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Drug target BAFF is regulated by testosterone

New results could help select patients who might benefit most from BAFF inhibitors for autoimmune diseases.

Many autoimmune conditions such as multiple sclerosis and rheumatoid arthritis are more common in women than men. A clue about this disparity is that high levels of the male sex hormone testosterone and its receptor correlate with low numbers of immune system B cells. In addition, a genetic variant of B-cell activating factor (BAFF) is linked to risk of autoimmunity. A BAFF inhibitor is approved as a therapy for some autoimmune diseases.

A mechanism connecting these clues was recently published in Nature Communications by an international collaboration led by Professor Åsa Tivesten, Sahlgrenska University Hospital, Göteborg, Sweden.

“BAFF is an interesting protein because it’s a target for treating autoimmune diseases.”

“BAFF is an interesting protein because it’s a target for treating autoimmune diseases,” Tivesten says. “But not much is known about BAFF regulation. Our main finding was that testosterone regulates BAFF.”

The Tivesten group normally studies how sex hormones affect cardiovascular disease risk. As the researchers follow their results, though, they are finding links to the immune system. For example, they recently published about T-cell involvement in atherosclerosis induced by testosterone deficiency.

“Our long-term goal,” Tivesten says, ”is the mechanism of testosterone protection against atherosclerosis. When we bump into something interesting about B and T cells, though, we explore it by finding good immunologists to work with.”

For the BAFF study, Tivesten’s collaborators included Mikael Karlsson’s group at Karolinska Institute and Shannon Turley’s group at Genentech in San Francisco, USA.

A testosterone-BAFF-nervous system connection

Using mouse models, Tivesten’s group found that testosterone regulates spleen stromal cells that produce BAFF. BAFF is required for B-cell survival, so testosterone may influence development of autoimmunity via BAFF. The researchers also found that serum testosterone status correlates with BAFF levels in men.

An additional, unexpected finding came from expression profiling and other data on spleen stromal cells. The results showed that testosterone’s effects on spleen B-cell numbers depend on the sympathetic nervous system.

“Even they were surprised with these results.”

“The Turley group specializes in stromal cells,” Tivesten says, “and even they were surprised with these results. The findings support nervous regulation of the stromal cell compartment as a potential way to modulate immune reactions and autoimmunity.”

The Tivesten lab continues to focus their research on sex hormones and atherosclerosis. They felt it important to publish their basic research findings on BAFF and the immune system, however, because of the potential clinical implications.

“It has to be tested in trials,” Tivesten says, “but this information could give important guidance about how to select patients suitable for BAFF inhibitor treatment.”

REFERENCE

Wilhelmson AS, Rodriguez ML, Stubelius A, Fogelstrand P, Johansson I, Buechler MB, Lianoglou S, Kapoor VN, Johansson ME, Fagman JB, Duhlin A, Tripathi P, Camponeschi A, Porse BT, Rolink AG, Nissbrandt H, Turley SJ, Carlsten H, Mårtensson I-L, Karlsson MCI, Tivesten Å. Testosterone is an endogenous regulator of BAFF and splenic B cell number. Nature Communications. 2018;9:2067

Photo of Åsa Tivesten: Magnus Gotander