A Highly Expressed Human Protein, Apolipoprotein B-100, Serves as an Autoantigen in a Subgroup of Patients With Lyme Disease

Abstract

To discover novel autoantigens associated with Lyme arthritis (LA), we identified T-cell epitopes presented in vivo by human leukocyte antigen (HLA)-DR molecules in patients' inflamed synovial tissue or joint fluid and tested each epitope for autoreactivity. Using this approach, we identified the highly expressed human protein, apolipoprotein B-100 (apoB-100), as a target of T- and B-cell responses in a subgroup of LA patients. Additionally, the joint fluid of these patients had markedly elevated levels of apoB-100 protein, which may contribute to its autoantigenicity. In patients with antibiotic-refractory LA, the magnitude of apoB-100 antibody responses correlated with increased numbers of plasma cells in synovial tissue, greater numbers and activation of endothelial cells, and more synovial fibroblast proliferation. Thus, a subset of LA patients have high levels of apoB-100 in their joints and autoreactive T- and B-cell responses to the protein, which likely contributes to pathogenic autoimmunity in patients with antibiotic-refractory LA.

Annexin A2 is a target of autoimmune T and B cell responses associated with synovial fibroblast proliferation in patients with antibiotic-refractory Lyme arthritis

“…First, as was shown with both ECGF and apoB-100 [13, 14], autoantibodies to annexin A2 typically develop early in the illness in patients with erythema migrans, months before the onset of arthritis. B. burgdorferi spirochetes bind plasminogen and its activator, which facilitate spreading of the organism in the tick and in the host [30, 31].…”

“…With this approach, we previously identifed two novel autoantigens in Lyme disease, endothelial cell growth factor (ECGF) and apolipoprotein B-100 (apoB-100) [13, 14]. With each autoantigen, autoantibodies were found in about 10% of patients with EM, and T and B cell responses were present in 15–30% of patients with LA.…”

“…With each autoantigen, autoantibodies were found in about 10% of patients with EM, and T and B cell responses were present in 15–30% of patients with LA. In patients with antibiotic-refractory LA, autoantibodies to ECGF correlated with the histologic finding of obliterative microvascular lesions in synovial tissue [15], whereas autoantibodies to apo-B-100 correlated with higher numbers and activation of endothelial cells in the tissue and greater synovial fibroblast proliferation [14]. These correlations suggested that autoimmune responses to ECGF or apoB-100 may have specific pathologic consequences, relating primarily to synovial microvasculature.…”

Two rheumatoid arthritis–specific autoantigens correlate microbial immunity with autoimmune responses in joints

“…We have developed an approach for antigen detection in chronic inflammatory arthritides, in which HLA-DRpresented peptides (T cell epitopes) are identified directly from patients' inflamed synovial tissue, synovial fluid mononuclear cells (SFMCs), or peripheral blood mononuclear cells (PBMCs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tested for immunogenicity using patients' samples (19)(20)(21)(22)(23)(24).…”

Matrix metalloproteinase-10 is a target of T and B cell responses that correlate with synovial pathology in patients with antibiotic-refractory Lyme arthritis

“…Usually 1–3 immunogenic HLA-DR-presented self-peptides, or candidate autoantigens, have been identified from the 100–150 non-redundant self-peptides isolated from each patient. In Lyme disease, these peptides were derived from the source protein endothelial cell growth factor (ECGF) [35] or apolipoprotein B-100 (apoB-100) [36], from annexin A2 in both RA and LA [37], and from N-acetylglucosamine-6-sulfatase and filamin A in RA. In Lyme disease, autoantibodies to each of these self-antigens (but minimal, if any, T cell responses) were found in a subset of patients with EM early in the infection.…”