Autoantibodies are highly prevalent in non–SARS-CoV-2 respiratory infections and critical illness

Abstract

The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non–SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non–SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

Autoantibodies to Interferons in Infectious Diseases

“…Very recent anti-cytokine aAbs were found in >50% of critically ill patients with non-SARS-CoV-2 infections, i.e., caused by other viral and fungal pathogens, as well as known or suspected bacterial pathogens [ 52 ]. These aAbs were far more common in infected versus uninfected patients and, importantly, were seen not only in multiple respiratory viral infections, but also in the non-respiratory bacterial infections observed in patients admitted to the intensive care unit (ICU).…”

“…To our knowledge, the presence of anti-IFN-III aAbs were described in patients with non-SARS-CoV-2 respiratory infections, where they seemed to display a neutralizing activity [ 52 ].…”

Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

“…Despite the strong association between general possession of anti-IFN-I autoAbs and severe viral infections, it remains to be determined whether there might be a normal physiological role for low-level, transient, development of anti-IFN-I autoAbs that act to dampen certain inflammatory states, particularly given the observed widespread and fluctuating instances of these autoAbs during many acute viral infections [11,[57][58][59][60][61][62][63]. While some individuals may then go on to aberrantly maintain anti-IFN-I autoAbs in their blood and be highly susceptible to severe viral disease, the precise levels of these autoAbs and the IFN-I subtypes/epitopes that they must target to effectively compromise innate antiviral immunity still need to be dissected in order to define a clear 'correlate of susceptibility'.…”

“…Acute viral infections and systemic inflammation are also potential triggers for the production of high amounts of endogenous IFN-Is. Consequently, anti-IFN-I autoAbs have been reported in several of these situations, for example with acute HIV-1, SARS-CoV-2, influenza virus, and hepatitis A, B, or C virus infections [11,[57][58][59][60][61][62][63], with a potentially IFN-stimulating vaccine dose [64], and during acute respiratory distress syndrome or severe sepsis [65] (Fig. 1).…”

“…1). Acute viral infections in general can trigger autoAbs against a range of IFN and non-IFN molecules [60,61,66]. While levels of such induced autoAbs probably naturally decline after a few months [56,59,62], some rare individuals exposed to IFN-I have been described to remain positive for anti-IFN-I autoAbs for many years [56,67].…”