B cells can be self-reactive in lupus, producing autoantibodies that mistakenly target a person’s own cells and tissues. People with lupus have a type of antibody called VH4-34 antibodies, which have been shown to correlate with lupus flares. However, what these antibodies bind to is unknown. Dr. Meffre previously found that VH4-34 antibodies bind to naturally occurring gut bacteria. Gut bacteria can contribute to the development of lupus, and several studies have shown that a “leaky gut,” where bacteria pass through the intestinal wall into the bloodstream, can occur in people with SLE. He and his team will test the hypothesis that lupus flares are associated with the escape of gut bacteria into the bloodstream, causing the production of B cells that produce VH4-34 antibodies.

Dr. Meffre will collect stool samples from healthy individuals, individuals with quiescent lupus (no active symptoms or flares), and those with active disease to identify what gut bacteria VH4-34 antibodies bind to. He will explore whether different strains of bacteria are recognized by antibodies in patients with quiescent versus active disease and what specific structures the antibody binds to on these strains of bacteria. Lastly, Dr. Meffre will assess the types and amounts of bacteria in the blood of these individuals to detect whether bacteria typically found in the gut have leaked into the blood.

What this means for people with lupus:

By identifying the bacteria that bind VH4-34 antibodies and are associated with disease activity, Dr. Meffre’s study could lead to the development of novel therapeutic strategies targeting these bacteria, preventing flares and decreasing disease activity in people with lupus.

The etiology of systemic lupus erythematosus (SLE) is not well understood but the production of autoreactive B cells plays a key role in SLE pathophysiology. Patients with SLE display an altered IgG+ memory B cell compartment that contains Ig variable heavy chain (VH) 4-34 gene segment-expressing clones, which are rarely associated with IgG immune responses in healthy donors (HD) or patients with other autoimmune diseases. A study from Sanz and colleagues revealed that the presence of unmutated or weakly mutated VH4-34 antibodies correlated with flares in patients with SLE, but the nature of the antigens recognized by these clones remains unknown. Unmutated VH4-34-encoded antibodies display intrinsic self-reactivity associated with the presence of the AVY tripeptide motif in the framework region 1 (FWR1) that is essential for the recognition of the I/i carbohydrates on the surface of red blood cells. However, we showed that VH4-34-encoded IgG antibodies that retained unmutated the AVY tripeptide motif also bind lysates from commensal bacteria. Our data therefore suggested that SLE flares may be associated with a breach of gut microbiota into the host, which results in the production of VH4-34+IgG+ B cells from naïve B cells. Indeed, several studies support a defective containment of gut microbiota in SLE. In addition, gut bacteria have also been shown to contribute to disease development. Our preliminary analysis of VH4-34-encoded antibodies cloned from single IgG+ memory B cells from several patients with SLE now reveal that these recombinant antibodies bind specific commensal bacteria strains in SLE stools but not HD stools. Our main hypothesis is that SLE flares are associated with the defective containment of gut commensal bacteria, which trigger the expansion of peripheral B cells expressing VH4-34-encoded antibodies. In addition, we postulate that the presence of VH4-34targeted Intestinibacter bartlettii specifically in the stool of some patients with SLE but not healthy donors is associated with severe disease. To accomplish these goals, we propose to characterize the VH4-34-targeted commensal bacteria in the stools of patients with SLE with either quiescent or active disease. We will also determine and quantify the bacterial load in the blood of these patients with SLE.

By identifying the commensal bacteria associated with disease activity, our research has the potential to improve the condition of patients in that we may be able to prevent flares or decrease disease activity by specifically targeting these bacteria.