Why an overactive immune system attacks the bodies of people with lupus but still leaves them vulnerable to infection

by Andrew Monteith, The Conversation

edited by Gaby Clark, reviewed by Andrew Zinin

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Despite having an overactive immune system, people with lupus may still struggle to fight bacterial infections. My team and I found that this paradox may result from chronic inflammation pushing their immune cells toward the wrong kind of response.

To understand why an overactive immune system can still fail to control bacterial infection, we focused on neutrophils, white blood cells that are among the first to respond when bacteria enter the body. Neutrophils can release webs of DNA and antimicrobial proteins called neutrophil extracellular traps, or NETs, that can trap bacteria, limiting their spread and killing them.

Scientists often discuss these traps as if they are all the same, but the body can produce NETs through different pathways, and they do not all work equally well.

For example, healthy neutrophils responding to infection from Staphylococcus aureus can sense lactate, a chemical byproduct made by the bacteria. That signal helps trigger neutrophils to release a type of NET that serves as a trap rich in antibacterial proteins but also kills the neutrophil.

In lupus, my team and I found that inflammatory molecules interfere with this antibacterial response in mice. These signals reduced levels of a protein needed to sense bacterial lactate. At the same time, another inflammatory molecule pushed neutrophils toward another form of NET that they could release more quickly, sparing the neutrophil but less effective at killing bacteria.

The result is not an immune system that is weak, but an immune response that is highly active but misdirected.

Why it matters

Lupus is usually described as an autoimmune disease in which the immune system attacks the body's own tissues. But serious infections are also a major concern for people with lupus. Some of that risk comes from medications that suppress the immune system, but the disease itself can also alter how immune cells function.

Our findings help explain why more inflammation does not necessarily mean better protection from infection. The type and timing of the immune response matter.

We also found that treatments currently used for lupus can correct specific defects in these neutrophil pathways. Our results do not show that people taking standard lupus treatments will have fewer infections, but they do suggest that existing therapies can correct immune defects that may contribute to susceptibility to infection.

What still isn't known

The immune system is more complicated than one cell type or one response. Although we found that standard lupus treatments reduced the number of bacteria in several organs in lupus-prone mice, they did not significantly improve survival compared with untreated mice. Other immune cells, tissue damage and additional features of lupus likely contribute to poor outcomes during infection.

There is also an ongoing debate about what neutrophil extracellular traps actually do in lupus. Some studies have found that disrupting pathways required for NETs to form does not necessarily improve lupus, challenging the idea that simply making more NETs drives the disease.

Our findings suggest that what kind of NET neutrophils make and under what circumstances may be more important questions for lupus. During infection, lupus neutrophils may produce a type of NET that is less effective at killing bacteria while still releasing inflammatory material. That combination of poor infection control together with an inappropriate inflammatory response might exacerbate lupus.

What's next

My team and I are now focused on understanding how different types of NETs affect autoimmune disease and infection. Rather than treating all NETs as the same response, we want to define how different NETs are generated, what they contain and whether particular kinds are protective or harmful in different contexts.

Understanding how lupus changes the type of NET response produced during infection may help explain why disease activity, infection risk and treatment response vary among patients.

Journal information: Cell Press Blue

Key medical concepts

Extracellular Trap, NeutrophilBacterial InfectionsNeutrophils

Clinical categories

Allergy and immunologyRheumatologyInfectious diseases Provided by The Conversation Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

Andrew Zinin

Master's in physics with research experience. Long-time science news enthusiast. Plays key role in Science X's editorial success. Full profile →

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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