Ectopic Germinal Centres with B and T Cells and Follicular Dendritic Cell Networks in Urethral Stricture Tissue: Possible Avenue for Immunological Treatments

Abstract

Background The underlying cause of a urethral stricture can sometimes be obscure. It is possible that an injury to the urethra induces an immunological cascade that generates scar tissue and fibrosis, eventually resulting in a stricture. If such immunological reactions could be better elucidated, immunological therapies could possibly emerge. Objective To evaluate if ectopic germinal centres exist in urethral stricture disease. Design, setting, and participants Resected stricture specimens from 45 patients undergoing open bulbar urethroplasty with excision and anastomosis were assessed. Histopathological characteristics, such as fibrosis (grade I–III), inflammation, and sclerosis, were evaluated using immunostaining for CD3 (T cells), CD20 (B cells), and CD21 (follicular dendritic cells). Outcome measurements and statistical analysis The primary outcome measure was the presence or absence of a germinal centre. The secondary outcome was evaluation of any correlation between the degree of fibrosis and germinal centres. Fisher’s exact test was used for univariate analysis. Results and limitations In six patients, ectopic germinal centres were found. In ten patients, there was no inflammation at all. There was no correlation found between the degree of fibrosis and the abundance of immunohistochemically detected immune cells. Conclusions Ectopic germinal centres, with B and T cells as well as follicular dendritic cell networks, do exist in urethral stricture disease. This finding may open up for novel research avenues on the possibility of adopting immunological treatments for urethral stricture disease. Patient summary In patients with a narrowing of the urethra due to any kind of trauma, we looked for the presence of centres of immunological reaction in urethral tissue. We identified these immunological centres (also called germinal centres) in some patients. This intriguing finding suggests that immunological treatments may have potential for men with scar tissue in a narrowed urethra.

Follicular dendritic cells

“…Transcriptomic analysis of FDCs revealed a wide range of molecules regulating the interaction between FDCs and B cells and the immune response (Rana et al, 2021). These include ICAM-1, VCAM-1, Aloisi & Pujol-Borrell, 2006;Ekerhult et al, 2021;Mak et al, 2014a;Tumanov et al, 2004;Ware, 2005). Animals lacking these cytokines fail to develop FDCs and fail to establish B cell follicles with subsequent disorganization of the secondary lymphoid organs (Cerny et al, 1988;Victoratos et al, 2006).…”

“…This allows FDCs to capture soluble antigens drained from the subcapsular sinuses and provides a protected environment in which antigens can be retained by FDCs for long periods without being captured by phagocytic cells (Bajenoff & Germain, 2009; Chaplin & Zindl, 2006; Kranich & Krautler, 2016). Therefore, FDCs form an interactive reticulum of immobile antigen‐retaining cells which engage the mobile T and B cells and other mobile cells trafficking through the follicles (Ekerhult et al, 2021; Szakal et al, 1983; Young & Brink, 2021). The circulation of B cells between the follicles and the marginal zone (Pikor & Mörbe, 2020) allows interaction between the antigens trapped on FDCs and marginal zone B cells (Cinamon et al, 2008; Turner & Mabbott, 2017).…”

“…FDCs have a crucial role in compartmentalizing lymphoid follicles; ablation of FDCs abolishes the characteristic lymphoid follicle architecture (Asano et al, 2004; De Togni et al, 1994; Ekerhult et al, 2021; Hanayama et al, 2002; Le Hir et al, 1995, 1996; Pasparakis et al, 1996; Rana et al, 2021). Interaction of B cells and FDCs is crucial for the generation of the characteristic follicular structures as discussed above.…”

“…In Vivo Labeling of FDCs and imaging analysis using immunofluorescent, confocal, two-photon, and multiphoton microscopes and imaging software(Anania et al, 2021;Reinhardt, 2018) allowed tissue imaging with tracking various cell types in the intact tissues over time.This allows analysis of the cell motility and their interactions with FDC networks in GCs. Subsequently, various studies have been performed using multiphoton microscopy to investigate the cellular dynamics and interactions of GC B cells, T follicular helper cells (Tfh), and FDC(Anania et al, 2021;Ekerhult et al, 2021;Heesters & van Megesen, 2021). Thus, in vivo detection of GC cells provided a better understanding of the role of FDCs in GC immune responses.8 | MORPHOLOGICAL DESCRIPTION OF FDCs 8.1 | Light microscopy…”

“…FDCs activation by TLR ligand enhances antibody responses and GC reaction indicating that FDC activation is needed for T cell costimulation(El Shikh et al, 2007;Kranich et al, 2008). Furthermore, stimulation of FDCs in the Peyer's patch by bacterial products in the gut are mediated by TLR ligands and is associated with induction of FDC-CXCL13, FDC-BAFF, and FDC-TGF-β1 secretion and enhances immunoglobulin production(Akkaya et al, 2020;Das et al, 2017;Heesters & van Megesen, 2021;Hughes et al, 2016;Rana et al, 2021;Young & Brink, 2021).11 | THE PHYSIOLOGICAL ROLES OF FDCs IN IMMUNITY 11.1 | Organization and maintenance of the lymphoid follicle histoarchitecture FDCs have a crucial role in compartmentalizing lymphoid follicles; ablation of FDCs abolishes the characteristic lymphoid follicle architecture(Asano et al, 2004;De Togni et al, 1994;Ekerhult et al, 2021;Hanayama et al, 2002;Le Hir et al, 1995Pasparakis et al, 1996;Rana et al, 2021). Interaction of B cells and FDCs is crucial for the generation of the characteristic follicular structures as discussed above.…”