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1102 Circulating B-Cell Precursor Cells As Potential Diagnostic and Therapeutic Biomarker in Patients with W­H­I­M SyndromeClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 203. Lymphocytes and Acquired or Congenital Immunodeficiency Disorders: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Diseases, Immune Disorders, immunodeficiency, neutropenia
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Ulrich Salzer, MD1*, Christoph B. Geier, MD, MSc1*, Maryssa Ellison, BS2*, Melis Yilmaz, MMSc2,3*, Caroline von Spee-Mayer, MD4*, Carsten Speckmann, MD4,5*, Stephan Ehl, MD, PhD4,5*, Olaf Neth, MD, PhD6*, Ana Pilar Garcia Garcia, MD7,8,9*, Angela Deya Martinez, MD7,8,9*, Laia Alsina, MD, PhD7,8,9*, Katja Sockel, MD10*, Catharina Schuetz, MD, MSc11,12*, David E. Potts, MMSc13*, Boglarka Ujhazi, MS13*, Krisztian Csomos, PhD13*, Jolan E. Walter, MD, PhD2,3,14* and Klaus Warnatz, MD1*

1Department of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany
2Division of Allergy and Immunology, Departments of Pediatrics and Medicine, University of South Florida Morsani College of Medicine, St. Petersburg, FL
3Division of Allergy and Immunology, Departments of Pediatrics, Johns Hopkins All Children's Hospital, St. Petersburg, FL
4Center of Chronic Immunodeficiency, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
5Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
6Paediatric Infectious Diseases, Rheumatology and Immunology Unit, University Hospital Virgen del Rocio, Institute of Biomedicine, Seville, Spain
7Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic Barcelona, Barcelona, Spain
8Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain
9Institut de Recerca Sant Joan de Déu, Barcelona, Spain
10Medical Clinic and Policlinic I, University Hospital Dresden, TU Dresden, Dresden, Germany
11Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
12Universitäts Centrum für Seltene Erkrankungen, University Hospital Carl-Gustav-Carus, Technische Universität Dresden, Dresden, Germany
13University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL
14Division of Allergy and Immunology, Massachusetts General Hospital for Children, Boston, MA


Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a combined immunodeficiency caused in most known cases by gain-of-function mutations in the CXCR4 gene. The wide spectrum of multisystem clinical presentations, often with incomplete penetrance and expressivity, can pose a diagnostic challenge. WHIM syndrome has historically been a clinicopathologic diagnosis, with myelokathexis being the pathognomonic feature of WHIM. As genetic testing is becoming readily available, sequencing of the CXCR4 gene is often used to confirm a clinical suspicion of WHIM syndrome by finding genetic variants. There is a need for additional easily accessible and noninvasive biomarkers for diagnosing WHIM syndrome. We hypothesize that B-cell compartment might also show pathognomonic features of WHIM syndrome.

Patients and Methods

We analyzed peripheral blood B-cell subsets in 13 patients diagnosed with WHIM syndrome from 8 families with pathogenic CXCR4 mutations using 9-multicolor flow cytometry after informed consent approval. Samples from 2 patients who received plerixafor were collected at baseline before and after treatment. The duration of treatment was approximately 6 months.


Using multicolor flow cytometry, we analyzed circulating B-cell subsets (CD10,CD19,CD21,CD27,CD38,IgA,IgD,IgG and IgM) in 13 patients (pediatric, n=7; adult, n=6) with WHIM syndrome (9 patients with p.Arg334Stop mutation, 2 patients with p.Val320Glufs*23 mutation, 1 patient with p.Ser338Stop mutation, and 1 patient with p.Ser346Stop mutation). We observed severe peripheral B-cell lymphopenia, accompanied by the presence of a consistent and specific scarce CD19+CD10+CD38+IgMIgDCD21CD27 B-cell subpopulation. A B-cell subpopulation with an equivalent marker expression pattern was not found in healthy controls (n=50) or in non-WHIM disease controls (n=20). The rare B-cell population found in WHIM syndrome was further characterized as belonging mostly to the pre–B-cell stage revealed by intracellular expression of IgM, CD179a (VpreB chain), and CD179b (lambda 5). The presence of these early B-cell precursors was independent of age and was stable over time in patients with WHIM syndrome. The number of these peripheral B-cell precursors found specifically in patients with WHIM syndrome was greatly reduced when the patients were treated with granulocyte colony-stimulating factor (G-CSF) or plerixafor; counts of the precursor cells returned to baseline after the patients discontinued plerixafor treatment.


Taken together, we identify a unique CD19+CD10+CD38+IgMIgDCD21CD27 B-cell subpopulation in patients with WHIM syndrome that might be used as a noninvasive biomarker to help identify patients with this rare primary combined immunodeficiency. In addition, these circulating B-cell precursors may be used to monitor response to therapy in patients with WHIM syndrome. The observed impact of G-CSF on the B-cell precursor population may be attributed to downregulation of CXCL12/CXCR4, which influences myelokathexis and impairs egression of the precursor population from the bone marrow but needs further experimental validation.

Disclosures: Yilmaz: X4 Pharmaceuticals, Inc.: Research Funding. Sockel: SOBI: Honoraria; Gilead: Honoraria; Active Biotech: Research Funding; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Potts: X4 Pharmaceuticals, Inc.: Other: Spouse is awarded grant for research efforts.; Immune Deficiency Foundation: Research Funding. Walter: Octapharma: Research Funding; X4 Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Consultancy; Grifols: Consultancy; Enzyvant: Consultancy; Regeneron: Consultancy; UptoDate: Other: Medical Writer; Pharmig: Membership on an entity's Board of Directors or advisory committees; ADMA Biologicals: Consultancy; MustangBio: Research Funding; Chiesi: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Warnatz: Bristol-Myers Squibb GmbH & Co.: Consultancy; LFB Biomedicaments: Consultancy; Takeda: Honoraria.

*signifies non-member of ASH