Original Article
Association of Chronic Lyme Arthritis with HLA-DR4 and HLA-DR2 Alleles
N Engl J Med 1990; 323:219-223July 26, 1990
- Abstract
- Abstract
Background and Methods.
A small percentage of patients infected with Borrelia burgdorferi have chronic Lyme arthritis that does not respond to antibiotic therapy. To learn whether genetically determined variations in the host immune response might account for such outcomes, we determined the immunogenetic profiles of 130 patients with various manifestations of Lyme disease.
Results.
Of the 80 patients with arthritis, 57 percent of those with chronic arthritis (12 to 48 months in duration) had the HLA-DR4 specificity; only 23 percent of those with arthritis of moderate duration (6 to 11 months) and only 9 percent of those with arthritis of short duration (1 to 5 months) had this specificity (P = 0.003). After the HLA-DR4-positive patients were excluded from each group, a secondary association was noted with HLA-DR2, which was found in 75 percent of the remaining patients with chronic arthritis and in 50 percent of those with arthritis of moderate duration, but in only 20 percent of those with arthritis of short duration (P = 0.023). Altogether, 25 of the 28 patients with chronic arthritis (89 percent) had HLA-DR2 or HLA-DR4, or both, as compared with 27 percent of those with arthritis of short duration (relative risk, 22; P = 0.00006). These HLA specificities appeared to act as independent, dominant markers of susceptibility. Nucleotide-sequence typing, performed in five patients with chronic arthritis, identified the HLA-DR2 allele as Dw2 (DRβ1*1501), and the HLA-DR4 alleles as Dw4, Dw14, and Dw13 (DRβ1*0401, DRβ1*0404, and DRβ1*0403, respectively). The presence of HLA-DR4 in patients with arthritis was associated with a lack of response to antibiotic therapy (P = 0.01).
Conclusions.
Particular Class II major histocompatibility genes determine a host immune response to B. burgdorferi that results in chronic arthritis and lack of response to antibiotic therapy. (N Engl J Med 1990; 323:219–23.)
Article Activity
- Article
LYME disease, which is caused by the tick-borne spirochete Borrelia burgdorferi, often begins with a characteristic skin lesion, erythema migrans, and is commonly followed by neurologic, cardiac, or joint abnormalities of variable duration.1 The involvement of the joints, which is seen in about 80 percent of patients, often begins with migratory joint pain and is frequently followed months later by brief attacks of oligoarthritis.2 During the second and third years of illness, the episodes of arthritis may last longer, and in about 10 percent of patients joint involvement becomes chronic, sometimes with erosion of cartilage and bone.2 , 3 The synovial lesions in such patients are similar to those seen in the other types of chronic inflammatory arthritis, including rheumatoid arthritis.4 , 5 In patients who later have arthritis, B. burgdorferi probably spreads to the joints early in the illness,2 but the fact that only a small percentage have chronic arthritis suggests that host factors determine the severity and duration of arthritis. Lyme arthritis can usually be treated successfully with antibiotic therapy.6 , 7 However, regardless of the antibiotic used and the number of courses given, in some patients the arthritis does not respond to treatment.
Susceptibility to a number of diseases with autoimmune features is associated with HLA specificities encoded by certain Class II, D-locus alleles of the major histocompatibility complex. The Class II molecules, expressed primarily on B cells and macrophages, bind and present antigen to T helper cells, which then initiate an immune response against these antigens. Genetic variations in the structure of Class II molecules are thought to influence the development of autoimmune responses, either by determining the type and manner of antigen binding or by influencing the composition of the T-cell repertoire in the development of self-tolerance during thymic maturation.
In an early study of 10 patients with chronic Lyme arthritis, 7 had HLA-DR2, and 4 had HLA-DR4,8 suggesting that the chronic joint involvement of this infectious disease might have an immunogenetic basis. To examine this hypothesis further, we determined the immunogenetic profiles of 130 patients with various manifestations of Lyme disease.
Methods
Selection of Patients
In 1983, in the first phase of the study, we selected 75 patients who had had skin, neurologic, or joint manifestations of Lyme disease for immunogenetic testing. Among them, 30 patients had had erythema migrans but no other manifestations of the illness; 20 patients had had Lyme meningitis, sometimes accompanied by cranial neuritis or radiculoneuritis; and 25 patients had had brief or prolonged episodes of Lyme arthritis. These groups included most of the patients we had seen in these categories who had not been treated with antibiotic therapy. From January 1985 through June 1987, in the second phase of the study, we tested all 55 patients with Lyme arthritis seen at Yale University at the time of their entry into a study of antibiotic treatment. The patients with arthritis were subdivided into three groups according to the length of the longest period of continual joint involvement — those who had arthritis of short duration (1 to 5 months), those who had arthritis of moderate duration (6 to 11 months), and those who had chronic arthritis (12 to 48 months). The study was approved by the Human Investigations Committee of Yale University, and informed consent was obtained from each patient.
All the patients in both phases of the study were white and came from five states along the northeastern coast of the United States. Their ages ranged from 7 to 72 years (median, 34); 72 were male, and 58 female. All had elevated titers of serum IgM or IgG antibody to B. burgdorferi, measured as previously described.9 , 10 For comparison, we studied 86 normal subjects, 53 men and 33 women, ranging in age from 18 to 54 years (median, 31), at the New York University Medical School. These subjects underwent HLA typing at the same time and with use of the same reagents as the patients with Lyme disease.
HLA-Typing Procedures
The HLA-A, B, C, DR, and DQ specificities were identified by standard lymphocyte-microcytotoxicity testing11 with use of a panel of local and exchanged alloantiserums.12 In five patients with chronic Lyme arthritis who were typed as HLA-DR4 or HLA-DR2, the complementary DNA of the DR β chain was sequenced. In these patients, 5 μg of total RNA was isolated from peripheral-blood mononuclear cells, and first-strand synthesis of complementary DNA was carried out with use of reverse transcriptase in the presence of primers (5′, codons -12 to -6; 3′, codons 105 to 112).13 After the addition of Taq polymerase, 25 cycles of polymerase-chain-reaction amplification were performed in a DNA thermal cycler (Perkin–Elmer–Cetus), as previously described.14 The amplified product was run on a gel, and the appropriate band was cloned into the plasmid pUC18 using SstI and SmaI restriction-enzyme sites. After transfection of XL1-blue Escherichia coli, 10 to 50 colonies with inserts were selected and grown. The constructs were characterized first by restriction-enzyme digestion and then sequenced by the dideoxy method.13
Statistical Analysis
For statistical analysis, the comparisons of HLA types in patients or normal subjects were made in two-by-two tables, from which the odds ratios were calculated. We have expressed the odds ratios in terms of the relative risk, as is customary in this field. The statistical significance of the relative risk was calculated by Fisher's exact test (two-tailed). In an attempt to nullify the possibility of chance association with a given allele, P values were multiplied by the number of specificities tested at each locus: seven for DR and three for DQ.
Results
Of the 75 selected patients with different manifestations of Lyme disease whom we tested in the first phase of the study, the frequencies of HLA-A, B, C, and D specificities in those with erythema migrans alone, meningitis, or arthritis were similar to those in the 86 normal subjects. However, when the group with joint involvement was stratified according to the duration of arthritis, 4 of the 9 patients with chronic arthritis (44 percent) but none of the 16 patients who had had shorter periods of arthritis had the HLA-DR4 specificity. In order to increase the size of the arthritis group and to avoid selection bias, we next tested all 55 patients with Lyme arthritis whom we saw during a subsequent 1 1/2-year period, at the time of their entry into antibiotic-treatment studies. In this larger, independent, unselected series, the frequency of HLA-DR4 was again increased in the 19 patients with chronic arthritis as compared with the 36 patients with shorter episodes of arthritis. Since the results from both phases of the study were similar, they are presented together here.
Immunogenetic Profiles of Patients with Lyme Arthritis
Among the 80 patients in both groups who had Lyme arthritis, the HLA-DR4 specificity was found in 57 percent of those with chronic arthritis (of 12 to 48 months' duration), in 23 percent of those with arthritis of moderate duration (6 to 11 months), and in only 9 percent of those with arthritis of short duration (1 to 5 months) (Table 1Table 1
Frequency of HLA-DR Specificities in 80 Patients with Lyme Arthritis and 86 Normal Subjects.). Therefore, the frequency of HLA-DR4 was significantly greater in patients with chronic arthritis than in those with arthritis of short duration (57 percent vs. 9 percent; relative risk, 13; P<0.003) or the normal subjects (57 percent vs. 31 percent; relative risk, 3; P<0.01). All 16 patients with chronic arthritis who had HLA-DR4 were heterozygous at the DR locus. Five had HLA-DR4 and HLA-DR3, four had HLA-DR4 and HLA-DR2, three had HLA-DR4 and HLA-DR1, and the remaining four had HLA-DR4 in association with a different DR specificity.A secondary association was noted with the HLA-DR2 specificity. This specificity was found in 43 percent of the patients with chronic arthritis and in 40 percent of those with arthritis of moderate duration, but in only 18 percent of those with arthritis of short duration (Table 1). Among patients with arthritis of moderate duration, the frequency of HLA-DR2 was higher than that of any other specificity, including HLA-DR4. After the exclusion of the HLA-DR4-positive patients in each group, the frequency of HLA-DR2 was significantly higher among the remaining patients with chronic arthritis than among those with arthritis of short duration (75 percent vs. 20 percent; relative risk, 12; P = 0.023) or the normal subjects (75 percent vs. 36 percent; relative risk, 5; P = 0.02). Taken together, 25 of the 28 patients with chronic arthritis had HLA-DR2, HLA-DR4, or both, as compared with only 6 of the 22 patients with arthritis of short duration (89 percent vs. 27 percent; relative risk, 22; P = 0.00006). Among the remaining three patients with chronic arthritis, two had HLA-DR1 alone, and one had HLA-DR3 and HLA-DR7.
During the second phase of the study, it was also possible to test for HLA-DRw52 and DRw53 and for the DQ specificities. Fourteen of the 16 patients with arthritis of short duration (88 percent) had HLA-DRw52, which is associated with HLA-DR3, -5, -w6, and -8; no patient with chronic arthritis had HLA-DRw6. In the above analysis, these specificities were independently associated with a lack of susceptibility to chronic arthritis. The frequency of HLA-DRw52 was significantly higher among patients with arthritis of short duration than among those with chronic arthritis (88 percent vs. 37 percent; relative risk, 0.05; P = 0.003) or those with arthritis of moderate duration (88 percent vs. 40 percent; relative risk, 0.1; P = 0.005) (Table 1). In contrast, the frequency of HLA-DRw53, which is associated with HLA-DR4, -7, and -9, tended to be higher among those with chronic arthritis, but this difference was not statistically significant — presumably because of the negative association of HLA-DR7 with chronic arthritis. The frequency of HLA-DQw3, which is associated with HLA-DR4 and -5, was higher in each group of patients with arthritis than among the normal subjects, but the differences were statistically significant only for patients with chronic arthritis as compared with normal subjects (74 percent vs. 32 percent; relative risk, 6; P = 0.003).
The frequencies of the HLA-A, B, and C specificities were not significantly different among the three groups of patients with Lyme arthritis. Of the 80 patients, 4 had HLA-B27, 3 of whom had chronic arthritis, but none had other manifestations of Reiter's syndrome or sacroiliitis. HLA-B7, a specificity that cross-reacts with HLA-B27, was found in 43 percent of the patients with chronic arthritis and in 37 percent of those with arthritis of short duration.
Nucleotide-Sequence Typing
To identify the alleles encoding the HLA-DR4 or DR2 specificity, we sequenced the genes that determine these specificities in five selected patients with chronic arthritis (Table 2Table 2
Nucleotide-Sequence Typing of the HLA-DRβ Chain in Five Representative Patients with Chronic Lyme Arthritis.). Three patients had the HLA-Dw14 or Dw4 allele (DRβ1*0404 or DRβ1*0401) encoding the DR4 specificity. A fourth patient had the HLA-Dw13 allele of DR4 (DRβ1*0403), but he also had the HLA-Dw2 allele of DR2 (DRβ1*1501). The fifth patient also had the HLA-Dw2 allele of DR2.DR Phenotypes and Response to Treatment
Of the 80 patients with Lyme arthritis, 60 were treated for their arthritis with antibiotic therapy. In 22 of the 60 patients, designated as responders, the arthritis improved during treatment and resolved completely within three months. The remaining 38 patients, classified as nonresponders, did not improve during treatment and continued to have joint involvement for more than three months thereafter. The age and sex of the patients, the duration of arthritis before treatment, and the antibiotics given were similar in the two groups. Of the 22 HLA-DR4-positive patients who were treated with antibiotics, the arthritis responded to treatment in only 2 (Table 3Table 3
Correlation of HLA-DR Specificities with the Results of Antibiotic Therapy in 60 Patients with Lyme Arthritis.). Only the presence of HLA-DR4 was significantly associated with the failure of treatment (P = 0.01).Discussion
These results provide evidence that chronic Lyme arthritis has an immunogenetic basis involving the HLA-DR4 specificity and, secondarily, HLA-DR2. Although 25 of the 28 patients with chronic arthritis had HLA-DR4 or DR2, only 3 had both. This is approximately the number that would be expected on the basis of the estimated gene frequencies in these patients. This similarity suggests that HLA-DR4 and DR2 alleles act as independent, dominant markers of susceptibility and that the presence of both does not confer additional risk.
Several European studies have also found an association between HLA-DR2 and DR4 and certain other manifestations of Lyme disease. In Czechoslovakia, in a study of 32 patients with meningopolyneuritis, 56 percent had HLA-DR2, and 46 percent had HLA-DR4.15 In Vienna, of 22 patients with acrodermatitis, 52 percent had HLA-DR2.16 However, in two other European studies, the frequency of HLA-DR2 or DR4 was not increased in patients with meningopolyneuritis or acrodermatitis.17 , 18 Borrelial encephalomyelitis, a newly described late neurologic manifestation of Lyme disease,19 may resemble multiple sclerosis, which is also associated with an increased frequency of HLA-DR2.20 It is not yet known, however, whether encephalomyelitis has an immunogenetic basis.
It is of great interest that both chronic Lyme arthritis and rheumatoid arthritis are associated with the presence of HLA-DR4.21 However, only certain subtypes of HLA-DR4 — those encoded by the Dw4, Dw14, and Dw15 alleles — are found in patients with rheumatoid arthritis, whereas two other subtypes, HLA-Dw10 and Dw13, are not.13 The former group of subtypes differs from the latter primarily by the presence of negatively charged amino acids at position 70, 71, or 74 in the third diversity (hypervariable) region of the HLA-DR β1 chain.21 , 22 Rheumatoid arthritis has a secondary association with the presence of HLA-DR1. Since HLA-DR1 has the same amino acid sequence as HLA-Dw4, Dw14, and Dw15 in the third diversity region, this unique alpha-helical structure has been postulated to specify the molecular basis for susceptibility to rheumatoid arthritis.21 , 22
Of the five patients with chronic Lyme arthritis in whom nucleotide-sequence typing was done, three had the common northern European white HLA-Dw4 or Dw14 allele, as is found in patients with rheumatoid arthritis. Although the fourth patient had the HLA-Dw13 allele, which is not associated with rheumatoid arthritis, this patient was heterozygous (HLA-DR4, DR2), and it is possible that the HLA-Dw2 allele could independently account for his susceptibility to chronic Lyme arthritis. The fifth patient had only HLA-Dw2 as the allele putatively responsible for chronic joint involvement. Although more than one HLA conformation may be important in chronic Lyme arthritis, the lack of an association with HLA-DR1 suggests that the conformation of the third diversity region that confers susceptibility to rheumatoid arthritis is not critical to the development of chronic Lyme arthritis.
In five of the patients with chronic Lyme arthritis, HLA-DR4 occurred together with HLA-DR3, a combination that is reminiscent of that seen in insulin-dependent juvenile diabetes, in which the relevant susceptibility structure is thought to be located on the HLA-DQ molecule.23 Arguing against a similarity in the molecular basis of susceptibility to these two diseases is the increased frequency of HLA-DR2 in Lyme arthritis and the fact that both of the patients with Lyme arthritis whom we tested had the Dw2 allele of HLA-DR2, which is associated with dominant resistance to insulin-dependent diabetes.
In patients with Lyme arthritis, only HLA-DR4 was significantly associated with a lack of response to antibiotic therapy. Since the frequency of treatment failure was not significantly increased in patients with the HLA-DR2 specificity, even after the exclusion of HLA-DR4-positive patients from the analysis, it is possible that the molecular basis of susceptibility may not be the same for both specificities. A recent report suggested that B. burgdorferi might trigger Reiter's syndrome or sacroiliitis, which did not respond to antibiotics, primarily in HLA-B27-positive patients.24 Although 3 of the 28 patients with chronic arthritis in our study had HLA-B27, none had spondyloarthropathy, and the frequency of this specificity was not greater than one would expect in the general population.
On the basis of these results, several alternative mechanisms can be postulated for the development of chronic Lyme arthritis in genetically susceptible persons. First, the Class II molecules of the HLA-DR4 or DR2 haplotype may combine with a distinct arthritogenic epitope of B. burgdorferi that has molecular mimicry with a component of the host. The interaction of T helper cells with this major histocompatibility complex may lead to an autoimmune response that continues for some time after the organism has been killed. Second, as a result of thymic selection, the Class II molecules may have chosen potentially autoreactive T-cell clones that can be triggered by a spirochetal peptide that functions as a superantigen.25 Conversely, during thymic maturation, these patients may have deleted T-cell clones necessary for the elimination of the spirochete. They may thus have persistent spirochetal infection accompanied by an ineffective immune response that causes "bystander" injury to the host. Because the causative agent of Lyme arthritis is known, this disease presents an important opportunity to determine the molecular interactions among the components of B. burgdorferi, specific Class II major histocompatibility molecules, and T-cell receptors that, in particular untoward combinations, lead to this form of chronic arthritis.
Supported by grants (AM-20358, RR-00125, AI-19411, and AM-35404) from the National Institutes of Health.
We are indebted to Ms. Joan Feld, Mr. Clinton Peters, Ms. Claire Kimpson, and Mr. Robert Grodzicki for laboratory assistance and to Ms. Elise Taylor for her help with the patients.
Source Information
From the Division of Rheumatology/Immunology, New England Medical Center, Tufts University School of Medicine, Boston (A.C.S.), and the Hospital for Joint Diseases and the Division of Rheumatology, Department of Medicine, New York University Medical Center, New York (E.D., R.W.). Address reprint requests to Dr. Steere at the Division of Rheumatology/Immunology, New England Medical Center, NEMC 406, 750 Washington St., Boston, MA 02111.
- References
References
1
Steere
Full Text | Web of Science | Medline2
Steere
Web of Science | Medline3
Lawson
Web of Science | Medline4
Johnston
Web of Science | Medline5
Steere
CrossRef | Web of Science | Medline6
Steere
Full Text | Web of Science | Medline7
Liu 8
Steere
Web of Science | Medline9
Berardi
CrossRef | Web of Science | Medline10
Craft
CrossRef | Web of Science | Medline11
Nunez-Roldan
CrossRef | Web of Science | Medline12
Matsuyama
Web of Science | Medline13
Gregersen
CrossRef | Web of Science | Medline14
Merryman
CrossRef | Web of Science | Medline15
Majsky
CrossRef | Web of Science | Medline16
Kristoferistsch
CrossRef | Web of Science | Medline17
Pfluger
CrossRef | Web of Science18
Van Doom PA, Brand A, Vermeulen M, Wokke JHJ. Antibodies against neural tissue and DR2 antigen in patients with Bannwarth's syndrome. Presented at the conference on Lyme borreliosis update Europe, Baden/Vienna, June 2–4, 1987.
19
Ackermann
CrossRef | Web of Science | Medline20
Tiwari JL, Terasaki PI. HLA and disease associations. New York: Springer-Verlag, 1985:152–67.
21
Winchester
CrossRef | Web of Science | Medline22
Gregersen
CrossRef | Web of Science | Medline23
Todd
CrossRef | Web of Science | Medline24
Weyand
CrossRef | Web of Science | Medline25
White
CrossRef | Web of Science | Medline
- Citing Articles (103)
Citing Articles
1
Judith Miklossy. (2011) Emerging roles of pathogens in Alzheimer disease. Expert Reviews in Molecular Medicine 13,
CrossRef2
Eugene D. Shapiro, Sunil K. Sood. 2011. Prognosis of Persons with Lyme Borreliosis. , 213-223.
CrossRef3
Chinmoy Bhate, Robert A. Schwartz. (2011) Lyme disease. Journal of the American Academy of Dermatology 64:4, 619-636
CrossRef4
A. C. Steere, E. E. Drouin, L. J. Glickstein. (2011) Relationship between Immunity to Borrelia burgdorferi Outer-surface Protein A (OspA) and Lyme Arthritis. Clinical Infectious Diseases 52:Supplement 3, s259-s265
CrossRef5
S. A. Plotkin. (2011) Correcting a Public Health Fiasco: The Need for a New Vaccine against Lyme Disease. Clinical Infectious Diseases 52:Supplement 3, s271-s275
CrossRef6
Hans-Iko Huppertz, Frank Dressler. 2011. LYME DISEASE. , 579-590.
CrossRef7
Judith Miklossy. (2011) Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. Journal of Neuroinflammation 8:1, 90
CrossRef8
A. Kaminsky. (2009) Eritemas figurados. Actas Dermo-Sifiliográficas 100, 88-109
CrossRef9
Raquel Nunes Fialho, Luís Martins, João Paulo Pinheiro, Bruno Filipe Bettencourt, Ana Rita Couto, Margarida Rodrigues Santos, Maria José Peixoto, Francisco Garrett, João Leal, Ana Maria Tomás, Jácome Bruges-Armas. (2009) Role of human leukocyte antigen, killer-cell immunoglobulin-like receptors, and cytokine gene polymorphisms in leptospirosis. Human Immunology 70:11, 915-920
CrossRef10
M. Widhe, C. Ekerfelt, S. Jarefors, B. H. Skogman, E. M. Peterson, S. Bergström, P. Forsberg, J. Ernerudh. (2009) T-Cell Epitope Mapping of the Borrelia garinii Outer Surface Protein A in Lyme Neuroborreliosis. Scandinavian Journal of Immunology 70:2, 141-148
CrossRef11
Dean T Nardelli, Erik L Munson, Steven M Callister, Ronald F Schell. (2009) Human Lyme disease vaccines: past and future concerns. Future Microbiology 4:4, 457-469
CrossRef12
Robert Ball, Sean V. Shadomy, Abbie Meyer, Brigitte T. Huber, Mary S. Leffell, Andrea Zachary, Michael Belotto, Eileen Hilton, Marthe Bryant-Genevier, Martin E. Schriefer, Frederick W. Miller, M. Miles Braun. (2009) HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccination. Arthritis & Rheumatism 60:4, 1179-1186
CrossRef13
Margherita Milone, Amiram Katz, Anthony A. Amato, Carl A. Soderland, Miruna Segarceanu, Nathan P. Young, H. Royden Jones. (2009) Sporadic late onset nemaline myopathy responsive to IVIg and immunotherapy. Muscle & NerveNA-NA
CrossRef14
Jennifer C. Miller, Ying Ma, Hillary Crandall, Xiaohui Wang, Janis J. Weis. (2008) Gene expression profiling provides insights into the pathways involved in inflammatory arthritis development: Murine model of Lyme disease. Experimental and Molecular Pathology 85:1, 20-27
CrossRef15
Henry M. Feder. (2008) Lyme Disease in Children. Infectious Disease Clinics of North America 22:2, 315-326
CrossRef16
Yoram A. Puius, Robert A. Kalish. (2008) Lyme Arthritis: Pathogenesis, Clinical Presentation, and Management. Infectious Disease Clinics of North America 22:2, 289-300
CrossRef17
Elise E. Drouin, Lisa Glickstein, William W. Kwok, Gerald T. Nepom, Allen C. Steere. (2008) Human homologues of a Borrelia T cell epitope associated with antibiotic-refractory Lyme arthritis. Molecular Immunology 45:1, 180-189
CrossRef18
Eric L. Brown, Stephen E. Ullrich, Michael Pride, Margaret L. Kripke. (2007) The Effect of UV Irradiation on Infection of Mice with Borrelia burgdorferi¶. Photochemistry and Photobiology 73:5, 537
CrossRef19
Kristin M Corapi, Marc I White, Charlotte B Phillips, Lawren H Daltroy, Nancy A Shadick, Matthew H Liang. (2007) Strategies for primary and secondary prevention of Lyme disease. Nature Clinical Practice Rheumatology 3:1, 20-25
CrossRef20
J. Pourel, I. Chary-Valckenaere. (2007) Borreliosis de Lyme. EMC - Aparato Locomotor 40:2, 1-14
CrossRef21
Allen C. Steere, Sheryn M. Angelis. (2006) Therapy for Lyme arthritis: Strategies for the treatment of antibiotic-refractory arthritis. Arthritis & Rheumatism 54:10, 3079-3086
CrossRef22
Salvatore Benvenga, Libero Santarpia, Francesco Trimarchi, Fabrizio Guarneri. (2006) Human Thyroid Autoantigens and Proteins of Yersinia and Borrelia Share Amino Acid Sequence Homology That Includes Binding Motifs to HLA-DR Molecules and T-Cell Receptor. Thyroid 16:3, 225-236
CrossRef23
Alison Abbott. (2006) Lyme disease: Uphill Struggle. Nature 439:7076, 524-525
CrossRef24
2005. Hypertension (High Blood Pressure). .
CrossRef25
2005. Tick (Arachnida, Acarina). .
CrossRef26
Hillary Crandall, Ying Ma, Diane M. Dunn, Rhianna S. Sundsbak, James F. Zachary, Peter Olofsson, Rikard Holmdahl, John H. Weis, Robert B. Weiss, Cory Teuscher, Janis J. Weis. (2005) Bb2Bb3 Regulation of Murine Lyme Arthritis Is Distinct from Ncf1 and Independent of the Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase. The American Journal of Pathology 167:3, 775-785
CrossRef27
Arnaud Dupeyron, Jehan Lecocq, Benoît Jaulhac, Marie-Eve Isner-Horobeti, Philippe Vautravers, Julien Cohen-Solal, Christelle Sordet, Jean-Louis Kuntz. (2004) Sciatica, disk herniation, and neuroborreliosis. A report of four cases. Joint Bone Spine 71:5, 433-437
CrossRef28
Lorraine Johnson, Raphael B Stricker. (2004) Treatment of Lyme disease: a medicolegal assessment. Expert Review of Anti-infective Therapy 2:4, 533-557
CrossRef29
S. K. Singh, H. J. Girschick. (2004) Lyme borreliosis: from infection to autoimmunity. Clinical Microbiology and Infection 10:7, 598-614
CrossRef30
Allen C. Steere, Lisa Glickstein. (2004) Elucidation of Lyme arthritis. Nature Reviews Immunology 4:2, 143-152
CrossRef31
Gerald Stanek, Franc Strle. (2003) Lyme borreliosis. The Lancet 362:9396, 1639-1647
CrossRef32
Mark S Hanson, Robert Edelman. (2003) Progress and controversy surrounding vaccines against Lyme disease. Expert Review of Vaccines 2:5, 683-703
CrossRef33
Juan Anguita, Michael N Hedrick, Erol Fikrig. (2003) Adaptation of Borrelia burgdorferi in the tick and the mammalian host. FEMS Microbiology Reviews 27:4, 493-504
CrossRef34
Eugene D. Shapiro. (2002) Long-Term Outcomes of Persons with Lyme Disease. Vector-Borne and Zoonotic Diseases 2:4, 279-281
CrossRef35
R. Mark Wooten, Ying Ma, R. Alyson Yoder, Jeanette P. Brown, John H. Weis, James F. Zachary, Carsten J. Kirschning, Janis J. Weis. (2002) Toll-Like Receptor 2 Plays a Pivotal Role in Host Defense and Inflammatory Response to Borrelia burgdorferi. Vector-Borne and Zoonotic Diseases 2:4, 275-278
CrossRef36
Arthur Weinstein, Michael Britchkov. (2002) Lyme arthritis and post-Lyme disease syndrome. Current Opinion in Rheumatology 14:4, 383-387
CrossRef37
Elena M Massarotti. (2002) Lyme arthritis. Medical Clinics of North America 86:2, 297-309
CrossRef38
Mary Elizabeth Wilson. (2002) Prevention of tick-borne diseases. Medical Clinics of North America 86:2, 219-238
CrossRef39
Kai W. Wucherpfennig. (2001) Mechanisms for the induction of autoimmunity by infectious agents. Journal of Clinical Investigation 108:8, 1097-1104
CrossRef40
G A Poland. (2001) Prevention of Lyme disease: a review of the evidence.. Mayo Clinic Proceedings 76:7, 713-724
CrossRef41
R.Mark Wooten, Janis J Weis. (2001) Host–pathogen interactions promoting inflammatory Lyme arthritis: use of mouse models for dissection of disease processes. Current Opinion in Microbiology 4:3, 274-279
CrossRef42
Allen C Steere, Dawn Gross, Abbie L Meyer, Brigitte T Huber. (2001) Autoimmune Mechanisms in Antibiotic Treatment-Resistant Lyme Arthritis. Journal of Autoimmunity 16:3, 263-268
CrossRef43
Gregory A. Poland, Robert M. Jacobson. (2001) The prevention of Lyme disease with vaccine. Vaccine 19:17-19, 2303-2308
CrossRef44
Eric L. Brown, Stephen E. Ullrich, Michael Pride, Margaret L. Kripke. (2001) The Effect of UV Irradiation on Infection of Mice with Borrelia burgdorferi¶. Photochemistry and Photobiology 73:5, 537
CrossRef45
Renate Claus, Thomas Bittorf, Hermann Walzel, Josef Brock, Robert Uhde, Doris Meiske, Ulrich Schulz, Dirk Hobusch, Karin Schumacher, Mathias Witt, Frank Bartel, Stefan Hausmann. (2000) High Concentration of Soluble HLA-DR in the Synovial Fluid: Generation and Significance in “Rheumatoid-like” Inflammatory Joint Diseases. Cellular Immunology 206:2, 85-100
CrossRef46
E. D. Shapiro, M. A. Gerber. (2000) Lyme Disease. Clinical Infectious Diseases 31:2, 533-542
CrossRef47
Jarrno Oksi, Merja Marjamaki, Jukka Nikoskelainen, Matti K Viljanen. (1999) Bowelia Burgorferi Detected by Culture and PCR in Clinical Relapse of Disseminated Lyme Borreliosis. Annals of Medicine 31:3, 225-232
CrossRef48
Sarah L Parry, Frances C Hall, Jennifer Olson, Thomas Kamradt, Grete Sønderstrup. (1998) Autoreactivity versus autoaggression: a different perspective on human autoantigens. Current Opinion in Immunology 10:6, 663-668
CrossRef49
Sanford P. Solomon, Eileen Hilton, Barbara S. Weinschel, Simcha Pollack, Elizabeth Grolnick. (1998) Psychological factors in the prediction of Lyme disease course. Arthritis Care & Research 11:5, 419-426
CrossRef50
Robert B Nadelman, Gary P Wormser. (1998) Lyme borreliosis. The Lancet 352:9127, 557-565
CrossRef51
Beniamino Cacciapuoti, Simonetta Ciarrocchi, Lorenzo Ciceroni. (1998) The Complement-killing of Borrelia burgdorferi. Target Antigens and Sensitizing Antibodies. Zentralblatt für Bakteriologie 288:1, 121-129
CrossRef52
L SIGAL. (1998) Lyme borreliosis (Lyme disease): interactions of Borrelia burgdorferi sensu lato with human (and other mammalian) hosts. Bulletin de l'Institut Pasteur 96:3, 189-206
CrossRef53
Leonard H. Sigal. (1998) MUSCULOSKELETAL MANIFESTATIONS OF LYME ARTHRITIS. Rheumatic Disease Clinics of North America 24:2, 323-351
CrossRef54
Leonard H. Sigal. (1998) Pitfalls in the diagnosis and management of Lyme disease. Arthritis & Rheumatism 41:2, 195-204
CrossRef55
Andréa Dessen, C.Martin Lawrence, Susan Cupo, Dennis M. Zaller, Don C. Wiley. (1997) X-Ray Crystal Structure of HLA-DR4 (DRA*0101, DRB1*0401) Complexed with a Peptide from Human Collagen II. Immunity 7:4, 473-481
CrossRef56
P. Oschmann, H. J. Wellensiek, W. Zhong, W. Dorndorf, K. W. Pflughaupt. (1997) Relationship between theBorrelia burgdorferi specific immune response and different stages and syndromes in neuroborreliosis. Infection 25:5, 292-297
CrossRef57
T. Häupl, S. Landgraf, P. Netusil, N. Biller, C. Capiau, P. Desmons, P. Hauser, G.-R. Burmester. (1997) Activation of monocytes by three OspA vaccine candidates: lipoprotein OspA is a potent stimulator of monokines. FEMS Immunology & Medical Microbiology 19:1, 15-23
CrossRef58
Carlos D. Rose, Stephen C. Eppes. (1997) INFECTION-RELATED ARTHRITIS. Rheumatic Disease Clinics of North America 23:3, 677-695
CrossRef59
Leonard H. Sigal. (1997) LYME DISEASE:A Review of Aspects of Its Immunology and Immunopathogenesis. Annual Review of Immunology 15:1, 63-92
CrossRef60
Allen C. Steere. (1997) DIAGNOSIS AND TREATMENT OF LYME ARTHRITIS. Medical Clinics of North America 81:1, 179-194
CrossRef61
Heidrun Knigge, Markus M. Simon, Stefan C. Meuer, Michael D. Kramer, Reinhard Wallich. (1996) The outer surface lipoprotein OspA ofBorrelia burgdorferi provides co-stimulatory signals to normal human peripheral CD4+ and CD8+ T lymphocytes. European Journal of Immunology 26:10, 2299-2303
CrossRef62
Kathleen Petri Seiler, Janis J Weis. (1996) Immunity to Lyme disease: protection, pathology and persistence. Current Opinion in Immunology 8:4, 503-509
CrossRef63
Ariadna Sadziene, A. G. Barbour. (1996) Experimental immunization against Lyme borreliosis with recombinant Osp proteins: An overview. Infection 24:2, 195-202
CrossRef64
Dieter Ebert, William D. Hamilton. (1996) Sex against virulence: the coevolution of parasitic diseases. Trends in Ecology & Evolution 11:2, 79-82
CrossRef65
Janet L. Davis, Kirk R. Winward, Emilia C. Lonardo, Robert B. Nussenblatt, David M. Meisler, Tsung Dao Lee. (1996) Association of Propionibacterium acnes endophthalmitis with HLA-DQw5. Ocular Immunology and Inflammation 4:1, 25-32
CrossRef66
M. A. Cimmino, G. L. Moggiana, Maria Parisi, S. Accardo. (1996) Treatment of Lyme arthritis. Infection 24:1, 91-94
CrossRef67
Marie Valešova, H. Mailer, J. Havlík, Dagmar Hulínská, Jana Hercogová. (1996) Behandlung der Lyme-Arthritis. Infection 24:1, 98-102
CrossRef68
Michael V. Norgard, Scott I. Baker, Justin D. Radolf. (1995) Chemiluminescent analysis of Borrelia burgdorferi penicillin-binding proteins using ampicillin conjugated to digoxigenin. Microbial Pathogenesis 19:4, 257-272
CrossRef69
Samuel M. Behar, Steven A. Porcelli. (1995) Mechanisms of autoimmune disease induction. Arthritis & Rheumatism 38:4, 458-476
CrossRef70
Markus M. Simon, Gaby Nerz, Michael D. Kramer, Ursula Hurtenbach, Ulrich E. Schaible, Reinhard Wallich. (1995) The outer surface lipoprotein A of Borrelia burgdorferi provides direct and indirect augmenting/co-stimulatory signals for the activation of CD4+ and CD8+ T cells. Immunology Letters 45:1-2, 137-142
CrossRef71
Maria Jonsson, Teodor Elmros, Sven Bergström. (1995) Subcutaneous implanted chambers in different mouse strains as an animal model to study genetic stability during infection with Lyme disease Borrelia. Microbial Pathogenesis 18:2, 109-114
CrossRef72
P. Toivanen, A. Toivanen. (1995) Role of Micro-organisms in the Pathogenesis of Arthritis: Lessons from Reactive and Lyme Arthritis. Scandinavian Journal of Rheumatology 24:s101, 191-197
CrossRef73
H. -I. Huppertz, G. Horneff, U. Neudorf, H. Karch. (1994) Acute childhood neuroborreliosis with a selective immune response to a low molecular weight protein expressed byBorrelia garinii. European Journal of Pediatrics 153:12, 898-902
CrossRef74
Allen C. Steere, Robert E. Levin, Philip J. Molloy, Robert A. Kalish, James H. , Abraham Iii, Nancy Y. Liu, Christopher H. Schmid. (1994) Treatment of lyme arthritis. Arthritis & Rheumatism 37:6, 878-888
CrossRef75
DAVID H. E. REES, JOHN S. AXFORD. (1994) Lyme disease: A rare but clinically important disease in the UK. Equine Veterinary Journal 26:3, 175-177
CrossRef76
(1994) Treatment of late (stage III) disease. The Lancet 343:8904, 1018-1020
CrossRef77
Pinals, Robert S.. (1994) Polyarthritis and Fever. New England Journal of Medicine 330:11, 769-774
Full Text78
Karen Roessner, Jennifer Q. Russell, Sheldon M. Cooper, Ralph C. Budd, Erol Fikrig, Richard A. Flavell. (1994) Prominent T lymphocyte response toBorrelia burgdorferi from peripheral blood of unexposed donors. European Journal of Immunology 24:2, 320-324
CrossRef79
Nocton, James J.Dressler, FrankRutledge, Barbara J.Rys, Paul N.Persing, David H.Steere, Allen C.. (1994) Detection of Borrelia burgdorferi DNA by Polymerase Chain Reaction in Synovial Fluid from Patients with Lyme Arthritis. New England Journal of Medicine 330:4, 229-234
Full Text80
Rahn, Daniel W., . (1994) Lyme Disease -- Where's the Bug?. New England Journal of Medicine 330:4, 282-283
Full Text81
Thomas Häupl, Gabriele Hahn, Michael Rittig, Andreas Krause, Christoph Schoerner, Ulrich Schönherr, Joachim R. Kalden, Gerd R. Burmester. (1993) Persistence ofborrelia burgdorferi in ligamentous tissue from a patient with chronic lyme borreliosis. Arthritis & Rheumatism 36:11, 1621-1626
CrossRef82
J. Gutiérrez, M. Palermo, M. C. Maroto, M. Abellan. (1993) Atypical bilateral symmetric erosive chronic polyarthritis in the course of lyme disease. European Journal of Clinical Microbiology & Infectious Diseases 12:10, 787-789
CrossRef83
Spach, David H.Liles, W. ConradCampbell, Grant L.Quick, Robert E.Anderson, Donald E. Jr.Fritsche, Thomas R.. (1993) Tick-Borne Diseases in the United States. New England Journal of Medicine 329:13, 936-947
Full Text84
Peter Herzer. (1993) Rheumatic manifestations in Lyme borreliosis. Clinics in Dermatology 11:3, 401-406
CrossRef85
J. Sieper, J. Braun, M. Reichardt, U. Eggens. (1993) The value of specific antibody detection and culture in the diagnosis of reactive arthritis. Clinical Rheumatology 12:2, 245-252
CrossRef86
Michael R. Liebling, Midori Jane Nishio, Annette Rodriguez, Leonard H. Sigal, Tian Jin, James S. Louie. (1993) The polymerase chain reaction for the detection ofborrelia burgdorferi in human body fluids. Arthritis & Rheumatism 36:5, 665-675
CrossRef87
D. P. Singal, W. W. Buchanan. (1993) Human leucocyte antigens (HLA) and rheumatic diseases: HLA class ii antigen-associated diseases. Inflammopharmacology 2:1, 47-61
CrossRef88
(1993) ABSTRACT. Acta Paediatrica 82:s387, 1-76
CrossRef89
Beniamino Cacciapuoti, Lorenzo Ciceroni, Luigi Fontana, Roberto Perricone. (1993) Complement Activation and Sensitizing Antibodies in Lyme Borreliosis. A Microbial Adherence Immobilization Assay for Borrelia burgdorferi (MAIA-BB). Zentralblatt für Bakteriologie 278:1, 102-111
CrossRef90
G. Gialdroni Grassi. (1993) Tetracyclines — extending the atypical spectrum. International Journal of Antimicrobial Agents 3, S31-S46
CrossRef91
L.C. Miller, E.A. Lynch, S. Isa, C.A. Dinarello, J.W. Logar, A.C. Steere. (1993) Balance of synovial fluid IL-1β and IL-1 receptor antagonist and recovery from Lyme arthritis. The Lancet 341:8838, 146-148
CrossRef92
C. D. Reimers, U. Neubert, W. Kristoferitsch, K. H. Pflüger, W. R. Mayr. (1992) Borrelia burgdorferi infection in Europe: An HLA-related disease?. Infection 20:4, 197-200
CrossRef93
Hidetoshi Kaneoka, Kou-Ching Hsu, Yoshihiko Takeda, Gordon C. Sharp, Robert W. Hoffman. (1992) Molecular Genetic Analysis of HLA—DR and HLA—DQ Genes Among Anti—U1-70-kd Autoantibody Positive Connective Tissue Disease Patients. Arthritis & Rheumatism 35:1, 83-94
CrossRef94
Michael Ehrenstein, David Isenberg. (1991) Autoimmunity associated with infection: leprosy, acute rheumatic fever and Lyme disease. Current Opinion in Immunology 3:6, 930-935
CrossRef95
Ulrich E. Schaible, Michael D. Kramer, Reinhard Wallich, Thao Tran, Markus M. Simon. (1991) ExperimentalBorrelia burgdorferi infection in inbred mouse strains: Antibody response and association of H-2 genes with resistance and susceptibility to development of arthritis. European Journal of Immunology 21:10, 2397-2405
CrossRef96
Robert T. Schoen, John M. Aversa, Daniel W. Rahn, Allen C. Steere. (1991) Treatment of refractory chronic Lyme arthritis with arthroscopic synovectomy. Arthritis & Rheumatism 34:8, 1056-1060
CrossRef97
R. Edelman. (1991) Perspective on the development of vaccines against Lyme disease. Vaccine 9:8, 531-532
CrossRef98
Szer, Ilona S., Taylor, Elise, Steere, Allen C., . (1991) The Long-Term Course of Lyme Arthritis in Children. New England Journal of Medicine 325:3, 159-163
Full Text99
Natalino H. Yoshinari, Bruce N. Reinhardt, Allen C. Steere. (1991) T cell responses to polypeptide fractions ofBorrelia burgdorferi in patients with lyme arthritis. Arthritis & Rheumatism 34:6, 707-713
CrossRef100
Giovina Ruberti, Ann B. Begovich, Allen C. Steere, William Klitz, Henry A. Ehrlich, C. Garrison Fathman. (1991) Molecular analysis of the role of the HLA class II genes DRB1, DQA1, DQB1, and DPB1 in susceptibility to lyme arthritis. Human Immunology 31:1, 20-27
CrossRef101
V. Prasad. (1991) Lyme disease from a physician's point of view. International Journal of Acarology 17:1, 37-40
CrossRef102
Daniel W. Rahn. (1991) Lyme disease: Clinical manifestations, diagnosis, and treatment. Seminars in Arthritis and Rheumatism 20:4, 201-218
CrossRef103
(1991) Chronic Lyme Arthritis and HLA Alleles. New England Journal of Medicine 324:2, 129-129
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