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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antigen-specific immunity is due to the generation of a multitude of both immunoglobulins and T-cell receptors through a process designated V(D)J recombination. In vitro reconstitution of this system has taught us a great deal about the molecular mechanism underlying this site-specific recombination process. Hence, it became obvious that the initial steps of the reaction are carried out by the lymphocyte-specific proteins RAG1 and RAG2 (recombination-activating genes), with the help of members of the high mobility group protein family of DNA-binding proteins, HMG1 or HMG2. Structural resemblance between RAG1 and a prokaryotic recombinase, the Salmonella Hin Recombinase, together with mechanistic similarities between V(D)J recombination and bacterial transposition reactions, make it likely that these different processes have evolved from a common ancestral recombination system. The second step in V(D)J recombination is catalysed by the ubiquitous DNA double-strand break repair machinery. The link between V(D)J recombination and double-strand break repair was established through some mutational complementation groups, including the murine SCID mutation (severe combined immunodeficiency), which were shown to be defective in both V(D)J recombination and double-strand break repair. The multisubunit DNA-dependent protein kinase appears to be a key player in these processes. Thus, from an evolutionary point of view, antigen-specific immunity in mammals, e.g., humans and mice, appears to be the result of an evolutionary combination of two unrelated systems involved in DNA metabolism.
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PMID:RAGged repair: what's new in V(D)J recombination. 937 76

During B and T lymphocyte development, immunoglobulin and T cell receptor genes are assembled from the germline V, (D) and J gene segments (Lewis, S.M., 1994. The mechanism of V(D)J joining: lessons from molecular, immunological and comparative analyses. Adv. Immunol. 56, 27-150). These DNA rearrangements, responsible for immune system diversity, are mediated by a site specific recombination machinery via recognition signal sequences (RSSs) composed of conserved heptamers and nonamers separated by spacers of 12 or 23 nucleotides (Lewis, S.M., 1994. The mechanism of V(D)J joining: lessons from molecular, immunological and comparative analyses. Adv. Immunol. 56, 27-150). Recombination occurs only between a RSS with a 12mer spacer and a RSS with a 23mer spacer (Lewis, S.M., 1994. The mechanism of V(D)J joining: lessons from molecular, immunological and comparative analyses. Adv. Immunol. 56, 27-150). RAG1 and RAG2 proteins cleave precisely at the RSS-coding sequence border leading to flush signal ends and coding ends with a hairpin structure (Eastman, M., Leu, T., Schatz, D., 1996. Initiation of V(D)J recombination in vitro obeying the 12/23 rule. Nature 380, 85-88; Roth, D.B., Menetski, J.P., Nakajima, P.B., Bosma, M.J., Gellert, M., 1992. V(D)J recombination: broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes. Cell 983-991: Roth, D.B., Zhu, C., Gellert. M., 1993. Characterization of broken DNA molecules associated with V(D)J recombination. Proc. Natl. Acad. Sci. USA 90, 10,788-10,792; van Gent, D., McBlane, J.. Sadofsky, M., Hesse, J., Gellert, M., 1995. Initiation of V(D)J recombination in a cell-free system. Cell 81, 925-934). Signal ends join, forming a signal joint. The hairpin coding ends are opened by a yet unknown endonuclease, and are further processed to form the coding joint (Lewis, S.M., 1994. The mechanism of V(D)J joining: lessons from molecular, immunological and comparative analyses. Ad. Immunol. 56, 27-150.) The murine scid mutation has been shown to affect coding joints, but much less signal joint formation. In this study we demonstrate that the murine scid mutation inhibits correct signal joint formation when both coding ends contain homopolymeric sequences. We suggest that this finding may be due to the function of the SCID protein as an assembly component in V(D)J recombination.
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PMID:Signal joint formation is inhibited in murine scid preB cells and fibroblasts in substrates with homopolymeric coding ends. 1047 10

Development of a small animal model for the in vivo study of human immunity and infectious disease remains an important goal, particularly for investigations of HIV vaccine development. NOD/Lt mice homozygous for the severe combined immunodeficiency (Prkdcscid) mutation readily support engraftment with high levels of human hematolymphoid cells. However, NOD/LtSz-scid mice are highly radiosensitive, have short life spans, and a small number develop functional lymphocytes with age. To overcome these limitations, we have backcrossed the null allele of the recombination-activating gene (Rag1) for 10 generations onto the NOD/LtSz strain background. Mice deficient in RAG1 activity are unable to initiate V(D)J recombination in Ig and TCR genes and lack functional T and B lymphocytes. NOD/LtSz-Rag1null mice have an increased mean life span compared with NOD/LtSz-scid mice due to a later onset of lymphoma development, are radioresistant, and lack serum Ig throughout life. NOD/LtSz-Rag1null mice were devoid of mature T or B cells. Cytotoxic assays demonstrated low NK cell activity. NOD/LtSz-Rag1null mice supported high levels of engraftment with human lymphoid cells and human hemopoietic stem cells. The engrafted human T cells were readily infected with HIV. Finally, NOD/LtSz-Rag1null recipients of adoptively transferred spleen cells from diabetic NOD/Lt+/+ mice rapidly developed diabetes. These data demonstrate the advantages of NOD/LtSz-Rag1null mice as a radiation and lymphoma-resistant model for long-term analyses of engrafted human hematolymphoid cells or diabetogenic NOD lymphoid cells.
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PMID:NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells. 1067 87

Langerhans cells (LCs) are immature dendritic cells (DCs) present in the skin epithelium. Upon Ag exposure, they migrate to the draining lymph nodes where they mature into potent stimulators of naive T cells. The aim of this study was to investigate the influence of T cells on LC migration and maturation. Therefore, the in vivo migration and maturation of LCs after sensitization with the hapten FITC was compared between C57BL/6 or BALB/c mice used as positive controls, and recombination activating gene (RAG) 1 knockout (-/-) mice or SCID mice used as T cell-deficient mice. Phenotypically, there was no difference between migrated LCs from RAG1-/- or SCID mice vs normal C57BL/6 or BALB/c mice: both populations of FITC+ cells had a dendritic morphology and a mature phenotype as they expressed high levels of MHC class II molecules and costimulatory molecules CD80, CD86, and CD54. Sorted migrated LCs of RAG1-/- or SCID mice were efficient stimulators of allogeneic T cells and Ag-specific CD4+ T cells. The same results were found if migrated LCs were fixed instead of irradiated, excluding the possibility that LCs derived from RAG1-/- or SCID mice would mature in the presence of T cells during the stimulation tests. Importantly, fixed migrated LCs of RAG1-/- mice were also efficient stimulators of cytotoxic CD8+ T cells. These data suggest that T cells are not required for full maturation of LCs.
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PMID:Langerhans cells that have matured in vivo in the absence of T cells are fully capable of inducing a helper CD4 as well as a cytotoxic CD8 response. 1087 36

The proteins encoded by RAG1 and RAG2 can initiate gene recombination by site-specific cleavage of DNA in immunoglobulin and T-cell receptor (TCR) loci. We identified a new homozygous RAG1 gene mutation (631delT) that leads to a premature stop codon in the 5' part of the RAG1 gene. The patient carrying this 631delT RAG1 gene mutation died at the age of 5 weeks from an Omenn syndrome-like T(+)/B(- )severe combined immunodeficiency disease. The high number of blood T-lymphocytes (55 x 10(6)/mL) showed an almost polyclonal TCR gene rearrangement repertoire not of maternal origin. In contrast, B-lymphocytes and immunoglobulin gene rearrangements were hardly detectable. We showed that the 631delT RAG1 gene can give rise to an N-terminal truncated RAG1 protein, using an internal AUG codon as the translation start site. Consistent with the V(D)J recombination in T cells, this N-terminal truncated RAG1 protein was active in a plasmid V(D)J recombination assay. Apparently, the N-terminal truncated RAG1 protein can recombine TCR genes but not immunoglobulin genes. We conclude that the N-terminus of the RAG1 protein is specifically involved in immunoglobulin gene rearrangements.
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PMID:N-terminal truncated human RAG1 proteins can direct T-cell receptor but not immunoglobulin gene rearrangements. 1089 52

Periodically the World Health Organization and currently the International Union of Immunology Societies publish a classification of primary immunodeficiency diseases (PID) that includes diagnostic and therapeutic guidelines. The latest of these publications dates from 1999 and includes a new group of PID, the proliferative autoimmune syndromes. Furthermore, new forms of severe combined immunodeficiency (SCID) and of recessive autosomal agammaglobulinemia are described. From the publication of this classification until the end of the year 2000 a minimum of three new PIDs have been described and a further two should probably be added. Progress in the molecular biology of these diseases has given rise not only to more accurate diagnosis but also to greater insight into the clinical spectrum of these diseases. A mutation or deletion in a gene can provoke the complete absence of its product; sometimes expression is partial or normal but functional activity is absent or defective. In certain cases, partial or defective activity causes variant forms of the disease presenting symptomatology or atypical cellular phenotype. In other cases, this is not cause of the variant form, which can appear in interfamilial cases sharing the same mutation. In these cases, these differences can be attributed to environmental factors or to other genes able to modify the affected gene. In this article we provide examples of variant forms in several PIDs. Some are late onset forms, such as X-linked agammaglobulinemias diagnosed in adults, since until diagnosis, clinical symptomatology was minimal. In adenosine-deaminase deficiency, a serious and highly lymphoproliferative form of SCID, patients have been described whose symptomatology began after the age of 20 years. Another SCID, RAG1 and RAG2 recombinase deficiency, may produce a typical form with a characteristic T-B-NK + phenotype, Omenn's syndrome, or forms with an unexpected T-B + NK + phenotype. Deficiency in common gamma chain receptor for IL-2 may produce phenotypical variants that can lead to diagnostic error. X-linked lymphoproliferative syndrome may present as fulminant infectious mononucleosis, as leukemia or lymphoma or as hipo- or agammaglobulinemia. Possibly, some patients diagnosed with common variable immunodeficiency or with x-linked agammaglobulinemia do in fact have this syndrome. Chronic granulomatous disease is usually of early-onset, but late-onset forms have been described. In one case the first clinical manifestation was produced when the patient was 60 years old. The above examples serve to highlight that, even though PIDs are usually suspected by pediatricians, in some cases the diagnosis may be missed by internists or non-pediatricians. Moreover, the clinical and laboratory findings of these variant forms must be determined to carry out an early diagnosis, which is essential for a favorable therapeutic outcome.
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PMID:[Primary immunodeficiencies. Clinical features and variant forms]. 1143 82

Mutations of the RAG1 or RAG2 protein that eliminate their recombination activity result in T-B-severe combined immunodeficiency (SCID), whereas mutations retaining partial recombination activity lead to Omenn syndrome, a peculiar SCID characterized by increased host T cells and absence of circulating B cells. The prognosis of this disease is fatal, unless hematopoietic stem cell transplantation is performed. This study reports a case of atypical SCID, carrying RAG1 mutations. The patient survived for 6 years without hematopoietic stem cell transplantation. The missense mutation, tested by in vivo recombination assay, revealed residual recombination activity. By the age of 5 years, the patient developed host B cells, but not T cells, possibly due to engrafted maternal T cells. In addition, the host B cells were able to produce antibodies, including anti-herpes simplex virus-antibodies. The fact that host B cells could produce antibodies in this patient could explain not only the mild phenotype observed but also, at least in part, how patients with Omenn syndrome produce immunoglobulin E and sometimes immunoglobulin M, as the same missense mutation of RAG1 gene has been reported in a patient with Omenn syndrome.
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PMID:Identification of anti-herpes simplex virus antibody-producing B cells in a patient with an atypical RAG1 immunodeficiency. 1152 Jul 96

Much evidence supports the conclusion that immunological responses to donor-specific incompatibilities are a major factor in producing "chronic" transplant rejection, including the arteriopathy (atherosclerosis) commonly present. Our experiments explored the effects of altered immunological responsiveness to these Ags on the formation of arteriopathy in transplanted mouse hearts. Specific immunological nonreactivity, or tolerance, was induced either by neonatal administration of allogeneic spleen cells (from F(1) donors between class I-mismatched donor and recipient strains), resulting in "classical" immunological tolerance, or by bone marrow infusion to suitably prepared adult recipients, either fully MHC mismatched or class I mismatched, yielding "mixed chimerism." Both approaches obviated systemic graft-versus-host effects. In both groups, donor-specific skin grafts survived perfectly and donor cell chimerism persisted. Specific Abs were undetectable in all recipients. Most transplants to either group of tolerant recipients developed striking vasculopathy in their coronary arteries (12 of 15 in neonatal tolerance and 15 of 23 in mixed chimeras). Neointimal infiltrates included CD4 and CD8 T cells and macrophages. Only 2 of 29 contemporary isotransplants showed any evidence of vasculopathy. Recipients essentially incapable of T and B cell responses (C.B-17/SCID and RAG1(-/-)) were also used. Transplants into these animals developed vasculopathy in 16 of 31 instances. Accordingly, in this setting, vasculopathy develops in the presence of H-2 gene-determined incompatibility even with minimal conventional immune reactivity. Perhaps innate responsiveness, that could include NK cell activity, can create such arteriopathic lesions. More evidence is being sought regarding this process.
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PMID:Tolerance, mixed chimerism, and chronic transplant arteriopathy. 1169 46

The protein products of the recombination activating genes (RAG1 and RAG2) initiate the formation of immunoglobulin (Ig) and T-cell receptors, which are essential for B- and T-cell development, respectively. Mutations in the RAG genes result in severe combined immunodeficiency disease (SCID), generally characterized by the absence of mature B and T lymphocytes, but presence of natural killer (NK) cells. Biochemically, mutations in the RAG genes result either in nonfunctional proteins or in proteins with partial recombination activity. The mutated RAG genes of 9 patients from 7 families were analyzed for their recombination activity using extrachromosomal recombination substrates, rearrangement of endogenous Ig loci in RAG gene-transfected nonlymphoid cells, or the presence of Ig gene rearrangements in bone marrow (BM). Recombination activity was virtually absent in all 6 patients with mutations in the RAG core domains, but partial activity was present in the other 3 RAG-deficient patients, 2 of them having Omenn syndrome with oligoclonal T lymphocytes. Using 4-color flow cytometry, we could define the exact stage at which B-cell differentiation was arrested in the BM of 5 RAG-deficient SCID patients. In 4 of 5 patients, the absence of recombination activity was associated with a complete B-cell differentiation arrest at the transition from cytoplasmic (Cy) Igmu(-) pre-B-I cells to CyIgmu(+) pre-B-II cells. However, the fifth patient showed low frequencies of precursor B cells with CyIgmu and surface membrane IgM, in line with the partial recombination activity of the patient's mutated RAG gene and the detection of in-frame Ig gene rearrangements in BM.
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PMID:The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. 1220 Mar 79

We have investigated the role of Toxoplasma gondii-derived heat shock protein 70 (TgHSP70) as a B cell mitogen by measuring proliferative responses in vitro. TgHSP70 induced prominent proliferative responses in murine B cells derived not only from T gondii-infected but also from uninfected mice. Nude mice responded to TgHSP70; however, severe combined immunodeficiency, RAG1-/- B6, and microMT mice failed to respond. B220+ spleen cells showed marked proliferation after stimulation with TgHSP70, but neither CD4+ nor CD8+ population responded. This unresponsiveness of CD4+ and CD8- T cells to TgHSP70 was antigen presenting cells independent. These data indicate that TgHSP70 induced the proliferation of B cells but not T cells. Polymyxin B, a potent inhibitor of lipopolysaccharide (LPS), did not eliminate TgHSP70-induced proliferation. C3H/HeN mice responded well to TgHSP70 stimulation; however, C3H/HeJ mice carrying a point mutation in the Toll-like receptor (TLR) 4 failed to respond. This indicates that TLR4 is required for TgHSP70-induced B cell activation. The involvement of TLR4 in the TgHSP70-induced proliferative responses of spleen cells was also shown by the use of TLR4-/- mice. But TgHSP70-induced, but not LPS-induced, spleen cell proliferation was observed in MyD88-/- mice, indicating that the MyD88 molecule was involved in LPS-induced proliferation but not in TgHSP70-induced proliferation.
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PMID:Toxoplasma gondii-derived heat shock protein HSP70 functions as a B cell mitogen. 1265 80


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