Clinical associations of anticentromere antibodies and antibodies to topoisomerase i. a study of 355 patients

169

134

Objective. To determine the frequency, clinical associations, and any major histocompatibility complex correlations of antifibrillarin antibodies in patients with systemic sclerosis (SSc).Methods. Antifibrillarin antibodies were determined by indirect immunofluorescence, immunoblotting, and immunoprecipitation, and HLA class I1 alleles by DNA oligotyping, in a large cohort of SSc patients.Results. Antifibrillarin was found in 8% of 335 SSc sera and was significantly more common in blacks (16%) than whites (S%), in males (33%) than females (14%), and in patients with cardiac, renal, or gut involvement. The HLA class I1 haplotype DRBZ *Z302, DQBZ*0604 was found significantly more frequently in SSc patients with antifibrillarin compared with racematched normal controls and 260 SSc patients without antifibrillarin. In addition, 1 or more of the HLA-DQB1

Section: Discussionmentioning

confidence: 99%

Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic, and clinical analysis

Goldstein

et al. 1996

169

134

“…All sera were tested blindly. ANAs were determined by indirect immunofluorescence (IIF) on HEp-2 cells (Antibodies Inc., Davis, CA) (performed by J-LS) (32). SSc-specific autoantibodies were determined at the end of the study as follows.…”

Section: Methodsmentioning

confidence: 99%

Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: A twenty‐year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis

Koenig

Fritzler

Roussin

et al. 2008

537

371

Objective. To identify in patients with Raynaud's phenomenon (RP) independent markers that predict progression to definite systemic sclerosis (SSc) and to determine in patients with progression to SSc the type and sequence of microvascular damage and its relationship to SSc-specific autoantibodies.Methods. Consecutive patients referred for evaluation of RP who had no definite connective tissue disease were evaluated for microvascular damage by nailfold capillary microscopy (NCM) and for anticentromere (anti-CENP-B), anti-Th/To, anti-topoisomerase I, and anti-RNA polymerase III (anti-RNAP III) autoantibodies by specific assays. Patients were studied prospectively.Results. Of the 586 patients who were followed up for 3,197 person-years, 74 (12.6%) developed definite SSc. A characteristic sequence of microvascular damage was identified, starting with enlarged capillaries, followed by capillary loss, and then by capillary telangiectases. Definite SSc was diagnosed in close temporal relationship to capillary loss. Enlarged capillaries, capillary loss, and SSc-specific autoantibodies independently predicted definite SSc. Anti-CENP-B and antiTh/To antibodies predicted enlarged capillaries; these autoantibodies and anti-RNAP III predicted capillary loss. Each autoantibody was associated with a distinct time course of microvascular damage. At followup, 79.5% of patients with 1 of these autoantibodies and abnormal findings on NCM at baseline had developed definite SSc. Patients with both baseline predictors were 60 times more likely to develop definite SSc. The data validated the proposed criteria for early SSc.Conclusion. In RP evolving to definite SSc, microvascular damage is dynamic and sequential, while SScspecific autoantibodies are associated with the course and type of capillary abnormalities. Abnormal findings on NCM at baseline together with an SSc-specific autoantibody indicate a very high probability of devel-

“…ANAs have been associated with different clinical manifestations and various degrees of SSc severity. For example, anti-topo I are usually associated with more diffuse cutaneous SSc (4,5), whereas anti-CENP-B are detected predominantly in patients with limited cutaneous SSc (4,6,7). Also, anti-topo I are strongly associated with pulmonary fibrosis in SSc (6,8), while pulmo-nary arterial hypertension is more common in patients with anti-CENP-B (9).…”

Section: Second Topo I-anti-topo I Complex Binding Can Then Trigger mentioning

confidence: 99%

DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti–topoisomerase I autoantibodies from systemic sclerosis patients

Hénault¹,

Robitaille²,

Senécal³

et al. 2006

110

Objective. Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis due to excessive and dysregulated collagen production by fibroblasts. Previously, we reported that anti-DNA topoisomerase I (anti-topo I) antibodies bound specifically to fibroblast surfaces; however, we had not identified their antigenic target. We undertook this study to characterize the target of anti-topo I antibodies on fibroblasts and the effects of their binding.Methods. Purified topo I or topo I released from apoptotic cells was tested for surface binding to a number of human cell types by cell-based enzyme-linked immunosorbent assay, flow cytometry, and indirect immunofluorescence. Antibodies purified from SSc patient and normal control sera were used to detect topo I binding. The consequences of topo I and anti-topo I binding to fibroblasts were assessed by coculture with THP-1 monocytes.Results. The autoantigen topo I itself was found to bind specifically to fibroblasts in a dose-dependent and saturable manner, where it was recognized by anti-topo I from SSc patients. The binding of anti-topo I subsequently stimulated adhesion and activation of cocultured monocytes. Topo I released from apoptotic endothelial cells was also found to bind specifically to fibroblasts.Conclusion. The findings of this study thus confirm and extend the findings of our previous study by showing that topo I binding to fibroblast surfaces is both necessary and sufficient for anti-topo I binding. Second, topo I-anti-topo I complex binding can then trigger the adhesion and activation of monocytes, thus providing a plausible model for the amplification of the fibrogenic cascade in anti-topo I-positive SSc patients.