University Hospital of Cologne
Dr. Hirotsugu Oda
CECAD Research Center
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.