Dear Editor,
CARD11 protein along with BCL 10 and MALT1 form a CBM signalosome complex which are essential for T and B cell proliferation. Germline CARD11 mutations can cause severe combined immunodeficiency (SCID), combined immunodeficiency (CID) and atopy, or B cell expansion with NF- kB and T cell anergy (BENTA) disease. Biallelic loss-of-function mutations of CARD11 gene have been described in patients with SCID phenotype presenting with severe respiratory infection particularly caused by pneumocystis jirovecii (PJP) [1–3]. This condition can be fatal unless rescued by hematopoietic stem cell transplantation (HSCT). To date, two patients have undergone matched donor HSCT [1.2]. We describe a successful outcome following a novel haploidentical HSCT in this condition.
A 9-month-old boy with multiple respiratory viral infections needing prolonged hospitalizations and failure to thrive showed negative HIV testing, pan hypogammaglobulinemia, normal numbers of B lymphocytes, CD4 T cells, CD8 T cells and natural killer cells, but a high number of transitional B cells with absent T regulatory cells. Whole exome sequencing showed a homozygous pathogenic two base pair deletion in exon 25 of CARD11 gene on chromosome 7 (chr7:2946366_2946367delAT) that resulted in a frameshift and premature truncation of the protein 78 amino acids downstream to codon 1124 (p.Met1124ValfsTer78).
Despite prophylactic IVIG and PJP prophylaxis he continued to have repeated severe viral respiratory infections and failure to thrive. A haploidentical stem cell transplant was planned due to the lack of a suitable matched donor when the child was 3 years old using father as donor after appropriate evaluation.
Conditioning therapy consisted of Rabbit ATG (2.5 mg/kg on day -9 to day-7), Fludarabine (30 mg/m2 on day-6 to day-2), Treosulfan (12 gm/m2 on day-6 to day-4) and Thiotepa (10 mg/kg on day-3 in 2 divided doses). GCSF-mobilized peripheral blood stem cells were collected and processed by negative selection for TCR-αβ and CD19. There was 3.92 log reduction of the TCR-αβ T cells. A small fraction of the graft was also used to collect and freeze memory RO cells after CD45 RA depletion. Graft engineering was achieved using the Miltenyi Biotec CliniMACS system. Infused product had CD34+ cells of 15 × 106 cells/kg of the recipient. TCR-αβ T cells and TCR-gamma-delta T cells in the infused product were 20,000 and 10.1 × 106 cells/kg of the recipient, respectively. No GvHD prophylaxis was used. Rapid neutrophil engraftment and platelet engraftment was noted by D + 11.
Early cytomegalovirus viraemia was noted. CD45 RO memory cells aid in immune reconstitution and pathogen-specific activity, and hence thawed 0.15 × 106/kg of donor memory RO cells were infused on D + 15 to control CMV along with the addition of ganciclovir. Following this infusion, the child rapidly developed biopsy proven stage three liver GVHD without evidence of skin or gut involvement. Rapid response to methylprednisolone and ciclosporin was seen. Steroid treatment was tapered within four weeks and ciclosporin was tailed off by D + 120. By six months, there was evidence of B cell engraftment and IgG levels were maintained. CD4 T cells and T regulatory cells also showed good recovery (Fig. 1). The patient is now forty-two months post-transplant with normal growth, development and immune profile with no infections of note.
Fig. 1.
Lymphocyte subsets post HSCT
Ex-vivo TCR αβ and CD19 depleted haploidentical stem cell transplantation is being adopted worldwide in benign and malignant settings with the advantages of robust early engraftment along with acceptable GVHD rates. The use of CD45RO donor memory cell addback offers a distinct advantage of adoptive transfer of antiviral immunity [4]. This approach is also being increasingly used in HSCT in malignant conditions due to its anti-leukaemia properties. Although this approach removes most of the alloreactive naïve T cell population, there remains a risk of GVHD which often is relatively easier to treat [5].
Repeated and severe viral infections in infancy, PJP infections, presence of pan-hypogammaglobulinemia, high transitional B cells and absent Treg cells provide important clues in diagnosing this condition. To our knowledge, this is the first report of a child who has undergone a T-cell depleted haploidentical HSCT with CD45 RA-depleted memory T-cell addback in this condition.
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Conflict of interest
Authors have nothing to disclose.
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References
- 1.Stepensky P, Keller B, Buchta M, Kienzler AK, Elpeleg O, Somech R, Cohen S, Shachar I, Miosge LA, Schlesier M, Fuchs I (2013) Deficiency of caspase recruitment domain family member 11 (CARD11), causes profound combined immunodeficiency in human subjects. J Allergy Clin Immunol 131(2):477–485 [DOI] [PubMed] [Google Scholar]
- 2.Greil J, Rausch T, Giese T, Bandapalli OR, Daniel V, Bekeredjian-Ding I, Stütz AM, Drees C, Roth S, Ruland J, Korbel JO (2013) Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency. J Allergy Clin Immunol 131(5):1376–1383 [DOI] [PubMed] [Google Scholar]
- 3.Fuchs S, Rensing-Ehl A, Pannicke U, Lorenz MR, Fisch P, Jeelall Y, Rohr J, Speckmann C, Vraetz T, Farmand S, Schmitt-Graeff A, Krüger M, Strahm B, Henneke P, Enders A, Horikawa K, Goodnow C, Schwarz K, Ehl S (2015) Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency. Blood 126(14):1658–1669. 10.1182/blood-2015-03-631374 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Dunaikina M, Zhekhovtsova Z, Shelikhova L, Glushkova S, Nikolaev R, Blagov S, Khismatullina R, Balashov D, Kurnikova E, Pershin D, Muzalevskii Y (2021) Safety and efficacy of the low-dose memory (CD45RA-depleted) donor lymphocyte infusion in recipients of αβ T cell-depleted haploidentical grafts: results of a prospective randomized trial in high-risk childhood leukemia. Bone Marrow Transpl 56(7):1614–1624 [DOI] [PubMed] [Google Scholar]
- 5.Touzot F, Neven B, Dal-Cortivo L, Gabrion A, Moshous D, Cros G, Chomton M, Luby JM, Terniaux B, Magalon J, Picard C (2015) CD45RA depletion in HLA-mismatched allogeneic hematopoietic stem cell transplantation for primary combined immunodeficiency: a preliminary study. J Allergy Clin Immunol 135(5):1303–1309 [DOI] [PubMed] [Google Scholar]