The greatest remaining clinical problem in Lyme disease (LD) is that some patients do not have complete resolution of signs or symptoms with antibiotic therapy. In recent years, we have studied this problem intensively in patients with Lyme arthritis in whom synovitis persists for months or years after spirochetal killing with antibiotics, called antibiotic-refractory arthritis. We have hypothesized that this disease course results from infection-induced autoimmunity with excessive inflammation and immune dysregulation in joints. However, until recently, identification of pathogenic autoantigens has remained elusive. Using discovery-based proteomics combined with clinical translational research, we recently identified endothelial cell growth factor (ECGF), the first known autoantigen that induces T and B cell responses in some patients with LD. In addition, we have preliminary information that the third component of complement and cytokeratin 10 may also serve as autoantigens. Our first specific aim in this grant application is to determine the clinica correlates of autoimmunity to ECGF or other candidate autoantigens across the spectrum of LD, including its post-infectious syndromes, to assess whether these responses are specific for LD, and to learn whether they occur only with U.S. B. burgdorferi (Bb) strains or also with European genospecies of the spirochete. Second, we plan to use the same proteomic and translational research approach that we employed successfully in the identification of ECGF to identify other candidate autoantigens. Third, we will determine spirochetal and host factors, including types of Bb strains and interactions with host cells, which are necessary for the induction of immune responses to ECGF of other candidate autoantigens, and we will characterize the adaptive immune response to these autoantigens in target tissues or fluids.
These aims will allow us to determine whether autoimmunity to ECGF occurs as a part of a wider spectrum of Bb-induced immune responses, to ascertain the resulting clinical pictures, to identify other candidate autoantigens, and to delineate mechanisms responsible for these responses. We anticipate that a test for these antibody responses will become a part of the clinical evaluation of LD. Such information will help physicians to treat patients with LD more appropriately and effectively.

Public Health Relevance

Our work involves efforts to understand spirochetal and host factors that play a role in the pathogenesis of post-infectious Lyme disease syndromes, such as antibiotic- refractory arthritis. This grant would allow us to expand our observation that autoimmunity to endothelial cell growth factor (ECGF) can occur as a part of the spectrum of B. burgdorferi-induced immune responses, to identify other candidate autoantigens, to delineate mechanisms that account for these responses, and to define the clinical consequences of such untoward host responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI101175-01A1
Application #
8501754
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Breen, Joseph J
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$256,163
Indirect Cost
$108,943
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Glatz, Martin; Means, Terry; Haas, Josef et al. (2017) Characterization of the early local immune response to Ixodes ricinus tick bites in human skin. Exp Dermatol 26:263-269
Wang, Qi; Drouin, Elise E; Yao, Chunxiang et al. (2017) Immunogenic HLA-DR-Presented Self-Peptides Identified Directly from Clinical Samples of Synovial Tissue, Synovial Fluid, or Peripheral Blood in Patients with Rheumatoid Arthritis or Lyme Arthritis. J Proteome Res 16:122-136
Lochhead, Robert B; Strle, Klemen; Kim, Nancy D et al. (2017) MicroRNA Expression Shows Inflammatory Dysregulation and Tumor-Like Proliferative Responses in Joints of Patients With Postinfectious Lyme Arthritis. Arthritis Rheumatol 69:1100-1110
Arvikar, Sheila L; Crowley, Jameson T; Sulka, Katherine B et al. (2017) Autoimmune Arthritides, Rheumatoid Arthritis, Psoriatic Arthritis, or Peripheral Spondyloarthritis Following Lyme Disease. Arthritis Rheumatol 69:194-202
Crowley, Jameson T; Strle, Klemen; Drouin, Elise E et al. (2016) Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis. J Autoimmun 69:24-37
Cerar, Tjasa; Strle, Franc; Stupica, Dasa et al. (2016) Differences in Genotype, Clinical Features, and Inflammatory Potential of Borrelia burgdorferi sensu stricto Strains from Europe and the United States. Emerg Infect Dis 22:818-27
Steere, Allen C; Strle, Franc; Wormser, Gary P et al. (2016) Lyme borreliosis. Nat Rev Dis Primers 2:16090
Lahey, Lauren J; Panas, Michael W; Mao, Rong et al. (2015) Development of a Multiantigen Panel for Improved Detection of Borrelia burgdorferi Infection in Early Lyme Disease. J Clin Microbiol 53:3834-41
Pianta, Annalisa; Drouin, Elise E; Crowley, Jameson T et al. (2015) Annexin A2 is a target of autoimmune T and B cell responses associated with synovial fibroblast proliferation in patients with antibiotic-refractory Lyme arthritis. Clin Immunol 160:336-41
Steere, Allen C; Arvikar, Sheila L (2015) Editorial commentary: what constitutes appropriate treatment of post-Lyme disease symptoms and other pain and fatigue syndromes? Clin Infect Dis 60:1783-5

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