Comments for:
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
Response letter to: Contribution of plasma cells and B-cells to hidradenitis suppurativa pathogenesis
Submitter: Roisin Hambly | roisin.hambly@ucd.ie
Authors: Roisin Hambly, Solene Gatault, Barry Moran, Anna Malara, Sean Kearns, Conor M Smith, Walter Kolch, Jean M Fletcher, Brian Kirby
University College Dublin, Ireland
Published October 2, 2020
To the editor,
We read with interest the research by Gudjonsson et al1 which reported B cells and plasma cells, and their associated increases in immunoglobulin production and complement activation, as key players in the pathogenesis of hidradenitis suppurativa (HS). Genes associated with B cell responses were the most upregulated genes in bulk RNA-sequencing (RNA-Seq) of HS lesional skin compared with matching control skin. Genes associated with immunoglobulin biosynthesis were increased in HS skin and blood. When HS skin was compared to psoriasis and atopic dermatitis, bulk RNA-Seq identified B cells in the top 3 cell signatures for HS. Interactions between B cells and plasma cells and other immune cell components were identified through single cell RNA-Seq of HS skin. CyTOF imaging identified plasma cells and B cells as the main infiltrating leukocyte population in HS. They also identified that TNFα was localized to CD138+ plasma cells. These findings may have translational implications for the treatment of HS, which has only one licensed treatment, adalimumab (anti-TNFα), effective in approximately 50% of patients.2
When findings such as this are identified through novel techniques such as RNA-Seq and CyTOF imaging, it is important to corroborate using other established laboratory techniques. B cells have been suggested to play a role in the pathogenesis of HS following identification using immunostaining and histology. 3-6 Abundant expression of immunoglobulin genes have been reported in the HS skin transcriptome.7, 8 Our research group identified a significant increase in the number of CD20+ B cells and CD138+ plasma cells in HS lesional skin compared with uninvolved HS skin using immunohistochemistry.9 We examined mRNA expression levels of B cell transcription factors and observed an increased expression of plasma cell-associated genes in HS lesions.9 Using flow cytometry we demonstrated a significant increase in the frequency of switched memory B cells, plasma cells and plasmablasts between HS and healthy control PBMC, as well as a significantly increased frequency and overall number of CD19+ B cells in HS lesional skin compared with healthy controls.9 Increased circulating plasma cells have also been identified in HS patients.6 Anti-TNFα has been reported to significantly attenuate B cell activation following RNA-Seq analysis.10 Rituximab (anti-CD20) demonstrated anti-inflammatory effects in HS explant cultures11, and there is one case report showing successful treatment of HS with rituximab.5 Taken together, this information represents an exciting avenue for further exploration of B cells and plasma cells as therapeutic targets for HS.
Authors: Roisin Hambly,1,2 Solene Gatault,3,4 Barry Moran,5 Anna Malara,6 Sean Kearns,6 Conor M Smith,5 Walter Kolch,3,7 Jean M Fletcher,5,8 Brian Kirby.1,2,4
Affiliations:
1. The Charles Centre, Department of Dermatology, St Vincent’s University Hospital, Elm Park, Dublin 4.
2. University College Dublin School of Medicine and Medical Sciences, Dublin.
3. Systems Biology Ireland, School of Medicine, University College Dublin, Dublin.
4. Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin.
5. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin.
6. Clinical Research Centre, St Vincent’s University Hospital, Dublin.
7. Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4.
8. School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Conflict of interest
BK has acted as consultant for MSD, Janssen, Abbvie, Celgene, Almirall, Lilly, Leo, Pfizer and UCB; received unrestricted research grants from MSD, Pfizer, Abbvie and Janssen and progressed clinical trials sponsored by Abbvie, MSD, Janssen and UCB.
Acknowledgments
RH is currently supported by an academic training grant under the Irish Clinical Academic Training Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z)
References:
1. Gudjonsson JE, Tsoi LC, Ma F, Billi AC, Van Straalen KR, Vossen ARJV, et al. Contribution of plasma cells and B-cells to hidradenitis suppurativa pathogenesis. JCI Insight. 2020.
2. Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa. N Engl J Med. 2016;375:422-34.
3. van der Zee HH, de Ruiter L, Boer J, van den Broecke DG, den Hollander JC, Laman JD, et al. Alterations in leucocyte subsets and histomorphology in normal-appearing perilesional skin and early and chronic hidradenitis suppurativa lesions. Br J Dermatol. 2012;166:98-106.
4. van der Zee HH, Laman JD, de Ruiter L, Dik WA, Prens EP. Adalimumab (antitumour necrosis factor-alpha) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study. Br J Dermatol. 2012;166:298-305.
5. Takahashi K, Yanagi T, Kitamura S, Hata H, Imafuku K, Iwami D, et al. Successful treatment of hidradenitis suppurativa with rituximab for a patient with idiopathic carpotarsal osteolysis and chronic active antibody-mediated rejection. J Dermatol. 2018;45:e116-e7.
6. Byrd AS, Carmona-Rivera C, O'Neil LJ, Carlucci PM, Cisar C, Rosenberg AZ, et al. Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa. Sci Transl Med. 2019;11.
7. Blok JL, Li K, Brodmerkel C, Jonkman MF, Horvath B. Gene expression profiling of skin and blood in hidradenitis suppurativa. Br J Dermatol. 2016;174:1392-4.
8. Hoffman LK, Tomalin LE, Schultz G, Howell MD, Anandasabapathy N, Alavi A, et al. Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature. PLoS One. 2018;13:e0203672.
9. Musilova J, Moran B, Sweeney CM, Malara A, Zaborowski A, Hughes R, et al. Enrichment of Plasma Cells in the Peripheral Blood and Skin of Patients with Hidradenitis Suppurativa. J Invest Dermatol. 2020;140:1091-4 e2.
10. Lowe MM, Naik HB, Clancy S, Pauli M, Smith KM, Bi Y, et al. Immunopathogenesis of hidradenitis suppurativa and response to anti-TNFα therapy. JCI Insight. 2020.
11. Vossen A, Ardon CB, van der Zee HH, Lubberts E, Prens EP. The anti-inflammatory potency of biologics targeting TNF-alpha, IL-17A, IL-12/23 and CD20 in hidradenitis suppurativa: an ex vivo study. Br J Dermatol. 2019.
