Study Identifies Single-Gene Mutation Linked to Lupus

In two distinct research endeavors, German scientists have pinpointed the singular genetic mutation associated with the incurable autoimmune disorder lupus. This breakthrough paves the way for the development of novel therapeutic strategies and the ability to conduct tests for the mutation, facilitating early detection of the disease.

Lupus triggers the immune system to assault the body’s tissues and organs, leading to inflammation in vital areas such as the kidneys, brain, central nervous system, blood vessels, lungs, and heart. Successful treatment relies on early detection of the disease, allowing for the management of inflammation before it inflicts irreversible damage to organs.

Lupus has a hereditary component, influenced by several genes, and it disproportionately affects women compared to men. Scientists at the Max Planck Institute for Infection Biology in Germany delved into the genetics of lupus, uncovering a mechanism capable of triggering the disease.

A Focus on Toll-like Receptor 7 (TLR7) Regulation

The innate immune system rapidly reacts to invading pathogens, but to avoid it attacking the body, a balance must be maintained. The researchers specifically investigated these control mechanisms, concentrating on a receptor called Toll-like receptor 7 (TLR7), which, when overactive, has been observed to instigate autoimmune disease in mice.

TLR7 identifies the genetic material of viruses and bacteria, initiating an immune response. For a prompt reaction, a specific quantity of TLR7 needs to be present in immune cells, and these cells maintain equilibrium by continuously producing and breaking down the receptors.

Olivia Majer, one of the study’s corresponding authors, explained, “We wanted to understand what happens when this balance is disturbed.”

In their investigation of TLR7, the researchers demonstrated that a protein complex called BORC is essential for degrading TLR7 within immune cells. Furthermore, BORC relies on another protein, UNC93B1, to execute the degradation process accurately. Any errors in the process result in the failure to degrade TLR7, leading to its accumulation in the cells.

“In previous mouse experiments conducted a few years ago at the University of Berkeley in California, we were already aware that an excess of these receptors poses a problem,” explained Majer.

BORC and UNC93B1’s Role in Immune System Overdrive Leading to Lupus-like Autoimmune Responses

An abundance of receptors can drive the immune system toward an autoimmune response, resembling what is observed in lupus. Until the current study, neither BORC nor UNC93B1 had been linked to the disease.

The pieces fell into place when Fabian Hauck, the co-corresponding author of the study and an expert in congenital immune disorders at the Ludwig Maximilian University Hospital in Munich, verified the presence of the UNC93B1 mutation in a patient with childhood-onset lupus. Upon examination, they discovered that the single-gene mutation led to reduced BORC interaction and the accumulation of TLR7.

Alongside the Max Planck study published in Science Immunology, a separate investigation by researchers from the Technical University of Dresden (TU Dresden), also in Germany, explored UNC93B1 gene mutations and their correlation with lupus.

The researchers focused on four patients from two families exhibiting symptoms of systemic lupus erythematosus (SLE), the most prevalent form of lupus. Given the rarity of SLE in very young children, they sought a genetic explanation and identified the UNC93B1 mutation in all family members.

Similar to Majer and Hauck’s study, these researchers found that UNC93B1 mutations led to the selective overactivation of TLR7, triggering an autoimmune assault and subsequent inflammation. Additionally, they observed that this heightened activation promoted the survival of self-reactive B cells, producing autoantibodies targeting the body’s own cells and sustaining the autoimmune attack. Consequently, they concluded that UNC93B1 regulates the activity of receptors like TLR7 to prevent autoimmunity.

UNC93B1/TLR7 Axis Identified as Key Player in Lupus Pathogenesis

Min Ae Lee-Kirsch, the corresponding author of the study, stated, “Our study establishes a direct causal link between an overactive UNC93B1/TLR7 axis and lupus pathogenesis and suggests that inhibiting overactive TLR7 could be therapeutically effective. Consequently, our findings are anticipated to expedite the further development of TLR7 inhibitors for patients with SLE and related autoimmune diseases.”

Collectively, these studies pave the way for novel therapeutic strategies that could potentially prevent the onset of the destructive inflammation characteristic of the disease. Moreover, incorporating testing for UNC93B1 mutations may become a component of lupus treatment, ensuring early disease detection.

Both studies were published in the journal Science Immunology. The Max Planck Institute study can be accessed here; the TU Dresden study here.

Read the original article on: New Atlas

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