Lupus Panniculitis Immunoprofiling Reveals a Cytotoxic, Type 1-Skewed T-Cell Response With Signs of Metabolic...

Lupus panniculitis (LP) is a neglected, often treatment-refractory subtype of cutaneous lupus erythematosus. It is characterized by inflammation of subcutaneous adipose tissue, and the pathomechanisms are poorly understood. We sought to explore the cellular and molecular signatures of LP and their relationship to systemic lupus erythematosus. We performed imaging mass cytometry (IMC; LP n = 8, Healthy Control (HC) n = 6) and targeted transcript profiling by NanoString nCounter (Human Immunology Panel, 579 genes; LP n = 9, HC n = 9). LP lesions showed extensive septal leukocyte infiltration. The infiltrate consisted predominantly of T cells (48%), followed by B cells (14%) and antigen-presenting cells (APCs). T cells exhibited a cytotoxic (CD8⁺, GranzymeB⁺) and skin-homing (CLA⁺) phenotype, with upregulation of Th1 markers. They closely interacted with M1 macrophages. B cells displayed strong spatial interactions with naïve T cells. NanoString analyses revealed upregulation of T- and B-cell receptor signaling pathway genes, antigen presentation-related genes (MHC-I/II), and Th1 associated programs (STAT1/IRF1), together with activation of innate immune, complement, and pattern-recognition receptor pathways. This was paralleled by strong upregulation of IDO1, a key enzyme in tryptophan metabolism, and inversely correlated, reduced AHR expression. Our data provide new pathomechanistic insights into LP, highlighting overlaps with systemic lupus, but also LP-specific features. This may pave the way for adopting more targeted treatment approaches for LP.