BAFF: A Fulcrum Between Resistance to Infection & Autoimmunity

Maristella Steri, PhD, research fellow at the Instituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato in Italy, and colleagues reported that a TNFSF13B variant that encodes the cytokine and drug target B cell activating factor (BAFF) is associated with multiple sclerosis and systemic lupus erythematosus (SLE). They detailed the effects at the population, cellular and molecular levels in the April 27 issue of The New England Journal of Medicine.¹

The complex BAFF system includes the BAFF receptor (BAFF-R), B-cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin-ligand interactor (TACI). Researchers have studied the role of BAFF in animal models of autoimmunity and found that it appears to play a role in syndromes resembling human SLE and Sjögren’s syndrome. These findings, and others, have increasingly led researchers to focus on B cells as a therapeutic target for autoimmune diseases.

Dr. Steri and colleagues turned their efforts to individuals in Sardinia, who despite their reputation for longevity, also happen to have the highest incidence rate of multiple sclerosis. Their research revealed the TNFSF13B variant is an associated disease-risk allele that upregulates humoral immunity, as documented by increased levels of soluble BAFF, B lymphocytes and immunoglobulins. The insertion-deletion variant, GCTCTàA, creates a risk allele by the insertion of A. They found that the mutation yields a shorter transcript that escapes microRNA inhibition and increases the production of soluble BAFF, which is associated with upregulated humoral immunity. However, the effects of BAFF-var are broad, and the investigators note that the role of specific B cells in the pathogenesis of multiple sclerosis and SLE remain unclear.

“Besides supporting BAFF as a target in multiple sclerosis and SLE, our results have implications for clinical research,” write the authors in their discussion. “A pertinent one, to be assessed in further studies, would be that patients stratified according to BAFF-var status [may] show a differential benefit from anti-BAFF therapies. One might also anticipate that patients carrying BAFF-var would have a weaker response to B-cell depleting therapies owing to a faster resurgence of memory B cells.” They note, however, that this expectation runs counter to clinical experience, which has found that patients with SLE and higher levels of BAFF actually have poorer and shorter clinical responses to rituximab than patients with lower levels of BAFF.

Evolution & Autoimmunity
The investigators then performed population genetic signatures that revealed that the autoimmunity variant has been evolutionarily advantageous. Specifically, they posit that BAFF-var may have been positively selected for in the Sardinian population because it contributes to resistance to Plasmodium falciparum or P. vivax malaria.

“Overall, the evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they conclude.

If true, it would be another example of a mutation that provides advantages to the fitness of mutants, while at the same time leading to disease.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

Reference

1. Steri M, Orrù V, Idda ML, et al. Overexpression of the cytokine BAFF and autoimmunity risk. N Engl J Med. 2017 Apr 27;376(17):1615–1626. doi: 10.1056/NEJMoa1610528.