The recombination activating enzymes RAG1 and RAG2 are essential to the process of V(D)J rearrangement in B and T cells and thus to the development of normal immune function. Mutations in RAG1 or RAG2 can lead to a spectrum of disorders, ranging from typical (B-)(T-) severe combined immunodeficiency to Omenn's syndrome. We present a unique presentation of RAG1 deficiency.
We report on a 6-month-old girl who presented with severe respiratory distress, which continued to progress despite antibiotic therapy but seemed to respond to treatment with corticosteroids. The patient exhibited no erythroderma or eosinophilia, and her lymphoid organs were not enlarged.
Investigation of the immune system showed normal numbers of CD3+ T cells, which expressed either CD4 or CD8. Subsequent analysis of the T-cell receptor demonstrated that nearly all CD3+ T cells were clonal; one clone expressed CD4, whereas the other expressed CD8. The extremely restricted T-cell repertoire and the lack of circulating B cells prompted analysis of the RAG1 gene, which revealed a novel homozygous thymine to cytosine substitution at nucleotide position 2686.
This case underscores the importance of more extensive evaluation of the immune system even when widely available, standard, flow cytometric analysis shows normal numbers of T cells that express CD4 or CD8, especially in the absence of circulating B cells.
"Cells surface markers of peripheral blood mononuclear cells, lymphocyte proliferative responses to mitogens, analysis of signal joint (sj) T-cell receptor excision circles (TRECs), adenosine deaminase (ADA), and purine nucleoside phosphorylase (PNP) enzyme activity were determined as previously described [Douek et al., 2000; Grunebaum et al., 2004; Zhang et al., 2005]. "
[Show abstract][Hide abstract] ABSTRACT: Inherited immune deficiencies are a heterogeneous group of diseases that can be either isolated, with the immune defect being the exclusive manifestation, or associated with other abnormalities. We report on two sisters, born to consanguineous parents of Sri-Lankan descent, who presented in infancy with immunodeficiency, gonadal dysgenesis, and fatal lung fibrosis. Immune studies demonstrated combined humoral and cellular abnormalities including reduced immunoglobulin production, an absence of lymphoid tissue, markedly reduced T-lymphocyte numbers and function and reduced newly thymus-derived T-cells. Both infants succumbed to rapidly progressive lung fibrosis. Autopsy showed dysgenetic gonads bearing no discernible oocytes. In both, karyotypes were normal female (46,XX). Comparative genome hybridization and analysis of genes known to be associated with severe immune defects in infancy or gonadal dysgenesis showed no abnormality. The distinct findings in these two sisters have not been reported before and thus suggest a hitherto unknown autosomal recessive condition that includes immune dysfunction, gonadal dysgenesis, and pulmonary fibrosis.
American Journal of Medical Genetics Part A 01/2008; 146A(1):8-14. DOI:10.1002/ajmg.a.32014 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe combined immunodeficiency (SCID) is a heterogeneous group of diseases that are invariably fatal in infancy unless treated by hematopoietic stem cell replacement. For many years we have worked to better manage patients affected by SCID through rapid and accurate diagnosis followed by treatment aimed at achieving long-lasting immune reconstitution. By extensive immunological, biochemical, and genetic studies of patient samples, and with the realization of differences between human and murine T cell development, we have successfully been able to identify some of the molecular defects causing SCID. Among these discoveries, we described the first mutated signal transduction protein in T cells (ZAP-70); the first genetic defect leading to SCID and autoimmune phenomena (IL2R alpha); and, recently, the critical importance of CD3delta in the development of T cells. Our efforts have significantly advanced the understanding of the role of some of the signal-transducing proteins in T cell maturation and function. This review summarizes several of these discoveries and some of their impact on our understanding of T cells development, function, and homeostasis in humans.
Immunologic Research 02/2006; 35(1-2):117-26. DOI:10.1385/IR:35:1:117 · 3.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bone marrow transplantation (BMT) using stem cells obtained from a family-related, HLA-identical donor (RID) is the optimal treatment for patients with severe combined immune deficiency (SCID). In the absence of an RID, HLA-mismatched related donors (MMRDs) are often used. However, compared with RIDs, use of MMRDs for BMT is associated with reduced survival and inferior long-term immune reconstitution. Use of HLA-matched unrelated donors (MUDs) represents another potential alternative for BMT.
To compare outcomes and immune reconstitution in a large cohort of patients with SCID who received RID, MUD, or MMRD BMT.
Retrospective study of medical records from 94 infants diagnosed as having SCID who received BMT between 1990 and 2004 at 1 Canadian and 1 Italian pediatric referral center. Thirteen, 41, and 40 patients received RID, MUD, and MMRD BMT, respectively.
Survival and graft failure, along with incidence of graft-vs-host disease, infections, and other complications; immune reconstitution was assessed in children who survived for more than 2 years after BMT.
Survival after RID BMT was highest. Twelve (92.3%) of 13 patients who received RID BMT, 33 (80.5%) of 41 who received MUD BMT, and 21 (52.5%) of 40 patients who received MMRD BMT survived. Compared with MMRD BMT, survival was significantly higher with RID (P = .008) or with MUD (P = .03). Graft failures and need for repeat BMT were more common in patients receiving MMRD BMT than in those who underwent MUD BMT. Long-term reconstitution of a full T-cell repertoire was achieved more frequently following MUD BMT (94.7%) than after MMRD BMT (61.1%) (P = .02). Acute graft-vs-host disease was documented in 73.1% of patients following MUD BMT but in only 45% after MMRD BMT (P = .009). Conversely, interstitial pneumonitis was observed more frequently after MMRD BMT (14 [35.0%] of 40) than after MUD BMT (3 [7.3%] of 41; P = .002).
Our study suggests that in the absence of a relative with identical HLA, MUD BMT may provide better engraftment, immune reconstitution, and survival for patients with SCID than MMRD BMT.
JAMA The Journal of the American Medical Association 03/2006; 295(5):508-18. DOI:10.1001/jama.295.5.508 · 35.29 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.