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Centrum für Chronische Immundefizienz - CCI

Research Group "Human B-cell immunodeficiency"

Prof. Dr. Klaus Warnatz

The research group „Human B-cell immunodeficiency“ is concerned with primary and secondary immunodeficiency disorders of the adult. At the interface of clinical and basic science, the classification, diagnostics and pathogenesis of clinically relevant disorders are at the centre of our interest.

CV

since 2008Senior Consultant, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg
2006Habilitation in Internal Medicine
2006-2008Consultant, Div. of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg
1999-2006Resident, Div. of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg
1997-1999 Post Doc, PD Dr. Hermann Eibel, KFR, University of Freiburg
1994-1997Post Doc, Prof. D. Carson, University of California at San Diego, USA
1991-1994 Resident, Dept. Gastroenterology, University Medical Clinic Rechts der Isar, TU München
1984-1991Study of Medicine in Aachen

Research Areas

Primary Immunodeficiencies in Adults

While most primary immunodeficiency disorders already present during childhood, some disorders manifest preferentially later in life. The most common form is the common variable immunodeficiency (CVID). This diagnosis comprises a very heterogeneous group of idiopathic antibody deficiency syndromes. Genetic as well as environmental factors contribute to its manifestation in most patients. A much less common immunodeficiency of the adult is the idiopathic CD4 lymphopenia (ICL). The clinical picture resembles the HIV-infection. The underlying pathogenesis is not yet understood.

 

Summary

Common variable immunodeficiency (CVID) represents the most common immunodeficiency of the adult. CVID is a heterogeneous antibody deficiency syndrome. While central B cell development usually occurs undisturbed, peripheral antigen driven B cell differentiation into memory B cells or long lived plasma cells is often disrupted. CVID patients usually present with recurrent bacterial infections of the respiratory and gastrointestinal tract. A subgroup of patients is characterized by autoimmune manifestations, lymphoproliferation and or granulomatous inflammation. The research of our group is focused on

  • a pathogenetically and clinically relevant classification of CVID
  • the discovery of monogenetic defects causing CVID
  • the characterization of B cell intrinsic defects of differentiation
  • the characterization of defects in germinal centre formation
  • the characterization of the immune dysregulation in patients with secondary disease manifestations.

The aim is a better pathogenetic understanding of the various underlying defects in order to improve diagnosis and treatment of patients with CVID.

Cooperation Partner

EURO-PADnet - European Network of primary antibody deficiency syndromes

Funding

  • EURO-PADnet, European FP7
  • CRC620, DFG
  • CCI Tandemproject, BMBF

Publications

Wehr, C., T. Kivioja, C. Schmitt, B. Ferry, T. Witte, E. Eren, M. Vlkova, M. Hernandez, D. Detkova, P. R. Bos, G. Poerksen, B. H. von, U. Baumann, S. Goldacker, S. Gutenberger, M. Schlesier, C. F. Bergeron-van der, G. M. Le, P. Debre, R. Jacobs, J. Jones, E. Bateman, J. Litzman, P. M. van Hagen, A. Plebani, R. E. Schmidt, V. Thon, I. Quinti, T. Espanol, A. D. Webster, H. Chapel, M. Vihinen, E. Oksenhendler, H. H. Peter, and K. Warnatz. 2008. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 111:77.

Warnatz, K., and M. Schlesier. 2008. Flow cytometric phenotyping of common variable immunodeficiency. Cytometry B Clin. Cytom. 74B:261.

Goldacker, S., R. Draeger, K. Warnatz, D. Huzly, U. Salzer, J. Thiel, H. Eibel, M. Schlesier, and H. H. Peter. 2007. Active vaccination in patients with common variable immunodeficiency (CVID). Clin. Immunol. 124:294

Horn, J., V. Thon, D. Bartonkova, U. Salzer, K. Warnatz, M. Schlesier, H. H. Peter, and B. Grimbacher. 2007. Anti-IgA antibodies in Common Variable Immunodeficiency (CVID): Diagnostic workup and therapeutic strategy. Clin. Immunol. 122:152.

Bossaller, L., J. Burger, R. Draeger, B. Grimbacher, R. Knoth, A. Plebani, A. Durandy, U. Baumann, M. Schlesier, A. A. Welcher, H. H. Peter, and K. Warnatz. 2006. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol. 177:4927.

Warnatz, K., L. Bossaller, U. Salzer, A. Skrabl-Baumgartner, W. Schwinger, B. M. van der, J. J. van Dongen, M. Orlowska-Volk, R. Knoth, A. Durandy, R. Draeger, M. Schlesier, H. H. Peter, and B. Grimbacher. 2006. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107:3045.

Ferry, B. L., J. Jones, E. A. Bateman, N. Woodham, K. Warnatz, M. Schlesier, S. A. Misbah, H. H. Peter, and H. M. Chapel. 2005. Measurement of peripheral B cell subpopulations in common variable immunodeficiency (CVID) using a whole blood method. Clin. Exp. Immunol. 140:532.

Grimbacher, B., A. Hutloff, M. Schlesier, E. Glocker, K. Warnatz, R. Drager, H. Eibel, B. Fischer, A. A. Schaffer, H. W. Mages, R. A. Kroczek, and H. H. Peter. 2003. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat. Immunol. 4:261

Groth, C., R. Drager, K. Warnatz, G. Wolff-Vorbeck, S. Schmidt, H. Eibel, M. Schlesier, and H. H. Peter. 2002. Impaired up-regulation of CD70 and CD86 in naive (CD27-) B cells from patients with common variable immunodeficiency (CVID). Clin. Exp. Immunol. 129:133.

Warnatz, K., C. Wehr, R. Drager, S. Schmidt, H. Eibel, M. Schlesier, and H. H. Peter. 2002. Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology 206:502.

Warnatz, K., A. Denz, R. Drager, M. Braun, C. Groth, G. Wolff-Vorbeck, H. Eibel, M. Schlesier, and H. H. Peter. 2002. Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 99:1544.

Summary

Idiopathic CD4 Lymphocytopenia (ICL) was first described by the Center of Disease Control in 1993 as a HIV-negative immunodeficiency characterized by the reduction of CD4 T cells below 300/µl or 20% of T cells. Like in HIV infection patients often manifest with opportunistic infections. Despite numerous case reports, little systematic research of this rare immunodeficiency has been performed in order to elucidate the underlying immunologic condition.

Publications

Walker, U. A., and K. Warnatz. 2006. Idiopathic CD4 lymphocytopenia. Curr. Opin. Rheumatol. 18:389.

Warnatz, K., R. Draeger, M. Schlesier, and H. H. Peter. 2000. Successful IL-2 therapy for relapsing herpes zoster infection in a patient with idiopathic CD4+ T lymphocytopenia. Immunobiology 202:204.

Secondary Immunodeficiency in Adults

With increasingly powerful therapeutic options for autoimmune as well as malignant diseases, secondary immunodeficiency leading to failure of vaccination and increased susceptibility to infections becomes more and more evident. The susceptibility to infection can be generalized or more specific. Severe leukopenia or lymphopenia due to immunosuppressive therapy cause a broad spectrum of infectious diseases, while the re-activation of tuberculosis under anti TNFa therapy for example is the expression of a rather selective immunodeficiency. Currently, we are still lacking good surrogate markers for the susceptibility and manifestation of secondary immunodeficiency in many instances. This, however, is important information for the planning and surveillance of immunosuppressive therapies. Therefore one focus of the research group is the characterization of the immune system under various immunosuppressive regiments.

 

Summary

Immunosuppressive therapy is applied in the treatment of autoimmune diseases and post transplantation. While it is difficult to separate immune dysregulation secondary to effects of therapy from the underlying disease in autoimmune disorders, changes in the immune system of patients post transplant allow more readily to evaluate the impact of immunosuppressive regimes on the immune system. In a first approach we currently analyze the effect of calcineurin and mTOR inhibitors on the specific immune system in patients post renal transplantation. In a second trial we investigate alterations of circulating peripheral lymphocyte subpopulations in patients with long term anti-TNF therapy.

Cooperation Partners

  • Division of Nephrology, Medical Center - University of Freiburg

Funding

  • Pharmaceutical Companies (Novartis, Wyeth, Abbott)

Publications

PubMed

Impact of Rituximab on Immunoglobulin Concentrations and B Cell Numbers after Cyclophosphamide Treatment in Patients with ANCA-Associated Vasculitides. Venhoff N, Effelsberg NM, Salzer U, Warnatz K, Peter HH, Lebrecht D, Schlesier M, Voll RE, Thiel J. PLoS One. 2012;7(5):e37626. Epub 2012 May 21.

CCL18 -- Potential Biomarker of Fibroinflammatory Activity in Chronic Periaortitis. Kollert F, Binder M, Probst C, Uhl M, Zirlik A, Kayser G, Voll RE, Peter HH, Zissel G, Prasse A, Warnatz K. J Rheumatol. 2012 May 15. [Epub ahead of print]

Common variable immunodeficiency (CVID): exploring the multiple dimensions of a heterogeneous disease. Salzer U, Unger S, Warnatz K. Ann N Y Acad Sci. 2012 Feb;1250:41-9. doi: 10.1111/j.1749-6632.2011.06377.x. Epub 2012 Feb 2. Review.

Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, Plebani A, Lougaris V, Quinti I, Thon V, Litzman J, Schlesier M, Warnatz K, Thiel J, Rolink AG, Eibel H. J Immunol. 2012 Jan 1;188(1):497-503. Epub 2011 Nov 28.

Genetic CD21 deficiency is associated with hypogammaglobulinemia. Thiel J, Kimmig L, Salzer U, Grudzien M, Lebrecht D, Hagena T, Draeger R, Völxen N, Bergbreiter A, Jennings S, Gutenberger S, Aichem A, Illges H, Hannan JP, Kienzler AK, Rizzi M, Eibel H, Peter HH, Warnatz K, Grimbacher B, Rump JA, Schlesier M. J Allergy Clin Immunol. 2012 Mar;129(3):801-810.e6. Epub 2011 Oct 27.

Outcome of allogeneic stem cell transplantation in adults with common variable immunodeficiency. Rizzi M, Neumann C, Fielding AK, Marks R, Goldacker S, Thaventhiran J, Tarzi MD, Schlesier M, Salzer U, Eibel H, Warnatz K, Finke J, Grimbacher B, Peter HH. J Allergy Clin Immunol. 2011 Dec;128(6):1371-1374.e2. Epub 2011 Sep 17. 

Analysis of bulk and virus-specific CD8+ T cells reveals advanced differentiation of CD8+ T cells in patients with common variable immunodeficiency. Kuntz M, Goldacker S, Blum HE, Pircher H, Stampf S, Peter HH, Thimme R, Warnatz K. Clin Immunol. 2011 Nov;141(2):177-86. doi: 10.1016/j.clim.2011.07.006. Epub 2011 Aug 5.

Btk is a positive regulator in the TREM-1/DAP12 signaling pathway. Ormsby T, Schlecker E, Ferdin J, Tessarz AS, Angelisová P, Köprülü AD, Borte M, Warnatz K, Schulze I, Ellmeier W, Horejsí V, Cerwenka A. Blood. 2011 Jul 28;118(4):936-45. Epub 2011 Jun 9.

T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency. Ochtrop ML, Goldacker S, May AM, Rizzi M, Draeger R, Hauschke D, Stehfest C, Warnatz K, Goebel H, Technau-Ihling K, Werner M, Salzer U, Eibel H, Schlesier M, Peter HH. Blood. 2011 Jul 14;118(2):309-18. Epub 2011 May 16.

Telomere-dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency. Visentini M, Cagliuso M, Conti V, Carbonari M, Mancaniello D, Cibati M, Siciliano G, Giorda E, Keller B, Warnatz K, Fiorilli M, Quinti I. Eur J Immunol. 2011 Mar;41(3):854-62. doi: 10.1002/eji.201040862. Epub 2011 Feb 2.

CD21low B cells in common variable immunodeficiency do not show defects in receptor editing, but resemble tissue-like memory B cells. Rakhmanov M, Gutenberger S, Keller B, Schlesier M, Peter HH, Warnatz K. Blood. 2010 Nov 4;116(18):3682-3. 

Common variable immunodeficiency at the end of a prospering decade: towards novel gene defects and beyond. Eibel H, Salzer U, Warnatz K. Curr Opin Allergy Clin Immunol. 2010 Dec;10(6):526-33. Review.

Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Pérez de Diego R, Sancho-Shimizu V, Lorenzo L, Puel A, Plancoulaine S, Picard C, Herman M, Cardon A, Durandy A, Bustamante J, Vallabhapurapu S, Bravo J, Warnatz K, Chaix Y, Cascarrigny F, Lebon P, Rozenberg F, Karin M, Tardieu M, Al-Muhsen S, Jouanguy E, Zhang SY, Abel L, Casanova JL. Immunity. 2010 Sep 24;33(3):400-11. Epub 2010 Sep 9.

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Rohr J, Beutel K, Maul-Pavicic A, Vraetz T, Thiel J, Warnatz K, Bondzio I, Gross-Wieltsch U, Schündeln M, Schütz B, Woessmann W, Groll AH, Strahm B, Pagel J, Speckmann C, Janka G, Griffiths G, Schwarz K, zur Stadt U, Ehl S. Haematologica. 2010 Dec;95(12):2080-7. Epub 2010 Sep 7.

Fatal adult-onset antibody deficiency syndrome in a patient with cartilage hair hypoplasia. Horn J, Schlesier M, Warnatz K, Prasse A, Superti-Furga A, Peter HH, Salzer U. Hum Immunol. 2010 Sep;71(9):916-9. Epub 2010 Jun 9.

B cell receptor-mediated calcium signaling is impaired in B lymphocytes of type Ia patients with common variable immunodeficiency. Foerster C, Voelxen N, Rakhmanov M, Keller B, Gutenberger S, Goldacker S, Thiel J, Feske S, Peter HH, Warnatz K. J Immunol. 2010 Jun 15;184(12):7305-13. Epub 2010 May 21.

A homozygous CARD9 mutation in a family with susceptibility to fungal infections. Glocker EO, Hennigs A, Nabavi M, Schäffer AA, Woellner C, Salzer U, Pfeifer D, Veelken H, Warnatz K, Tahami F, Jamal S, Manguiat A, Rezaei N, Amirzargar AA, Plebani A, Hannesschläger N, Gross O, Ruland J, Grimbacher B. N Engl J Med. 2009 Oct 29;361(18):1727-35.

Disseminated tuberculosis in a patient with idiopathic CD4+ lymphocytopenia. Thoden J, Venhoff N, Daskalakis M, Schmitt-Gräeff A, Dräger R, Schlesier M, Warnatz K, Peter HH. Rheumatology (Oxford). 2009 Oct;48(10):1329-30. Epub 2009 Aug 11.

Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Rakhmanov M, Keller B, Gutenberger S, Foerster C, Hoenig M, Driessen G, van der Burg M, van Dongen JJ, Wiech E, Visentini M, Quinti I, Prasse A, Voelxen N, Salzer U, Goldacker S, Fisch P, Eibel H, Schwarz K, Peter HH, Warnatz K. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13451-6. Epub 2009 Jul 29.

B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Böhm J, Kienzler AK, Pan-Hammarström Q, Hammarström L, Rakhmanov M, Schlesier M, Grimbacher B, Peter HH, Eibel H. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13945-50. Epub 2009 Aug 6.

Cryptococcosis in HIV-negative immunodeficiency. Warnatz K. Clin Adv Hematol Oncol. 2008 Jun;6(6):448-52. Review.

Flowcytometric phenotyping of common variable immunodeficiency. Warnatz K, Schlesier M. Cytometry B Clin Cytom. 2008 Sep;74(5):261-71.

Hepatitis E and jaundice in an HIV-positive pregnant woman. Thoden J, Venhoff N, Miehle N, Klar M, Huzly D, Panther E, Jilg N, Kunze M, Warnatz K. AIDS. 2008 Apr 23;22(7):909-10.

The EUROclass trial: defining subgroups in common variable immunodeficiency. Wehr, C., T. Kivioja, C. Schmitt, B. Ferry, T. Witte, E. Eren, M. Vlkova, M. Hernandez, D. Detkova, P. R. Bos, G. Poerksen, B. H. von, U. Baumann, S. Goldacker, S. Gutenberger, M. Schlesier, C. F. Bergeron-van der, G. M. Le, P. Debre, R. Jacobs, J. Jones, E. Bateman, J. Litzman, P. M. van Hagen, A. Plebani, R. E. Schmidt, V. Thon, I. Quinti, T. Espanol, A. D. Webster, H. Chapel, M. Vihinen, E. Oksenhendler, H. H. Peter, and K. Warnatz. Blood 2008 111:77.

Flow cytometric phenotyping of common variable immunodeficiency. Warnatz, K., and M. Schlesier. Cytometry B Clin. Cytom. 2008 74B:261.

Active vaccination in patients with common variable immunodeficiency (CVID). Goldacker, S., R. Draeger, K. Warnatz, D. Huzly, U. Salzer, J. Thiel, H. Eibel, M. Schlesier, and H. H. Peter. Clin. Immunol. 2007 124:294

Anti-IgA antibodies in Common Variable Immunodeficiency (CVID): Diagnostic workup and therapeutic strategy. Horn, J., V. Thon, D. Bartonkova, U. Salzer, K. Warnatz, M. Schlesier, H. H. Peter, and B. Grimbacher. Clin. Immunol. 2007 122:152.

ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. Bossaller, L., J. Burger, R. Draeger, B. Grimbacher, R. Knoth, A. Plebani, A. Durandy, U. Baumann, M. Schlesier, A. A. Welcher, H. H. Peter, and K. Warnatz. J. Immunol. 2006 177:4927.

Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Warnatz, K., L. Bossaller, U. Salzer, A. Skrabl-Baumgartner, W. Schwinger, B. M. van der, J. J. van Dongen, M. Orlowska-Volk, R. Knoth, A. Durandy, R. Draeger, M. Schlesier, H. H. Peter, and B. Grimbacher. Blood 2006 107:3045.

Measurement of peripheral B cell subpopulations in common variable immunodeficiency (CVID) using a whole blood method. Ferry, B. L., J. Jones, E. A. Bateman, N. Woodham, K. Warnatz, M. Schlesier, S. A. Misbah, H. H. Peter, and H. M. Chapel. Clin. Exp. Immunol. 2005 140:532.

Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Grimbacher, B., A. Hutloff, M. Schlesier, E. Glocker, K. Warnatz, R. Drager, H. Eibel, B. Fischer, A. A. Schaffer, H. W. Mages, R. A. Kroczek, and H. H. Peter. Nat. Immunol. 2003 4:261

Impaired up-regulation of CD70 and CD86 in naive (CD27-) B cells from patients with common variable immunodeficiency (CVID). Groth, C., R. Drager, K. Warnatz, G. Wolff-Vorbeck, S. Schmidt, H. Eibel, M. Schlesier, and H. H. Peter. Clin. Exp. Immunol. 2002 129:133.

Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Warnatz, K., C. Wehr, R. Drager, S. Schmidt, H. Eibel, M. Schlesier, and H. H. Peter. Immunobiology 2002 206:502.

Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Warnatz, K., A. Denz, R. Drager, M. Braun, C. Groth, G. Wolff-Vorbeck, H. Eibel, M. Schlesier, and H. H. Peter. Blood. 2002 99:1544.

Idiopathic CD4 lymphocytopenia. Walker, U. A., and K. Warnatz. Curr. Opin. Rheumatol. 2006 18:389.

Successful IL-2 therapy for relapsing herpes zoster infection in a patient with idiopathic CD4+ T lymphocytopenia. Warnatz, K., R. Draeger, M. Schlesier, and H. H. Peter. Immunobiology. 2000 202:204.

Team

Group Leader
Klaus Warnatzklaus.warnatz@uniklinik-freiburg.de270-77640

 

Assistant

Beate Rollerbeate.roller@uniklinik-freiburg.de270-77640

 

Postdoctoral Fellows

Bärbel Kellerbaerbel.keller@uniklinik-freiburg.de270-77691
Eunhee Cindy Leeeunhee.lee@uniklinik-freiburg.de270-71060

 

Walter-Hitzig Fellow

Karina Mescouto de Melokarina.mescouto.melo@uniklinik-freiburg.de270-71060

 

PhD Students

Susanne Ungersusanne.unger@uniklinik-freiburg.de270-77727

 

MD Students

Mirjam Teckentrupmirjam.teckentrup@uniklinik-freiburg.de270-71060
Christian Kannechristian.kanne@uniklinik-freiburg.de
Marlene Reinckemarlene.reincke@uniklinik-freiburg.de270-71060
Verena Koemmverena.koemm@uniklinik-freiburg.de270-77640

 

Technicians

Sylvia Gutenbergersylvia.gutenberger@uniklinik-freiburg.de270-71060
Ina Stumpfina.stumpf@uniklinik-freiburg.de270-77727
Contact

Prof. Dr. med. Klaus Warnatz

MEDICAL CENTER - UNIVERSITY OF FREIBURG
Center for Chronic Immunodeficiency
at Center for Translational Cell Research

Breisacher Str. 115
79106 Freiburg
Germany

Phone: +49 (0)761 270-77640 (Secretary)
Fax: +49 (0)761 270-77600
klaus.warnatz@uniklinik-freiburg.de