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Immunological Evaluation of Patients Affected with Jacobsen Syndrome Reveals Profound Not Age-Related Lymphocyte Alterations

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Abstract

Purpose

Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited.

Methods

Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected.

Results

Recurrent infections were registered in 6/12 patients (50%), while bleeding episodes in 2/12 (16.7%). White blood cell and absolute lymphocyte counts were reduced in 8/12 (66.7%) and 7/12 (58.3%) patients, respectively. Absolute numbers of CD3+ and CD4+ T cells were reduced in 8/12 (66.7%) and 7/12 (58.3%), respectively. Of note, recent thymic emigrants (RTE) were reduced in all tested patients (9/9), with T-cell receptor excision circle analysis (TRECs) showing a similar trend in 8/9 patients; naïve CD4+ T cells were low only in 5/11 patients (45.4%). Interestingly, B-cell counts, IgM memory B cells, and IgM serum levels were reduced in 10/12 (83.3%) patients. Natural killer (NK) cell counts were mostly normal but the percentages of CD16+CD56low/− cells were expanded in 7/7 patients tested. The observed immunological alterations did not correlate with patients’ age. Finally, responses to proliferative stimuli were normal at presentation for all patients, although they may deteriorate over time.

Conclusions

Our data suggest that patients affected with JS may display important numeric and maturational alterations in the T-, B-, and NK-cell compartments. These findings suggest that JS patients should be regularly monitored from an immunological point of view.

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Acknowledgements

We would like to thank the patients, the patients’ families, and the nurses for their collaboration and efforts. Several of the authors are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (project identification no. 739543).

Funding

The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/ 2007–2013 under grant agreement no 201549 (EURO-PADnet HEALTH- F2–2008–201549) and grant from the Italian Ministry of Research GR- 2010–2315762. The research leading to these results also received funding from the “Fondazione C. Golgi,” Brescia, Italy, and the Jeffrey Modell Foundation. We thank “Fondazione Città della Speranza ONLUS (https://cittadellasperanza.org/)” for their support to our scientific work.

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Author notes

  1. Manuela Baronio, Francesco Saettini, Luisa Gazzurelli, Daniele Moratto and Vassilios Lougaris contributed equally.

Authors and Affiliations

  1. Pediatrics Clinic and “A. Nocivelli” Institute for Molecular Medicine, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy

    Manuela Baronio, Luisa Gazzurelli, Stefano Rossi, Raffaele Badolato, Alessandro Plebani & Vassilios Lougaris

  2. Pediatric Hematology Oncology Unit, Department of Pediatrics, University of Milano Bicocca, MBBM Foundation, Monza, Italy

    Francesco Saettini

  3. Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy

    Antonio Marzollo & Linda Rossini

  4. “Fondazione Città della Speranza”, Institute of Pediatric Research, Padua, Italy

    Antonio Marzollo

  5. Department of Health Sciences, Pediatric Immunology Unit, Meyer Children’s University Hospital, University of Florence, Florence, Italy

    Silvia Ricci, Canessa Clementina & Lodi Lorenzo

  6. Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria of Bologna, Bologna, Italy

    Daniele Zama

  7. Department of Clinical and Experimental Medicine, Unit of Allergology and Clinical Immunology, University of Florence, Florence, Italy

    Boaz Palterer

  8. Flow Cytometry Unit, Clinical Chemistry Laboratory, ASST Spedali Civili, Brescia, Italy

    Marco Chiarini & Daniele Moratto

  9. CREA (AIL Center for Hemato-Oncologic Research), Diagnostic Department, ASST Spedali Civili of Brescia, Brescia, Italy

    Alessandra Sottini & Luisa Imberti

  10. Pediatric Oncohematology Unit, ASST Spedali Civili of Brescia, Brescia, Italy

    Chiara Gorio

Authors
  1. Manuela Baronio
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  2. Francesco Saettini
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  3. Luisa Gazzurelli
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  4. Stefano Rossi
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  5. Antonio Marzollo
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  6. Silvia Ricci
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  10. Lodi Lorenzo
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  11. Marco Chiarini
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  19. Vassilios Lougaris
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Contributions

M.B., F.S., L.G., S.R., A.M., S.R., D.Z., A.P., D.M., V.L. designed the work and coordinated the project; M.B., F.S., L.G., S.R., A.M., S.R., D.M., B.P., C.C., L.L., M.C., A.S., L.I., C.G., L.R. R.B., A.P., D.M., V.L. contributed with clinical, immunological, and molecular data; M.B., L.G., S.R., A.M., S.R., A.P., D.M., V.L. analyzed the data and wrote the manuscript; all authors approved the final version of the manuscript.

Corresponding author

Correspondence to Vassilios Lougaris.

Ethics declarations

Ethics Approval

The study was approved from the local hospital Ethical Committee and was conducted in accordance with the 1964 Helsinki Declaration.

Consent to Participate

Informed consent was collected from all patients or their legal guardians.

Consent for Publication

Informed consent was collected from all patients or their legal guardians.

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The authors declare no competing interests.

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Supplementary Information

Below is the link to the electronic supplementary material.

10875_2021_1169_MOESM1_ESM.pdf

Supplementary file1 (PDF 115 KB) Supplementary Table 1. Detailed hematologic and immunologic evaluation of twelve patients with Jacobsen Syndrome

10875_2021_1169_MOESM2_ESM.pdf

Supplementary file2 (PDF 84 KB) Supplementary Figure 1. Flow cytometry representation of natural killer cells distribution in Jacobsen Syndrome patients. Representative cytofluorimetric panels of CD3-CD16/CD56+ NK cells, in which it is highlighted the relative proportion of CD16+CD56dim (dark pink) and CD16+CD56low/- (pink) cells, are shown for Pt9 (right) compared to an age-matched heathy control (HC) (left)

10875_2021_1169_MOESM3_ESM.pdf

Supplementary file3 (PDF 158 KB) Supplementary Figure 2. Long term immunological follow-up of a single patient with Jacobsen Syndrome. Patient’s parameters over a 6-year follow up period: A) WBCs (absolute counts), B) lymphocytes (absolute counts), C) serum IgA, D) serum IgM, E) CD4 naïve (percentages) F) CD4 RTE (percentages), G) CD8 naïve (percentages) H) switched memory (percentages), I) IgM memory cells (percentages) compared to aged matched healthy controls’ range (grey full area). L) Mitogen proliferative response to anti-CD3 MoAb, anti-CD3 MoAb + IL2, PHA, over time. = reduced response compared to control

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Baronio, M., Saettini, F., Gazzurelli, L. et al. Immunological Evaluation of Patients Affected with Jacobsen Syndrome Reveals Profound Not Age-Related Lymphocyte Alterations. J Clin Immunol 42, 365–374 (2022). https://doi.org/10.1007/s10875-021-01169-2

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