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The nonobese diabetic (NOD) mouse strain has a genetic deficiency in natural killer (NK) cells. This defect underlies this strain's utility in several experimental settings; in particular, it promotes engraftment of human tissue in NOD hosts during the generation of 'humanized' mouse models. We have mapped the major NK-cell defect in the NOD vs. C57BL/6 (B6) strain to an inadequately expressed Il15 allele. Treatment of NOD mice with a reagent that specifically enhances interleukin (IL)-15 bioavailability normalized NK-cell numbers and activity in the absence of nonspecific stimulation. These findings raise the possibility of exploiting reagents that impact the IL-15 receptor pathway to facilitate construction of humanized mouse models on non-NOD genetic backgrounds. type 1 diabetes | gene mapping | cytotoxicity | genetic variation doi: 10.1073/pnas1004492107

Null alleles of the gene encoding NEMO (NF-[kappa]B essential modulator) are lethal in hemizygous mice and men, whereas hypomorphic alleles typically cause a syndrome of immune deficiency and ectodermal dysplasia. Here we describe an allele of Ikbkg in mice that impaired Toll-like receptor signaling, lymph node formation, development of memory and regulatory T cells, and Ig production, but did not cause ectodermal dysplasia. Degradation of I[kappa]B[alpha], which is considered a primary requirement for NEMO-mediated immune signaling, occurred normally in response to Toll-like receptor stimulation, yet ERK phosphorylation and NF-[kappa]B p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond I[kappa]B[alpha] degradation, and offers a biochemical explanation for rare immune deficiencies in man. mutagenesis | N-ethyl-nitrosourea | nuclear factor-[kappa]B essential modulator | p65 | Toll-like receptor www.pnas.org/cgi/doi/10.1073/pnas.0915098107

B-cell survival depends on signals induced by B-cell activating factor (BAFF) binding to its receptor (BAFF-R). In mice, mutations in BAFF or BAFF-R cause B-cell lymphopenia and antibody deficiency. Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene. Removing most of the BAFF-R transmembrane part, the deletion precludes BAFF-R expression. Without BAFF-R, B-cell development is arrested at the stage of transitional B cells and the numbers of all subsequent B-cell stages are severely reduced. Both siblings have lower IgG and IgM serum levels but, unlike most CVID patients, normal IgA concentrations. They also did not mount a T-independent immune response against pneumococcal cell wall polysaccharides but only one BAFF-R-deficient sibling developed recurrent infections. Therefore, deletion of the BAFF-R gene in humans causes a characteristic immunological phenotype but it does not necessarily lead to a clinically manifest immunodeficiency. B lymphopenia | primary immunodeficiency | recessive mutation

Hypomorphic mutations in DNA ligase IV (LIG4) cause a human syndrome of immunodeficiency, radio-sensitivity, and growth retardation due to defective DNA repair by the nonhomologous end-joining (NHEJ) pathway. Lig4-null mice are embryonic lethal, and better mouse models are needed to study human LigIV syndrome. We recently identified a viable mouse strain with a Y288C hypomorphic mutation in the Lig4 gene. [Lig4.sup.Y288C] mice exhibit a greater than 10-fold reduction of LigIV activity in vivo and recapitulate the immunodeficiency and growth retardation seen in human patients. Here, we have demonstrated that the [Lig4.sup.Y288C] mutation leads to multiple defects in lymphocyte development and function, including impaired V(D)J recombination, peripheral lymphocyte survival and proliferation, and B cell class switch recombination. We also highlight a high incidence of thymic tumors in the [Lig4.sup.Y288C] mice, suggesting that wild-type LigIV protects against malignant transformation. These findings provide explanations for the complex lymphoid phenotype of human LigIV syndrome., Introduction Nonhomologous end joining (NHEJ) is one of the main pathways for repair of DNA double-strand breaks (DSBs) (1). The pathway comprises 6 core components: Ku70, Ku80, DNA-dependent protein kinase [...]

Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-[alpha]/[beta] and IFN-[gamma]. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-[alpha]/[beta] and IFN-[gamma] signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients' cells, therefore, displayed impaired but not abolished responses to both IFN-[alpha] and IFN-[gamma]. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-[gamma]1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-[alpha]/[beta], IFN-[gamma], IFN-[gamma]1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections., Introduction STAT1 is a key signaling component of IFN responses. There are 2 STAT1 mRNAs, STAT1[alpha] and STAT1B, which use distinct polyadenylation sites. STAT1[alpha] is transcribed and spliced from 25 [...]

The clinical phenotype studies of three siblings from one kindred with a clinical syndrome of immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, thrombocytopenia, muscular hypotonia, and defective enamel dentition are reported. The lack of store-operated [Ca.sup.2+] entry due to defects in ORAI1 or stromal interaction molecule 1 (STIM1) which interferes with immune function might cause immunodeficiency, auto-immune disease, and myopathy.

Author(s): Thomas R Bauer, Jr [1]; James M Allen [2]; Mehreen Hai [1]; Laura M Tuschong [1]; Iram F Khan [2]; Erik M Olson [2]; Rima L Adler [1]; Tanya [...]

The lack of genetic means has been a serious limitation in studying mosquito immunity. We generated Relish-mediated immune deficiency (RMID) by transforming Aedes aegypti with the [DELTA]Rel transgene driven by the vitellogenin (Vg) promoter using the pBac[3xP3-EGFP, afm] vector. A stable transformed line had a single copy of the Vg-[DELAT]Rel transgene. The Vg-[DELAT]Rel transgene expression was highly activated by blood feeding, and transgenic mosquitoes were extremely susceptible to the infection by Gram-negative bacteria. This RMID phenotype was characterized by severely reduced postinfection levels of antimicrobial peptides genes, defensin and cecropin. Crossing the RMID line with the wild-type strain produced the same RMID phenotype, indicating its dominant nature, whereas crossing with the Vg-def transgenic line, in which Defensin A was activated by blood feeding, restored the immunity to Enterobacter cloacae.

The bare lymphocyte syndrome (BLS), a rare severe combined immunodeficiency that is autosomal recessive, is discussed in relation to molecular clues about major histocompatibility complex (MHC) class II genes and their transcriptional regulation. Complementation group A cells have defects in the class II transactivator (CIITA), deficiencies in the complementation groups B,C, and E exist, and CIITA and the regulatory-factor X (RFX) complex are integral parts of MHC class II expression.

Interleukin-2 (IL-1) signaling and inherited immunodeficiency are discussed in connection with current understanding of the related cytokine receptors, the Janus (Jak) family of tyrosine kinases, and the family of signal transducers and activators of transcription (STAT) transcription factors. Cytokine signaling pathways that control T-cell expansion and apoptosis are still not well understood, but it can be seen that downstream regulation of cytokine responses is surprisingly complex and that some targets for therapeutic intervention exist.

Interferon consensus sequence binding protein (ICSBP)-mutant mice were analyzed to determine the role of ICSBP in the antiviral responses of the immune system and chronic myelogenous leukemia (CML). ICSBP mutants exhibited normal antiviral responses to vesicular stomatitis virus indicating that the interferon, B and T lymphocytic system was not altered by ICSBP- deficiency. However, the mutant mice died after being infected with the lymphocytic choriomeningitis virus. Furthermore, the mutants exhibited hematologic neoplasia that is characteristic of CML.

The 350-kDa polypeptide (p350) subunit of the protein DNA-dependent protein kinase (DNA-PK) is not present in cells obtained from severe combined immunodeficiency mice and in the Chinese hamster, in which there are defects in double-strand break (DSB) repair, suggesting that DNA-PK is a major component of DSB repair and that the 'scid' gene encodes the p350 protein. The DNA-PK has three polypeptide subunits, Ku-70, Ku-80 and p350. A centromeric portion of human chromosome 8 that overcomes the scid defect brings back p350 activity.