Targeting the epigenetic histone modifier BMI-1 in B cells restored effective humoral immune responses to control chronic viral infection in mice, according to new multicenter Australian study led by immunologists at Monash University in Melbourne, Victoria.

By identifying BMI-1 levels as being a key determinant of productive antibody responses to chronic viral infection, the study has important therapeutic implications for both infectious diseases and immune disorders in which pathogenic antibodies play a role.

In such diseases, BMI-1 could potentially be targeted with a small-molecule inhibitor to deplete pre-existing detrimental plasma cells, the study authors reported in the November 29, 2021, edition of Nature Immunology.

"While effective antibodies are the cornerstone of successful vaccine protection, there are a number of immune disorders in which pathogenic antibodies play a role in morbidity," said study leader Kim Good-Jacobson, an associate professor in the Biomedicine Discovery Institute at Monash University.

"In particular, pathogenic antibodies are seen in infectious diseases such as in dengue virus, and in antibody-mediated autoimmune disorders, including systemic lupus erythematosus," Good-Jacobson told BioWorld Science.

These and chronic viral infections, including HIV and hepatitis C, so far have evaded control by an antibody-mediated vaccine, which can lead to irreparable and potentially fatal organ damage if left untreated.

Ineffective antibody-mediated responses are known to be a critical characteristic of chronic viral infections, but currently our understanding of the intrinsic mechanisms driving this process remains unclear.

This was investigated in the new Nature Immunology study, in which deep-sequencing, genetic tools and small-molecule inhibitors were used to show that a dysfunctional B-cell fate in viral infections was determined by BMI-1.

Specifically, the researchers discovered that targeting the epigenetic modifier in mice improved humoral immune responses to chronic rodent lymphocytic choriomeningitis (LCM) virus infection.

BMI-1 was targeted "using a genetic mouse model in which the Bmi1 gene is deleted in B cells and, in another set of experiments, we administered a small-molecule inhibitor to BMI-1," explained Good-Jacobson.

With both approaches, "we could reduce problematic immune complexes and antibody-producing cells," she said.

"In the mouse genetic model, we further showed that the quality of antibody produced had improved, in that it had better neutralizing ability and was more able to stimulate innate cell function, thereby accelerating viral clearance."

Compared to animals with acute LCM infection, BMI-1 was demonstrated to be upregulated by germinal center B cells in mice with the chronic viral infection, which correlated with changes to chromatin accessibility.

"We showed that modulating Bmi1 expression changed chromatin accessibility at key genes that are important for producing effective B-cell responses," noted Good-Jacobson. "The delicate balance of gene expression... is critically important for generating high-quality antibody-producing cells and protective memory B-cell subsets at the right time."

Besides accelerating LCM viral clearance, B cell-intrinsic Bmi1 deletion was also demonstrated to reduce enlargement of the spleen, or splenomegaly, and to restore splenic structural architecture.

Splenomegaly can be a sign that the immune system isn't working properly.

Moreover, Good-Jacobson said, "normal spleen structure is critical, in order for immune cells to work properly and collaboratively to produce an immune response and clear virus from the body."

Deletion of Bmi1 was further shown to restore c-Myc expression in B cells, together with improved quality of antibody and coupled with reduced antibody-secreting cell numbers.

A protein that can control gene expression, c-Myc plays key roles in many parts of the body. It is also an oncogene, and there are cancers in which c-Myc and BMI-1 [synergize] to produce proliferating cancer cells, said Good-Jacobson.

"In B cells, c-Myc normally fine-tunes the antibody response, so its expression is exquisitely timed in only a small number of B cells," she noted.

"Chronic viral infection in mice turns c-Myc on in many more B cells, which may contribute to a low-quality antibody response. Bmi1 deletion restored c-Myc expression to appropriate levels, which correlated with a better antibody response."

Importantly, by using an experimental small-molecule inhibitor of murine BMI-1, PTC-028, the researchers were able to deplete antibody-secreting cells and prohibit detrimental immune complex formation in vivo.

Taken together, these findings show that BMI-1 is a crucial immune modifier that controls antibody-mediated responses in chronic viral infection.

Targeting BMI-1 with a small-molecule inhibitor might therefore be used to treat chronic viral infections and inhibitors of epigenetic regulators are currently in clinical trials for various indications.

"There are a number of cancers, such as lymphomas, for which small-molecule inhibitors of epigenetic regulators are in clinical trials," said Good-Jacobson.

However, "because epigenetic regulators such as BMI-1 are important in many different parts of the body, our next step will be to work on ways to deliver drugs directly to B cells.