Induction of broadly reactive influenza antibodies increases susceptibility to autoimmunity

Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing conserved influenza epitopes greatly outnumber antibodies reactive against variable epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors. Autoantigen arrays were performed at Microarray and Immune Phenotyping Core Facility of University of Texas Southwestern Medical Center (UTSW) and carried out as described previously (Li et al., 2007). Briefly, serum samples from HKx31-infected mice, treated with rapamycin or PBS for 14 days, were frozen and sent to UTSW. The sera were pre-treated with DNase I and incubated on autoantigen arrays, and the bound antibodies were detected using a Cy3 labeled anti-mouse IgG (532nm) or Cy5 labeled anti-mouse IgM (635nm) to generate Tiff images. 012993_Slide1: Autoantigen Microarray Super Panel (128 antigen panel) https://microarray.swmed.edu/products/product/autoantigen-microarray-super-panel-128-antigen-pan/ 012995_Slide2: Autoantigen Microarray Panel IV https://microarray.swmed.edu/products/product/autoantigen-microarray-panel-iv/