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Abstract Number: 1708

The Pathogenic Role of Immune Complexes Containing Scleroderma-Specific Autoantibodies in the Inductor Phase of the Disease

Cecilia B. Chighizola1, Elena Raschi2, Laura Cesana2, Silvana Zeni3, Maria Orietta Borghi4 and Pier Luigi Meroni5,6, 1Rheumatology, Istituto Auxologico Italiano, University of Milan, Cusano Milanino, Italy, 2Istituto Auxologico Italiano, Milan, Italy, 3Division of Rheumatology, Istituto G. Pini, Milano, Italy, 4Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy, 5Department of Clinical Sciences and Community Health, Division of Rheumatology, Istituto G. Pini, Milan, Italy, 6Chair and Division of Rheumatology, Gaetano Pini Institute, University of Milan, Milan, Italy

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: autoantibodies, pathogenesis and systemic sclerosis

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic sclerosis (SSc) is a chronic autoimmune condition characterized by excessive tissue fibrosis, microvascular alterations and immune dysfunction with the production of peculiar autoantibodies. These autoantibodies are highly specific for SSc diagnosis, and provide the most reliable tool to predict disease subset and the pattern of internal organ involvement. Despite such diagnostic and prognostic role, no evidence supporting the pathogenic potential of these autoantibodies has to date been raised.

Therefore the aim of this study is to evaluate for the first time the pathogenicity of immune complexes (IC) from scleroderma patients in the inductor phase of the disease, using skin fibroblasts from healthy controls as cellular in vitro model.  

Methods: Fibroblasts have been isolated from skin biopsies obtained from healthy controls and then cultured in adequate conditions. IC have been purified from sera of scleroderma patients bearing different autoantibody specificities (antibodies against centromeric proteins [ACA], DNA topoisomerase I [ATA], RNA polymerase [ARA] and Th/To [anti-Th/To]) or of healthy controls using polyethylen glycol precipitation. Cell cultures have been incubated with pathologic and control IC and with cell activating agonists as TLR3 [Poly(I:C)] and TLR4 (LPS) ligands. Several parameters of fibroblast activation have been assessed in the different experimental conditions. In particular, mRNA levels of type I interferons (IFN-alpha and IFN-beta) have been investigated by real-Time PCR; ICAM-1 expression has been evaluated by cell-ELISA and the secretion of IL-6 and IL-8 in culture supernatants has been measured by commercial ELISA kits. Furthermore, the involvement of intracellular signaling pathways culminating with the activation of  p38 MAPK, NFkB and JNK has been assessed by Western Blotting.


Results: Stimulation of normal skin fibroblasts with pathologic IC induced a significant increase in the gene expression levels of both IFN-alpha and IFN-beta; similar results have been observed in the presence of TLR agonists but not of control IC. In addition, the expression of ICAM-1 and the secretion of IL-6 and IL-8 were up-regulated by Poly(I:C), LPS and IC from scleroderma patients but not from healthy controls. Further, pathologic IC induced the activation of p38 MAPK, NFkB and JNK.

 

Conclusion: Our data provide the first demonstration of the pathogenic role of IC isolated from scleroderma patients with different autoantibody specificities in the inductor phase of SSc. Indeed, pathologic IC can interact with normal skin fibroblasts, inducing a pro-inflammatory phenotype mediated by p38 MAPK, NFkB and JNK. These evidences fit well with the diagnostic and prognostic role of scleroderma-specific autoantibodies, providing novel insights into SSc etiopathogenesis and potentially leading to new treatment strategies.

 


Disclosure:

C. B. Chighizola,
None;

E. Raschi,
None;

L. Cesana,
None;

S. Zeni,
None;

M. O. Borghi,
None;

P. L. Meroni,
None.

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