August 30, 2022

A new mechanism for lupus

Vanderbilt researchers describe a new mechanism for the most common form of lupus and suggest a new treatment approach to this autoimmune disease.

Systemic lupus erythematosus (SLE) — the most common form of lupus — is an autoimmune disease that causes widespread inflammation and tissue damage. David Harrison, MD, and colleagues have now described a new mechanism responsible for SLE. 

They found that in humans with SLE and in two mouse models, isoLG-adducts (reactive molecules called isolevuglandins bound to proteins) accumulate in antigen-presenting immune cells, and autoantibodies form against these adducts. In addition, isoLGs bind to a transcription factor and reduce expression of C1q, part of the complement system, which is associated with SLE. Treatment of SLE-prone mice with a specific isoLG scavenger (2-HOBA) reduced multiple parameters of autoimmunity, lowered blood pressure, attenuated kidney injury and reduced inflammatory gene expression. 

The findings, reported in JCI Insight, demonstrate that isoLG-adducts play an essential role in generating and maintaining systemic autoimmunity and hypertension in SLE and suggest that scavenging isoLGs with molecules such as 2-HOBA may be a useful treatment approach.

Other authors of the study include first author David Patrick, MD, PhD, Néstor de la Visitación, PhD, Jaya Krishnan, Wei Chen, MD, PhD, Michelle Ormseth, MD, MSCI, C. Michael Stein, MD, Sean Davies, PhD, Venkataraman Amarnath, PhD, Leslie Crofford, MD, Jonathan Williams, PhD, Shilin Zhao, PhD, Charles Smart, Sergey Dikalov, PhD, Anna Dikalova, PhD, Liang Xiao, Justin Van Beusecum, PhD, Mingfang Ao, Agnes Fogo, MD, and Annet Kirabo, DVM, MSc, PhD. 

The research was supported by the National Institutes of Health (grants HL130497, HL140016, HL129941, HL134895, GM007569, HL144050, HL153789, HL151069), Department of Veterans Affairs, American Heart Association, and Kleberg Foundation.