From Variant to Mechanism: An Integrative Approach Uncovers TLR8-Driven Immune Dysregulation 

Scientists have discovered how a rare variant in the TLR8 gene — an essential component of the body’s first line of defense against viral infections — can upset immune balance. In two siblings, the mutation caused recurrent infections, chronic inflammation, and autoimmune complications. The findings shed new light on how alterations in innate immune receptors contribute to inborn errors of immunity.

With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Determining whether a specific DNA change is truly disease-causing remains one of the central challenges in modern clinical immunology.

In a new study, computational structural modeling was combined with laboratory-based functional assays to move beyond gene discovery and pinpoint the biological consequences of a rare TLR8 mutation (A518T) identified in two siblings suffering from recurrent infections, chronic inflammation, and autoimmune complications. The project brought together researchers from the Leibniz Institute of Virology, the Centre for Structural Systems Biology, Klinikum Bad Bramstedt, German Center for Child and Adolescent Health (DZKJ), the University Medical Center Hamburg-Eppendorf, Ludwig Maximilian University of Munich, the Zentrum für Humangenetik, Tübingen and the Center for Genomics and Transcriptomics (CeGaT) in Tübingen, combining expertise in virology, structural biology, clinical medicine and genomics.

How TLR8 Influences Immunity

The tlr8 gene provides instructions for building Toll-like receptor 8, an important sensor in the immune system. This receptor helps the body detect genetic material from viruses and bacteria and triggers immune responses to eliminate them. But when its activity is not properly controlled, it can also overstimulate the immune system and contribute to inflammation and autoimmunity.

After identifying the shared TLR8 mutation through genetic sequencing, the team conducted in-depth functional studies using the patients’ immune cells and in vitro systems. They found that key immune warning signals — particularly a pathway controlled by a molecule called NF-κB — were switched on more strongly in the carriers of the mutation than in the normal population. The patients’ cells also produced higher levels of inflammatory substances, showing that the mutation makes the receptor overly active (gain-of-function). 

Paradoxically, the total amount of TLR8 protein in the cells was lower than normal because the mutated protein was degraded more quickly. However, computational modeling conducted by scientists from the research department of Integrative Virology at the Leibniz Institute of Virology revealed a key structural change: The A518T mutation introduced additional water-mediated hydrogen bonds that stabilized the active TLR8 homodimer interface. 

The result was a molecular imbalance: even though there was less protein overall, immune signaling remained unusually strong and persistent.

Bridging Genetics and Function

Beyond clarifying the cause of disease in the siblings, the study highlights the value of integrating computational structural biology with experimental immunology as a complementary strategy for interpreting rare genetic variants in key immune genes.

“By bridging computational modeling and functional validation, the research provides a roadmap to break down uncertain genetic findings, which together with structural and molecular-level interpretation, can be leveraged for diagnosis and personalized care for patients with rare immune disorders”, said Prof. Marcus Altfeld, head of the research department Virus Immunology at the Leibniz-Institute of Virology.

Because TLR8 is naturally involved in detecting viral and bacterial infections, these findings also offer valuable context for understanding how innate immunity senses pathogens, with broad relevance to viral immunology.

Orginal Publication

Skenteris NT, Luttermann E, Nair S, Evangelakos I, Pujantell M, Eggers M, Hausmann F, Bérouti M, Padoan B, Flomm FJ, Claussen JM, Grünhagel B, Salfelder A, Beifuss B, Biskup S, Blümke P, Rading K, Hildebrandt H, Matschl U, Giesemann-Jansen S, Hennesen J, Nikolaev VO, Kutsche M, Kubisch C, Koch-Nolte F, Tomas NM, Tolosa E, Lütgehetmann M, Stahl FR, Hornung V, Bunders MJ, Schlein C, Topf M, Kötter I, Altfeld M. Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome. JCI Insight. 11(4):e187422. doi: 10.1172/jci.insight.187422.