Histone H2A-Reactive B Cells Are Functionally Anergic in Healthy Mice With Potential to Provide Humoral Protection Against HIV-1

Abstract

Peripheral tolerance is essential for silencing weakly autoreactive B cells that have escaped central tolerance, but it is unclear why these potentially pathogenic B cells are retained rather than being eliminated entirely. Release from peripheral tolerance restraint can occur under certain circumstances (i.e., strong TLR stimulus), that are present during infection. In this regard, we hypothesized that autoreactive B cells could function as a reserve population that can be activated to contribute to the humoral immune response, particularly with pathogens, such as HIV-1, that exploit immune tolerance to avoid host defense. In this study, we identify a population of autoreactive B cells with the potential to neutralize HIV-1 and experimentally release them from the functional restrictions of peripheral tolerance. We have previously identified murine monoclonal antibodies that displayed autoreactivity against histone H2A and neutralized HIV-1 in vitro. Here, we identify additional H2A-reactive IgM monoclonal antibodies and demonstrate that they are both autoreactive and polyreactive with self and foreign antigens and are able to neutralize multiple clades of tier 2 HIV-1. Flow cytometric analysis of H2A-reactive B cells in naïve wildtype mice revealed that these B cells are present in peripheral B cell populations and we further document that murine H2A-reactive B cells are restrained by peripheral tolerance mechanisms. Specifically, we show endogenous H2A-reactive B cells display increased expression of the inhibitory mediators CD5 and phosphatase and tensin homolog (PTEN) phosphatase and fail to mobilize calcium upon immunoreceptor stimulation; all characterized markers of anergy. Moreover, we show that toll-like receptor stimulation or provision of CD4 T cell help induces the in vitro production of H2A-reactive antibodies, breaking tolerance. Thus, we have identified a novel poly/autoreactive B cell population that has the potential to neutralize HIV-1 but is silenced by immune tolerance.

SARS-CoV-2 infection relaxes peripheral B cell tolerance

“…Weakly autoreactive B cells that are allowed to escape bone marrow selection to exist in the periphery may provide evolutionary protection against pathogens that use molecular mimicry since weak autoreactive antibodies often cross-react against pathogenic epitopes (Rosenspire and Chen, 2015). Indeed, we and others have demonstrated that autoreactive antibodies can neutralize multiple tiers of HIV-1 virus (Agazio et al, 2020;Schroeder et al, 2017;Verkoczy and Diaz, 2014). Given that autoreactive B cells may overcome anergy in the presence of strong inflammation and TLR ligands, such as is found with active viral infection, B ND cells could be a reservoir of uniquely poised anti-viral B cells.…”

Autoreactive Antibodies Associated with Castleman Disease Triad

“…In this scenario, CD tumor burden and associated IL-6 production break peripheral tolerance, which precipitated the patient's rheumatologic symptoms. There are anecdotal reports in the literature of pathogen-driven or sterile inflammatory settings that result in transient autoantibody production [ 3 , 13 ]. Preexisting, autoreactive B cells found in healthy individuals could be released from peripheral restrain and contribute to the autoimmune pathophysiology observed and in presented in this report.…”