Characterizing antigen specificities of skin-infiltrating B and plasma cells in cutaneous lupus reveals anti-nuclear and hemidesmosome-specific targets

Summary: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that causes tissue damage across multiple organ systems, including the skin. Cutaneous lupus erythematosus (CLE) can occur in the presence or absence of SLE, and patients with isolated CLE can progress to SLE. B cells are known to contribute to SLE disease initiation and progression via multiple mechanisms, yet the role of skin-infiltrating B and plasma cells in CLE pathogenesis and progression is not clear. Prior studies demonstrate CLE lesional B cells forming diffuse infiltrates or pseudofollicular structures, suggesting a role in antigen-presentation and T cell activation. Here, we interrogate the antigen specificities of B and plasma cells in CLE skin lesions to investigate the potential roles of CLE lesional B and plasma cells in disease pathogenesis. We expressed and purified recombinant IgG (rIgG) using B cell receptor (BCR) heavy and light chain sequences obtained from single-cell RNA sequencing of skin-infiltrating B and plasma cells in CLE skin lesions from 2 patients with CLE and concurrent SLE. This panel of 29 rIgG was purified and rIgG specificities were evaluated using reactivity assays including antinuclear antibody (ANA) ELISA, extractable nuclear antigen ELISA, autoantibody microarray, skin immunofluorescence, and phage immunoprecipitation-sequencing (PhIP-Seq) to identify putative antigen specificities of the B and plasma cells from CLE skin lesions. rIgG that specifically bound skin hemidesmosome proteins as well as ANA targets were identified, suggesting a potential role for skin-lesional B and plasma cells in promoting tissue damage in CLE. Alicia J. Little¹, Aster Workineh², Mackenzie Sky¹, Roy Jiang¹, Afia Kuragu¹, Arthy Suresh¹, Steven Kleinstein^{3, 4}, Caleigh Mandel-Brehm³, Kevin O'Connor^{5, 6}, Joe Craft^{7, 6} 1. Dermatology, Yale School of Medicine, New Haven, CT, United States. 2. Yale School of Medicine, New Haven, CT, United States. 3. Pathology, Yale School of Medicine, New Haven, CT, United States. 4. BIDS, Yale School of Medicine, New Haven, CT, United States. 5. Neurology, Yale School of Medicine, New Haven, CT, United States. 6. Immunobiology, Yale School of Medicine, New Haven, CT, United States. 7. Rheumatology, Yale School of Medicine, New Haven, CT, United States. Adaptive and Auto-Immunity