Session Type: Abstract Submissions (ACR)
Background/Purpose: Macrophage activation syndrome (MAS) is the rheumatic disease-associated member of a group of hyperinflammatory syndromes characterized by uncontrolled cytokine storm manifest as unremitting fevers, cytopenias, splenomegaly, hepatitis, coagulopathy, multisystem organ failure, and death in its most severe form. The clinical features of MAS are shared with other hyperinflammatory syndromes, of which genetic defects in cytotoxicity have provided insight into the pathogenesis driving viral-triggers of disease. However, severe defects in cellular cytotoxicity have not been found in patients with MAS making it unclear how viral infection can trigger hyperinflammation in this condition.
Methods: C57Bl/6, interferon (IFN)γ-/-, and IFNα-/-mice were infected with LCMV Armstrong and treated with or without interleukin (IL)-10 receptor blockade. Survivial, weight loss, splenomegaly, cytopenias, and serum cytokine levels were measured after viral infection.
Results: Wildtype mice treated with IL-10 receptor blockade succumbed to MAS-like hyperinflammation manifest as weight loss, splenomegaly, bicytopenias, and hypercytokinemia during LCMV infection. IFNγ-/- and IFNα-/-mice were not protected from LCMV-induced disease in this model, as they developed severe weight loss, splenomegaly, cytopenias, hypercytokinemia, and more severe mortality when IL-10 receptor was blocked.
Conclusion: IL-10 receptor blockade leads to heightened immunopathology in the setting of LCMV infection similar to MAS-like hyperinflammatory disease. Unlike other hyperinflammatory syndromes, this immunopathology is independent of IFNγ and IFNα, and highlights the capacity of other inflammatory mediators to cause viral-induced hyperinflammation during IL-10 receptor blockade. Furthermore, these data highlight a novel mechanism that could contribute to MAS-like disease whereby defects in IL-10 production and/or sensing could exacerbate hyperinflammatory immunopathology induced by viral infection without genetic defects in cellular cytotoxicity.
L. K. Weaver,
E. M. Behrens,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-10-receptor-blockade-during-lcmv-infection-results-in-macrophage-activation-syndrome-like-disease-in-mice/