Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Area of Science:

• Immunology
• Autoimmunity
• Dermatology

Background:

• LL37 plays a dual role in psoriasis, promoting autoreactivity via plasmacytoid dendritic cells (pDCs) and Type I interferon (IFN-I) production, and acting as an autoantigen for Th17 cells.
• In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is targeted by autoantibodies, but its role in T-cell activation in SLE remains unclear.

Purpose of the Study:

• To investigate LL37-specific T-cell responses in SLE patients.
• To compare LL37-specific T-cells in SLE with those in psoriasis.
• To explore the antigenic specificity and functional role of LL37-specific T-cells in SLE pathogenesis.

Main Methods:

• Analysis of circulating T-cells responding to LL37 in SLE patients.
• Phenotypic characterization of LL37-specific T-cells using markers like CXCR5 and Bcl-6.
• Assessment of T-follicular helper (T_FH)-like features and IL-21 expression.
• In vitro co-culture experiments with B-cells to evaluate antibody production.
• Detection of citrullinated LL37 (cit-LL37) in SLE tissues and assessment of T-cell reactivity to cit-LL37.

Main Results:

• 45% of SLE patients exhibited circulating T-cells strongly reactive to LL37, correlating with anti-LL37 antibodies and disease activity.
• LL37-specific T-cells in SLE displayed a T_FH-like phenotype (CXCR5/Bcl-6, IL-21), unlike psoriatic Th17 cells.
• SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro.
• Abundant cit-LL37 was found in SLE tissues, and SLE T-cells showed significantly higher reactivity to cit-LL37 compared to native LL37.
• Psoriatic T-cells showed much less reactivity to cit-LL37.

Conclusions:

• LL37-specific T-cells in SLE have a distinct T_FH-like functional specialization and target citrullinated LL37.
• These findings implicate LL37-specific T-cells in the stimulation of pathogenic autoantibodies in SLE.
• Autoantigen specificity may be independent of the autoantigen itself, but rather driven by disease-specific environments that promote T-cell polarization and autoantigen modification.