Impaired Interleukin‐27–Mediated Control of <scp>CD</scp>4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome

Madej

et al. 2021

JCM

The upregulation of IFN pathways and their stimulated genes is associated with primary Sjögren’s syndrome (pSS). The recent studies also indicate the involvement of interferon γ (IFNγ) in the pathogenesis of pSS. The study aimed to assess the clinical and immunological activity depending on the concentration of IFNγ in the peripheral blood in pSS patients. Methods: The study group consisted of patients over 18 years of age with a confirmed diagnosis of pSS. Based on the collected data, disease activity was assessed using the EULAR Sjögren’s syndrome disease activity index (ESSDAI) and the EULAR Sjögren’s syndrome patient reported index (ESSPRI). Results: Among 40 pSS patients, 33 (82%) showed increased levels of IFNγ. The group with positive IFNγ was younger (43 years) than the group with negative IFNγ (57 years) (p < 0.05). In the positive IFNγ group, the time to diagnosis was shorter (p < 0.05). There was a difference in ESSDAI among patients with and without IFNγ (p < 0.05). There were no differences between the groups in ESSPRI and the presence of cryoglobulins, specific anti-SSA, and anti-SSB antibodies and in C3 and C4 hypocomplementemia. RF occurred in both groups with a similar frequency (p = 0.6), but in patients with IFNγ presence, significantly higher RF titers were observed (34.9 vs. 10.5; p < 0.05). Conclusion: In the group of patients with positive IFNγ, the mean value of RF and ESSDAI was higher. This group was also younger than patients with pSS without IFNγ.

Section: Discussionmentioning

confidence: 99%

The Clinical and Immunological Activity Depending on the Presence of Interferon γ in Primary Sjögren’s Syndrome—A Pilot Study

Madej

et al. 2021

JCM

“…This is exemplified by observations in rheumatoid arthritis where the pro‐inflammatory role of IL‐6 contrasts with the more nuanced contribution of IL‐27, which inhibits the formation of ectopic lymphoid structures within the inflamed synovium [93]. Similar studies in T cells emphasize the opposing functions of IL‐6 and IL‐27 in determining the effector characteristics of CD4 + T cells [92–96]. At least in part, these differences are attributable to structural and sequence differences between the cytokine receptors.…”

Section: The Complexities Linked To Jak‐stat Signallingmentioning

confidence: 96%

Making sense of IL‐6 signalling cues in pathophysiology

et al. 2021

Self Cite

Unravelling the molecular mechanisms that account for functional pleiotropy is a major challenge for researchers in cytokine biology. Cytokine–receptor cross‐reactivity and shared signalling pathways are considered primary drivers of cytokine pleiotropy. However, reports epitomized by studies of Jak‐STAT cytokine signalling identify interesting biochemical and epigenetic determinants of transcription factor regulation that affect the delivery of signal‐dependent cytokine responses. Here, a regulatory interplay between STAT transcription factors and their convergence to specific genomic enhancers support the fine‐tuning of cytokine responses controlling host immunity, functional identity, and tissue homeostasis and repair. In this review, we provide an overview of the signalling networks that shape the way cells sense and interpret cytokine cues. With an emphasis on the biology of interleukin‐6, we highlight the importance of these mechanisms to both physiological processes and pathophysiological outcomes.

Mediators of Inflammation

“…Tissue-derived factors that may regulate IL-17A expression in CD4 − and CD4 + T cell compartments include IL-27. Thus, IL-27 display an inhibitory effect on IL-17A secretion in PBMC cultures of SS patients and not RA patients or age-matched healthy donors [ 121 ]. Further, induction of experimental sialadenitis in IL-27receptor subunit alpha knockout mice aggravates the formation of ectopic lymphoid structures in SGs, as compared to wild-type mice, a finding that can be restored by IL-17A neutralization [ 121 ].…”

Section: The Role Of Il-17a In Sjögren's Syndromementioning

confidence: 99%

A Mechanistic Insight into the Pathogenic Role of Interleukin 17A in Systemic Autoimmune Diseases

Bisoendial

Lubberts

2022

Interleukin 17A (IL-17A) has been put forward as a strong ally in our fight against invading pathogens across exposed epithelial surfaces by serving an antimicrobial immunosurveillance role in these tissues to protect the barrier integrity. Amongst other mechanisms that prevent tissue injury mediated by potential microbial threats and promote restoration of epithelial homeostasis, IL-17A attracts effector cells to the site of inflammation and support the host response by driving the development of ectopic lymphoid structures. Accumulating evidence now underscores an integral role of IL-17A in driving the pathophysiology and clinical manifestations in three potentially life-threatening autoimmune diseases, namely, systemic lupus erythematosus, Sjögren’s syndrome, and systemic sclerosis. Available studies provide convincing evidence that the abundance of IL-17A in target tissues and its prime source, which is T helper 17 cells (Th17) and double negative T cells (DNT), is not an innocent bystander but in fact seems to be prerequisite for organ pathology. In this regard, IL-17A has been directly implicated in critical steps of autoimmunity. This review reports on the synergistic interactions of IL-17A with other critical determinants such as B cells, neutrophils, stromal cells, and the vasculature that promote the characteristic immunopathology of these autoimmune diseases. The summary of observations provided by this review may have empowering implications for IL-17A-based strategies to prevent clinical manifestations in a broad spectrum of autoimmune conditions.