Scientists Discover Why Lupus Patients Have Faulty Immune Defense Genes—And It Could Change Treatment

A groundbreaking study reveals that genes normally designed to protect us from infections are malfunctioning in systemic lupus erythematosus (SLE) patients, and these same genes are significantly overexpressed in active disease. Scientists analyzed 453 genes associated with primary immunodeficiency (PID)—rare genetic conditions that weaken immune defense—and discovered they overlap with lupus risk factors far more than expected by chance, suggesting a profound link between infection-fighting pathways and lupus development.

What's the Connection Between Infection-Fighting Genes and Lupus?

Systemic lupus erythematosus is an autoimmune disease where the immune system mistakenly attacks the body's own tissues, causing widespread inflammation and damage. Researchers at AMPEL BioSolutions hypothesized that genes responsible for fighting infections might play a hidden role in lupus development. When they compared 453 known primary immunodeficiency genes to lupus genetic risk factors, they found something striking: these infection-defense genes overlapped with lupus risk loci significantly more often than would occur by random chance, and more substantially than their overlap with other autoimmune conditions.

The team organized these 453 genes into 18 distinct cellular and functional groups, each controlling different aspects of immune defense. When they examined blood samples and immune cells from lupus patients, they discovered that many of these genes were overexpressed—meaning they were producing more protein than normal—particularly in patients with active disease.

Which Immune Cells Show the Biggest Gene Overexpression?

The researchers mapped specific patterns of overexpressed genes to particular immune cell types. The findings revealed that certain primary immunodeficiency genes were most active in:

• T Cells: White blood cells that coordinate immune responses and were found to have elevated expression of multiple PID genes in lupus patients
• Classical Monocytes: Immune cells that engulf pathogens and were showing increased activity of infection-defense genes
• Non-Classical Monocytes: A specialized subset of monocytes involved in inflammatory responses that displayed overexpression patterns linked to disease activity

Importantly, the degree of gene overexpression correlated directly with measures of lupus disease activity, meaning patients with more active disease showed higher levels of these infection-fighting genes.

Can These Genes Predict Who Has Lupus?

The research team used machine learning—a form of artificial intelligence—to test whether patterns of these gene expressions could identify lupus patients. The results were promising: using only the primary immunodeficiency genes as input, the algorithms achieved 80% accuracy in distinguishing lupus patients from healthy controls, and 74% accuracy in identifying active lupus from inactive lupus. This suggests these genes could eventually become biomarkers—measurable indicators—for disease diagnosis and severity assessment.

"PID genes are not only genetically associated with SLE but are also broadly over-expressed, particularly in active disease," the researchers noted, highlighting how these findings reveal "the profound link between pathways governing host defense and SLE immunopathogenesis". This connection suggests that therapeutic strategies targeting these overactive infection-defense pathways could offer new treatment options for lupus patients.

The discovery opens a new avenue for understanding why lupus develops and progresses. Rather than viewing lupus solely as a breakdown in immune tolerance, scientists now recognize that dysregulation of genes normally protecting against infection may be a core driver of the disease. Future research will likely focus on developing drugs that can selectively modulate these overactive pathways, potentially offering more precise treatments than current broad-spectrum immunosuppressants.