AUTHOR=Munroe Melissa E. , Young Kendra A. , Guthridge Joel M. , Kamen Diane L. , Gilkeson Gary S. , Weisman Michael H. , Ishimori Mariko L. , Wallace Daniel J. , Karp David R. , Harley John B. , Norris Jill M. , James Judith A. 

TITLE=Pre-Clinical Autoimmunity in Lupus Relatives: Self-Reported Questionnaires and Immune Dysregulation Distinguish Relatives Who Develop Incomplete or Classified Lupus From Clinically Unaffected Relatives and Unaffected, Unrelated Individuals

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.866181

DOI=10.3389/fimmu.2022.866181

ISSN=1664-3224

ABSTRACT=<p>Systemic lupus erythematosus (SLE) is propelled by pathogenic autoantibody (AutoAb) and immune pathway dysregulation. Identifying populations at risk of reaching classified SLE is essential to curtail inflammatory damage. Lupus blood relatives (Rel) have an increased risk of developing SLE. We tested factors to identify Rel at risk of developing incomplete lupus (ILE) or classified SLE vs. clinically unaffected Rel and healthy controls (HC), drawing from two unique, well characterized lupus cohorts, the lupus autoimmunity in relatives (LAUREL) follow-up cohort, consisting of Rel meeting &lt;4 ACR criteria at baseline, and the Lupus Family Registry and Repository (LFRR), made up of SLE patients, lupus Rel, and HC. Medical record review determined ACR SLE classification criteria; study participants completed the SLE portion of the connective tissue disease questionnaire (SLE-CSQ), type 2 symptom questions, and provided samples for assessment of serum SLE-associated AutoAb specificities and 52 plasma immune mediators. Elevated SLE-CSQ scores were associated with type 2 symptoms, ACR scores, and serology in both cohorts. Fatigue at BL was associated with transition to classified SLE in the LAUREL cohort (<italic>p≤0.01</italic>). Increased levels of BLyS and decreased levels of IL-10 were associated with type 2 symptoms (p<italic>&lt;0.05</italic>). SLE-CSQ scores, ACR scores, and accumulated AutoAb specificities correlated with levels of multiple inflammatory immune mediators (<italic>p&lt;0.05</italic>), including BLyS, IL-2Rα, stem cell factor (SCF), soluble TNF receptors, and Th-1 type mediators and chemokines. Transition to SLE was associated with increased levels of SCF (<italic>p&lt;0.05</italic>). ILE Rel also had increased levels of TNF-α and IFN-γ, offset by increased levels of regulatory IL-10 and TGF-β (<italic>p&lt;0.05</italic>). Clinically unaffected Rel (vs. HC) had higher SLE-CSQ scores (<italic>p&lt;0.001</italic>), increased serology (<italic>p&lt;0.05</italic>), and increased inflammatory mediator levels, offset by increased IL-10 and TGF-β (<italic>p&lt;0.01</italic>). These findings suggest that Rel at highest risk of transitioning to classified SLE have increased inflammation coupled with decreased regulatory mediators. In contrast, clinically unaffected Rel and Rel with ILE demonstrate increased inflammation offset with increased immune regulation, intimating a window of opportunity for early intervention and enrollment in prevention trials.</p>