Partial immune reconstitution after bone marrow transplantation in a boy with recombination activating gene 1 defect

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Severe combined immunodeficiencies (SCID) are a group of rare congenital disorders characterized by the impairment of both humoral and cell-mediated immunity, lymphopenia and low or absent antibody levels. They usually manifest in the first months of life with severe and recurring infections leading to death. Bone marrow transplantation (BMT) needs to be considered as soon as possible after a diagnosis of SCID because these disorders usually run an unpredictable course and may rapidly prove fatal.1,2

Recombination activating gene-1 (RAG-1) and RAG-2 are the two essential and tissue-specific components for the generation of antigen-binding diversity by assembly of the variable (V), diversity (D), and joining (J) domain exons at the inmunoglobulin and T-cell receptor (TCR) gene loci during lymphocyte development. RAG-1 and RAG-2 deficiencies are autosomal recessive diseases (Online Mendelian Inheritance in Man, OMIM™. Johns Hopkins University, Baltimore, MD. MIM number: 179615, 7/12/2002. World Wide Web URL: that result in a functional inability to form antigen receptors through genetic recombination leading to primary inmunodeficiencies in humans. Additionally, patients with SCID secondary to RAG mutations may have Omenn syndrome, characterized by the presence of a substantial number of oligoclonal activated T cells associated with autoreactive manifestations.4

A 4-month-old child, who had no previous family history of SCID, was referred to our hospital after 3 weeks with prolonged fever episodes, laryngitis, sores in palate, tongue, and anal margin. He presented a low height-weight growth. ADA or PNP deficiencies were not identified, but the immunologic findings were consistent with a T-B-SCID. Immunophenotype analysis showed the following percentages and absolute number of lymphocyte subpopulations: CD3+5.5%–72/μl, CD3+CD4+5.3%–70/μl, CD3+CD8+0.2%–3/μl, CD19+7.5%–98/μl, and CD16+CD56+/CD3–87.5%–1149/μl. The serum immunoglobulins were: IgG 62 mg/dl, IgA <2 mg/dl, IgM 11 mg/dl and the proliferative response to several mitogens and anti-CD3 stimulus (stimulus involving TCR) was markedly reduced (except when IL-2 was used as costimulus).

A recombination deficiency was suspected, and the molecular genetic analysis of RAG-1 showed a heterozygous change C1982T in the first base of codon 624, resulting in the conversion of arginine to cysteine (Arg624Cys).5 The second mutation in RAG-1 gene was not found.

Before BMT, the patient received an appropriate anti-infections therapy, an intestinal decontamination through nonabsorbable antibiotics, oral antifungal drugs, and immunoglobulins administration. The patient underwent an HLA-identical BMT at 7 month from his healthy brother. The BM was unmanipulated and no conditioning regimen was administered. The patient does not present acute or chronic GVHD.

Immunological reconstitution is summarised in Table 1. Despite T and B lymphopenia, normal lymphoproliferative response to several mitogens were detectable after BMT. Immunoglobulin administration was initiated on day −47 and was stopped on day +180, from then onwards, the patient's immunoglobulins values were normal except for the persistent low IgG2 serum level. The child was vaccinated against poliomyelitis, hepatitis B, tetanus, diphtheria, pneumococcal, and Haemophilus influenzae type B capsular polysaccharide 2 years after BMT. Specific antibody production against Haemophilus influenzae type B and pneumococcal capsular polysaccharide were evaluated due to IgG2 subclass deficiency after the immunoglobulin administration was stopped. The results show an impaired specific immunoglobulin production against Haemophilus influenzae type B (prevaccine IgG: 0.04 mg/dl; post-vaccine IgG: 0.15 mg/dl; normal postvaccine range IgG: >2 mg/dl) and also against Pneumococco capsular polysaccharide (prevaccine IgG: 0.4 mg/dl and IgG2: 0.1 mg/dl; post-vaccine IgG: 2.5 mg/dl and IgG2: 0.4 mg/dl; normal post-vaccine range IgG >5.3 mg/dl and IgG2 >2.4 mg/dl).

Table 1 Immune reconstitution after BMTa,b,c,d

IgG subclass deficiency is frequently associated with bacterial infections, the most common identified selective antibody deficiency is an impaired response to polysaccharide antigens such as those present in capsule of Streptococcus pneumoniae and Haemophilus influenzae type b. Since IgG2 is the predominant antibody produced in response to some polysaccharide antigens, it is possible that patients with decreased IgG2 levels may have an altered response to infections with encapsulated bacteria,6 but in our case this has not happened throughout the 7 years clinical evolution without any type of prophylaxis.

We report a 7 years' follow up of a SCID patient due to a RAG-1 defect, who received an allogenic BMT from his HLA-identical brother and maintain T and B lymphopenia and isolated IgG2 deficiency. Despite incomplete immune reconstitution our patient has not had any life-threatening complications (opportunistic or encapsulated bacteria infections), his general condition is good and acute or chronic GVHD has not been observed.


  1. 1

    Ochs HD, Edward-Smith CI, Puck JM . Primary Immunodeficiencies Diseases: A Molecular and Genetic Approach. Oxford University Press: New York, 1999.

  2. 2

    Buckley RH, Schiff SE, Schiff SI et al. Hematopoietic stem cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999; 340: 508–516.

  3. 3

    Schwarz K, Gauss GH, Ludwig L et al. Rag mutations in human B cell-negative SCID. Science 1996; 274: 97–99.

  4. 4

    Villa A, Santagata S, Bozzi F et al. V(D)J recombination activity leads to Omenn syndrome. Cell 1998; 93: 885–896.

  5. 5

    Villa A, Sobacchi C, Notarangelo LD et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 2001; 97: 81–88.

  6. 6

    Siber GR, Schur PH, Aisenberg HC et al. Correlation between serum IgG2 concentrations and the antibody response to bacterial polysaccharide antigens. N Engl J Med 1990; 323: 1387–1392.

  7. 7

    Comans-Bitter WM, de Groot R, van den Beemd R et al. Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations. J Pediatr 1997; 130: 388–393.

  8. 8

    Jolliff CR, Cost KM, Stivrins PC et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem 1982; 28: 126–128.

  9. 9

    García-Pérez MA, Paz-Artal E, Corell A et al. Mutations of CD40 ligand in two patients with hyper-IgM syndrome. Immunobiology 2003; 207: 285–294.

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We thank Paloma de Pablos and Paloma Paule for excellent technical assistance. J Muñoz-Robles and MJ Del Rey contributed equally to this work.

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