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. 2015 Oct;160(2):336-41.
doi: 10.1016/j.clim.2015.07.005. Epub 2015 Jul 15.

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

Annalisa Pianta  1 , Elise E Drouin  2 , Jameson T Crowley  2 , Sheila Arvikar  2 , Klemen Strle  2 , Catherine E Costello  3 , Allen C Steere  2
Affiliations

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

Annalisa Pianta et al. Clin Immunol. 2015 Oct.

Abstract

In this study, autoantibody responses to annexin A2 were found in 11-15% of 278 patients with Lyme disease, including in those with erythema migrans (EM), an early sign of the illness, and in those with antibiotic-responsive or antibiotic-refractory Lyme arthritis (LA), a late disease manifestation. In contrast, robust T cell reactivity to annexin A2 peptides was found only in patients with responsive or refractory LA. In LA patients, annexin A2 protein levels, which were higher in the refractory group, correlated with annexin A2 antibody levels in sera and synovial fluid. In addition, in patients with antibiotic-refractory LA who had anti-annexin A2 antibodies, synovial tissue had intense staining for annexin A2 protein, greater synovial fibroblast proliferation and more tissue fibrosis. Thus, a subset of LA patients had T and B cell responses to annexin A2, and in the refractory group, annexin A2 autoantibodies were associated with specific pathologic findings.

Keywords: Annexin A2; Autoantigen; Borrelia burgdorferi; Lyme arthritis; Lyme disease.

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Figures

Fig. 1
Fig. 1
T cell reactivity against annexin A2 peptides in Lyme disease patients and healthy control subjects. PBMCs from patients with erythema migrans (EM), antibiotic-responsive Lyme arthritis (LA res), antibiotic-refractory Lyme arthritis (LA ref) and healthy controls (HC) subjects were incubated with a set of 4 annexin A2 peptides (1 μM each), phytohemagglutinin (positive control), or no peptide (negative control), and assayed for IFN-γ secretion using ELISpot assay. A positive response was defined as >3 standard deviation (SD) above the mean of the HC subjects (area above the shaded region). Each symbol indicates the value in an individual subject. The horizontal lines represent the mean values of each group. The P-value for the corresponding statistical comparisons are indicated.
Fig. 2
Fig. 2
Determination of IgG anti-annexin A2 antibody levels as assessed by ELISA. Plates were coated with recombinant human annexin-A2 and incubated with serum from patients or control subjects. All serum samples were tested in duplicates. Positivity was defined as >3 SD above the mean value of healthy control (HC) subjects (area above the shaded region). Symbols represent values in individual patients and horizontal lines show mean values. Only significant P values are shown. HC = healthy control; Flu = influenza; EM = erythema migrans; LA res = antibiotic-responsive Lyme arthritis; LA ref = antibiotic-refractory Lyme arthritis; RA = rheumatoid arthritis; SpA = spondyloarthropathies, OA = osteoarthritis.
Fig. 3
Fig. 3
Determination of serum or synovial fluid (SF) annexin-A2 protein levels as assessed by sandwich ELISA. Positivity was defined as >3 SD above the mean value of healthy control (HC) subjects (area above the shaded region). Symbols represent values in individual patients and horizontal lines show mean values. Only significant P values are shown. HC = healthy control; Flu = influenza; EM = erythema migrans; LA res = antibiotic-responsive Lyme arthritis; LA ref = antibiotic-refractory Lyme arthritis; RA = rheumatoid arthritis; SpA = spondyloarthropathies, OA = osteoarthritis.
Fig. 4
Fig. 4
Correlations between annexin A2 antibody titers in serum and annexin A2 protein levels in serum, synovial fluid or synovial tissue of patients with Lyme arthritis, rheumatoid arthritis, spondyloarthropathies, or healthy control subjects. Annexin A2 antibody titers correlation with serum annexin A2 protein levels (A) or synovial fluid annexin A2 protein levels (B) in Lyme arthritis patients. Correlation between annexin A2 antibody titers and synovial tissue annexin A2 protein levels as determined by immunohistochemistry (IHC) in patients with Lyme arthritis (C). Correlation between annexin A2 antibody titers and serum annexin A2 protein levels in patients with rheumatoid arthritis (D), spondyloarthropathies (E), or healthy control subjects (F). Ab = antibody.
Fig. 5
Fig. 5
Histologic findings in synovial tissue stratified by annexin A2 antibody (Ab) responses. The samples analyzed were from 9 patients with antibiotic-refractory Lyme arthritis: 4 had negative annexin A2 Ab responses and 5 had positive responses. The slides were stained with hematoxylin and eosin, or trichrome (for fibrosis) (A), or with antibodies to cell surface markers or to annexin A2 (B). Data are shown as box plots. Each box represents the 25th to 75th percentiles. Lines inside the boxes represent the median values. Lines outside the boxes represent the 5th and the 95th percentiles. The P-value for the corresponding statistical comparisons is indicated.
Fig. 6
Fig. 6
Findings in synovial tissue pertaining to annexin A2 protein expression, synovial fibroblasts, and fibrosis in 2 representative LA patients who did or did not have anti-annexin A2 antibodies. The sections were stained with rabbit polyclonal antibody against annexin A2, rabbit polyclonal antibody against vimentin (fibroblast), or trichrome (fibrosis). Low-power and high-power views are shown. In the upper panels, the tissue in patient 1 (Pt 1), who had anti-annexin A2 antibodies, showed marked annexin A2 expression, dense synovial fibroblasts, and intense fibrosis. In the lower panels, the tissue in patient 2 (Pt 2), who did not have anti-annexin A2 antibodies, showed minimal annexin A2 expression, less dense synovial fibroblasts, and minimal fibrosis. Ab = antibody.
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