Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis
Johann E. Gudjonsson, Lam C. Tsoi, Feiyang Ma, Allison C. Billi, K.R. van Straalen, A.R.J.V. Vossen, H.H. van der Zee, Paul W. Harms, Rachael Wasikowski, Christine M. Yee, Syed M. Rizvi, Xianying Xing, Enze Xing, Olesya Plazyo, Chang Zeng, Matthew T. Patrick, Margaret M. Lowe, Richard E. Burney, Jeffrey H. Kozlow, Jill R. Cherry-Bukowiec, Yanyun Jiang, Joseph Kirma, Stephan Weidinger, Kelly C. Cushing, Michael D. Rosenblum, Celine Berthier, Amanda S. MacLeod, John J. Voorhees, Fei Wen, J. Michelle Kahlenberg, Emanual Maverakis, Robert L. Modlin, Errol P. Prens
Johann E. Gudjonsson, Lam C. Tsoi, Feiyang Ma, Allison C. Billi, K.R. van Straalen, A.R.J.V. Vossen, H.H. van der Zee, Paul W. Harms, Rachael Wasikowski, Christine M. Yee, Syed M. Rizvi, Xianying Xing, Enze Xing, Olesya Plazyo, Chang Zeng, Matthew T. Patrick, Margaret M. Lowe, Richard E. Burney, Jeffrey H. Kozlow, Jill R. Cherry-Bukowiec, Yanyun Jiang, Joseph Kirma, Stephan Weidinger, Kelly C. Cushing, Michael D. Rosenblum, Celine Berthier, Amanda S. MacLeod, John J. Voorhees, Fei Wen, J. Michelle Kahlenberg, Emanual Maverakis, Robert L. Modlin, Errol P. Prens
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Research Article Dermatology Immunology

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis

Abstract

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.

Authors

Johann E. Gudjonsson, Lam C. Tsoi, Feiyang Ma, Allison C. Billi, K.R. van Straalen, A.R.J.V. Vossen, H.H. van der Zee, Paul W. Harms, Rachael Wasikowski, Christine M. Yee, Syed M. Rizvi, Xianying Xing, Enze Xing, Olesya Plazyo, Chang Zeng, Matthew T. Patrick, Margaret M. Lowe, Richard E. Burney, Jeffrey H. Kozlow, Jill R. Cherry-Bukowiec, Yanyun Jiang, Joseph Kirma, Stephan Weidinger, Kelly C. Cushing, Michael D. Rosenblum, Celine Berthier, Amanda S. MacLeod, John J. Voorhees, Fei Wen, J. Michelle Kahlenberg, Emanual Maverakis, Robert L. Modlin, Errol P. Prens

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Figure 7

Increased immunoglobulin production and antibody diversity in HS skin and complement activation.

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Increased immunoglobulin production and antibody diversity in HS skin an...
Box-and-whisker plots of BCR CDR3 expressions (A). The y axis shows normalized log-transformed BCR CDR3 expression. The x axis represents patient group. In all cases there were more BCR CDR3 sequences detected in HS skin compared with control healthy skin. Box-and-whisker plots of BCR gene segment expression. The y axis shows normalized log-transformed BCR gene segment expression. The x axis represents patient group. The Shannon diversity index for BCR CDR3 gene segment is plotted on the y axis. The x axis represents patient group. HS skin had a significantly more diverse BCR repertoire (B). Beta diversity–based principal coordinates analysis (PCoA) of BCR CDR3 sequences. Sample matrix was generated using Jaccard dissimilarities, and respective profiles were compared by PCoA. Each color represents 1 patient group, HS (red) and control (blue). This analysis revealed clear separation for κ and λ light chains but not Ig heavy chain (C) Hierarchical clustering of expressed TCR V/J gene segment expression. Heatmaps by clonal abundance across sample sets. Note good separation of HS from controls based upon clonal abundances in BCR κ and λ repertoires. Components of the complement pathway (C1q) and breakdown products of activated complement components (C3b, C4d) were increased in HS skin, particularly in the deeper layers of the skin (n = 3) (scale bar: 100 μm) (D). Complement receptors, CR1 and CR2, were increased in the deeper layers of HS, along with IgG1 immune complex deposition (n = 3) (scale bar: 100 μm) (E). Immunofluorescence of B cells (CD20) and plasma cells (CD138) showed primary localization of TNF to the plasma cell population in HS skin (n = 3) (scale bar: 50 μm) (F). For A and B, the bold vertical line represents the median, and the upper and lower limits of the box represent the interquartile range (IQR). The whiskers represent 1.5× IQR.