Study in focus 1:  Combination of Two Monoclonal Anti–Citrullinated Protein Antibodies Induced Tenosynovitis, Pain, and Bone Loss in Mice in a Peptidyl Arginine Deiminase‐4–Dependent Manner

The link between the PADI-4 enzyme and ACPA has always aroused curiosity on how infectious agents induce autoimmunity in RA. Krishnamurthy and colleagues used two monoclonal anti-citrulinated anti-peptic ACPAs, C03 (targeting osteoclasts) and B09 (targeting synovial fibroblasts) cloned from synovial plasma cells of an RA patient. This reacted with citrullinated, and other post-translationally modified proteins in both wild-type and PAD4-deficient mice. With the infusion of monoclonal ACPAs, the mice developed increased sensitivity to mechanical stimuli, osteo-architectural disturbance, subclinical synovitis with tendon sheath enhancements on MRI and focal cell infiltrations on histopathology. This study demonstrated that tenosynovitis in ACPA positive individuals appears shortly before macroscopic arthritis and can contribute to pain and bone loss. This research paves the way for further studies to intervene therapeutically at the stage of ACPA-induced tenosynovitis and pain.

Study in focus 2: Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus

Immunometabolism is a major determinant of how SLE behaves. Currently, we do not have direct methods to target immunometabolism. The work by Voss and colleagues provide an outlook on how iron metabolism can be targeted therapeutically in lupus. Voss and colleagues explored the role of transferrin receptor in T cell dysfunction in SLE. Using a CRISPR screen of genes handling iron on T cells, transferrin receptor (CD71) was identified as critical for TH1 and inhibitory for induced Treg (iTreg). CD71 and iron uptake was enhanced in SLE-prone T cells. Blocking this led to reduced intracellular iron and mTORC1 signaling, inhibiting TH1 and TH17 and enhancing iTregs and clinically renal parameters improved. These findings suggest that T cell iron uptake can be a novel therapeutic target in SLE.

References:

1. Krishnamurthy A, Circiumaru A, Sun J, Kisten Y, Damberg P, Sakuraba K, et al. Combination of Two Monoclonal Anti–Citrullinated Protein Antibodies Induced Tenosynovitis, Pain, and Bone Loss in Mice in a Peptidyl Arginine Deiminase‐4–Dependent Manner. Arthritis Rheumatol. 2023 Feb;75(2):164–70.
2. Voss K, Sewell AE, Krystofiak ES, Gibson-Corley KN, Young AC, Basham JH, et al. Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus. Sci Immunol. 2023 Jan 20;8(79):eabq0178.