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Radboud University, 31 januari 2023, Promotores : Joosten, L.A.B., Netea, M.G. Co-promotor : Crisan, T.O., Contains fulltext : 286408.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 296488.pdf (Publisher’s version ) (Closed access)

Objective There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. Methods A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. Results The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: asymptomatic hyperuricaemia', asymptomatic monosodium urate crystal deposition', asymptomatic hyperuricaemia with monosodium urate crystal deposition', gout', tophaceous gout', erosive gout', first gout flare' and recurrent gout flares'. There was consensus agreement that the label gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). Conclusion Consensus agreement has been established for the labels and definitions of eight gout disease states, including gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

Contains fulltext : 232459.pdf (Publisher’s version ) (Open Access), A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed "trained immunity." We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using β-glucan (from Candida albicans) and Bacillus Calmette-Guérin as examples. For complete details on the use and execution of this protocol, please refer to Repnik et al. (2003) and Bekkering et al. (2016).

Contains fulltext : 232538.pdf (Publisher’s version ) (Open Access), BACKGROUND: Interleukin (IL)-1 family cytokines and their receptors have important roles in innate and partly in adaptive immunity. The family consists of 11 members of which IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ are considered pro-inflammatory and IL-1Ra, IL-36Ra, IL-37 and IL-38 anti-inflammatory. Whereas IL-1β has a known pivotal role in gout, increasing evidence suggests other IL-1 family members are also involved in the pathogenesis of hyperuricemia and gout flares. FINDINGS: Studies indicate IL-1α, like IL-1β, plays an essential role in the pathogenesis of gout flares. IL-18, although elevated in patients with gout, does not contribute to MSU crystal-induced inflammation, but may be involved in the subsequent development of cardiovascular disease in individuals with gout. The role of the pro-inflammatory cytokine IL-36 in gout remains elusive. In contrast, IL-1Ra, IL-33, IL-37 and IL-38 inhibit MSU crystal-induced inflammation and therefore have therapeutic potential for treatment of gout flares. In addition to existing IL-1β blockers, several new therapeutics to treat gout are being developed either inhibiting the transcription or maturation of IL-1β. CONCLUSION: In this review, IL-1 family cytokines are discussed in the context of hyperuricemia and gout. Finally, current and novel therapeutic options for targeting IL-1 are reviewed.

Contains fulltext : 236292.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 218310.pdf (Publisher’s version ) (Closed access), OBJECTIVE: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout. METHODS: Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout. RESULTS: We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71x10(-5)). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry. CONCLUSION: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.

Contains fulltext : 218719.pdf (Publisher’s version ) (Open Access), Trained immunity is a process in which innate immune cells undergo functional reprogramming in response to pathogens or damage-associated molecules leading to an enhanced non-specific immune response to subsequent stimulation. While this capacity to respond more strongly to stimuli is beneficial for host defense, in some circumstances it can lead to maladaptive programming and chronic inflammation. Gout is characterized by persistent low-grade inflammation and is associated with an increased number of comorbidities. Hyperuricemia is the main risk factor for gout and is linked to the development of comorbidities. Several experimental studies have shown that urate can mechanistically alter the inflammatory capacity of myeloid cells, while observational studies have indicated an association of hyperuricemia to a wide spectrum of common adult inflammatory diseases. In this review, we argue that hyperuricemia is a main culprit in the development of the long-term systemic inflammation seen in gout. We revisit existing evidence for urate-induced transcriptional and epigenetic reprogramming that could lead to an altered functional state of circulating monocytes consisting in enhanced responsiveness and maladaptive immune responses. By discussing specific functional adaptations of monocytes and macrophages induced by soluble urate or monosodium urate crystals and their contribution to inflammation in vitro and in vivo, we further enforce that urate is a metabolite that can induce innate immune memory and we discuss future research and possible new therapeutic approaches for gout and its comorbidities.

Contains fulltext : 221449.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 202134.pdf (publisher's version ) (Open Access)

Contains fulltext : 209663.pdf (publisher's version ) (Closed access)

Contains fulltext : 154611.pdf (publisher's version ) (Open Access), Thyroid cancer is the most common endocrine malignancy. Despite having a good prognosis in the majority of cases, when the tumor is dedifferentiated it does no longer respond to conventional treatment with radioactive iodine, the prognosis worsens significantly. Treatment options for advanced, dedifferentiated disease are limited and do not cure the disease. Autophagy, a process of self-digestion in which damaged molecules or organelles are degraded and recycled, has emerged as an important player in the pathogenesis of different diseases, including cancer. The role of autophagy in thyroid cancer pathogenesis is not yet elucidated. However, the available data indicate that autophagy is involved in several steps of thyroid tumor initiation and progression as well as in therapy resistance and therefore could be exploited for therapeutic applications. The present review summarizes the most recent data on the role of autophagy in the pathogenesis of thyroid cancer and we will provide a perspective on how this process can be targeted for potential therapeutic approaches and could be further explored in the context of multimodality treatment in cancer and personalized medicine.