Classical Disease-Specific Autoantibodies in Systemic Sclerosis: Clinical Features, Gene Susceptibility, and Disease Stratification

Abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by abnormalities in microcirculation, extracellular matrix accumulation, and immune activation. Autoantibodies are markers of immune abnormalities and provide diagnostic and predictive value in SSc. Anti-topoisomerase antibodies (ATAs), anticentromere antibodies (ACAs), and anti-RNA polymerase antibodies (ARAs) are the three classical specific antibodies with the highest availability and stability. In this review, we provide an overview of the recent progress in SSc research with respect to ATAs, ACAs, and ARAs, focusing on their application in distinguishing clinical phenotypes, such as malignancy and organ involvement, identifying genetic background in human leukocyte antigen (HLA) or non-HLA alleles, and their potential roles in disease pathogenesis based on the effects of antigen-antibody binding. We finally summarized the novel analysis using ATAs, ACAs, and ARAs on more detailed disease clusters. Considering these advantages, this review emphasizes that classical SSc-specific autoantibodies are still practical and have the potential for patient and risk stratification with applications in precise medicine for SSc.

Keywords: anti-RNA polymerase antibodies; anti-topoisomerase antibodies; anticentromere antibodies; clinical manifestations; disease stratification; gene; systemic sclerosis.

Figure 1

Direct combination of antibodies and antigens in systemic sclerosis. (A) CENP-B were released from the apoptotic ECs. Then, the extracellular CENP-B bound to the contractile-type PASMCs via CCR3. Next, the binding of CENP-B to the contractile SMCs stimulated migration in the wound healing assays. The exact way of production of ATAs was known. When combined with CCR3-binding CENP-B, ATAs may abolish vascular self-repair, further leading to angiopathy. (B) TOPO I was released from apoptotic ECs and some of them were oxidized to AOPP. Then, TOPO I was bound to the bystander fibroblasts via CCR7 or HS proteoglycans. DCs loaded with selected TOPO I could activate the intrinsic TOPO I–specific T cells. The activated special T cells produced IL-2 or IL-6 and communicated with B cells through the interactions of MHC-TCR and CD40-CD40L. T cell–dependent B cells were activated, thereby becoming TOPO I–specific B cells and resulting in ATAs. Binding TOPO I recruited circulating ATAs and composed ICs, which could induce the adhesion and activation of circulating monocytes. Abatacept-regulated dysfunction T cells. Rituximab and ibrutinib may be used as B-cell depletion therapy. CENP-B, centromere proteins B; EC, endothelial cell; PASMC, Pulmonary artery smooth muscle cells; CCR, CC chemokine receptor; SMC, smooth muscle cell; AOPP, advanced oxidation protein products; HS, heparan sulfate.

Figure 2

ACAs and CENP-B: CENP-B bound to CCR3. Then, the cross-talk between CCR3 and EGFR, which was mediated by the MMPs-dependent processing of pro HB-EGF, activated MAPK pathway, and production of proinflammatory cytokines such as IL-8, and promoted the migration of contractile-type PASMCs, further leading to vascular self-repair. ATAs from patients with SSc, when combined with CCR3-binding CENP-B, abolished the abovementioned pathway and inhibited the vascular self-repair. EGFR, epidermal growth factor receptor; MMP, matrix metalloproteinase; HB-EGF, heparin-binding EGF-like growth factor; MAPK, mitogen activated protein kinase.

Figure 3

ATAs and topo I: Reinforcement of pathological functions. (A) The combination of TOPO I and fibroblasts could be suppressed by using brefeldin A, and oxidized TOPO I may have increased the antigenicity. The potential intracellular signaling pathway stimulated by TOPO I was the phosphorylation of phospholipase Cγ1, c-Raf, ERK-1/2, and p38 MAPK, which stimulated the migration of fibroblast. Cytokine-like effects of TOPO I in the pathway could be inhibited by CCL21. (B) TOPO I bound to HS proteoglycans on the fibroblast surface, as well as the accumulation of TOPO I on cell surfaces by ATAs could contribute to the initiation of an inflammatory cascade stimulating the fibrosis. The effect could be inhibited by heparin through the interference with TOPO I binding and the consequent accumulation of TOPO I-ATA ICs could be restrained with decreased monocyte adhesion, proinflammatory factors, and fibrosis.