Session Title: Innate Immunity and Rheumatic Disease
Session Type: Abstract Submissions (ACR)
Background/Purpose: The complement system, a major component of innate immunity, likely plays an important role in the pathogenesis of rheumatoid arthritis (RA). Factor H (fH) is an endogenous regulator of the alternative pathway (AP) that binds surface polyanions in combination with the C3-derived fragments C3b and C3d initially through its carboxy-terminal domain containing short consensus repeats (SCR) 19-20, thereby inhibiting both AP activation and engagement of the AP amplification loop. We have shown that the AP is uniquely both necessary and sufficient for the development of collagen antibody-induced arthritis (CAIA) in mice. However, the mechanisms whereby normal control of the AP is overcome and injury develops are unknown. The hypothesis pursued in the current studies is that fH plays a critical role in regulating the AP in immune complex-initiated injury in CAIA. We have examined the role of fH in CAIA by inhibiting its binding to tissues through administration of a recombinant dominant negative inhibitor containing murine SCR19-20 (rfH19-20), which impairs fH surface AP regulation, and the use of gene-targeted fH deficient mice.
Methods: CAIA was induced in C57BL/6 WT, fH-/- and fH+/- mice by injecting four anti-type II collagen (CII) mAbs i.p. on day 0 and lipopolysaccharide (LPS) i.p. on day 3. Intraperitoneal injections of 100 and 300 μg/mouse of rfH19-20 were carried out 15 min after the injection of mAb to CII on day 0 and again 15 min after LPS on day 3. Blood was drawn intraorbitally from all mice at day 0 prior to injection of mAb to CII, at day 3 prior to LPS injection, and at day 10 prior to sacrifice. All mice were sacrificed on day 10 for histopathologic scoring of injury and immunohistochemical analysis of C3 deposition. Control experiments were performed using rfH3-5 which does not inhibit fH binding to tissues. The absolute levels of C3, fH and C5a in serum of mice were measured by ELISA.
Results: Both doses of rfH19-20 significantly increased the clinical disease activity score (DAS) using a sub-maximal dose (0.5 mg/mouse) of anti-CII mAbs. Scores for histopathologic injury and C3 deposition on the surface of the cartilage and in the synovium increased with treatment in an identical fashion. No significant differences in the DAS were observed when WT mice were treated with 300 µg/mouse of control rfH3-5. fH-/- mice, compared with WT mice, were resistant to CAIA due to the significantly reduced serum levels of C3. WT and fH+/- mice have identical serum levels of C3, but fH+/- mice have ~30% reduced levels of fH. WT and fH+/- mice developed indistinguishable DAS using a sub-maximal dose as well as a maximum dose (8 mg) of anti-CII mAb. In addition, though, the DAS at day 10 in fH+/- mice treated with 300 µg/mouse of rfH19-20 increased to 5.5 ± 0.65 compared with untreated fH+/- mice which was 1.75 ± 0.25 (p < 0.05).
Conclusion: We show for the first time that endogenous fH makes a significant contribution to regulating immune complex-induced injury in CAIA through binding to target surfaces via SCR19-20 and blocking AP activation and amplification.
N. K. Banda,
V. P. Ferreira,
M. K. Pangburn,
Complement Technology Inc,
W. P. Arend,
V. M. Holers,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/endogenous-complement-factor-h-plays-an-important-role-in-controlling-immune-complex-induced-inflammatory-arthritis/