A study published in the journal Cornea provides new evidence that the pro-inflammatory cytokine interleukin-21 (IL-21) may contribute to the development and severity of Sjögren’s syndrome.
Primary Sjögren’s syndrome (pSS) is an autoimmune disease causing dry eyes and dry mouth, and featuring mononuclear and plasma cell infiltration in the salivary and lacrimal glands.
Recent research indicates that this cytokine may play a significant role in the pathogenesis of Sjögren syndrome through effects on interferon signaling, and the stimulation of IL-17 helper T cells (Th17) and plasma-cell differentiation or B cell hyperactivity (SK Kwok et al., Nat Rev Rheumatol. 2015 Jan 13. doi: 10.1038/nrrheum.2014, 225; FG Kroese et al., Expert Rev Clin Immunol, 2014, 4:483).
In the Cornea publication, Lim SA and colleagues from the Catholic University of Korea, Seoul, Korea, report the presence of increased tear interleukin-21 levels and higher IL-21 gene expression in the conjunctiva of patients with Sjögren syndrome. Importantly, the tear level of this cytokine correlated with markers of disease activity in these patients.
Currently, there is no definitive treatment for Sjogren’s syndrome, and therapies are basically symptomatic (R Hal Scofield, 2011). It is known that interleukin-21 is involved in the differentiation of Th17 cells that are major players in autoimmunity. Thus, taking into consideration previous reports implicating the involvement of of this cytokine, the study may suggests new therapeutic developments directed at the underlying pathophysiology of Sjogren’s syndrome.
A 2016 study, report elevated interleukin-21 expression of invariant natural killer T (iNKT) cells, which, along with the increased IL-21R expression of B cells, may contribute to the enhanced B cell activation in in Sjögren’s syndrome (SS). Interestingly, B cells expressing enhanced IL-21R on surface were typically positive for surface antigen CD5. Of note, significant increase in expression of IL-21R was found only in the group of extraglandular manifestations (EGMs), compared to the control values.
In a 2020 study, Elena Pontarini et al. identify T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph), interleukin-21 and the inducible T-cell costimulator (ICOS) pathway as major pathogenic players in Sjögren’s syndrome (SS) immunopathology.
Of note, T-follicular-helper (Tfh) and recently described pathogenic peripheral-helper T-cells (Tph) are key mediators in (autoreactive) B-cell differentiation through inducible T-cell costimulator (ICOS)-ICOS-L interaction and interleukin-21 production.
T follicular helper cells (Tfh) are a specialized subset of CD4+ T cells that were first identified in the human tonsil. They play a critical role in protective immunity helping B cells produce antibody against foreign pathogens. Tfh are located in secondary lymphoid organs (SLOs), including the tonsil, spleen and lymph nodes.
Recent work indicate the presence of alternative interleukin-21-producing Tfh-like cells (also designated ‘pathogenic T peripheral helper cells (Tph)’) that are able to localise at inflammatory sites.
The authors report a Tfh-cell signature, interleukin-21 and the ICOS-costimulatory pathway as the most upregulated gene clusters and that IL-21 mRNA was highly upregulated in SG with ectopic germinal centres (GC) and lesional Tfh-like cells. Of both Tfh and Tph-like cells in parotid MALT-L and ELS+ SG displayed heterogeneity in cytokine production with expanded populations of single interleukin-21, single interferon (IFN)-γ and double IL-21/IFN-γ producers.
A 2021 study by Jose Loureiro-Amigo identify CXCL13, BAFF, interleukin-21 (IL-21), and IL-22 as potential biomarkers of primary Sjögren’s syndrome (pSS) activity, reporting that IL-21 and IL-22 are associated with disturbances of lymphocyte subpopulations in pSS. As per these authors, the combination of serum CXCL13, BAFF, and PD-L2 levels allows discrimination between pSS and Sicca syndrome.
Another 2021 study by Xiaomin Chen et al. report that the expression of the interleukin-21-inducible genes (IL-21, IL-21R, JAK3, STAT1, HLA-B, CCR7 and CXCL10), the so-called IL-21 signature genes, was significantly increased in pSS patients. Importantly, these authors identify a strong correlation between IL-21-relevant genes and IFN signature genes. Thus IL-21 signalling is also associated with the IFN signature.
A third 2021 study included ninety‐nine pSS patients, diagnosed by the 2016 ACR/EULAR classification criteria, and cytokine quantification was performed by Multiplex assay. This study reports higher IFN‐γ, IL‐17F, IL‐21, IL‐23, IL‐4, and IL‐31 levels in pSS patients.
Of the Th2 cytokines that showed results not previously reported in pSS are the IL‐25 and IL‐31. IL‐25 has been only reported in pSS at the local level: high mRNA expression in LSG biopsy, and it had been related to inducing type 2 innate lymphoid cells. Regarding the Th17 profile, a high concentration of IL‐17F was observed. On the other hand, IL‐21 and IL‐23 are not widely studied, but the results about IL-21 correlate with the studies mentioned above.