Infectious Diseases and Pediatric Immunology

Our research in the infection-immune area focuses on the four disease groups

• Cystic fibrosis (CF, cystic fibrosis)
• Immunodeficiencies
• Autoinflammatory diseases
• Asthma and allergic diseases

Basic understanding of disease pathophysiology provides the basis for developing new drugs and the identification of new markers, which reflect the clinical course of disease, and the response to therapy (biomarkers).

Background of our research

• Research priorities
  • Cystic Fibrosis
  • neutrophilic suppressor cells
  • chemokine receptors
• Ongoing projects
• Completed projects
• Selected Publications

Background of our research

The immune system protects the body against pathogens very efficiently. White blood cells circulate through the body every day. When pathogens enter the body (eg in the respiratory tract), the so-called white blood cells migrate to the place of combat enemy contact and those with different weapons. The contact zones between hosts and pathogens same complex battlefields with advancing cell and hiding in biofilm bacteria. Here is a basic understanding of the aggressor (pathogens) and the defense mechanisms (leukocytes) are essential to develop new therapeutic approaches.

• Cystic fibrosis (CF, cystic fibrosis)is the most common lethal hereditary-disease. CF is not yet curable, so it is the focus of numerous research efforts. In the lungs of CF patients develop a chronic (lasting for years) confrontation between leukocytes and bacteria. Here, the bacteria are usually not eliminated but survive in biofilms. DNA Networks, which are released by leukocytes clog the airways and worsen lung function in cystic fibrosis. Our research has the goal to prolong the survival of CF patients by identifying new therapeutic targets relevant.
• Immunodeficiencies: "infections" are the most common reason to go to a pediatrician. Most infections are nothing more than a healthy immune response to pathogens or other environmental stresses dar. This banal infections are distinguished by rare infections, leading to severe disease and require more intensive medical treatment. This means that the vast majority of infections in children are benign and a physiological response to the environment, which serves to strengthen the immune system. If "repeated infections", e.g. Middle ear infections, tonsillitis, or pneumonia, but very frequently and / or occur in an unusual degree of severity, should be made a continuing investigation. In rare cases, hide behind such complaints immunodeficiencies. These are inherent weaknesses in the immune system, which make the patient more susceptible to infections and require special treatment. Immunodeficiencies are divided into primary (congenital) and secondary (acquired, eg HIV / AIDS) immunodeficiencies. We investigate the immunological pathomechanisms, which play a role in immune defects with the aim of new biomarkers and / or therapeutic approaches for these diseases to find.
• Autoinflammatory diseases: These diseases are characterized by an excessive and without inflammatory reaction occurring infectious stimuli ("auto-inflammation") from. The mechanisms underlying this excessive and harmful activation of the immune system underlie, are so far poorly understood.
• Asthma and allergic disease: Patients with asthma show that excess T-helper cell type 2 (Th2) immune response. We are working on new methods of gene therapy for the immunological balance in asthma to modulate / correct.

Research priorities

Cystic fibrosis

CF is a multiorgan disease, with v.a. gastrointestinal and pulmonary symptoms in the foreground. After gastrointestinal problems can be treated successfully with medication, the CF lung disease are not yet adequately treated, which means that CF patients to die more than 90% of their lung disease. In CF airways, there is a chronic interaction between leukocytes and pathogens (especially bacteria). We try to better understand this complex interaction.

Neutrophil suppressor cells

Neutrophil suppressor cells (NSC) is a subgroup of myeloid derived suppressor cells (MDSC) MDSC dar. are a heterogeneous population of cells that appear in tumors significantly increased in the peripheral blood and suppress T-cell responses. Although the role of suppressor cells, neutrophils has been described mainly in tumor immunology, there is growing evidence of their immunomodulatory role in infection and inflammation. We want to answer the question of whether neutrophils suppressor cells in inflammatory diseases in childhood and adolescence, such as have an impact on the childlike rheumatic disease activity. As an outlook, it is conceivable, then use these cells therapeutically by suitable ex vivo expansion process in these diseases.

Chemokine receptors

Our preliminary work shows (J Immunol 2008, Nat Med, 2007) that the two chemokine receptors CXCR1 and CXCR2 play a crucial role in the pathogenesis of CF lung disease. To investigate the role of CXCR1 and CXCR2 in this context to understand better, we work in cooperation with the University of Ulm on the biochemical and immunological characterization of human and murine CXCR1 / 2 receptors. We are working to identify genetic CXCR1/2 variants and to analyze whether they are compatible with clinical progression of CF patients.

Ongoing projects

Completed projects

Selected Publications

• Hector A, Schäfer H, Pöschel S, Fischer A, Fritzsching B, Ralhan A, Carevic M, Öz H, Zundel S, Hogardt M, Bakele M, Rieber N, Riethmueller J, Graepler-Mainka U, Stahl M, Bender A, Frick JS, Mall M and Hartl D. Regulatory T cell impairment in cystic fibrosis patients with chronic Pseudomonas infection. Am J Respir Crit Care Med, 2015 Jan 29
• Bakele M, Joos M, Burdi S, Allgaier N, Pöschel S, Fehrenbacher B, Schaller M, Marcos V, Kümmerle-Deschner J, Rieber N, Borregaard N, Yazdi A, Hector A and Hartl D. Localization and functionality of the inflammasome in neutrophils. J Biol Chem. 2014
• Rieber N, Gille C, Köstlin N, Schäfer I, Spring B, Ost M, Spieles H, Kugel HA, Pfeiffer M, Heininger V, Alkhaled M, Hector A, Mays L, Kormann M, Zundel S, Fuchs J, Handgretinger R, Poets CF and Hartl D. Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses. Clin Exp Immunol. 2013 Oct
• Griese M, Kappler M, Eismann C, Ballmann M, Junge S, Rietschel E, van Koningsbruggen-Rietschel S, Staab D, Rolinck-Werninghaus C, Mellies U, Köhnlein T, Wagner T, König S, Teschler H, Heuer HE, Kopp M, Heyder S, Hammermann J, Küster P, Honer M, Mansmann U, Beck-Speier I, Hartl D, Fuchs C and Hector A. Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial. Am J Respir Crit Care Med. 2013 Jul 1
• Hartl D, Latzin P, Hordijk P, Marcos V, Rudolph C, Woischnik M, Krauss-Etschmann S, Koller B, Reinhardt D, Roscher A., Roos D and Griese M. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nature Medicine 2007, Dec;13(12):1423-30. Selected for Faculty of 1000 Biology
• Lee CG*, Hartl D*, Koller B, Chen NY, Matsuura H, da Silva CA, Humbles A, Kearley J, Coyle A, Chupp G, Reed J, Flavell RA, Elias JA. Role of breast regression protein 39 in Th2 and IL-13-induced tissue responses and leukocyte apoptosis. The Journal of Experimental Medicine. 2009 May 11;206(5):1149-66; *equal contribution
• B. Koller, M. Kappler, P. Latzin, S. Takyar, M. Schreiner, A. Gaggar, M. Kormann, M. Griese, Hartl D. TLR expression on neutrophils at the pulmonary site of infection – TLR1/TLR2-mediated upregulation of TLR5 expression in CF lung disease. The Journal of Immunology 2008, 181: 2753-2763
• Hartl D, C. H. He, B. Koller, C. A. Da Silva, R. Homer, C. G. Lee, J. Elias. Acidic mammalian chitinase is secreted via an ADAM17/EGFR-dependent pathway and stimulates chemokine production by pulmonary epithelial cells. The Journal of Biological Chemistry 2008, Sep 29
• Hartl D, B. Koller, C.G. Lee, G. Chupp, J. Elias Novel biomarkers in asthma - chemokines and chitinase-like proteins. Current Opinion in Allergy & Clinical Immunology. 2009, February, 9(1):60-66
• Hartl D, S. Krauss-Etschmann, B. Koller, P.L. Hordijk, T. W. Kuijpers, E. Eber, V. Marcos, I. Bittmann, O. Eickelberg, M. Griese, J. Elias, D. Roos. Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. The Journal of Immunology. 2008 Dec 1;181(11):8053-8067
• Hartl D, Latzin P, Zissel G, Krane M, Krauss-Etschmann S, Griese M. Chemokines indicate allergic bronchopulmonary aspergillosis in cystic fibrosis patients. American Journal of Respiratory and Critical Care Medicine, 2006 Jun 15;173(12):1370-6