Session Type: Abstract Submissions (ACR)
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.
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.
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.
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.
Actelion Pharmaceuticals US,
M. O. Becker,
AbbVie, Pfizer, UCB, Roche,
AbbVie, BMS, Pfizer, Merck, MedImmune, UCB, Roche,
AbbVie, BMS, Pfizer, Merck, UCB, Roche,
Actelion Pharmaceuticals US,
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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/