Lupus trigger unveiled

A single genetic mutation can cause lupus, an autoimmune disease leading to severe inflammation. Researchers at the Max Planck Institute for Infection Biology discovered a mechanism in children that triggers lupus. This mechanism usually controls the amount of a specific immune receptor that recognizes the genetic material of pathogens. 

When disrupted, the receptors accumulate, causing the immune system to recognize the body’s genetic material. A lupus patient with this disrupted mechanism due to a single mutation was identified in collaboration with physicians. This finding sheds light on how lupus can be triggered in some cases.

The quick response of the innate immune system against invaders is crucial. Researchers at the Max Planck Institute for Infection Biology, led by Olivia Majer, study control mechanisms to prevent it from harming the body. They focus on Toll-like receptor 7, which identifies the genetic material of viruses and bacteria, activating an immune response. Understanding these controls helps balance the system’s solid but nonspecific defense until the adaptive immune system takes over.

For a quick immune response, a balance of receptors is crucial. Olivia Majer’s team studied the impact when this balance is disrupted. They focused on a protein complex called BORC and found it’s necessary for degrading Toll-like receptor 7 in cells. BORC requires another protein, UNC93B1, for proper degradation. 

If this process fails, the receptor accumulates in immune cells, causing problems. Too many receptors can lead to recognizing the body’s genetic material, triggering an immune response against itself, a factor in lupus. Although this was known from mouse experiments, BORC and UNC93B1 had just been linked to human lupus.

Confirmation of the findings came via phone. Fabian Hauck, who specializes in immune disorders at Ludwig Maximilian University Hospital, Munich, learned about Olivia Majer’s research when one of his patients had a mutation in the gene for a protein called UNC93B1. Majer’s team precisely identified this protein.

Majer said, “When I got the first call from Fabian Hauck, I thought it was too good to be true. But within eight busy weeks of joined effort, we were able to confirm that the mutation in UNC93B1 was the cause of this patient’s lupus.”

Hauck and Majer’s findings, published in Science Immunology, reveal a new mechanism triggering a severe form of lupus manifesting in infancy. Collaborating with researchers from the Technical University of Dresden, they identified UNC93B1 mutations associated with lupus. 

This discovery could transform lupus treatment by incorporating mutation testing and offering new therapeutic approaches. Previously, treatment focused on inflammation suppression. Targeting the newly discovered mechanism may prevent inflammation, reducing the disease burden for those with lupus.

The study represents a pivotal moment in lupus research, unraveling the genetic intricacies that contribute to the onset of the disease. Identifying UNC93B1 mutations as a lupus trigger opens up promising avenues for personalized treatments and preventive strategies, marking a significant advancement in the understanding and management of lupus.

Journal reference:

1. Harshita Mishra, Clarire Schlack-Leigers et al., Disrupted degradative sorting of TLR7 is associated with human lupus. Science Immunology. DOI: 10.1126/sciimmunol.adi9575.