A pinboard by
Alicia Derrac Soria

PhD student, Cardiff University


Using experimental models of rheumatoid arthritis in order to understand and regulate inflammation.

Inflammation, is part of the immune system's response to infection and tissue damage, and it's crucial to the healing process. When the body signals an injury, your immune system sends out an army of white blood cells to surround and protect the area. In this way, inflammation is a good thing, because it protects the body.

Chronic inflammation, however, is different. White blood cells flood the problem area and end up attacking nearby healthy tissues and organs. This often goes unnoticed until significant damage is done, and it can lead to autoimmunity.

Rheumatoid Arthritis (RA), is one of the most common forms of autoimmune disease, affecting ~ 1% of the global adult population and causing painful stiffness, swelling and damage to the joints. Currently, approximately 40-44 % of RA patients do not respond to current frontline biologics, due, in part, to the high heterogeneity of the disease.

We know cytokines play a major role in autoimmune diseases. Cytokines allow immune cells to deliver information to each other, they bind to receptors on target cells and activate a complex cascade of intercellular signals.

My PhD focuses on testing different novel therapies that target these signalling pathways in an experimental model of inflammatory arthritis. By injecting these therapeutic substances into the inflamed joint, we are able to switch on and off the molecules responsible for this inflammation, and hopefully reduce the signs and symptoms of this condition, improve physical functioning and reduce mortality.

My long-term goal is to gain an improved understanding of the underlying inflammatory processes that drive RA progression. This understanding will lead to new and better forms of treatment for Rheumatoid Arthritis and other autoimmune diseases.


Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells.

Abstract: IL-6 responses are classically orchestrated via a membrane-bound IL-6R (CD126) alpha subunit (classical IL-6R signaling) or through a soluble form of this cognate receptor (IL-6 trans signaling). Appraisal of IL-6R expression on human and mouse T cells emphasized that IL-6R expression is closely linked with that of CCR7 and CD62L. In this regard, infiltrating effector T cells from clinical and experimental peritonitis episodes lose IL-6R expression, and anti-CD3/CD28 Ab costimulation of peripheral T cells in vitro leads to a downregulation in IL-6R expression. Consequently, IL-6 signaling through membrane-bound IL-6R seems to be limited to naive or central memory T cell populations. Loss of IL-6R expression by activated T cells further suggests that these effector cells might still retain IL-6 responsiveness via IL-6 trans signaling. Using IL-6R-deficient mice and recombinant tools that modulate the capacity of IL-6 to signal via its soluble receptor, we report that local control of IL-6 trans signaling regulates the effector characteristics of the T cell infiltrate and promotes the maintenance of IL-17A-secreting CD4(+) T cells. Therefore, we concluded that classical IL-6R signaling in naive or central memory CD4(+) T cells is required to steer their effector characteristics, whereas local regulation of soluble IL-6R activity might serve to maintain the cytokine profile of the Th cell infiltrate. Therefore, the activation status of a T cell population is linked with an alteration in IL-6 responsiveness.

Pub.: 20 Jan '10, Pinned: 25 Jan '18

IL-6 Trans-Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane.

Abstract: Vascular endothelial growth factor (VEGF) is implicated in the peritoneal membrane remodeling that limits ultrafiltration in patients on peritoneal dialysis (PD). Although the exact mechanism of VEGF induction in PD is unclear, VEGF concentrations in drained dialysate correlate with IL-6 levels, suggesting a link between these cytokines. Human peritoneal mesothelial cells (HPMCs), the main source of IL-6 and VEGF in the peritoneum, do not bear the cognate IL-6 receptor and are thus unable to respond to classic IL-6 receptor signaling. Here, we investigated whether VEGF release by HPMCs is controlled by IL-6 in combination with its soluble receptor (IL-6 trans-signaling). Although treatment with either IL-6 or soluble IL-6 receptor (sIL-6R) alone had no effect on VEGF production, stimulation of HPMCs with IL-6 in combination with sIL-6R promoted VEGF expression and secretion through a transcriptional mechanism involving STAT3 and SP4. Conditioned medium from HPMCs cultured with IL-6 and sIL-6R promoted angiogenic endothelial tube formation, which could be blocked by silencing SP4. In vivo, induction of peritoneal inflammation in wild-type and IL-6-deficient mice showed IL-6 involvement in the control of Sp4 and Vegf expression and new vessel formation, confirming the role of IL-6 trans-signaling in these processes. Taken together, these findings identify a novel mechanism linking IL-6 trans-signaling and angiogenesis in the peritoneal membrane.

Pub.: 12 Nov '16, Pinned: 25 Jan '18

Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis.

Abstract: Ectopic lymphoid-like structures (ELSs) reminiscent of secondary lymphoid organs often develop at sites of chronic inflammation where they contribute to immune-mediated pathology. Through evaluation of synovial tissues from rheumatoid arthritis (RA) patients, we now show that low interleukin-27 (IL-27) expression corresponds with an increased incidence of ELS and gene signatures associated with their development and activity. The presence of synovial ELS was also noted in mice deficient in the IL-27 receptor (IL-27R) after the onset of inflammatory arthritis. Here, pathology was associated with increased synovial expression of pro-inflammatory cytokines, homeostatic chemokines, and transcriptional regulators linked with lymphoid neogenesis. In both clinical and experimental RA, synovial ELS coincided with the heightened local expression of cytokines and transcription factors of the Th17 and T follicular helper (Tfh) cell lineages, and included podoplanin-expressing T cells within lymphoid aggregates. IL-27 inhibited the differentiation of podoplanin-expressing Th17 cells, and an increased number of these cells were observed in IL-27R-deficient mice with inflammatory arthritis. Thus, IL-27 appears to negatively regulate ELS development in RA through control of effector T cells. These studies open new opportunities for patient stratification and treatment.

Pub.: 30 Sep '15, Pinned: 25 Jan '18