Disease relevance of Rag2

• Here we report that infecting Rag2-deficient C57BL/6 Apc(Min/+) mice with an intestinal bacterial pathogen, Helicobacter hepaticus, significantly promotes mammary carcinoma in females and enhances intestinal adenoma multiplicity by a tumor necrosis factor alpha (TNFalpha)-dependent mechanism [1].
• IL-4 treatment significantly accelerated the development of colitis in immunodeficient recipients (recombinase-activating gene-2 (Rag2)(-/-)) of CD4(+)CD45RB(high) T cells [2].
• Early death and severe lymphopenia caused by ubiquitous expression of the Rag1 and Rag2 genes in mice [3].
• Recently, we generated an active disease mouse model for pemphigus vulgaris by adoptive transfer of splenocytes from immunized desmoglein 3-/- mice to Rag2-/- mice [4].
• However, the amount of osteolysis and cytokine production induced by polyethylene particles was not substantially affected by the lack of lymphocytes in Pfp/Rag2 double knock out mice [5].

Psychiatry related information on Rag2

• To exclude any role of host APC, MHC incompatible Rag2(- / -) mice (H-2(b)) were used as recipients for the Id(+) B and Id-specific T cells, with similar results [6].

High impact information on Rag2

• Immune-deficient Rag2(-/-) mice were used as nuclear donors for transfer into enucleated oocytes, and the resulting blastocysts were cultured to isolate an isogenic embryonic stem cell line [7].
• RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination [8].
• RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement [9].
• Therefore, loss of RAG-2 function in vivo results in total inability to initiate V(D)J rearrangement, leading to a novel severe combined immune deficient (SCID) phenotype [9].
• Because the SCID phenotype was the only obvious abnormality detected in RAG-2 mutant mice, RAG-2 function and V(D)J recombinase activity, per se, are not required for development of cells other than lymphocytes [9].

Chemical compound and disease context of Rag2

• The findings demonstrate that both RAG-2 SCID and B-cell-deficient mice, but not T-cell- or C5-deficient mice, have increased susceptibility to the development of disseminating anaerobic infections [10].
• Here we show that local administration of the selective CB(2) agonist JWH-133 at 50 microg/day to Rag-2(-/-) mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells [11].
• We show that Proteus vulgaris O25 (PO25) lipopolysaccharide (LPS) induced an anaphylactoid reaction not only in wild-type and in lipid A non-responding mice but also in recombinase-activating gene-2-deficient (RAG-2(-/-)) and in mast cell-deficient (W/Wv) animals [12].
• Liposomal mitoxantrone formulations exhibiting different drug-release characteristics were injected i.v. in mice bearing human carcinoma xenografts: A431 human squamous cell carcinoma and LS180 human colon cell carcinoma in SCID/RAG 2 mice [13].
• High message expression by northern blotting was detected in intestine, kidney, lung, SCID, and Rag-2(-/-) thymus, and 2-deoxyguanosine-treated fetal thymic rudiment, but not in skeletal muscle, liver, heart, testis, and brain [14].

Biological context of Rag2

• RORgammat expression was elevated after pre-TCR signaling, and RORgammat promoted gene rearrangement in CD4+, CD8+ cells by inhibiting cell division, promoting survival via Bcl-X(L), and inducing Rag2 [15].
• A congenic strain (called 'ZORI' here) with defects in Rag1 and Rag2 expression, thymocyte maturation and peripheral T cell homeostasis has been developed [16].
• Using a mouse model, we show that expression of an inducible muHC transgene in Rag2-/- pro-B cells induces down-regulation of the following: (a) TdT protein, (b) a transgenic green fluorescent protein reporter reflecting endogenous Rag2 expression, and (c) Rag1 primary transcripts [17].
• It has been suggested that pre-B cell receptor (pre-BCR) signals are responsible for down-regulation of the VDJH-recombinase machinery (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing further rearrangement on the second HC allele [17].
• Using a transient transfection assay, we demonstrate that the recombination activating genes Rag1 and Rag2 direct site-specific rearrangement on an artificial substrate in poorly differentiated as well as in differentiated nonlymphoid cell lines [18].

Anatomical context of Rag2

• The products of the Rag1 and Rag2 genes drive genomic V(D)J rearrangements that assemble functional immunoglobulin and T cell antigen receptor genes [19].
• Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells [19].
• Fetal liver cells from Lsh-/- were used as a source of hematopoietic precursors to reconstitute lymphoid development in Rag2-/- mice [20].
• Prior transfer of 3 x 10(5) CD25+ CD4 T cells into Rag2-/- recipients prevented disease upon subsequent transfer of CD25- CD4 T cells, whereas 3 x 10(4) regulatory T cells (Tregs) did not, despite the fact that there were equal total numbers of Tregs in the host at the time of transfer of CD25- CD4 T cells [21].
• This was achieved by the intraperitoneal injection of CD34(+) precursor cells into newborn Rag2(-/-) gammac(-/-) mice that lack T, B, and NK cells [22].

Associations of Rag2 with chemical compounds

• Rag2(-/-) mice reconstituted with Ppia(-/-) splenocytes were also cyclosporine resistant, indicating that this property is intrinsic to Ppia(-/-) immune cells [23].
• We previously reported that fatty streak development of immunodeficient ApoE(-/-)/recombination activating gene 2 (RAG-2(-/-)) double-deficient mice was insensitive to estradiol [24].
• The ontogeny of B cells in the thymus of normal, CD3 epsilon knockout (KO), RAG-2 KO and IL-7 transgenic mice [25].
• Pro-B cells from RAG2/BTK-DKO mice did not differentiate into pre-B cells following CD79b cross-linking, although tyrosine phosphorylation of cellular proteins including Erk1/2 and phospholipase C-gamma2 was induced in the same manner as RAG2-KO mice [26].
• Moreover, in these mature lymphocyte cell lines there was no evidence of synergy in the regulation of RAG-1 and RAG-2 mRNA upon stimulation with CLA and caffeine [27].
• Mutation of a conserved tryptophan residue in the RAG-2 PHD finger abolished binding to H3K4me3 and greatly impaired recombination of extrachromosomal and endogenous immunoglobulin gene segments [28].

Physical interactions of Rag2

• Apart from showing that Sp1 interacts within the RAG-2 promoter, we also demonstrate that the Sp1-binding site is necessary for the high-level activation of this promoter [29].
• Identification of two catalytic residues in RAG1 that define a single active site within the RAG1/RAG2 protein complex [30].
• Inhibition of this phosphorylation by p27Kip1 stabilizes the RAG2 protein in the nucleus [31].

Enzymatic interactions of Rag2

• BTK is phosphorylated after cross-linking of CD79b on RAG2-deficient pro-B cells [26].
• Complementation of RAG-2-deficient blastocysts with mutant ES cells heterozygous for a targeted mutation that deletes all immunoglobulin heavy-chain joining (JH) gene segments (JH+/-) also leads to generation of chimeras with normal B and T cells [32].

Regulatory relationships of Rag2

• Recently, we developed a PV mouse model by adoptive transfer of splenocytes from recombinant Dsg3-immunized Dsg3(-/-) mice to Rag2(-/-) immunodeficient mice that expressed Dsg3 [33].
• Our work and that of others subsequently revealed that RAG-2 promoter expression is positively regulated by BSAP (PAX-5) and c-Myb transcription factors in B- and T-lineage cells, respectively [29].
• To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2(-/-) mice and wild-type mice [34].
• Injection of recombinant IL-13 induced worm expulsion in otherwise incompetent RAG2-/- mice [35].
• Bone marrow cells from immunoglobulin HC transgenic RAG-2-/- mice have up-regulated expression of germ-line kappa LC gene transcripts and down-regulated expression of lambda 5 surrogate LCs (SLCs) [36].

Other interactions of Rag2

• The recombination activating genes, RAG-1 and RAG-2, are likely to encode components of the V(D)J site-specific recombination machinery [37].
• Reconstitution of B cells in Rag-2(-/-) mice with a mixture of p50(-/-)/p65(-/-) fetal liver cells and Rag-2(-/-) bone marrow cells revealed that the generation of marginal zone B cells requires the expression of NF-kappa B in developing B cells, as opposed to supporting cells [38].
• In contrast to expectation, the data presented here indicate that development of malignant thymic lymphoma in Atm(-/-) mice is not prevented by loss of RAG-2 and thus is not dependent on V(D)J recombination [39].
• CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation [40].
• Mutation of the RAG-2 promoter for Pax-5- and GATA-3-binding sites results in the reduction of promoter activity in B cells and T cells [41].

Analytical, diagnostic and therapeutic context of Rag2

• The current studies were undertaken to examine this issue in a model of adoptive transfer of antigen-specific B cells and T cells into histoincompatible Rag2(-/-) mice [42].
• A simple technique for generating probes for RNA in situ hybridization: an adjunct to genome mapping exemplified by the RAG-1/RAG-2 gene cluster [43].
• Gene therapy of RAG-2-/- mice: sustained correction of the immunodeficiency [44].
• A PCR of 35 cycles disclosed expression of RAG-1 but not RAG-2 in morulae and blastocysts [45].
• We show that the earliest fetal thymus (FT) cells from Rag2(-/-) mice, when cultured individually in a thymic organ culture system, produced 150-1,800 CD25(+) cells [46].

References