University Hospital of Cologne
We are focused on defining the genetic and molecular mechanisms underlying human inflammatory disorders, called “autoinflammatory diseases”. Our ultimate goal is to propose novel molecular-targeted therapies for patients with autoinflammatory disorders by combining genetics and molecular immunology approaches.
Our research: Autoinflammatory diseases are caused by genetic hyperactivation of innate immunity. Despite recent advancements in sequencing technologies, more than 50% the patients still lack genetic diagnosis, thus hampering effective targeted therapies. By investigating patient samples and associated animal models, we are specifically focusing on two aspects of autoinflammatory diseases:
1) Cell death-induced autoinflammation
2) Autoinflammation and fibrosis
Our successes: Dr. Oda and the team in the National Institutes of Health previously discovered a novel autoinflammatory diseases caused by genetic hyperactivation of TNF-induced cell death, termed “CRIA” (Cleavage-resistant RIPK1-Induced Autoinflammation). CRIA is caused by missense mutations in RIPK1 disrupting its caspase cleavage residue. We identified that these uncleavable RIPK1 then cause a gain-of-function by its non-sequestered kinase and scaffold activities, resulting in deregulated cell death-induced inflammation in CRIA patients and associated animal models (Lalaoui et al., Nature, 2020). We further reported a novel patient with HOIP deficiency with genetic impairments in LUBAC, the E3 ligase complex for linear ubiquitylation. Immunological and transcriptomic investigations discovered a specific type I interferon-mediated pathology underlying the autoinflammation of the patient (Oda et al., Front Immunol, 2018).
1) Develop genetics-guided targeted therapies for autoinflammatory diseases
2) Establish patient-originated novel hypotheses to inform basic immunology
Our methods/techniques: We are taking an innovative trans-disciplinary approach by combining clinical genome sequencing and bioinformatic analyses with molecular immunology experiments.
Figure 1: Concept of human genetics-guided bridging of clinical medicine and basic research.
Figure 2: Colitis in a patient with LUBAC deficiency.
Figure 3: Adenoidal spectral flowcytometry from a patient with LUBAC deficiency showing specific reduction of germinal center B cells (arrowhead).
Figure 4: Genetic diagnosis-guided treatment response in arthritis (left) and colitis (right) to anti-TNF therapies in a patient with LUBAC deficiency.