Mathijs Willemsen

Objectives: NLRC4-associated autoinflammatory diseases (NLRC4-AID) cover a clinical spectrum from relatively mild familial cold autoinflammatory syndrome 4 (FCAS4) to life-threatening macrophage activation syndrome (MAS). Free IL-18 has been shown to pathogenically promote MAS, but the pathological relevance of free IL-18 in NLRC4-AID without MAS has not been explored. We investigated free IL-18 and related cytokines in five germline p.S445P and one somatic p.V341L NLRC4-AID patients without MAS. Methods: Clinical, genetic and laboratory data, as well as serum samples were obtained from NLRC4-AID patients without MAS. Human IL-6, soluble CD25, CXCL9, CXCL10, IL-12p70, IFN-γ, total IL-18, IL-1β, TNF-α and IL-1Ra were assessed using a bead-based assay. Free IL-18 was assessed using a proprietary ELISA. Results: Total and free IL-18 were elevated both in the FCAS4 patients and the NLRC4-AID patient harbouring a heterozygous somatic NLRC4 variant restricted to the haematopoietic compartment. Despite the association between free IL-18 and MAS, we found no relevant correlation between total and free IL-18 and laboratory markers of inflammation or MAS. Accordingly, MAS-associated cytokines IFN-γ, CXCL9 and CXCL10 were not elevated in NLRC4-AID patients without MAS. Conclusion: Germline and somatic NLRC4-AID without MAS are associated with elevated levels of both total and free IL-18. Our findings in the somatic NLRC4-AID patient suggest that free IL-18 originating from the haematopoietic system alone is not sufficient to drive MAS. Our findings indicate that IL-18 is necessary but not sufficient to drive MAS and suggest a pathological role of IL-18 beyond MAS in NLRC4-AID.

Autoinflammation of unknown origin remains amongst the most enigmatic of systemic autoinflammatory disorders (SAID), with systemic autoinflammatory symptoms in the absence of a molecular or clinical diagnosis with a recognized SAID. Here, we aim to understand the immunological process behind patients with autoinflammation of unknown origin. We collect samples from 36 patients manifesting recent disease activity across 30 European medical centers, and employ deep immunophenotyping and plasma proteomics to compare to 58 healthy controls and an additional demographically similar cohort comprising 92 SAID patients. Machine-learning approaches identify key immunological changes, including the upregulation of CD38 and HLA across T cell subsets and the upregulation of acute-phase plasma proteins in autoinflammation of unknown origin patients. The immunological traits of these previously poorly characterised patients partially phenocopy Still’s disease presentation. Thus, this study identifies potential biomarkers and disease mediators in autoinflammation of unknown origin.

Dear Editor, Deficiencies of early components of the classical complement pathway are associated with an increased risk of SLE. There is a hierarchy of disease susceptibility and severity according to the position of the deficient protein in the classical complement pathway. SLE penetrance in C1q deficiency is 90%, and patients generally present with severe disease, whereas only 10–20% of C2-deficient patients develop SLE, with a disease severity comparable to sporadic SLE [ 1, 2]. C1q inhibits type I IFN (T1IFN) release, and its deficiency is associated with upregulated T1IFN signalling [ 3, 4]. Increased T1IFN signalling in C1q deficiency is proposed to explain the association with SLE [ 3]. It is unknown whether T1IFN signalling is also increased in other, more common early complement deficiencies, such as C2 deficiency (estimated prevalence in European population 1 in 20 000) [ 2]. We identified only one C2-deficient patient in the literature for whom T1IFN signalling was assessed [ 4]. In the present report, we investigate the association between C2 deficiency, T1IFN signalling and autoimmunity in a kindred with C2 deficiency and primary SS (pSS). The UZ/KU Leuven ethics committee approved this study (S52653).

Rheumatology key messageInflammatory aortitis is added to the clinical spectrum of HIGM syndrome

The pandemic spread of the novel coronavirus SARS-CoV-2 is due, in part, to the immunological properties of the host-viral interaction. The clinical presentation varies greatly from individual to individual, with asymptomatic carriers, mild to moderate-presenting patients and severely affected patients. Variation in immune response to SARS-CoV-2 may underlie this clinical variation. Using a high dimensional systems immunology platform, we have analyzed the peripheral blood compartment of 6 healthy individuals, 23 mild-to-moderate COVID-19 patients and 20 severe COVID-19 patients. We identify distinct immunological signatures in the peripheral blood of the mild-to-moderate and severe COVID-19 patients, including T cell lymphopenia, more consistent with peripheral hypo-than hyper-immune activation. Unique to the severe COVID-19 cases was a large increase in the proportion of IL-10-secreting regulatory T cells, a lineage known to possess anti-inflammatory properties in the lung. Annotated data is openly available ( https://flowrepository.ors/experiments/2713 ) with clinical correlates, as a systems immunology resource for the COVID-19 research community.