Original Article
Brief Report
An Immunodeficiency Disease with RAG Mutations and Granulomas
N Engl J Med 2008; 358:2030-2038May 8, 2008
- Abstract
We describe three unrelated girls who had an immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. All three girls had severe complications after viral infections, including B-cell lymphoma associated with Epstein–Barr virus (EBV). Other findings were hypogammaglobulinemia, a diminished number of T and B cells, and sparse thymic tissue on ultrasonography. Molecular analysis revealed that the patients were compound heterozygotes for mutations in recombination activating gene 1 or 2 (RAG1 or RAG2). In each case, both parents were heterozygous carriers of a RAG mutation. The mutations were associated with reduced function of RAG in vitro (3 to 30% of normal activity). The parents and one sibling in the three families were healthy.
Media in This Article
Figure 1
Facial Lesions and Histopathological Specimens.Figure 2
Mutations in RAG1 and RAG2 and Pedigrees of the Patients.Article Activity
- Article
Severe combined immunodeficiency disease (SCID) comprises a heterogeneous group of immunodeficiency diseases, one of which is caused by a null mutation in both alleles of RAG1 or RAG2.1,2 This form of SCID accounts for approximately 20% of cases. The heterodimeric RAG enzyme recombines subgenic elements at the immunoglobulin and T-cell–receptor loci, thereby generating the variable part of antigen-binding receptor genes, a process termed V(D)J recombination. The RAG complex is active in precursor T cells and B cells, which cannot develop without RAG activity. Null mutations of both alleles of RAG1 or RAG2 cause the classic SCID phenotype, with absent T cells and B cells. Hypomorphic missense mutations of RAG1 or RAG2, which allow residual RAG activity, occur in the Omenn syndrome, in which the main features are hepatosplenomegaly, lymphadenopathy, eosinophilia, elevated serum IgE levels, and infiltration of various tissues, notably the skin and the gastrointestinal tract, by oligoclonal populations of T cells.3 The Omenn syndrome can have a fatal outcome despite stem-cell transplantation.3
We describe a type of primary immunodeficiency disease with RAG1 or RAG2 mutations that diminish RAG activity and allow the maturation of a limited number of T and B cells. Three girls under the age of 10 years from three different families presented with extensive granulomatous disease involving the skin, mucous membranes, and internal organs.
Case Reports
Patient 1
At the age of 2.5 years, Patient 1, the daughter of nonconsanguineous parents, was referred to the University Children's Hospital Düsseldorf because of papulonodular skin lesions on the face and limbs. During the previous year, the lesions had failed to respond to treatment with topical corticosteroids (Table 1Table 1
Characteristics of the Patients and the Granulomas. and Figure 1AFigure 1Facial Lesions and Histopathological Specimens.). The medical history was otherwise unremarkable, and the patient had received standard immunizations without complications.A skin biopsy showed parakeratosis, epidermal hyperplasia, and lichenoid lymphocytic infiltrates with few neutrophils in the upper dermis. In the middle and lower dermis were nodular collections of epithelioid cells (Figure 1B) surrounded by moderately dense lymphocytic infiltrates and some neutrophils (Figure 1C). Some of the epithelioid cells were multinucleated, and some of the lymphocytes had atypical nuclei. Some of the epithelioid histiocyte collections had a central zone of necrosis (Figure 1D).
In immunohistochemical studies, the epithelioid cells were positive for CD68, and the lymphocytes were positive for CD3 and CD8 and negative for CD79a and CD4. Paraffin-fixed skin-biopsy samples, examined by seminested, multiplex polymerase-chain-reaction (PCR) assay, showed clonal rearrangements of the gene encoding T-cell receptor γ. These findings supported a diagnosis of small-cell pleomorphic T-cell lymphoma. Biopsies of bone marrow and liver did not reveal clear evidence of systemic involvement. Immunologic abnormalities were considered to be secondary to the presumed lymphoma.
The child was treated with chemotherapy for T-cell lymphoma, but numerous new papulonodular efflorescences developed, and the existing lesions progressed. After the lesions failed to improve after 4 months of chemotherapy, the treatment was stopped and the diagnosis of T-cell lymphoma was reconsidered. A primary immunodeficiency was suspected, since there was profound hypogammaglobulinemia (Table 2Table 2
Immunologic Analysis.), and tissue infiltrates of clonal CD8+ T cells had been described in a patient with common variable idiopathic immunodeficiency.7 Periodic acid–Schiff (PAS), Giemsa, and Ziehl–Neelsen staining of skin-biopsy specimens showed no evidence of fungi, leishmania, or mycobacteria, and PCR assays for mycobacterium tuberculosis and Whipple's bacilli were negative (Table 2 of the Supplementary Appendix, available with the full text of this article at www.nejm.org).Molecular studies identified compound heterozygous mutations in RAG1 (Table 3Table 3
Missense RAG Mutations.). When the patient was 5.7 years of age, a tumor of the right tonsil developed. On histologic examination, the tumor was a diffuse large B-cell lymphoma with clonal IgH genes and expression of CD20, CD79a, and CD30. In situ hybridization of the tumor for EBV-encoded small RNA (EBER) was strongly positive. She was treated with rituximab, which led to partial remission. At 6 years of age, the patient underwent hematopoietic stem-cell transplantation from an HLA-matched unrelated donor. More than 3 years after transplantation, the patient is not receiving any medication, the skin lesions have disappeared, and immune functions are normal.Patient 2
At the age of 7.5 years, Patient 2, the daughter of nonconsanguineous parents, was referred to the University Children's Hospital Ulm for evaluation of an immunodeficiency. Her 6-year-old brother was healthy. At the age of 9 months, she had severe varicella with hepatitis and bacterial superinfection. At 27 months of age, multiple, treatment-resistant ulcerative skin lesions developed on her limbs and face (Fig. 1 of the Supplementary Appendix). Skin-biopsy specimens showed changes similar to those in Patient 1: nodular collections of epithelioid cells surrounded by moderately dense lymphocytic infiltrates with some neutrophils. However, no necrosis was observed. Extensive testing failed to conclusively reveal microbiologic agents (Table 2 of the Supplementary Appendix). In an attempt to treat the lesions, regular subcutaneous immunoglobulin injections were started when the patient was 4 years old. At 6.5 years of age, nodular lesions developed on her tongue; these lesions had a histologic similarity to the cutaneous lesions (Fig. 1 of the Supplementary Appendix). PAS, Giemsa, and Ziehl–Neelsen staining showed no pathogens in either skin or tongue. PCR assays for mycobacterium tuberculosis and Whipple's bacilli that were performed on a tongue-biopsy specimen were negative. Similar granulomatous changes were also noted in biopsy specimens of the adenoids and the lung, which were obtained because of respiratory complications (pneumonias, bronchiectasis, and atelectasis).
Results of immunohistochemical analysis of the tongue lesion were similar to findings in Patient 1. Studies of the tongue-biopsy specimens with seminested, multiplex PCR showed a polyclonal population of T cells (Table 1 of the Supplementary Appendix). Therapy with corticosteroids, dapsone, and clofazimine was ineffective. Cyclosporine treatment led to deterioration of skin lesions. Repeated skin grafting was necessary after partial destruction of the Achilles tendon by progressive ulceration. Immunophenotyping of blood cells revealed low numbers of T and B cells but a normal number of natural killer cells (Table 2). Thymic tissue was undetectable on ultrasonography. Molecular studies revealed compound heterozygous RAG1 mutations.
Hematopoietic stem-cell transplantation from an HLA-matched unrelated donor was performed when the patient was 8.5 years old. More than a year after transplantation, no new skin lesions have developed, and the patient is receiving immunosuppressive therapy for chronic graft-versus-host disease.
Patient 3
At the age of 9.9 years, Patient 3, the only child of nonconsanguineous parents, was referred to the University Children's Hospital Düsseldorf with a history of recurrent pneumonia beginning at the age of 2 years. Otherwise, she had an uneventful early childhood. At 8.5 years of age, she had a severe varicella infection complicated by encephalitis and the acute respiratory distress syndrome. An immunologic evaluation that was performed when she was 9.9 years old showed profound hypogammaglobulinemia with low numbers of T and B cells (Table 2). At the age of 10.5 years, she was found to have massive splenomegaly with hypodense infiltrates on ultrasonography. Splenic biopsy revealed granulomas with epithelioid cells. Staining with PAS, Giemsa, and Ziehl–Neelsen was negative. PCR assays for mycobacterium tuberculosis and Whipple's bacilli that were performed on the splenic specimen were negative (Fig. 2 of the Supplementary Appendix).
Immunophenotyping of the lesion showed a polyclonal population of T cells (Table 2). Small nodular infiltrates consistent with granulomatous disease were seen on computed tomography of the lungs. The results of bronchoalveolar lavage were inconclusive. Molecular analysis, which was performed when the patient was 10.7 years old, revealed compound heterozygous mutations in RAG2. The patient's condition is stable on regular IgG infusions, and she is being evaluated for stem-cell transplantation.
Molecular Findings
The parents of each of the three children gave informed consent to carry out the investigations described below.
Compound heterozygous mutations in RAG1 or RAG2 were identified in all three patients (Figure 2Figure 2
Mutations in RAG1 and RAG2 and Pedigrees of the Patients. and Table 3). None of the mutations were detected in 105 healthy control subjects who were matched for white race (data not shown). The functional significance of the mutations was evaluated in primary human dermal fibroblasts that were cotransfected with substrate vectors that allow scoring for V(D)J recombination efficiency and expression plasmids coding for wild-type or mutant RAG1 or RAG2 proteins (Table 4Table 4
Percentage of Cells with V(D)J Recombination.). The percentages of recombination-positive cells in the subpopulation of transfected fibroblasts varied from less than 5% to approximately 30% of the positive control. Lacking suitable monoclonal antibodies against human RAG proteins, we measured RNA stability of the in vitro transfectants as a surrogate. All RNAs were equally well expressed, as assessed by semiquantitative reverse-transcriptase PCR.Mutations in the nucleotide-binding oligomerization domain–containing 2 (NOD2) gene have been implicated in various granulomatous diseases (e.g., Crohn's disease, Blau syndrome, and early-onset sarcoidosis). Since our patients had granulomas in various organs, we checked their NOD2 genotypes by genomic sequencing. No changes in the predicted amino acid sequences, as compared with those of wild-type alleles, were detected (data not shown).
Discussion
We describe three girls with a primary immunodeficiency disease associated with hypomorphic mutations in one of the two recombinase activating genes (RAG1 and RAG2). Two of the three patients (Patients 1 and 3) had either no or insignificant infections in infancy or early childhood.
The histologic findings in various organs were notable for granulomas containing CD68+ epithelioid cells and CD8+ T cells, which were polyclonal in two of the three patients. In peripheral blood, there were diminished numbers of T and B cells but a normal number of natural killer cells. The proportion of activated T cells (HLA-DR+) was increased, and most T cells were of the memory type (CD45RO+).
The clinical findings in the three children were clearly distinct from those of classical SCID (null mutations of both RAG alleles and no RAG activity), the Omenn syndrome (a missense mutation of at least one RAG allele with retention of some RAG activity), and atypical SCID (a missense mutation of at least one RAG allele but with features that are not typical of the Omenn syndrome).8,9 In contrast to our patients, those with atypical SCID are children of consanguineous parents, present with threatening infections during infancy, and do not have granulomatous disease. Of five such patients who underwent hematopoietic stem-cell transplantation in infancy or early childhood, two survived and three died of severe cytomegalovirus infection.
The mutations we found in RAG genes have been detected in other patients with a different phenotype.10 The R507W mutation in Patient 1 has also been detected in an infant who had a skin rash, eosinophilia, slight lymphopenia, and normal levels of IgG but decreased IgA and IgM. Another child with a heterozygous R737H mutation (found in Patient 1) presented at the age of 1 month with typical Omenn syndrome. One of the mutations found in Patient 2 (R975W, RAG1) has been reported in a patient with the Omenn syndrome but with a different amino acid exchange (R975Q).3 The other mutation in Patient 2 and both mutations in Patient 3 (RAG2) have not been reported previously.
Functional analysis of RAG alleles showed V(D)J recombination activity varying between less than 5% in RAG mutants of Patients 1 and 2 and approximately 30% in RAG mutants of Patients 1 and 3, making it highly likely that the RAG mutations caused the impaired V(D)J recombination. Residual functional RAG1 or RAG2 allows a low level of T-cell production.3,10,11 The presence of CD4+/CD45RA+ cells in all three of our patients may reflect production of naive T cells by the thymus. Spectratyping of T-cell receptors in Patients 1 and 3 revealed a diverse repertoire. This finding was unexpected, since patients with SCID or the Omenn syndrome have no T cells or a population of T cells with a very restricted receptor repertoire.12 The number of T cells in our patients is decreased, but the late onset and low incidence of repeated or life-threatening infections may indicate that the T-cell repertoire is sufficiently broad and competent for protection against microbes, at least for a limited period.
The late onset and the presence of functional T cells could be related to somatic mosaicism in T cells or engraftment of maternal T cells. Somatic mosaicism has been observed repeatedly in patients with SCID that is caused by adenosine deaminase deficiency or with X-linked SCID (a deficiency in the interleukin-2–receptor common γ chain). The mosaicism results from a mutation that reverts the mutation in adenosine deaminase or X-linked SCID to a wild-type mutant.13-15 In our three patients, revertants were excluded by genomic sequencing of sorted CD3, CD19, and CD14 cells in which we found only the disease-causing mutations. Engraftment of maternal T cells, which can also lead to partial immunologic reconstitution resulting in a milder phenotype, was excluded by HLA typing of CD3 T cells in all three patients.
It is unclear whether the granulomas in our patients are the reactive sarcoid-like granulomas found in other primary immunodeficiency disorders, especially in granulomatous common variable immunodeficiency disease.7,16-19 In a cohort of 19 adults with this disease, we found no functionally relevant RAG1 or RAG2 mutations (data not shown). Furthermore, we did not see resolution of granulomas after treatment with intravenous immunoglobulin, as has been noted in some patients with common variable immunodeficiency.18,19 Extensive and repeated tests revealed no pathogen in the granulomas, but it is possible that the lesions were a reaction to an undetected low-virulence pathogen, comparable to “sterile” granuloma formation seen in patients with chronic granulomatous disease. It is also possible that, apart from the RAG mutations, other mutations in modifier genes may be responsible for the granulomas.
The late onset and atypical clinical picture of the forms of RAG1 or RAG2 deficiency we describe here may prompt the inappropriate use of chemotherapy or immunosuppression. RAG deficiency should be a consideration in older patients with evidence of combined humoral and cellular immunodeficiency and otherwise unexplained granulomatous lesions.
Supported by grants from the Jeffrey Modell Foundation (to Dr. Niehues), the Elterninitiative Kinderkrebsklinik (to Dr. Göbel and Dr. Niehues), the Forschungskommission der Medizinischen Fakultät, University of Düsseldorf (to Dr. Feyen), and the Deutsche Forschungsgemeinschaft and the Else Kröner Fresenius Foundation (to Dr. Borkhardt).
No potential conflict of interest relevant to this article was reported.
We thank E.M. Rump, S. Braun, T. Kersten, and I. Janz at the Institute for Clinical Transfusion Medicine and Immunogenetics and S. Bellert, W. Kus, G. Göbel, and E. Oellers in Düsseldorf for excellent technical assistance; D. Diallo, H. Kreipe, and P. Racz in Düsseldorf, Hannover, and Hamburg for their evaluations of histologic analyses; U. Salzer of the Department of Clinical Immunology and Rheumatology, University of Freiburg, for contributing samples from patients with common variable immunodeficiency; and J. Schaper, Düsseldorf, for evaluation of spleen sonography.
Source Information
From the Departments of Pediatrics and Adolescent Medicine (C.S., A.S., W.F.) and Internal Medicine (B.M.) and the Institute for Transfusion Medicine (U.P.), University Hospital Ulm, and the Institute for Clinical Transfusion Medicine and Immunogenetics (K.S.) — all in Ulm; the Department of Pediatric Oncology, Hematology, and Clinical Immunology, Children's Hospital, Universitäts Klinikum Düsseldorf, Heinrich Heine University, Düsseldorf (K.H., S.G., O.F., B.H., D.T.S., U.G., A.B., T.N.); and the Departments of Pathology (R.K.) and Dermatology (M.M.), University Hospital Aachen, Aachen — all in Germany; and the Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands (R.W.).
Address reprint requests to Dr. Niehues at the Center for Child and Adolescent Health, HELIOS Klinikum Krefeld, Academic Hospital, Heinrich Heine University of Düsseldorf, Lutherpl. 40, 47805 Krefeld, Germany, or at tim.niehues@helios-kliniken.de.
- References
References
1
Buckley RH . Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol 2004;22:625-655
CrossRef | Web of Science | Medline2
Schwarz K ,Gauss GH ,Bozzi F , et al. RAG mutations in human B cell-negative SCID. Science 1996;274:97-99
CrossRef | Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
Shearer WT ,Rosenblatt HM ,Gelman RS , et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 2003;112:973-980
CrossRef | Web of Science | Medline5
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
CrossRef | Web of Science | Medline6
Manfras BJ ,Rudert WA ,Trucco M ,Boehm BO . Analysis of the alpha/beta T-cell receptor repertoire by competitive and quantitative family-specific PCR with exogenous standards and high resolution fluorescence based CDR3 size imaging. J Immunol Methods 1997;210:235-249
CrossRef | Web of Science | Medline7
Marzano AV ,Berti E ,Alessi E ,Caputo R . Clonal CD8 infiltration of the skin in common variable immunodeficiency: a prelymphomatous stage? J Am Acad Dermatol 2001;44:710-713
CrossRef | Web of Science | Medline8
de Villartay JP ,Lim A ,Al-Mousa H , et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest 2005;115:3291-3299
CrossRef | Web of Science | Medline9
Ehl S ,Schwarz K ,Enders A , et al. A variant of SCID with specific immune responses and predominance of γδ T cells. J Clin Invest 2005;115:3140-3148
CrossRef | Web of Science | Medline10
Sobacchi C ,Marrella V ,Rucci F ,Vezzoni P ,Villa A . RAG-dependent primary immunodeficiencies. Hum Mutat 2006;27:1174-1184
CrossRef | Web of Science | Medline11
Villa A ,Santagata S ,Bozzi F , et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell 1998;93:885-896
CrossRef | Web of Science | Medline12
Signorini S ,Imberti L ,Pirivano S , et al. Intrathymic restriction and peripheral expansion of the T-cell repertoire in Omenn syndrome. Blood 1999;94:3468-3478
Web of Science | Medline13
Hirschhorn R ,Yang DR ,Puck JM ,Huie ML ,Jiang CK ,Kurlandsky LE . Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nat Genet 1996;13:290-295
CrossRef | Web of Science | Medline14
Stephan V ,Wahn V ,Le Deist F , et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med 1996;335:1563-1567
Full Text | Web of Science | Medline15
Hirschhorn R . In vivo reversion to normal of inherited mutations in humans. J Med Genet 2003;40:721-728
CrossRef | Web of Science | Medline16
Levine TS ,Price AB ,Boyle S ,Webster ADB . Cutaneous sarcoid-like granulomas in primary immunodeficiency disorders. Br J Dermatol 1994;130:118-120
CrossRef | Web of Science | Medline17
Kanathur N ,Byrd RP Jr ,Fields CL ,Roy TM . Noncaseating granulomatous disease in common variable immunodeficiency. South Med J 2000;93:631-633
Web of Science | Medline18
Mechanic LJ ,Dikman S ,Cunningham-Rundles C . Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997;127:613-617
Web of Science | Medline19
Pujol RM ,Nadal C ,Taberner R ,Diaz C ,Miralles J ,Alomar A . Cutaneous granulomatous lesions in common variable immunodeficiency: complete resolution after intravenous immunoglobulins. Dermatology 1999;198:156-158
CrossRef | Web of Science | Medline
- Citing Articles (27)
Citing Articles
1
Giuseppina Aloj, Giuliana Giardino, Leopoldo Valentino, Filomena Maio, Vera Gallo, Tiziana Esposito, Roberta Naddei, Emilia Cirillo, Claudio Pignata. (2012) Severe Combined Immunodeficiences: New and Old Scenarios. International Reviews of Immunology 31:1, 43-65
CrossRef2
Mirjam Burg, Menno C. Zelm, Gertjan J. A. Driessen, Jacques J. M. Dongen. (2012) New frontiers of primary antibody deficiencies. Cellular and Molecular Life Sciences 69:1, 59-73
CrossRef3
Despina Moshous, Isabelle Meyts, Sylvie Fraitag, Carl E.I. Janssen, Marianne Debré, Felipe Suarez, Jaan Toelen, Kris De Boeck, Tania Roskams, Antoine Deschildre, Capucine Picard, Christine Bodemer, Carine Wouters, Alain Fischer. (2011) Granulomatous inflammation in cartilage-hair hypoplasia: Risks and benefits of anti–TNF-α mAbs. Journal of Allergy and Clinical Immunology 128:4, 847-853
CrossRef4
H IJspeert, A C Lankester, J M van den Berg, W Wiegant, M C van Zelm, C M R Weemaes, A Warris, Q Pan-Hammarström, A Pastink, M J D van Tol, J J M van Dongen, D C van Gent, M van der Burg. (2011) Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide. Genes and Immunity 12:6, 434-444
CrossRef5
T. W. Kuijpers, H. IJspeert, E. M. M. van Leeuwen, M. H. Jansen, M. D. Hazenberg, K. C. Weijer, R. A. W. van Lier, M. van der Burg. (2011) Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood 117:22, 5892-5896
CrossRef6
Mirjam Burg, Andy R. Gennery. (2011) Educational paper. European Journal of Pediatrics 170:5, 561-571
CrossRef7
Kerstin Felgentreff, Ruy Perez-Becker, Carsten Speckmann, Klaus Schwarz, Krzysztof Kalwak, Gasper Markelj, Tadej Avcin, Waseem Qasim, E.G. Davies, Tim Niehues, Stephan Ehl. (2011) Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency. Clinical Immunology
CrossRef8
H. Bernuth, K. Schwarz, E.D. Renner, S. Ehl. (2011) Diagnostik primärer Immundefekte. Monatsschrift Kinderheilkunde 159:5, 434-442
CrossRef9
Liutao Du, Richard A. Gatti. (2011) Potential therapeutic applications of antisense morpholino oligonucleotides in modulation of splicing in primary immunodeficiency diseases. Journal of Immunological Methods 365:1-2, 1-7
CrossRef10
Erika Asai, Taizo Wada, Yasuhisa Sakakibara, Akiko Toga, Tomoko Toma, Takashi Shimizu, Sheela Nampoothiri, Kohsuke Imai, Shigeaki Nonoyama, Tomohiro Morio, Hideki Muramatsu, Yoshiro Kamachi, Osamu Ohara, Akihiro Yachie. (2011) Analysis of mutations and recombination activity in RAG-deficient patients. Clinical Immunology 138:2, 172-177
CrossRef11
L.Y.T. Chiam, M.M.M. Verhagen, A. Haraldsson, N. Wulffraat, G.-J. Driessen, M.G. Netea, C.M.R. Weemaes, M.M.B. Seyger, M. van Deuren. (2011) Cutaneous Granulomas in Ataxia Telangiectasia and Other Primary Immunodeficiencies: Reflection of Inappropriate Immune Regulation?. Dermatology 223:1, 13-19
CrossRef12
S. S. De Ravin, E. W. Cowen, K. A. Zarember, N. L. Whiting-Theobald, D. B. Kuhns, N. G. Sandler, D. C. Douek, S. Pittaluga, P. L. Poliani, Y. N. Lee, L. D. Notarangelo, L. Wang, F. W. Alt, E. M. Kang, J. D. Milner, J. E. Niemela, M. Fontana-Penn, S. H. Sinal, H. L. Malech. (2010) Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood 116:8, 1263-1271
CrossRef13
C. Cunningham-Rundles. (2010) How I treat common variable immune deficiency. Blood 116:1, 7-15
CrossRef14
J. E. Walter, F. Rucci, L. Patrizi, M. Recher, S. Regenass, T. Paganini, M. Keszei, I. Pessach, P. A. Lang, P. L. Poliani, S. Giliani, W. Al-Herz, M. J. Cowan, J. M. Puck, J. Bleesing, T. Niehues, C. Schuetz, H. Malech, S. S. DeRavin, F. Facchetti, A. R. Gennery, E. Andersson, N. R. Kamani, J. Sekiguchi, H. M. Alenezi, J. Chinen, G. Dbaibo, G. ElGhazali, A. Fontana, S. Pasic, C. Detre, C. Terhorst, F. W. Alt, L. D. Notarangelo. (2010) Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. Journal of Experimental Medicine 207:7, 1541-1554
CrossRef15
Catharina Schuetz, Tim Niehues, Wilhelm Friedrich, Klaus Schwarz. (2010) Autoimmunity, autoinflammation and lymphoma in combined immunodeficiency (CID). Autoimmunity Reviews 9:7, 477-482
CrossRef16
Tim Niehues, Ruy Perez-Becker, Catharina Schuetz. (2010) More than just SCID—The phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clinical Immunology 135:2, 183-192
CrossRef17
D. G. Paige, A. R. Gennery, A. J. Cant. 2010. The Neonate. , 1-85.
CrossRef18
Mary A. Slatter, Andrew R. Gennery. (2010) Primary immunodeficiencies associated with DNA-repair disorders. Expert Reviews in Molecular Medicine 12,
CrossRef19
Hasibe Artac, Banu Bozkurt, Beril Talim, Ismail Reisli. (2009) Sarcoid-like granulomas in common variable immunodeficiency. Rheumatology International 30:1, 109-112
CrossRef20
Carrie Simkus, Anamika Bhattacharyya, Ming Zhou, Timothy D. Veenstra, Jessica M. Jones. (2009) Correlation between recombinase activating gene 1 ubiquitin ligase activity and V(D)J recombination. Immunology 128:2, 206-217
CrossRef21
Srdjan Pasic, Slavisa Djuricic, Goran Ristic, Bojana Slavkovic. (2009) Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblings. Acta Paediatrica 98:6, 1062-1064
CrossRef22
Christine McCusker, Simon Hotte, Francoise Le Deist, Aaron F. Hirschfeld, David Mitchell, Van-Hung Nguyen, Remi Gagnon, Bruce Mazer, Stuart E. Turvey, Nada Jabado. (2009) Relative CD4 lymphopenia and a skewed memory phenotype are the main immunologic abnormalities in a child with Omenn syndrome due to homozygous RAG1-C2633T hypomorphic mutation. Clinical Immunology 131:3, 447-455
CrossRef23
ITAI PESSACH, JOLAN WALTER, LUIGI D. NOTARANGELO. (2009) Recent Advances in Primary Immunodeficiencies: Identification of Novel Genetic Defects and Unanticipated Phenotypes. Pediatric Research 65:Supplement, 3R-12R
CrossRef24
Jessica M. Jones, Carrie Simkus. (2009) The roles of the RAG1 and RAG2 “non-core” regions in V(D)J recombination and lymphocyte development. Archivum Immunologiae et Therapiae Experimentalis 57:2, 105-116
CrossRef25
Carrie Simkus, Michelle Makiya, Jessica M. Jones. (2009) Karyopherin alpha 1 is a putative substrate of the RAG1 ubiquitin ligase. Molecular Immunology 46:7, 1319-1325
CrossRef26
Luigi D. Notarangelo, Ricardo Sorensen. (2008) Is it necessary to identify molecular defects in primary immunodeficiency disease?. Journal of Allergy and Clinical Immunology 122:6, 1069-1073
CrossRef27
Alan P. Knutsen. (2008) Oligoclonal T Cells and B Cells in an Amish Girl With Atypical RAG-1 Deficient Severe Combined Immunodeficiency. Pediatric Asthma, Allergy & Immunology 21:3, 145-148
CrossRef
