Salt revs up allergy-activating immune cells

Add a possible new item to the list of reasons to limit your salt intake. Sodium chloride triggers the production of a type of immune cell that promotes allergies, possibly making people more susceptible to allergy-related ailments like eczema, according to a new study (Sci. Transl. Med. 2019, DOI: 10.1126/scitranslmed.aau0683). What’s more, people with eczema, which causes dry, itchy, and rashy skin, have a surprisingly high amount of salt in the regions of their skin that are inflamed.

Researchers have known for years that a type of immune cell called type 2 T helper cells, or T_H2 cells, drive allergic responses in diseases such as eczema and asthma. But they don’t know what triggers so-called naive T cells—immune cells that haven’t yet met their target allergen in the body—to take on the T_H2 identity. What researchers do know is that T_H2 cells seem to be busy these days; over the past several decades, the prevalence of allergies has surged.

Why more people are suffering from allergy-related conditions is unclear. The time frame for the spike is too short for a genetic explanation, reasons the new study’s lead author Christina Zielinski, an immunologist at the Technical University of Munich. So she and her team set out to look for factors in the cellular environment that might be driving the change. One that caught their eyes is salt intake. Human consumption of salt has increased dramatically during this time, with the advent of highly processed and “fast” foods.

To determine whether there was a salt-allergy connection, Zielinski’s team began by determining how much salt is normally present in human skin. They used a technique called neutron activation analysis, which bombards tissues with neutrons to precisely measure the concentration of ions they contain. They added that measured concentration of NaCl, 50 nM, to naive human T cells growing in a petri dish. The added salt, they found, boosted the cells’ production of inflammation-driving molecules called cytokines—specifically, cytokines IL4 and IL13, which are responsible for allergies. “We found that naive cells are becoming T_H2 cells, and that cells that are already T_H2 cells are producing more of these pro-allergic molecules.” Zielinski says.

Further studies found that this transformation occurs through two enzymes that are activated by changes in osmolarity. “We think that the T cells react to salt by sensing the change in the osmolarity of the cellular microenvironment,” Zielinski explains. When she and her colleagues disabled these osmolarity-sensing enzymes, the T cells produced fewer allergy-causing cytokines.

Finally, to probe how this mechanism might affect an actual allergic response, the researchers checked the salt concentration in the skin of people who have eczema and found that the inflamed areas on their skin had a 30-fold higher salt concentration than unaffected regions. “That was really very surprising,” Zielinski says. “No one has ever looked for salt in the skin, but there’s a direct correlation between the cell type that salt induces and the deposition of salt in the skin of these patients.”

People with eczema also tend to have more of a bacterium called Staphylococcus aureus on their skin. Researchers have never understood why, but this bacterium is known to flourish in high salt concentrations. “Sodium could really explain many features of the disease,” Zielinski says.

Previous work by other researchers had identified salt as a driver of autoimmune disease, but this study extends the link to allergies, says Jay Kolls, an immunologist at Tulane University in New Orleans. But he points out that other cells that sense changes in osmotic pressure carry specific sodium channels that immune cells don’t have. He thinks understanding the mechanism of how the immune cells sense osmolarity changes and couple that to transforming into T_H2 cells is the next important step.

Both Kolls and Zielinski note that it’s too early to say for sure whether dietary salt intake can cause this T_H2 cell boost, because the study doesn’t directly demonstrate the link between the salt in the cells and the salt at the surface of the skin. This connection remains to be tested directly—for example, by examining the effect of a high-salt diet in mice with an eczemalike condition.