in patients with Lyme arthritis has
previously been categorized into three groups based upon months of
active inflammation (5). We have expanded this categorization as
follows: a score of 1+ was given for arthritis lasting between 1 wk and
3 mo; 2+ for 4 to 6 mo; 3+ for 7 to 12 mo; and, 4+ for longer than 12
mo. Severity of active arthritis can be assessed by a number of means
including patient-reported pain evaluations, radiographic measurements
of joint destruction, and inflammation as determined by SF effusion
volume (23). We chose to measure disease severity based upon the volume
of fluid drained from the knee joint: a score of 1+ for 1 to 10 ml; 2+
for 11 to 30 ml; 3+ for 31 to 50 ml and 4+ for greater than 50 ml. This
measurement was the most reliable and least expensive means of
acquiring this type of information for each patient. The duration and
severity index were the sum of these two scores. The patients with Lyme
arthritis were treated with oral doxycycline, 100 mg twice a day for 1
to 2 mo, or with i.v. ceftriaxone, 2 g once a day for 1 to 2 mo
(Table I
). Two of these patient samples
were obtained before antibiotic treatment (TB and RA), whereas the
remaining eight patient samples were obtained after initiation or
completion of antibiotic therapy. The ten patients with Lyme arthritis
were seen at 3- to 6-month intervals after therapy to determine
duration of arthritis.
|
Peripheral blood and synovial fluid were obtained simultaneously on each patient with Lyme arthritis. Lymphocytes were isolated via Ficoll-Hypaque (Sigma Chemical Co., St. Louis, MO) centrifugation. Cells were plated in 96-well flat-bottom plates (Costar, Cambridge, MA) at a density of 3 to 5 x 105 cells/200 ml in serum-free medium (AIM-V, GIBCO, Grand Island, NY). Restimulations consisted of a 6 h polyclonal stimulus or a 48 h Ag recall. For the 6 h pulse, cells were stimulated with PMA (50 ng/ml) plus ionomycin (1 mg/ml) in the presence of 2 µM monensin (Sigma, St. Louis, MO). Monensin acts as a Golgi transport inhibitor, resulting in retention of intracellular cytokines, which facilitates FACS analysis (24). A 48 h recall Ag response was induced with a delipidated form of purified Bb outer surface protein A, nL-OspA, (6.25 mg/ml). During the final 5 h of stimulation, the cells were pulsed with anti-hCD3 (OKT3 1:10,000 dilution of ascites) and anti-hCD28 (1 mg/ml), a generous gift from Dr. Gordon Freeman (Dana-Farber Cancer Institutes, Boston, MA), in the presence of monensin (2 mM). This restimulation protocol allows for enhanced cytokine accumulation in the active cells, which aids in detection by FACS. Cells pulsed with anti-hCD3 and anti-hCD28 alone for 5 h show minimal cytokine production at this time point. This restimulation protocol was adapted from PharMingen (San Diego, CA).
Intracellular cytokine staining for FACS analysis
Following the in vitro restimulation, cells were transferred to
96-well V-bottom plates (Costar, Cambridge, MA) and centrifuged at 1600
rpm for 4 min. Staining protocols were adapted from PharMingen (San
Diego, CA). Cells were incubated with anti-hCD4-PerCP (Becton
Dickinson, San Jose, CA) in staining buffer (PBS–Mediatech, Cambridge,
MA; 0.1% NaN3–Sigma Chemical Co., St. Louis, MO; 1%
FCS–Intergen Co., Purchase, NY) for 30 min at 4°C in the dark. Cells
were then washed in staining buffer and fixed in 4% paraformaldehyde
for 20 min at 4°C in the dark. Cells were again washed with staining
buffer, followed by an incubation with anti-hIL4-PE and
anti-hIFN--FITC (PharMingen, San Diego, CA) in permeabilization
buffer (PBS, 0.1% NaN3, 1% FCS, 0.1% saponin–Sigma
Chemical Co., St. Louis, MO) for 30 min at 4°C in the dark. Finally,
cells were washed with permeabilization buffer and resuspended in
staining buffer for FACS analysis.
FACS analysis
Cells were analyzed on a FACScan flow cytometer (Becton Dickinson, San Jose, CA), equipped with a 480 nm Argon ion laser. 10,000 events were collected per sample. Data were analyzed with the LYSIS II program (Becton Dickinson, San Jose, CA).
PCR for detection of Bb DNA
An aliquot of SF was obtained without heparin for PCR testing, as previously described (6).
Statistical analysis
Individual variables were compared by using paired Student’s t-test analysis and are expressed as the mean ± one SD. Correlational analysis was performed on Th1:Th2 ratio and arthritis severity data and expressed as the Pearson coefficient (r).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The 10 patients with Lyme arthritis are representative of the
clinical spectrum of duration and severity of the disease (Table I
).
All Lyme patients experienced mild to severe arthritis, affecting
primarily the knee for 1 wk to 4 mo before diagnosis and treatment with
oral or i.v. antibiotics. At the mild end of the spectrum, patient
TB’s arthritis resolved within 2 wk after initiation of antibiotic
treatment. Similarly, patient RM resolved his arthritis within 6 wk
after starting antibiotic therapy. Patients JH, SM, AM, and RA required
between 2 to 4 mo for complete resolution of arthritis after the
initiation of therapy. At the far end of the spectrum, patients WA and
LB had arthritis that persisted for almost 2 years after multiple
courses of oral and i.v. antibiotics, thereby categorizing their
disease as treatment-resistant chronic Lyme arthritis. Finally,
patients MM and EM are currently receiving antibiotic treatment. Twelve
control patients were studied: 8 had rheumatoid arthritis, 2 had
psoriatic arthritis, 1 had spondyloarthritis, and 1 had chronic
monoarticular arthritis (Table II). Most
of these patients had had active arthritis from 1 to 20 years at the
time of testing.
|
in CD4+ T cells from SF
Peripheral blood and synovial fluid lymphocytes were briefly
pulsed in vitro for 6 h with the polyclonal stimulus of phorbol
ester and calcium ionophore (PMA/ionomycin). This in vitro incubation
allows for enhanced accummulation of cytokines only in cells that have
previously been activated in vivo, but not in quiescent cells (Fig. 1). Hence, in conjunction with the
addition of the Golgi transport inhibitor, monensin, we are able to
detect and distinguish the active, cytokine-producing cells from the
quiescent, non-cytokine producing cells, by cytofluorometric analysis
of intracellular cytokine expression. Monensin treatment for 6 h
does not affect the level of CD4 expressed on the cell surface,
compared with untreated cells. Furthermore, no difference in CD4
expression was detected between cells pulsed in vitro for 6 h with
PMA/ionomycin and unpulsed cells in the presence or absence of monensin
(data not shown). However, cells incubated with monensin longer than
6 h showed a marked decrease in surface CD4 expression (data not
shown). Intracellular cytokine staining for FACS analysis demonstrated
a dominant Th1 response in the SF of all Lyme arthritis patients
(22.7% ± 7.5% Th1 vs 5.8% ± 3.1% Th2; p < 0.001) (Fig. 1A). Similar findings were obtained with 11 control
patient SF samples (37.2% ± 14.6% Th1 vs 2.3% ± 2.4% Th2;
p < 0.001) (Fig. 1B). (Due to
limited cell numbers available, SF cells from one patient were not
simulated with PMA/ionomycin). The Th profile in the peripheral blood
of Lyme patients was variable for each patient and showed no
significant differences between Th1 and Th2 subset prevalence (4.6% ±
3.8% Th1 vs 2.9% ± 2.0% Th2; p = NS). However, Th1
cells represented a greater proportion of CD4+ T cells in
the SF as compared with the peripheral blood (22.7% ± 7.5% SF vs
4.6% ± 3.8% PBMC; p < 0.001) (Fig. 1A), whereas no significant differences were found
for Th2 cell localization. PBMC were not analyzed in the control
patient population. The ratio of Th1 to Th2 cells in joint fluid of
Lyme arthritis patients correlated with the severity of joint swelling.
In general, the greater the synovial effusion, the higher the Th1:Th2
ratio (r = 0.67, p < 0.05). A
trend was also apparent between an increased activity of SF Th2 cells
and a decreased duration and severity index score (Fig. 1A
and Table I). Insufficient patient history was available to determine
whether a similar correlation existed in the control patient
population. Analyzes of Th1:Th2 ratios covering a two-year period of
serial samples from a treatment-resistant chronic Lyme arthritis
patient, WA, have never revealed a significant presence of Th2 cells in
the SF (data not shown).
|
A critical question is whether this dominant Th1 response seen in
the SF is Ag-specific. Since limited numbers of donor cells prohibited
multiple antigenic reactivity testing, outer surface protein A (OspA)
of Bb was selected to restimulate SF cells and PBMC in
vitro, as T and B cell responses to OspA have previously been shown to
correlate with prolonged Lyme arthritis (25, 26). As shown by FACS
analysis, the intracellular cytokine staining of OspA restimulated
cells displayed a dominant Th1 profile in SF of all Lyme arthritis
patients tested (7.1% ± 5.7% Th1 vs 1.4% ± 2.3% Th2;
p < 0.025), which was significantly greater than that
in peripheral blood (7.1% ± 5.7% SF Th1 vs 1.3% ± 1.0% PBMC Th1;
p < 0.025), (Fig. 2A). (Patients RM and
EM were not examined for OspA reactivity due to limited cell
number availability). No significant differences were seen between the
percentages of Th2 cells in SF compared with periphery. Since this
Ag-specific response is relatively minor compared with the polyclonal
response (7.1% vs 22.7%), it was not possible to make a quantitative
statement regarding the ratio of OspA-reactive Th1 to Th2 cells and
disease severity. However, the presence or absence of this response
clearly indicates a qualitative difference between these patients.
|
B). Representative results are shown in Fig. 3A and 3B. Thus,
the Th1 response seen in the SF of patients with Lyme arthritis
represents a localized, Ag-specific response at the site of active
joint inflammation.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The present study shows that freshly isolated, polyclonal, Ag-specific T cells from actively inflamed joints of patients with various forms of chronic inflammatory arthritis have a dominant Th1 phenotype. Previous analyzes have demonstrated Th1-like cytokine expression patterns in synovial tissue and T cell clones derived from a variety of chronic inflammatory arthritides (27, 28, 29, 30, 31, 32). Synovial T cell clones derived from patients with Chlamydia- or Yersinia-induced reactive arthritis have been reported to express Th1 cytokines (27, 28, 29). Similarly, T cell clones obtained from the SF of a patient with Lyme arthritis stimulated with Bb Ags produced Th1-type cytokines (32). Comparable findings have been described for the inflammatory autoimmune disease rheumatoid arthritis (30, 33, 34, 35). Thus, the activation of cells able to produce Th1-type cytokines appears to be important in the pathogenesis of chronic inflammatory arthritis.
In an attempt to elucidate the population of active cells involved in
the propagation of Lyme arthritis we utilized intracellular cytokine
staining for FACS analysis, which allows a highly refined picture of
the polyclonal Th1/Th2 profile to be analyzed at the single cell level
with relative ease and accuracy. This technique quantifies individual
cytokine-producing cells present in the SF, thereby obviating need for
multiple in vitro restimulations that may result in outgrowth of
selected populations. With this method we were able to demonstrate a
higher prevalence of active Th1 cells in the SF compared with the
periphery in patients with Lyme arthritis (Fig. 1A).
We could detect no differences in the Th responses between patients who
either had a history of erythema migrans or who had a positive PCR test
for Bb DNA in SF, as compared with patients who were
negative for either of these parameters. Similarly, we showed that
patients with rheumatoid arthritis or other forms of chronic
inflammatory arthritis also have a dominance of Th1 cells in the SF.
This is consistent with the expectation that Th1 cells predominate in a
highly inflamed, localized environment such as the synovial space of
the knee (Fig. 1B).
Severity of Lyme arthritis correlates with the ratio of Th1:Th2 cells
In this study, the magnitude of the Th1:Th2 ratio in SF cells
correlated directly with the severity of joint swelling, suggesting
that Th1 cells play an important role in the pathogenesis of Lyme
arthritis. (Fig. 1A). Additionally, there was a trend between higher
levels of Th2 activity in the synovial fluid and lower duration and
severity index scores (Fig. 1A and Table I). Previous
studies have demonstrated the ability of the Th2 cytokine, IL-4, to
inhibit Th1-mediated inflammation (35, 36, 37, 38, 39, 40, 41, 42). These observations are
consistent with the findings in murine borreliosis where severity of
joint disease correlates with the type of Th response. Thus, our data
support the hypothesis that accumulation of Th2 cells in this highly
activated environment allows for down-regulation of the
pro-inflammatory Th1 cells, ultimately leading to resolution of the
arthritis.
We predict that all patients who resolve their disease are able to do
so by mounting a prominent Th2 response at the initiation of their
disease resolution. This is in contrast to patients with chronic,
treatment-resistant Lyme arthritis (WA and LB). FACS analysis of serial
samples of SF cells from patient WA, taken at various time points over
a two year period, never revealed the presence of Th2 cells (data not
shown). Examination of serial samples may determine the critical period
for development of a Th2 cell response capable of modulating the
pro-inflammatory Th1 response. The exact ratio of Th1:Th2 cells
necessary for down-regulation of the inflammatory response is unclear
at this time. Based upon these initial observations, it may not be
necessary to generate a response that is dominated by Th2 cells to
resolve disease, but rather, potentiate a "yet to be determined"
threshold of Th2 cell activity that is capable of modulating active Th1
cells. The developmental pathway leading to a Th1 or Th2 response is
under intense study, and it is clear that cytokines play a role in
precursor development. Nevertheless, it is critical to define
Ag-specificity of the Th2 cells present in the SF of the rapidly
treatment-responsive patient, as they do not appear to be OspA reactive
(Fig. 2A). This may offer new insight into protective
epitopes of Bb (43, 44, 45).
In the patients who did not have significant levels of Th2 cells
localized in the SF (Fig. 1A), the unopposed, highly
inflammatory Th1-dominant immune response in the joint space was
associated with ongoing inflammation, lasting for several months. This
pattern was particularly evident in patients WA and LB, who were unable
to resolve their arthritis 2 years after antibiotic therapy. Such Th1
cytokine production of IFN- has previously been associated with an
increase in production of IL-1 and TNF-
, both of which have been
shown to induce joint damage (35, 46).
Treatment-resistant chronic Lyme arthritis patients contain Bb Ag-specific Th1 cells localized to the synovial fluid
We provide evidence that the Th1 cells in the SF of patients with
Lyme arthritis contain cells that are Ag-specific for OspA of
Bb (Fig. 2A and 3B), while the
Th1 cells in the SF of control patients with other chronic inflammatory
arthritides are unreactive to OspA (Fig. 2B and
3B). Thus, we have demonstrated Ag-specificity in the
arthritic lesion. The question that now arises is, what mechanism is
responsible for continued inflammation in treatment-resistant chronic
Lyme arthritis patients? C3H mice infected with Bb resolve
their arthritis despite continued persistence of the spirochete (47).
Chronic treatment-resistant Lyme arthritis patients seem to be the
reverse. PCR testing of joint fluid for detection of spirochetes in
treatment-resistant chronic Lyme arthritis patients has yielded
negative results, despite the patients’ continuous joint inflammation
(Table I). Yet, we show in this study that these patients retain Th1
cell reactivity to OspA (Fig. 2A). This suggests that
the chronic Th1 response seen in the treatment-resistant chronic Lyme
arthritis patients (WA and LB) may not require the presence of the
spirochete for continued propagation of joint inflammation, but in
fact, may represent an autoimmune process. On the other hand,
spirochetes may have shed antigenic surface proteins into the joint
space. Such a scenario would result in negative PCR data, but would not
support our hypothesis of autoimmunity, as foreign Ag would still be
present. It is important to note, however, that all immunocompetent
mice, regardless of H-2 haplotype that determines the severity of the
initial arthritic reaction to Bb infection, resolve the
arthritic lesions (19, 21). Since this occurs despite continuous low
level of Bb infection (47) and the presence of the
HLA.DR*0401 transgene (48), it is likely that a factor other than
spirochete Ag induces a chronic arthritic response. The simplest
explanation is that mice do not have the cross-reactive autoantigen
that elicits the chronic response seen in treatment-resistant Lyme
arthritis patients. The search for such an autoantigen in these
patients is under investigation. Understanding the genetic basis for
the regulation of Th1 and Th2 cell differentiation in response to
infection with Borrelia burgdorferi will further illuminate
the process of protective, destructive and autoimmune response
development, respectively.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Brigitte T. Huber, Tufts University School of Medicine, Department of Pathology, 136 Harrison Avenue, South Cove 403, Boston, MA 02111. E-mail address:
3 Abbreviations used in this paper: Bb, Borrelia burgdorferi; SF, synovial fluid; RA, rheumatoid arthritis; OspA, outer surface protein A; NA, not available.
Received for publication June 25, 1997. Accepted for publication September 25, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in modulation of immunity to Borrelia burgdorferi in mice. J. Immunol. 155:2020.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  E. Tupin, M. R.-E.-I. Benhnia, Y. Kinjo, R. Patsey, C. J. Lena, M. C. Haller, M. J. Caimano, M. Imamura, C.-H. Wong, S. Crotty, et al. NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi PNAS, December 16, 2008; 105(50): 19863 - 19868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. van Maldegem, R. van Dijk, T. A. M. Wormhoudt, P. M. Kluin, R. Willemze, L. Cerroni, C. J. M. van Noesel, and R. J. Bende The majority of cutaneous marginal zone B-cell lymphomas expresses class-switched immunoglobulins and develops in a T-helper type 2 inflammatory environment Blood, October 15, 2008; 112(8): 3355 - 3361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Wang, M. M. Petzke, R. Iyer, H. Wu, and I. Schwartz Pattern of Proinflammatory Cytokine Induction in RAW264.7 Mouse Macrophages Is Identical for Virulent and Attenuated Borrelia burgdorferi J. Immunol., June 15, 2008; 180(12): 8306 - 8315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Iliopoulou, J. Alroy, and B. T. Huber CD28 Deficiency Exacerbates Joint Inflammation upon Borrelia burgdorferi Infection, Resulting in the Development of Chronic Lyme Arthritis J. Immunol., December 15, 2007; 179(12): 8076 - 8082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Dame, B. L. Orenzoff, L. E. Palmer, and M. B. Furie IFN-{gamma} Alters the Response of Borrelia burgdorferi-Activated Endothelium to Favor Chronic Inflammation J. Immunol., January 15, 2007; 178(2): 1172 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. N. Hedrick, C. M. Olson Jr., D. B. Conze, T. C. Bates, M. Rincon, and J. Anguita Control of Borrelia burgdorferi-Specific CD4+-T-Cell Effector Function by Interleukin-12- and T-Cell Receptor-Induced p38 Mitogen-Activated Protein Kinase Activity. Infect. Immun., October 1, 2006; 74(10): 5713 - 5717. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ghosh, R. Seward, C. E. Costello, B. D. Stollar, and B. T. Huber Autoantibodies from Synovial Lesions in Chronic, Antibiotic Treatment-Resistant Lyme Arthritis Bind Cytokeratin-10 J. Immunol., August 15, 2006; 177(4): 2486 - 2494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ghosh, A. C. Steere, B. D. Stollar, and B. T. Huber In Situ Diversification of the Antibody Repertoire in Chronic Lyme Arthritis Synovium J. Immunol., March 1, 2005; 174(5): 2860 - 2869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. I. Gergel and M. B. Furie Populations of Human T Lymphocytes That Traverse the Vascular Endothelium Stimulated by Borrelia burgdorferi Are Enriched with Cells That Secrete Gamma Interferon Infect. Immun., March 1, 2004; 72(3): 1530 - 1536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Willett, A. L. Meyer, E. L. Brown, and B. T. Huber An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope PNAS, February 3, 2004; 101(5): 1303 - 1308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Salazar, C. D. Pope, T. J. Sellati, H. M. Feder Jr, T. G. Kiely, K. R. Dardick, R. L. Buckman, M. W. Moore, M. J. Caimano, J. G. Pope, et al. Coevolution of Markers of Innate and Adaptive Immunity in Skin and Peripheral Blood of Patients with Erythema Migrans J. Immunol., September 1, 2003; 171(5): 2660 - 2670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Christopherson, E. L. Munson, D. M. England, C. L. Croke, M. C. Remington, M. L. Molitor, D. J. DeCoster, S. M. Callister, and R. F. Schell Destructive Arthritis in Vaccinated Interferon Gamma-Deficient Mice Challenged with Borrelia burgdorferi: Modulation by Tumor Necrosis Factor Alpha Clin. Vaccine Immunol., January 1, 2003; 10(1): 44 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Steere Lyme Disease N. Engl. J. Med., July 12, 2001; 345(2): 115 - 125. [Full Text] [PDF]
|
|
|
|
|
|
M. H. Moro, J. Bjornsson, E. V. Marietta, E. K. Hofmeister, J. J. Germer, E. Bruinsma, C. S. David, and D. H. Persing Gestational Attenuation of Lyme Arthritis Is Mediated by Progesterone and IL-4 J. Immunol., June 15, 2001; 166(12): 7404 - 7409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Glickstein, M. Edelstein, and J. Z. Dong Gamma Interferon Is Not Required for Arthritis Resistance in the Murine Lyme Disease Model Infect. Immun., June 1, 2001; 69(6): 3737 - 3743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Thomas, J. Anguita, S. W. Barthold, and E. Fikrig Coinfection with Borrelia burgdorferi and the Agent of Human Granulocytic Ehrlichiosis Alters Murine Immune Responses, Pathogen Burden, and Severity of Lyme Arthritis Infect. Immun., May 1, 2001; 69(5): 3359 - 3371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Trollmo, A. L. Meyer, A. C. Steere, D. A. Hafler, and B. T. Huber Molecular Mimicry in Lyme Arthritis Demonstrated at the Single Cell Level: LFA-1{{alpha}}L Is a Partial Agonist for Outer Surface Protein A-Reactive T Cells J. Immunol., April 15, 2001; 166(8): 5286 - 5291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Meyer, C. Trollmo, F. Crawford, P. Marrack, A. C. Steere, B. T. Huber, J. Kappler, and D. A. Hafler Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers PNAS, September 22, 2000; (2000) 190335897. [Abstract] [Full Text]
|
|
|
|
|
|
M. D. McKisic, W. L. Redmond, and S. W. Barthold Cutting Edge: T Cell-Mediated Pathology in Murine Lyme Borreliosis J. Immunol., June 15, 2000; 164(12): 6096 - 6099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Brown and S. L. Reiner Experimental Lyme Arthritis in the Absence of Interleukin-4 or Gamma Interferon Infect. Immun., July 1, 1999; 67(7): 3329 - 3333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Talkington and S. P. Nickell Borrelia burgdorferi Spirochetes Induce Mast Cell Activation and Cytokine Release Infect. Immun., March 1, 1999; 67(3): 1107 - 1115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Gross, T. Forsthuber, M. Tary-Lehmann, C. Etling, K. Ito, Z. A. Nagy, J. A. Field, A. C. Steere, and B. T. Huber Identification of LFA-1 as a Candidate Autoantigen in Treatment-Resistant Lyme Arthritis Science, July 31, 1998; 281(5377): 703 - 706. [Abstract] [Full Text]
|
|
|
|
 |
|
 J S H GASTON Will the increasing prevalence of atopy have a favourable impact on rheumatoid arthritis? Ann Rheum Dis, May 1, 1998; 57(5): 265 - 267. [Full Text]
|
|
|
|
|
|
A. L. Meyer, C. Trollmo, F. Crawford, P. Marrack, A. C. Steere, B. T. Huber, J. Kappler, and D. A. Hafler Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers PNAS, October 10, 2000; 97(21): 11433 - 11438. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
