Research Focus
Inherited defects of the immune system—referred to as primary immunodeficiencies (PIDs)—represent powerful, naturally occurring models to investigate key components of human immune function. Many PIDs present with features of autoimmunity or autoinflammation. Autoimmunity arises when the immune system mistakenly attacks the body’s own cells and tissues, failing to distinguish them from invading pathogens. While a wide range of human diseases involve autoimmune responses, the molecular mechanisms behind them often remain poorly understood.
Our research group focuses on elucidating the molecular mechanisms that regulate immune homeostasis, autoimmunity, and immune dysregulation by studying model diseases such as primary immunodeficiencies and inflammatory bowel disease. We employ advanced genomic technologies, including whole-exome sequencing of patient samples, to identify disease-causing mutations. These efforts are complemented by functional assays to validate molecular findings. Our overarching goal is to deepen the molecular understanding of immune-related disorders and contribute to the development of personalized, precision medicine strategies.
Genomics Approaches for Studying Immunodeficiency Disorders
Although autoimmune diseases have been extensively studied in animal models, clinical observations underscore the limitations of these systems—only a subset of patients benefit from therapies derived from such models. This highlights the pressing need for detailed, human-focused research into the pathophysiology of immune disorders.
We study patients with inherited immune system disorders—primary immunodeficiency diseases—which often manifest not only with increased susceptibility to infections but also with severe immune dysregulation and autoimmunity. These patients offer unique insights into the molecular basis of immune dysfunction.
Using cutting-edge genomics approaches, such as single nucleotide polymorphism (SNP) analysis and exome sequencing, we identify the underlying genetic mutations responsible for disease. Follow-up studies include molecular and cellular assays using cultured cells to explore the implicated biological pathways. These investigations enhance our understanding of immune system architecture and support the development of precision diagnostics and therapies.
Molecular Genetics of Childhood Leukemias
Our research also extends to the study of childhood blood cancers, particularly the molecular genetics of pediatric leukemias. In collaboration with other research groups at CeMM, we analyze the genomes of patients with leukemia to detect specific genomic aberrations. These findings are integrated with comprehensive drug-sensitivity profiling to uncover individual vulnerabilities of leukemic cells. This work serves as a proof-of-concept for personalized cancer therapy, aiming to tailor treatment strategies based on each patient’s unique molecular profile.
Biosketch
Kaan Boztug joined CeMM as principal investigator in 2011. He studied medicine at the Universities of Dusseldorf, Freiburg (DE), and London (UK), followed by graduate training with Iain L. Campbell at the Scripps Research Institute, La Jolla (USA) and postgraduate research and clinical training with Christoph Klein at Hanover Medical School (DE). His laboratory combines next-generation sequencing and molecular biological techniques with system biology approaches to understand the genetics and molecular pathomechanisms of rare disorders of hematopoiesis and immunity. In 2019, Kaan Boztug took over the agendas of scientific director at St. Anna Children’s Cancer Research Institute (CCRI). He is director of CeRUD Vienna Center for Rare and Undiagnosed Diseases and the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD). He holds a dual appointment as professor of pediatrics and adolescent medicine at MedUni Vienna and as consultant in pediatric hematology and oncology and head of immunology at St. Anna Children’s Hospital. He received a Starting Grant of the European Research Council (ERC) in 2012 and an ERC Consolidator Grant in 2018. In 2019, Kaan Boztug was awarded the Johann Wilhelm Ritter von Mannagetta Prize for Medicine of the Austrian Academy of Sciences. In 2022, he was awarded a corresponding membership in the Austrian Academy of Sciences (ÖAW) in the Division of Mathematics and Natural Sciences.
Selected Papers
Block J, Rashkova C, Castanon I, Zoghi S, Platon J, Ardy RC, Fujiwara M, Chaves B, Schoppmeyer R, van der Made CI, Jimenez Heredia R, Harms FL, Alavi S, Alsina L, Sanchez Moreno P, Ávila Polo R, Cabrera-Pérez R, Kostel Bal S, Pfajfer L, Ransmayr B, Mautner AK, Kondo R, Tinnacher A, Caldera M, Schuster M, Domínguez Conde C, Platzer R, Salzer E, Boyer T, Brunner HG, Nooitgedagt-Frons JE, Iglesias E, Deyà-Martinez A, Camacho-Lovillo M, Menche J, Bock C, Huppa JB, Pickl WF, Distel M, Yoder JA, Traver D, Engelhardt KR, Linden T, Kager L, Hannich JT, Hoischen A, Hambleton S, Illsinger S, Da Costa L, Kutsche K, Chavoshzadeh Z, van Buul JD, Antón J, Calzada-Hernández J, Neth O, Viaud J, Nishikimi A, Dupré L, Boztug K. Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency. N Engl J Med. 2023 Jun 21. (abstract)
Shahin T, Mayr D, Shoeb MR, Kuehn HS, Hoeger B, Giuliani S, Gawriyski LM, Petronczki ÖY, Hadjadj J, Bal SK, Zoghi S, Haimel M, Jimenez Heredia R, Boutboul D, Triebwasser MP, Rialland-Battisti F, Costedoat Chalumeau N, Quartier P, Tangye SG, Fleisher TA, Rezaei N, Romberg N, Latour S, Varjosalo M, Halbritter F, Rieux-Laucat F, Castanon I, Rosenzweig SD, Boztug K. Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation. Blood Adv. 2022 Apr 12;6(7):2444-2451. (abstract)
Shahin T et al. Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity. Sci Immunol. 2021 Nov 26;6(65):eabe3981. (abstract)
Wang L, Aschenbrenner D, Zeng Z, et al. Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice. Nat Genet. 2021 Apr;53(4):500-510. (abstract)
Kalinichenko A et al. RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis. Blood. 2021 Apr 15;137(15):2033-2045. (abstract)
Somekh I*, Thian M*, et al. CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis. Blood. 2019 Oct 31;134(18):1510-1516. (abstract)
Domínguez Conde C*, Petronczki ÖY*, Baris S*, Willmann KL*, et al. Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress. J Clin Invest. 2019 Oct 1;129(10):4194-4206. (abstract)
Serwas NK*, Hoeger B*, et al. Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis. Nat Commun. 2019 Jul 15;10(1):3106. (abstract)
Ozen A*, Comrie WA*, Ardy RC*, et al. CD55 deficiency, early-onset protein-losing enteropathy, and thrombosis. N Engl J Med. 2017 Jul 6;377(1):52-61. (abstract)
Salzer E, et al. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat Immunol. 2016 Dec;17(12):1352-1360. (abstract)
Dobbs K*, Zhang S-Y*, Domínguez Conde C*, Parolini S*, et al. Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections. New Engl J Med. 2015 Jun 18;372(25):2409-22. (abstract)
Woutsas S et al (2015). Hypomorphic mutation in TTC7A causes combined immunodeficiency wild mild structural intestinal defects. Blood. 2015 Mar 5;125(10):1674-6. (abstract)
Serwas NK et al (2015). Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflamm Bowel. 2015 Jan;21(1):40-7. (abstract)
Willmann KL*, Klaver S* et al (2014). Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nature Commun. 2014 Nov 19;5:5360. (abstract)
Ban SA et al (2014). Combined immunodeficiency evolving into predominant CD4+ lymphopenia caused by somatic chimerism in JAK3. J Clin Immunol. 2014 Nov;34(8):941-53. (abstract)
Boztug K, et al. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet. 2014 Sep;46(9):1021-7. (abstract)
Serwas NK et al (2014). Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T cell lymphopenia. Blood. 2014 Jul 24;124(4):655-7. (abstract)
Salzer E et al (2014). Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by loss-of-function mutation in IL21. J Allergy Clin Immunol. 2014 Jun;133(6):1651-9.e12. (abstract)
Salzer E*, Santos-Valente E* et al (2013). B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. Blood. 2013 Apr 18;121(16):3112-6. (abstract)
Santos-Valente et al (2013). A novel mutation in the complement component 3 gene in a patient with selective IgA deficiency. J Clin Immunol. 2013 Jan;33(1):127-33. (abstract)
Glocker EO*, Kotlarz D*, Boztug K* et al (2009). Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. New Engl J Med. 2009 Nov 19;361(21):2033-45. (abstract)
Boztug K et al (2009). A syndrome with congenital neutropenia and mutations in G6PC3. New Engl J Med. 2009 Jan 1;360(1):32-43. (abstract)
* shared first authorship
