Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS (2022) Mouat et al.

[Milo]

Abstract

While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts.

Here, we directly compared CD11c+T-bet+ ABCs using models of Epstein-Barr virus (EBV), gammaherpesvirus 68 (γHV68), multiple sclerosis (MS), and experimental autoimmune encephalomyelitis (EAE), and found that each drives the ABC population to opposing phenotypes.

EBV infection has long been implicated in MS, and we have previously shown that latent γHV68 infection exacerbates EAE.

Here, we demonstrate that ABCs are required for γHV68-enhanced disease.

We then show that the circulating ABC population is expanded and phenotypically altered in people with relapsing MS.

In this study, we show that viral infection and autoimmunity differentially affect the phenotype of ABCs in humans and mice, and we identify ABCs as functional mediators of viral-enhanced autoimmunity.

Excerpts:

Age-associated B cells (ABCs), also referred to as atypical B cells, are a unique subset of B cells found in humans and mice. They have been identified and characterized independently in the contexts of female aging, viral infection, and autoimmunity (1–3). In life, these are overlapping and intertwined occurrences. ABCs, defined by high expression of CD11c and T-bet and low expression of CD21, are primarily found in the spleen and secrete antiviral antibodies, autoantibodies, and cytokines and act as antigen-presenting cells (APCs) (1, 4, 5). The number of ABCs increases with age, particularly in females (3, 6–10). ABC numbers are also increased in people with autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS), and in a subset of people with common variable immunodeficiency that display autoimmune complications

Epstein-Barr virus (EBV) is a highly prevalent human gammaherpesvirus that establishes latency in B cells. EBV infects more than 90% of the adult population and is considered a causative agent of MS (26). The association between EBV and autoimmune disease was first demonstrated in 1979 when it was reported that peripheral blood lymphocytes from MS patients have an increased tendency to transform in vitro in response to EBV (27). Epidemiological findings support the association between EBV and MS; EBV is present in nearly 100% of people with MS, and seronegativity protects from disease (28–30). There is geographic overlap of infectious mononucleosis (IM), an immune system–driven syndrome usually caused by EBV, and MS (31), and a history of IM increases risk of developing MS (32, 33). A recent paper used U.S. military records of more than 10 million young adults to demonstrate that EBV infection precedes MS development and that EBV infection, but not other viral infections, increases the risk of MS development 32-fold (34). There is also robust clinical evidence for EBV’s contribution to MS. People with MS have higher titers of EBV-specific antibodies than healthy individuals (35), which correlate with disease activity (36), anti-EBV titers in the cerebrospinal fluid are elevated in those with MS (37), and T cells in people with MS display aberrant responses to EBV (38). Further work has demonstrated that EBV’s association with autoimmune disease extends to SLE and RA (39–44). The precise mechanism of EBV’s contribution to MS is incompletely understood, although multiple possible mechanisms have been proposed, including EBV infection of autoreactive B cells, molecular mimicry, bystander activation of autoreactive cells, EBV-infected B cell invasion of the central nervous system (CNS) and activation of human endogenous retrovirus-W, and EBV-induced cytokine response

Link to full text here

 

[CRG]

Link Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS Mouat et al, 2022 Open Access

 

[Milo]

Link Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS Mouat et al, 2022 Open Access

Yeah my finger tripped on the "post reply" early- The post has been updated.

I am curious about the "age-rassociated B-cells" and wonder whether @Jonathan Edwards has studied this B-cell population.

 

[Peter T]

For any one slow on the uptake like me EAE is seen as a model for MS in mice, see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981554/

Several different models of MS exist, but by far the best understood and most commonly used is the rodent model of experimental autoimmune encephalomyelitis (EAE). This model is typically induced by either active immunization with myelin-derived proteins or peptides in adjuvant or by passive transfer of activated myelin-specific CD4+ T lymphocytes. Mouse models are most frequently used because of the inbred genotype of laboratory mice, their rapid breeding capacity, the ease of genetic manipulation, and availability of transgenic and knockout mice to facilitate mechanistic studies. Although not all therapeutic strategies for MS have been developed in EAE, all of the current US Food and Drug Administration (FDA)-approved immunomodulatory drugs are effective to some degree in treating EAE, a strong indicator that EAE is an extremely useful model to study potential treatments for MS. Several therapies, such as glatiramer acetate (GA: Copaxone), and natalizumab (Tysabri), were tested first in the mouse model of EAE and then went on to clinical trials.