Tertiary lymphoid structures sustain cutaneous B cell activity in hidradenitis suppurativa
Margaret M. Lowe, Jarish N. Cohen, Madison I. Moss, Sean Clancy, James P. Adler, Ashley E. Yates, Haley B. Naik, Rashi Yadav, Mariela Pauli, Ian Taylor, Austin McKay, Hobart Harris, Esther Kim, Scott L. Hansen, Michael D. Rosenblum, Joshua M. Moreau
Margaret M. Lowe, Jarish N. Cohen, Madison I. Moss, Sean Clancy, James P. Adler, Ashley E. Yates, Haley B. Naik, Rashi Yadav, Mariela Pauli, Ian Taylor, Austin McKay, Hobart Harris, Esther Kim, Scott L. Hansen, Michael D. Rosenblum, Joshua M. Moreau
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Research Article Dermatology Immunology

Tertiary lymphoid structures sustain cutaneous B cell activity in hidradenitis suppurativa

Abstract

Hidradenitis suppurativa (HS) is a chronic skin condition affecting approximately 1% of the US population. HS skin lesions are highly inflammatory and characterized by a large immune infiltrate. While B cells and plasma cells comprise a major component of this immune milieu, the biology and the contribution of these cells in HS pathogenesis are unclear. We aimed to investigate the dynamics and microenvironmental interactions of B cells within cutaneous HS lesions. Combining histological analysis, single-cell RNA sequencing, and spatial transcriptomics profiling of HS lesions, we defined the tissue microenvironment relative to B cell activity within this disease. Our findings identified tertiary lymphoid structures (TLSs) within HS lesions and described organized interactions among T cells, B cells, antigen-presenting cells, and skin stroma. We found evidence that B cells within HS TLSs actively underwent maturation, including participation in germinal center reactions and class switch recombination. Moreover, skin stroma and accumulating T cells were primed to support the formation of TLSs and facilitate B cell recruitment during HS. Our data definitively demonstrated the presence of TLSs in lesional HS skin and point to ongoing cutaneous B cell maturation through class switch recombination and affinity maturation during disease progression in this inflamed nonlymphoid tissue.

Authors

Margaret M. Lowe, Jarish N. Cohen, Madison I. Moss, Sean Clancy, James P. Adler, Ashley E. Yates, Haley B. Naik, Rashi Yadav, Mariela Pauli, Ian Taylor, Austin McKay, Hobart Harris, Esther Kim, Scott L. Hansen, Michael D. Rosenblum, Joshua M. Moreau

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Figure 5

CXCL13-expressing Tph are increased in HS lesional skin.

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CXCL13-expressing Tph are increased in HS lesional skin. (A) UMAPs of CD...
(A) UMAPs of CD4+ T cell scRNA-Seq clusters from 5 HS lesions and 5 normal skin samples. (B) Row-normalized heatmap depicting pseudobulk scRNA-Seq counts of significantly upregulated (padj < 0.05) genes identified as B cell interaction partners in HS CD4+ T cell clusters versus healthy skin CD4+ T cell clusters. (C) UMAPs of CD4+ T cell scRNA-Seq clusters from HS lesions and healthy skin showing expression of a Tph/Tfh gene module. (D) Top 10 significantly enriched (padj < 0.05) GSEA results of Human MSigDB Collections C2 gene signatures comparing cluster 6 cells from HS lesional skin with all other clusters. NES, normalized enrichment score. (E) Violin plots of gene expression from clusters 3, 6, and 10 from HS lesions and normal skin showing expression of select genes. Data represent samples from 5 HS donors and 5 normal skin donors. (F) Spatial feature plot depicting expression of BCL6 and CXCR5 from an HS patient lesional section with a previously identified TLS. Red box inset highlights region where a TLS gene signature is enriched. (G) Photomicrograph of CD4 (red chromogen)/BCL6 (brown chromogen) IHC on an HS skin section highlighting a TLS (left) and the epidermis (right). Scale bar = 50 μm; inset scale bar = 5 μm; ****P < 0.0001, Wilcoxon test.