HLH Center of Excellence

Clinical

Immunobiology; translational research; immunologic methods development

Research

Clinical investigation of primary immunodeficiency disorders (with emphasis on disorders of immuno dysregulation and B-cell disorders); immuno-reconstitution following blood and marrow transplantation; diagnostic immunology (with emphasis on flow cytometry)

MD: University of Leiden, Leiden, The Netherlands, 1989.

PhD: University of Leiden, Leiden, The Netherlands, 2002.

Residency: Pediatrics, University of Florida, Gainesville, Florida, 1993.

Fellowship: Allergy/Immunology, Duke University Medical Center, Durham, North Carolina, 1995.

Fellowship: Clinical Laboratory Immunology, National Institutes of Health, Bethesda, Maryland, 2001.

Jodele S, Bleesing JJ, Mehta PA, Filipovich AH, Laskin BL, Goebel J, Pinkard SL, Davies SM. Successful early intervention for hyperacute transplant-associated thrombotic microangiopathy following pediatric hematopoietic stem cell transplantation. Pediatr Transplant. 2010 Nov 5.

Eckrich MJ, Yang E, Domm J, Ho R, Calder C, Manes B, Bleesing J, Frangoul H. A Unique Clinical Presentation of X-Linked Lymphoproliferative Syndrome With a Novel Mutation in SH2D1A and Review of the Literature. J Pediatr Hematol Oncol. 2010 Oct 21.

Marsh RA, Bleesing JJ, Filipovich AH. Using flow cytometry to screen patients for X-linked lymphoproliferative disease due to SAP deficiency and XIAP deficiency. J Immunol Methods. 2010 Oct 31;362(1-2):1-9.

Marsh RA, Villanueva J, Kim MO, Zhang K, Marmer D, Risma KA, Jordan MB, Bleesing JJ, Filipovich AH. Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clin Immunol. 2009 Jul;132(1):116-23.

Marsh RA, Villanueva J, Zhang K, Snow AL, Su HC, Madden L, Mody R, Kitchen B, Marmer D, Jordan MB, Risma KA, Filipovich AH, Bleesing JJ. A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency. Cytometry B Clin Cytom. 2009 Sep;76(5):334-44.

Hansen MD, Filipovich AH, Davies SM, Mehta P, Bleesing J, Jodele S, Hayashi R, Barnes Y, Shenoy S. Allogeneic hematopoietic cell transplantation (HCT) in Hurler's syndrome using a reduced intensity preparative regimen. Bone Marrow Transplant. 2008 Feb;41(4):349-53.

Bhatla D, Davies SM, Shenoy S, Harris RE, Crockett M, Shoultz L, Smolarek T, Bleesing J, Hansen M, Jodele S, Jordan M, Filipovich AH, Mehta PA. Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2008 Aug;42(3):159-65.

Zhang K, Johnson JA, Biroschak J, Villanueva J, Lee SM, Bleesing JJ, Risma KA, Wenstrup RJ, Filipovich AH. Familial haemophagocytic lymphohistiocytosis in patients who are heterozygous for the A91V perforin variation is often associated with other genetic defects. Int J Immunogenet. 2007 Aug;34(4):231-3.

Book Chapters

JJH Bleesing. Assays for B Cell and Germinal Center Development (unit 7.34). In Current Protocols in Immunology. JE Coligan, BE Bierer, DH Margulies, EM Shevach, W Strober (eds.). Hoboken: John Wiley & Sons, 2004.

JJH Bleesing, TA Fleisher, JM Puck. Autoimmune lymphoproliferative syndrome (ALPS). In Immunologic Disorders in Infants and Children. 5th ed. ER Stiehm, HD Ochs, JA Winkelstein (eds). Philadelphia, PA: WB Saunders, 2004.

Michael B. Jordan, MD Member, Langerhans Cell Histiocytosis Center 513-636-7287 michael.jordan@cchmc.org

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Michael B. Jordan, MD

Member, Langerhans Cell Histiocytosis Center

Member, Division of Immunobiology

Member, Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute

Academic Affiliations

Associate Professor, UC Department of Pediatrics

Phone 513-636-7287

Fax 513-803-1969

Email michael.jordan@cchmc.org

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Clinical

Histiocytic disorders: HLH and LCH

Research

Better understanding histiocytic disorders and developing novel therapies for them; regulation of the immune response; immunotherapy of cancer

MD: UT Southwestern, Dallas, TX, 1993.

Residency: Children's Hospital of Dallas, Dallas, TX, 1996.

Fellowship: The Children's Hospital, Denver, CO, 2002.

Certification: American Board of Pediatrics, 1996; Sub-board of Pediatric Heme/Onc, 2002.

Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, Mehta PA, Davies SM, Jordan MB, Bleesing JJ, Filipovich AH. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 23;116(26):5824-31.

Mehta PA, Vinks AA, Filipovich A, Bleesing J, Jodele S, Jordan MB, Marsh R, Tarin R, Edwards S, Fearing D, Lawrence J, Davies SM. Alternate-day micafungin antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study. Biol Blood Marrow Transplant. 2010 Oct;16(10):1458-62.

Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, Bleesing JJ, Zhang K, Filipovich AH. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. 2010 Aug 19;116(7):1079-82.

Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, Bleesing JJ, Filipovich AH, Zhang K. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer. 2010 Jul 15;55(1):134-40.

Lykens JE, Terrell CE, Zoller EE, Divanovic S, Trompette A, Karp CL, Aliberti J, Flick MJ, Jordan MB. Mice with a selective impairment of IFN-gamma signaling in macrophage lineage cells demonstrate the critical role of IFN-gamma-activated macrophages for the control of protozoan parasitic infections in vivo. J Immunol. 2010 Jan 15;184(2):877-85.

Lin AA, Tripathi PK, Sholl A, Jordan MB, Hildeman DA. Gamma interferon signaling in macrophage lineage cells regulates central nervous system inflammation and chemokine production. J Virol. 2009 Sep;83(17):8604-15.

Marsh RA, Villanueva J, Kim MO, Zhang K, Marmer D, Risma KA, Jordan MB, Bleesing JJ, Filipovich AH. Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clin Immunol. 2009 Jul;132(1):116-23.

Marsh RA, Villanueva J, Zhang K, Snow AL, Su HC, Madden L, Mody R, Kitchen B, Marmer D, Jordan MB, Risma KA, Filipovich AH, Bleesing JJ. A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency. Cytometry B Clin Cytom. 2009 Sep;76(5):334-44.

Jordan MB, Filipovich AH. Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step. Bone Marrow Transplant. 2008 Oct;42(7):433-7.

Wojciechowski S, Jordan MB, Zhu Y, White J, Zajac AJ, Hildeman DA. Bim mediates apoptosis of CD127(lo) effector T cells and limits T cell memory. Eur J Immunol. 2006 Jul;36(7):1694-706.

Rebecca A. Marsh, MD Clinical Director, Primary Immune Deficiency Program 513-803-9063 hlh@cchmc.org

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Rebecca A. Marsh, MD

Clinical Director, Primary Immune Deficiency Program

Co-Director, Diagnostic Immunology Laboratories

Member, Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute

Academic Affiliations

Associate Professor, UC Department of Pediatrics

Phone 513-803-9063

Fax 513-636-3549

Email hlh@cchmc.org

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BS: University of Tennessee, Knoxville, TN, 1998.

MD: Rush Medical College, Chicago, IL, 2003.

Residency: Rush University Medical Center, Chicago, IL, 2006.

Fellowship: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 2008.

Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, Villanueva J, Risma KA, Wei Q, Klein PS, Filipovich AH. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial hemophagocytic lymphohistiocytosis. Blood. 2011 Aug 31.

Marsh RA, Jordan MB, Filipovich AH. Reduced-intensity conditioning haematopoietic cell transplantation for haemophagocytic lymphohistiocytosis: an important step forward. British journal of haematology. 2011 Sep;154(5):556-63.

Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, Mehta PA, Davies SM, Jordan MB, Bleesing JJ, Filipovich AH. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 23;116(26):5824-31.

Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, Bleesing JJ, Filipovich AH, Zhang K. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatric blood & cancer. 2010 Jul 15;55(1):134-40.

Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, Bleesing JJ, Zhang K, Filipovich AH. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. 2010 Aug 19;116(7):1079-82.

Marsh RA, Bleesing JJ, Filipovich AH. Using flow cytometry to screen patients for X-linked lymphoproliferative disease due to SAP deficiency and XIAP deficiency. Journal of immunological methods. 2010 Oct 31;362(1-2):1-9.

Hinze CH, Lucky AW, Bove KE, Marsh RA, Bleesing JH, Passo MH. Leukocyte adhesion deficiency type 1 presenting with recurrent pyoderma gangrenosum and flaccid scarring. Pediatric dermatology. 2010 Sep-Oct;27(5):500-3.

Filipovich AH, Zhang K, Snow AL, Marsh RA. X-linked lymphoproliferative syndromes: brothers or distant cousins? Blood. 2010 Nov 4;116(18):3398-408.

Marsh RA, Villanueva J, Zhang K, Snow AL, Su HC, Madden L, Mody R, Kitchen B, Marmer D, Jordan MB, Risma KA, Filipovich AH, Bleesing JJ. A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency. Cytometry Part B, Clinical cytometry. 2009 Sep;76(5):334-44.

Marsh RA, Villanueva J, Kim MO, Zhang K, Marmer D, Risma KA, Jordan MB, Bleesing JJ, Filipovich AH. Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clinical immunology (Orlando, Fla). 2009 Jul;132(1):116-23.

Kimberly A. Risma, MD, PhD Director, Allergy and Immunology Fellowship Program 513-636-6771 kimberly.risma@cchmc.org

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Kimberly A. Risma, MD, PhD

Director, Allergy and Immunology Fellowship Program

Academic Affiliations

Associate Professor, UC Department of Pediatrics

Phone 513-636-6771

Fax 513-636-5835

Email kimberly.risma@cchmc.org

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Visit the Risma Lab website.

Clinical

Immune deficiency; immune dysregulation

Research

Pathophysiology of perforin missense mutations identified in individuals with hemophagocytic lymphohistiocytosis; molecular mechanisms of primary immune deficiency and dysregulation; natural killer cell and cytotoxic T lymphocyte cytotoxicity

Biography

Kimberly Risma, MD, PhD, is an associate professor in the Division of Allergy and Immunology at Cincinnati Children’s within the University of Cincinnati College of Medicine.

Dr. Risma graduated magna cum laude with a Bachelor of Arts in chemistry from Duke University in 1990 and was elected into The Phi Beta Kappa Society. She then matriculated at Case Western Reserve University (CWRU) School of Medicine in the Medical Scientist Training Program (MSTP). In 1996, she completed a PhD in pharmacology. She was selected by the leadership of the CWRU MSTP as the recipient of the 1997 Martin Wahl Memorial Fund Award, given annually to recognize the graduating MD, PhD student who has demonstrated the highest level of independence in research and excellence in research and clinical skills. She was also elected to Alpha Omega Alpha Society in 1997.

In 1997, she enrolled in a pediatrics residency at Cincinnati Children’s Hospital Medical Center/University of Cincinnati. During the residency program, Dr. Risma was awarded the pediatric resident teaching award by the medical students. She also engaged in translational research studies related to the genetics of asthma under the mentorship of Dr. Gurjit Hershey, resulting in a first author publication as a pediatric resident.

In 2000, Dr. Risma was accepted to the Allergy and Immunology Fellowship Program at Cincinnati Children’s. In addition to her clinical training, she pursued an innovative research project under the mentorship of Dr. Janos Sumegi and Dr. Alexandra Filipovich. She proposed a mechanism to study the structural and functional impact of perforin missense mutations identified in patients with hemophagocytic lymphohistiocytosis. In 2004 she was awarded the Nezelof Prize for best scientific presentation at the international meeting of the Histiocyte Society. The culmination of her fellowship research project was published in the Journal of Clinical Investigation, 2006.

Upon completion of her fellowship in 2005, Dr. Risma was appointed as an assistant professor in the Division of Allergy and Immunology at Cincinnati Children’s Hospital Medical Center within the UC Department of Pediatrics. In 2006 Dr. Risma received a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. Dr. Risma is the director of the Allergy and Immunology Fellowship Program at Cincinnati Children's, having served in this leadership position since August of 2012.

Dr. Risma's research program focuses on understanding the molecular mechanisms of immunodeficiency and immune dysregulation in children, especially as it relates to disorders of lymphocyte cytotoxicity. In addition to her research, she sees patients from all around the country in consultation for primary immune deficiency, immune dysregulation, and allergic disorders.

MD: Case Western Reserve University School of Medicine, Cleveland, OH, 1997.

PhD: Case Western Reserve University School of Medicine, Cleveland, OH, 1996.

Residency: Pediatrics, Cincinnati Children's Hospital Medical Center, 1997-2000.

Fellowship: Allergy / Immunology, Cincinnati Children's Hospital Medical Center.

Certification: Pediatrics, 2007; Allergy and Immunology, 2005.

Vrazo AC, Hontz AE, Figueira SK, Butler BL, Ferrell JM, Binkowski BF, Li J, Risma KA. Live cell evaluation of granzyme delivery and death receptor signaling in tumor cells targeted by human natural killer cells. Blood. 2015 Jun 29.

Carmo M, Risma KA, Arumugam P, Tiwari S, Hontz AE, Montiel-Equihua CA, Alonso-Ferrero ME, Blundell MP, Schambach A, Baum C, Malik P, Thrasher AJ, Jordan MB, Gaspar HB. Perforin gene transfer into hematopoietic stem cells improves
immune dysregulation in murine models of perforin deficiency. Mol Ther. 2015 Apr;23(4):737-45.

Li J, Figueira SK, Vrazo AC, Binkowski BF, Butler BL, Tabata Y, Filipovich A, Jordan MB, Risma KA. Real-Time Detection of CTL Function Reveals Distinct Patterns of Caspase Activation Mediated by Fas versus Granzyme B. J Immunol. 2014 Jul 15;193(2):519-28.

Mellor-Heineke S, Villanueva J, Jordan MB, Marsh R, Zhang K, Bleesing JJ, Filipovich AH, Risma KA. Elevated Granzyme B in Cytotoxic Lymphocytes is a Signature of Immune Activation in Hemophagocytic Lymphohistiocytosis. Front Immunol. 2013 Mar 22; 4:72.

Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr. 2012 Feb;24(1):9-15.

Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, Villanueva J, Risma KA, Wei Q, Klein PS, Filipovich AH. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011 Nov 24;118(22):5794-8.

Lykens JE, Terrell CE, Zoller EE, Risma K, Jordan MB. Perforin is a critical physiologic regulator of T-cell activation. Blood. 2011 Jul 21;118(3):618-26.

Sumegi J, Barnes MG, Nestheide SV, Molleran-Lee S, Villanueva J, Zhang K, Risma KA, Grom AA, Filipovich AH. Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis. Blood. 2011 Apr 14;117(15):e151-60.

Urrea Moreno R, Gil J, Rodriguez-Sainz C, Cela E, LaFay V, Oloizia B, Herr AB, Sumegi J, Jordan MB, Risma KA. Functional assessment of perforin C2 domain mutations illustrates the critical role for calcium-dependent lipid binding in perforin cytotoxic function. Blood. 2009 Jan 8;113(2):338-46.

Risma KA, Frayer RW, Filipovich AH, Sumegi J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J Clin Invest. 2006 Jan;116(1):182-92.

Kejian Zhang, MD, MBA Director, Molecular Genetics Laboratory 513-636-0121 kejian.zhang@cchmc.org

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Kejian Zhang, MD, MBA

Director, Molecular Genetics Laboratory

Academic Affiliations

Associate Professor, UC Department of Pediatrics

Phone 513-636-0121

Fax 513-636-2261

Email kejian.zhang@cchmc.org

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Clinical

Molecular genetics diagnosis of inherited immunodeficiency disorders and other genetic conditions

Research

Molecular defects and molecular diagnosis of primary immunodeficiency diseases; genetic aspects of predictive personalized medicine (pharmacogenetics)

MD: Tianjin Medical University, Tianjin, China, 1993.

MBA: College of Business Administration, University of Cincinnati, Cincinnati, OH, 2001.

Residency: Gong'an Hospital, Tianjin, China, 1993-1995.

Fellowship: Clinical Molecular Genetics Fellow, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 2002-2004.

Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R, Husami A, Kissell D, Nortman S, Chaturvedi V, Haines H, Young LR, Mo J, Filipovich AH, Bleesing JJ, Mustillo P, Stephens M, Rueda CM, Chougnet CA, Hoebe K, McElwee J, Hughes JD, Karakoc-Aydiner E, Matthews HF, Price S, Su HC, Rao VK, Lenardo MJ, Jordan MB. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349:436-440.

Lindsley AW, Qian Y, Valencia CA, Shah K, Zhang K, Assa’ad A. Combined Immune Deficiency in a Patient with a Novel NFKB2 Mutation. J Clin Immunol. 2014 Nov;34(8):910-5.

Valencia CA, Indugula SR, Mathur A, Wei C, Brown J, Dell S, Cole I, Connor J, Zhang K. Misleading results from saliva samples of post bone marrow transplanted patients in exome analyses. Published Blood. 2014 Jul 24;124(4):660-1.

Zhang K, Chadrakasan S, Chapman H, Valencia CA, Husami A, Kissell D, Johnson JA, Filipovich AH. Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood. 2014 Aug 21;124(8):1331-4.

Qian Y, Johnson J, Connor J, Valencia CA, Barasa N, Schubert J, Husami A, Kissell D, Zhang G, Weirauch M, Filipovich A, Zhang K. The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3. Pediatric Blood Cancer. 2014;61:1034–1040.

Theru Arumugam S, Husami A, Kissell D, Zhang W, Keddache M, Black AP, Tinkle BT, Greinwald JH, Zhang K. Performance Evaluation of the Next-Generation Sequencing Approach for Molecular Diagnosis of Hereditary Hearing Loss. Otolaryngol Head Neck Surg. 2013 Jun;148(6):1007-16.

Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, Villanueva J, Risma KA, Wei Q, Klein PS, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118:5794-5798

Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, Bleesing JJ, Filipovich AH, Zhang K. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer. 2010;55:134-140.

Zhang K, Biroschak J, Glass DN, Thompson SD, Finkel T, Passo MH, Binstadt BA, Filipovich A, Grom AA. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum. 2008;58:2892-2896.

Zhang K, Johnson JA, Biroschak J, Villanueva J, Lee SM, Bleesing JJ, Risma KA, Wenstrup RJ, Filipovich AH. Familial haemophagocytic lymphohistiocytosis in patients who are heterozygous for the A91V perforin variation is often associated with other genetic defects. Int J Immunogenet. 2007;34:231-233.

Grants