Antibody inhibitors of the interleukin-6 (IL-6) signaling pathway, such as tocilizumab and sarilumab, have been used to treat rheumatoid arthritis, chimeric antigen receptor T cell-induced cytokine storm, and severe COVID-19 pneumonia. Here, we solve the cryogenic electron microscopy structures of sarilumab and tocilizumab in complex with IL-6R to resolutions of 3.2 and 3.3 Å, respectively. These structures reveal that both tocilizumab and sarilumab bind to the D3 domain of IL-6R. The binding surfaces of the two antibodies largely overlap, but the detailed interactions are different. Functional studies of various mutants show results consistent with our structural analysis of the antibodies and IL-6R interactions. Structural comparisons with the IL-6/IL-6R/gp130 complex indicate that sarilumab and tocilizumab probably inhibit IL-6/IL-6R signaling by competing for the IL-6 binding site. In summary, this work reveals the antibody-blocking mechanism of the IL-6 signaling pathway and paves the way for future antibody discovery.

There has been intense debate on the mechanism of crustal recycling in subduction zones, and Fe–Mg isotopes may provide new constraints on this issue. This study reports Fe–Mg isotope data for mafic plutonic rocks from the eastern and central Gangdese arc, along with their associated trench sediments in southern Tibet. The δ²⁶Mg values of the eastern Gangdese arc rocks show negative correlations with (⁸⁷Sr/⁸⁶Sr)_i and (²⁰⁶Pb/²⁰⁴Pb)_i values, but positive correlations with ε_Nd(t) and ε_Hf(t) values. Conversely, the δ⁵⁶Fe values of the eastern Gangdese arc rocks show positive correlations with (⁸⁷Sr/⁸⁶Sr)_i and (²⁰⁶Pb/²⁰⁴Pb)_i values, but negative correlations with ε_Nd(t) and ε_Hf(t) values. The Mg and Fe isotopic compositions of the central Gangdese arc rocks are comparable with those of the eastern ones, but they do not correlate with Sr–Pb–Nd–Hf isotopic compositions. Notably, the Fe–Mg isotopic compositions of most arc rocks fall between those of local trench sediments and the mantle wedge. Combined qualitative analyses and quantitative simulations suggest that: (a) the Fe–Mg isotope variations observed in the eastern Gangdese arc rocks highlight the important role of source mixing between sediment‐derived melts and peridotite, whereas (b) the Fe–Mg isotope variations observed in the central Gangdese arc rocks reflect the superposition of carbonated serpentinite‐derived Mg‐rich fluids‐peridotite source mixing and source melting. The strong correlations between Fe–Mg isotope ratios and traditional geochemical tracers provide further evidence for the recycling of crustal materials in subduction zones via various types of slab‐derived fluids and melts.

Granitoids at convergent plate boundaries can be produced either by partial melting of crustal rocks (either continental or oceanic) or by fractional crystallization of mantle-derived mafic magmas. Whereas granitoid formation through partial melting of the continental crust results in reworking of the pre-existing continental crust, granitoid formation through either partial melting of the oceanic crust or fractional crystallization of the mafic magmas leads to growth of the continental crust. This category is primarily based on the radiogenic Nd isotope compositions of crustal rocks; positive ε_Nd(t) values indicate juvenile crust whereas negative ε_Nd(t) values indicate ancient crust. Positive ε_Nd(t) values are common for syn-collisional granitoids in southern Tibet, which leads to the hypothesis that continental collision zones are important sites for the net growth of continental crust. This hypothesis is examined through an integrated study of in situ zircon U-Pb ages and Hf isotopes, whole-rock major trace elements, and Sr-Nd-Hf isotopes as well as mineral O isotopes for felsic igneous rocks of Eocene ages from the Gangdese orogen in southern Tibet. The results show that these rocks can be divided into two groups according to their emplacement ages and geochemical features. The first group is less granitic with lower SiO₂ contents of 59.82−64.41 wt%, and it was emplaced at 50−48 Ma in the early Eocene. The second group is more granitic with higher SiO₂ contents of 63.93−68.81 wt%, and it was emplaced at 42 Ma in the late Eocene. The early Eocene granitoids exhibit relatively depleted whole-rock Sr-Nd-Hf isotope compositions with low (⁸⁷Sr/⁸⁶Sr)_i ratios of 0.7044−0.7048, positive ε_Nd(t) values of 0.6−3.9, ε_Hf(t) values of 6.5−10.5, zircon ε_Hf(t) values of 1.6−12.1, and zircon δ¹⁸O values of 5.28−6.26‰. These isotopic characteristics are quite similar to those of Late Cretaceous mafic arc igneous rocks in the Gangdese orogen, which indicates their derivation from partial melting of the juvenile mafic arc crust. In comparison, the late Eocene granitoids have relatively lower MgO, Fe₂O₃, Al₂O₃, and heavy rare earth element (HREE) contents but higher K₂O, Rb, Sr, Th, U, Pb contents, Sr/Y, and (La/Yb)_N ratios. They also exhibit more enriched whole-rock Sr-Nd-Hf isotope compositions with high (⁸⁷Sr/⁸⁶Sr)_i ratios of 0.7070−0.7085, negative ε_Nd(t) values of −5.2 to −3.9 and neutral ε_Hf(t) values of 0.9−2.3, and relatively lower zircon ε_Hf(t) values of −2.8−8.0 and slightly higher zircon δ¹⁸O values of 6.25−6.68‰. An integrated interpretation of these geochemical features is that both the juvenile arc crust and the ancient continental crust partially melted to produce the late Eocene granitoids. In this regard, the compositional evolution of syn-collisional granitoids from the early to late Eocene indicates a temporal change of their magma sources from the complete juvenile arc crust to a mixture of the juvenile and ancient crust. In either case, the syn-collisional granitoids in the Gangdese orogen are the reworking products of the pre-existing continental crust. Therefore, they do not contribute to crustal growth in the continental collision zone.

Compositions of island arc and back-arc basin basalts are often used to trace the recycling of subducted materials. However, the contribution of subducted components to the mantle source during initial arc rifting before back-arc basin spreading is not yet well constrained. The northernmost Mariana arc is ideal for studying this because the transition from rifting to back-arc spreading is happening here. Here we report major and trace element and Pb isotopic compositions of olivine-hosted melt inclusions from lavas erupted during initial rifting at 24°N (NSP-24) and compare them with those in active arc front at 21°N and mature back-arc basin at 18°N. NSP-24 high-K melt inclusions have highly radiogenic Pb compositions and are close to those of the HIMU end-member, suggesting the presence of this component in the magma source. The HIMU-like component may be stored in the over-riding plate and released into arc magma with rifting. HIMU-type seamounts may be subducted elsewhere beneath the Mariana arc, but obvious HIMU-type components appear only in the initial stages of arc rifting due to the low melting degree and being consumed during the process of back-arc spreading.