B cell epitope specificity in ANCA-associated vasculitis: does it matter?

Abstract

Pauci-immune idiopathic small-vessel vasculitis is strongly associated with the presence of antineutrophil cytoplasm autoantibodies (ANCA). Antibodies to PR3 predominate in patients with Wegener's granulomatosis; antibodies to myeloperoxidase (MPO) are found more frequently in patients with microscopic polyangiitis. There is increasing in vivo and in vitro evidence for a pathogenic role of ANCA in systemic vasculitis based on associations of ANCA with disease activity. If ANCA are pathogenic, why is the course of disease different from one patient to another? Antibodies can recognize different binding sites (epitopes) on their corresponding antigens. Differences in binding specificity may influence the pathogenic potential of the antibodies. Differences between epitope specificity of ANCA between patients or changes in epitope specificity of ANCA in time in an individual patient may, accordingly, result in differences in disease expression. This review will focus on epitope specificity of autoantibodies in systemic autoimmune diseases and especially on the epitope specificity of PR3- and MPO-ANCA. We will discuss whether PR3-ANCA or MPO-ANCA recognize different epitopes on PR3 and MPO, respectively, and whether the epitopes recognized by ANCA change in parallel with the disease activity of ANCA-associated vasculitis. Finally, we will speculate if the direct pathogenic role of ANCA can be ascribed to one relapse- or disease-inducing epitope. Characterization of relapse- or disease-inducing epitopes bound by PR3-ANCA and MPO-ANCA is significant for understanding initiation and reactivation of ANCA-associated vasculitis. Elucidating a disease-inducing epitope bound by ANCA may lead to the development of epitope-specific therapeutic strategies.

Fig. 1

The protein structure of PR3. (a) The amino acids, H⁴⁴, D⁹¹ and S¹⁷⁶ forming the catalytic triad are indicated with arrows and the two glycosylation sites on N¹⁰² and N¹⁴⁶ are indicated with lines [74]. SS indicates disulphide bridges. Bars below the protein indicate the location of identified epitopes recognized by PR3–ANCA. (b) Amino acid sequence of PR3 with areas that are surface exposed and have been identified as epitopes recognized by PR3–ANCA from patients with WG. Shown in bold, epitopes identified by Williams et al. [45]; italic epitopes were identified by van der Geld et al. [47]; underlined epitopes were identified by Griffith et al. [46]. In the grey boxes are the amino acids forming the catalytic triad of PR3. In white boxes are the pro- en C-terminal sequence. These sequences are removed upon processing of PR3 to a mature proteolytically active protein. Also in boxes are the two polymorphisms described in the PR3 sequence [–76]. Arrows indicate the start and end of the sequence corresponding to the complementary peptide of PR3 [29].

Fig. 2

Epitopes bound by PR3–ANCA in a three-dimensional model of PR3. Three-dimensional model of PR3 according to the coordinates provided by Fujinaga et al. [41]. Amino acids are numbered in agreement with the PR3 sequence published by Campanelli et al. [76]. α-Helixes are shown in coiles and the Β sheets are shown as arrows. The amino acids His44, Asp91 and Ser176 form the catalytic triad of PR3. Epitope regions of Fig. 1b are given; first epitopic region (dots), second region (stripes), third region (stripe-dot strip), fourth region (long lines) and fifth region (heavy line).

Fig. 3

MPO protein structure. (a) The peptide subunits of MPO. MPO is a covalently linked dimer, composed of two subunits each with one heavy and one light chain. Each half contains a haem group. The active site, histidine 416, is indicated. The five potential glycosylation sites are indicated with an arrow. (b) Amino acid sequence of MPO [77] with three areas (bold) that have been identified by Fuji et al. [63] as epitopes recognized by MPO–ANCA from patients with MPA. The overlap between two identified regions is underlined. Grey box: the histidine important for the enzymatic activity of MPO.