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Background: Rheumatoid factors (RFs) are autoantibodies that target the Fc region of IgG, and are found in patients with rheumatic diseases as well as in the healthy population. Many studies suggest that an immune trigger may (transiently) elicit RF responses. However, discrepancies between different studies make it difficult to determine if and to which degree RF reactivity can be triggered by vaccination or infection., Objective: We quantitatively explored longitudinal RF responses after SARS-CoV-2 vaccination and infection in a well-defined, large cohort using a dual ELISA method that differentiates between true RF reactivity and background IgM reactivity. In addition, we reviewed existing literature on RF responses after vaccination and infection., Methods: 151 healthy participants and 30 RA patients were included to measure IgM-RF reactivity before and after SARS-CoV-2 vaccinations by ELISA. Additionally, IgM-RF responses after a SARS-CoV-2 breakthrough infection were studied in 51 healthy participants., Results: Published prevalence studies in subjects after infection report up to 85% IgM-RF seropositivity. However, seroconversion studies (both infection and vaccination) report much lower incidences of 2-33%, with a trend of lower percentages observed in larger studies. In the current study, SARS-CoV-2 vaccination triggered low-level IgM-RF responses in 5.5% (8/151) of cases, of which 1.5% (2/151) with a level above 10 AU/mL. Breakthrough infection was accompanied by development of an IgM-RF response in 2% (1/51) of cases., Conclusion: Our study indicates that de novo RF induction following vaccination or infection is an uncommon event, which does not lead to RF epitope spreading., Competing Interests: TR and GW are inventors on a patent application based on the use of bioengineered IgG targets for the characterization of rheumatoid factor reactivity patterns. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Keijzer, Oskam, Ooijevaar-de Heer, Steenhuis, Keijser, Wieske, van Dam, Stalman, Kummer, Boekel, Kuijpers, ten Brinke, van Ham, Eftimov, Tas, Wolbink and Rispens.)

Monocytes are antigen-presenting cells (APCs) that play diverse roles in promoting or regulating inflammatory responses, but their role in T cell stimulation is not well defined. In inflammatory conditions, monocytes frequently show increased expression of CD169/Siglec-1, a type-I interferon (IFN-I)-regulated protein. However, little is known about the phenotype and function of these CD169 + monocytes. Here, we have investigated the phenotype of human CD169 + monocytes in different diseases, their capacity to activate CD8 + T cells, and the potential for a targeted-vaccination approach. Using spectral flow cytometry, we detected CD169 expression by CD14 + CD16 - classical and CD14 + CD16 + intermediate monocytes and unbiased analysis showed that they were distinct from dendritic cells, including the recently described CD14-expressing DC3. CD169 + monocytes expressed higher levels of co-stimulatory and HLA molecules, suggesting an increased activation state. IFNα treatment highly upregulated CD169 expression on CD14 + monocytes and boosted their capacity to cross-present antigen to CD8 + T cells. Furthermore, we observed CD169 + monocytes in virally-infected patients, including in the blood and bronchoalveolar lavage fluid of COVID-19 patients, as well as in the blood of patients with different types of cancers. Finally, we evaluated two CD169-targeting nanovaccine platforms, antibody-based and liposome-based, and we showed that CD169 + monocytes efficiently presented tumor-associated peptides gp100 and WT1 to antigen-specific CD8 + T cells. In conclusion, our data indicate that CD169 + monocytes are activated monocytes with enhanced CD8 + T cell stimulatory capacity and that they emerge as an interesting target in nanovaccine strategies, because of their presence in health and different diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Affandi, Olesek, Grabowska, Nijen Twilhaar, Rodríguez, Saris, Zwart, Nossent, Kalay, de Kok, Kazemier, Stöckl, van den Eertwegh, de Gruijl, Garcia-Vallejo, Storm, van Kooyk and den Haan.)

Rationale: Systemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited., Objectives: To evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome., Methods: Paired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured., Measurements and Main Results: In all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined., Conclusions: Critically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory "storm" in severe COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nossent, Schuurman, Reijnders, Saris, Jongerius, Blok, de Vries, Duitman, Vonk Noordegraaf, Meijboom, Lutter, Heunks, Bogaard and van der Poll.)

SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients., (Copyright © 2020 van den Berg and te Velde.)