Background/Purpose: Each year, up to one fifth of the United States population is infected with influenza virus. Although mortality rates are low, hundreds of thousands are hospitalized each year. Specific high risk groups, such as those with dysregulated immune systems, are in greater danger for complications from influenza. Further, infections are a common cause of hospitalizations and mortalities in patients with systemic lupus erythematosus (SLE). To understand the influenza immune response in SLE and the effect of infection on autoimmune disease in a controlled setting, we utilized the MRL-Fas(lpr) lupus-prone mouse model.

Methods: Female MRL-Fas(lpr) mice were infected with 200 EID⁵⁰ influenza A virus PR/8/34 H1N1. Mice were weighed daily as a measurement of morbidity and viral burden was determined by quantitative RT-PCR of the influenza M1 gene. Further, lung, kidney, and spleen samples were collected at various time points post infection to analyze pathology by H&E and PAS staining, cytokines by ELISA, and cellular composition by flow cytometry. Total antigen-specific cells were determined by stimulated cells overnight with inactivated influenza virus and intracellular staining for cytokines. Serum was collected to determine autoantibody concentrations by ELISA.  Apoptosis was examined in the spleen on paraffin-embedded spleen sections by TUNEL staining. Finally, the role of extrinsic apoptosis in influenza infected lupus-prone mice was examined by administration of 0.1 mM caspase-8 inhibitor (Z-IETD-FMK) and negative control (Z-FA-FMK) daily for six days.  

Results: MRL-Fas(lpr) mice accumulated more CD8+ T cells and more TNF-a influenza A virus specific T cells with less neutrophil accumulation in the lung by day 7 post infection (P<0.05). Moreover, increased extrinsic apoptosis during influenza infection led to a reduction of autoimmune disease symptoms with decreased splenomegaly (P<0.0005) and kidney disease (P<0.05). Unlike acute infection, following clearance of the influenza A virus, MRL-Fas(lpr) mice had severe complications during the contraction and resolution phase with widespread severe pulmonary inflammation. Lupus-prone mice had an increased lung severity score (P<0.05) with significantly more CD4+ and CD8+ T cells and myeloid cells compared to MRL control mice at day 40 post infection (P<0.005). Further, the improvement of autoimmune disease symptoms ceased following clearance of the viral infection and by day 40 was similar to PBS treated MRL-Fas(lpr) mice.

Conclusion: Our findings suggest that autoimmunity drives an enhanced influenza-specific immune response to clear infection, but that severe complications can arise during the resolution of pulmonary inflammation. We propose that problems with pulmonary infection in lupus may arise not from an inadequate antigen-specific immune response, but from sustained pulmonary inflammation and defective cellular clearance causing prolonged symptoms in patients. Additionally, influenza infection diminishes autoimmune disease responses rather than exacerbate autoimmune pathology in mice during the acute infection as a direct result of virus induced apoptosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/influenza-a-h1n1-virus-infection-triggers-severe-pulmonary-inflammation-in-lupus-prone-mice-following-viral-clearance/