Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose
Functional autoantibodies reactive to the angiotensin II type 1 receptor (AT1R) and endothelin 1 type A receptor (ETAR) were found in elevated levels in systemic sclerosis (SSc) patients, with clinical connections to lung involvement. Functional effects on T-lymphocyte migration were studied previously in vitro and first in vivo experiments on C57BL/6 mice demonstrated agonistic effects on lung architecture. Here, functional effects of anti-AT1R and anti-ETAR autoantibodies on inflammatory cell infiltration into lungs of mice deficient for the AT receptor and on their respective WT mice (129 x C57BL/6), were studied for the first time.
Methods
Female mice deficient for AT1a, AT1b, and AT2 receptor (ATR -/-, 129 x C57BL/6, n=5 per group) and WT controls (129 x C57BL/6, n=4 per group) were treated with SSc-IgG with elevated levels of anti-AT1R and anti-ETAR autoantibodies. In control experiments same groups were treated with healthy donor IgG (NC-IgG). IgG samples were transferred into ATR -/- and into WT groups five times over three months. Lungs were examined using histological staining and an index-system was developed to assess CD3+T-lymphocyte infiltration around vessels. Samples were analysed in a blinded fashion using imageJ software.
Results
Mice of the ATR -/- and WT group treated with SSc-IgG showed a dramatically decreased survival in both groups, with worst survival rate in the ATR -/- group. Groups with the control treatment NC-IgG showed a better survival compared to SSc-IgG, with a slightly lower survival rate in ATR -/- group, than in the WT group. Histological analyses of lungs revealed a statistically higher T-lymphocyte infiltration in both groups with SSc-IgG than with NC-IgG. Furthermore, ATR -/- group with SSc-IgG showed a statistically higher infiltration rate than WT group with SSc-IgG.
Conclusion
These preliminary experiments demonstrate a dramatic survival reduction by treatment with SSc-IgG containing anti-AT1R and anti-ETAR autoantibodies (SSc-IgG) in both groups, ATR -/- and WT. Moreover, a major inflammation in ATR -/- and in WT mice was induced by SSc-IgG, reflected by T-lymphocyte infiltration into lung tissue. Increased inflammation in ATR -/- vs. WT group by SSc-IgG, suggests a possible ETAR-mediated inflammation in ATR -/- mice. Anti-AT1R and anti-ETAR autoantibodies react presumably in a cross-reactive way and mice deficient for angiotensin-receptors could therefore enable detailed studies of ETAR-mediated effects, providing thereby a deeper understanding of involved mechanisms. Moreover, the data demonstrate the recruitment and activation of immune cells by autoantibodies and could as a result offer deeper insight into autoantibody-mediated T-lymphocyte recruitment and reveal potential therapeutic targets for treatment of SSc.
Disclosure:
A. Kill,
Actelion Pharmaceuticals US,
2;
C. Braesch,
None;
A. Kühl,
None;
J. Guenther,
None;
M. O. Becker,
None;
G. Burmester,
AbbVie, Pfizer, UCB, Roche,
2,
AbbVie, BMS, Pfizer, Merck, MedImmune, UCB, Roche,
5,
AbbVie, BMS, Pfizer, Merck, UCB, Roche,
8;
T. Walther,
None;
G. Riemekasten,
Actelion Pharmaceuticals US,
2,
CellTrend,
5.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/functional-autoantibodies-from-patients-with-systemic-sclerosis-reactive-to-angiotensin-ii-type-1-and-endothelin-1-type-a-receptor-induce-inflammatory-lymphocyte-infiltration-into-lungs-of-m/