Anti-centromere protein A antibodies in systemic sclerosis: Significance and origin

Abstract

Systemic sclerosis (SSc) is systemic, autoimmune, connective tissue disorder characterized by vascular abnormalities, collagen deposition (fibrosis), and the production of autoantibodies to nuclear proteins. About 20%–40% of patients have antibodies to centromere protein (CENP)-A or -B. Despite the known association of anti-CENP antibodies with certain clinical features of SSc, the role of these antibodies in SSc physiopathology is still poorly understood. To better understand the clinical significance and origin of these antibodies, we and others have been studying the epitopic motifs (amino acid contact sites) on CENP-A with the aim of determining whether other proteins can prime or be targeted by them. Here, we review published and ongoing studies aimed at defining the fine specificity and origin of anti–CENP-A antibodies. We describe progress made in identifying the CENP-A epitopic motif amino acids, and the discovery of one of these motifs in forkhead box protein E3 (FOXE-3), a transcription factor previously studied only for its role in the development of lens fiber cells. Moreover, we discuss preliminary evidence for a possible role of FOXE-3 in SSc pathogenesis and for the association of different subsets of anti–CENP-A antibodies, heterogeneously expressed among SSc patients, with some clinical correlates.

Introduction

Systemic sclerosis (SSc)¹ is a multisystem, autoimmune, connective tissue disorder that causes widespread fibrosis of the skin and internal organs. The clinical hallmarks of SSc are vascular abnormalities, excessive collagen synthesis, and high-titer autoantibody production to proteins of the nucleus and nucleolus [1], [2], [3], [4]. Among systemic autoimmune disorders, SSc is one of the most disabling and invalidating diseases, severely affecting the quality of life [5], [6]. Recent data have highlighted the poor efficacy of currently available drugs on skin sclerosis, interstitial lung disease, and pulmonary hypertension [7], the latter two conditions being the major causes of death in these patients. Because of the lack of effective medicines, the severity and the relatively rarity of this disease, which affects between 50 and 300 cases per million persons with an incidence ranging from 2.3 to 22.8 cases/million year [8], [9], SSc is listed as an orphan by Orphanet and the European League Against Rheumatism. Very little is known about the disease's pathogenesis, starting from early inflammatory events to fibrosis of the cutis and internal organs.

Immune system activation in SSc is demonstrated by the increase of B-cell activation markers [10], [11], by the ability of fibroblasts to trigger an oligoclonal T-cell response in the early stage of the disease [3], [12], and by the expression of antinuclear antibodies (ANA) [2], [13]. ANA are found in the sera of more than 95% of SSc patients, but their antigenic specificity varies with the clinical characteristics of the disease (Table 1) [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84]. The most frequently targeted autoantigens are alpha-topoisomerase, in 15%–40% of patients, and the centromere proteins (CENPs) [14], mainly protein A (CENP-A) and protein B (CENP-B), in 20%–40% of patients. Anti-alpha-topoisomerase antibodies (ATA) are more often found in patients with diffuse cutaneous involvement, interstitial lung disease [85], and renal involvement [2], [86]. By contrast, patients expressing anti-CENP antibodies (ACA) present a higher risk of developing pulmonary arterial hypertension and a lower risk of early interstitial lung disease in the early phase of the disease [21], [27]. In addition, ACA-positive patients more often present a limited cutaneous involvement and a slower development of nailfold capillary damage [2], [16], [30] than do SSc patients with other ANA. In fact, registry studies [24], [87] documented ACA in 80% of patients with limited cutaneous involvement but in only 10% of patients with diffuse skin involvement (reviewed in ref. [13]).

ACA and ATA are mutually exclusive in SSc, as the concomitant expression of both antibodies is extremely rare [24], [30], [81], [86]. ACA may be found in the sera of SSc patients even years before the disease manifests clinically, and they continue to be expressed throughout the disease course [88], [89]. Indeed, an elevated ACA titer is one criterion defining undifferentiated connective tissue disease at risk for SSc (early SSc) [90], [91]. Patients with Raynaud's phenomenon (RP) who also express ACA are at a higher risk of developing SSc than are RP patients without ACA [85], [92], [93], [94]. Finally, ACA are rarely found in other autoimmune diseases [95] or in healthy individuals [96].

All these considerations indicate that ACA are almost specific for SSc [97]. Moreover, the association of ACA with certain clinical features of SSc suggests that they have a role in the pathogenesis of this disease [98]. Here, we review our published and ongoing work on the significance and origin of ACA in these patients.