Search

ABSTRACTPhosphorus (P) deficiency severely constrains rice production in sub-Saharan Africa. Previous studies showed that P-dipping, involving localized application of P near the root zone, and MP3, a natural allele of OsTB1/FC1that enhances rice tillering, effectively improve rice growth and productivity in P-deficient soils in Madagascar. In the present study, we investigated the combined impact of these two technologies on the initial growth of transplanted rice in P-deficient soils using potted plants. Our experiments revealed that near-isogenic lines for MP3and fc1(the loss-of-function allele of OsTB1/FC1) promoted tillering and increased initial shoot biomass compared with the parental cultivar ‘Takanari’ when combined with P-dipping. The rise in shoot biomass would be attributed to increased P-uptake in the shoots, which were brought about by a continuous P-supply from the root zone due to P-dipping. Consequently, these combinations have the potential to enhance rice productivity in P-deficient paddy fields in sub-Saharan Africa.

Aside from its various biomedical effects, γ‐oryzanol is a biomarker for heat stress in rice (Oryza sativaL.). Recently, we found that a japonicacultivar Momiroman had the highest γ‐oryzanol among 92 cultivars. In the present study, we aimed to detect the quantitative trait locus (QTLs) for the concentrations of cycloartenyl ferulate (1), 24‐methylenecycloartanyl ferulate (2), and total γ‐oryzanol in the populations from a cross between Momiroman and an indicacultivar Takanari. We detected the QTLs for the concentrations of 1, 2, and/or total γ‐oryzanol on chromosomes 4, 5, 9, and 11. The Momiroman alleles at the QTLs on chromosomes 4, 5, and 11 increased the concentrations of 1, 2, and/or total γ‐oryzanol, whereas the Takanari alleles at the QTLs on chromosome 9 increased. Considering the literature data, the japonicaalleles at the QTLs on chromosomes 4, 5, and 11 may increase the concentrations of 1, 2, and/or total γ‐oryzanol in the indicagenetic background. This study revealed the QTLs for the concentrations of 1, 2, and/or total γ‐oryzanol on chromosomes 4, 5, 9, and 11, providing essential information for the development of cultivars with specific biomedical properties or heat stress resistance.

ABSTRACTPhosphorus (P) deficiency is a major yield constraint for lowland rice production in the tropics. As P-fertilizer resources are finite, alternative fertilizer management is needed for sustainable rice production. We examined whether farmyard manure (FYM), a major nutrient source for smallholder farms, can overcome issue in typical P-deficient lowlands in the central highlands of Madagascar. A multi-location trial in sites varying in altitude and soil P availability, clarified that the effect of both FYM and mineral P fertilizer application on grain yield greatly increased at higher elevation and when the soil oxalate-extractable P content was <100 mg kg−1. The yield increase was attributable to improved grain fertility, probably because FYM and mineral P applications decreased days to flowering and avoided low temperatures at late growth stages. Nutrient uptake assessment clarified that despite its relatively low P content, FYM had an equivalent effect on plant P uptake to those of mineral P fertilizer. We concluded that FYM application was effective in low-P availability soils at high altitude, as alternative of mineral P fertilizer. Further monitoring is required to assess the effect of consecutive FYM use on grain yield and plant nutrient uptake in the context of cold stress induced by P deficiency.

Grain weight decreases by heat stress during ripening in rice. Phenylpropanoid glycosides and γ‐oryzanol are biomarkers for heat stress. The relationships between grain weight and the concentrations of these compounds should be understood in order to use biomarkers to improve the heat tolerance of rice. In the present study, we aimed to determine the relationships between grain weight and the concentrations of these compounds in the japonicacultivar Koshihikari and the indicacultivar Takanari. In Koshihikari, the concentrations of 3',6‐di‐O‐sinapoylsucrose, 24‐methylenecycloartanyl ferulate, and total γ‐oryzanol had strong negative correlations with grain weight. Conversely, in Takanari, the concentrations of 3',6‐di‐O‐sinapoylsucrose and 3'‐O‐sinapoyl‐6‐O‐feruloylsucrose had negative correlations with grain weight, whereas those of 3',6‐di‐O‐feruloylsucrose and cycloartenyl ferulate had positive correlations with grain weight. Interestingly, the relationships between grain weight and the concentrations of 3',6‐di‐O‐sinapoylsucrose, 24‐methylenecycloartanyl ferulate, and total γ‐oryzanol appeared to be stronger in Koshihikari than in Takanari. The metabolisms of 3',6‐di‐O‐sinapoylsucrose, 24‐methylenecycloartanyl ferulate, and total γ‐oryzanol may be strongly correlated with grain weight reduction caused by heat stress in Koshihikari. The concentrations of 3',6‐di‐O‐sinapoylsucrose, 24‐methylenecycloartanyl ferulate, and total γ‐oryzanol may be powerful tools for improving the heat tolerance of japonicacultivars.

The majority of paddy fields in sub‐Saharan Africa (SSA) are characterized by nutrient‐poor soils. In such fields, tillering in rice (Oryza sativaL.) plants is severely restricted, which results in a reduced number of panicles and thus a decrease in grain yield. In this study, we evaluated the effects of a quantitative trait locus (QTL), associated with number of panicles and referred as MP3, on rice growth and grain yield in nutrient‐poor soils in Madagascar. We used a high‐yielding rice cultivar, Takanari, and its near‐isogenic line bearing the MP3allele (NIL‐MP3). A pot experiment with various P application rates demonstrated vigorous tillering in NIL‐MP3compared to Takanari from the early vegetative stage even under low P levels. This led to enlarged leaf area and thus increased biomass. We then conducted multiple field trials with a total of 12 experimental conditions using the two varieties. The experiments led to a range of grain yield from 1.3 to 4.1 t ha−1and a range in number of panicles from 107 to 270 m−2. The results revealed that NIL‐MP3produced a greater number of panicles and spikelets m−2(19 and 12%, respectively) than Takanari across all 12 experiments. Grain yield increased in NIL‐MP3under some experimental conditions. This study is the first of its kind to demonstrate that MP3increased number of panicles and spikelets and grain yield in the nutrient‐poor and low‐yielding soils of SSA. Thus, we conclude that MP3could become a prominent genetic resource for the improvement of rice yields in SSA.

ABSTRACTShoot morphology in rice plants changes in response to P deficiency. However, how genotypic variations in these morphological changes affect the canopy development and biomass production have hardly been explored. The study aimed to identify specific shoot morphological traits that confer biomass production under P deficiency. Four rice genotypes, including AZ-97 (WAS 63–22-5-9-10-1), which exhibits high performance under highly P-deficient fields in Madagascar, were grown for 56 days in flooded pots over several P application rates to simulate P-sufficient and moderately, severely, and extremely P-deficient conditions. AZ-97 had superior shoot P contents and biomass than Takanari, a high-yielding cultivar, and X265, a common high-yielding cultivar in Madagascar at severely to moderately P-deficient conditions. Shoot biomass was highly correlated with projected leaf area (PLA) from the early growth stage, and tiller number, leaf width, and leaf elongation rate explained the variations in PLA. These morphological traits reduced significantly with decreased P application rates, while reduction in AZ-97 was small relative to the other genotypes, even for equivalent shoot P contents. As the result, AZ-97 had greater PLA per unit of shoot P content at equivalent shoot P contents. The result indicates that lower sensitivity and degrees of change in shoot morphology when exposed to P deficiency stress could be a key trait facilitating the maintenance of captured radiation and subsequently influencing genotypic differences in external P uptakes and biomass production. AZ-97 is a potential donor with such traits that can offer an additional avenue for genetic improvement toward P-efficient rice production.AbbreviationsDAT: days after transplanting; LN: leaf number in the main stem; PLA: projected green leaf area; PUE: phosphorus use efficiency; SSA: Sub-Saharan Africa.

ABSTRACTThe enhancement of heat stress tolerance at anthesis is an important strategy to achieve sustainable rice production in the context of predicted global warming. In this study, we genetically analysed spikelet fertility under high temperature treatment (38°C) at anthesis using the three rice varieties, namely, Koshihikari and Takanari, which were developed in Japan, and IR64, which was developed in the Philippines. Genetic analysis of the F2population between Takanari and IR64 revealed a quantitative trait locus (QTL) on chromosome 4 that increased spikelet fertility with the Takanari allele and that was likely qHTSF4.1, a previously fine-mapped major QTL. Genetic analysis using chromosome segment substitution lines (CSSLs) carrying Koshihikari chromosome segments in the IR64 genetic background did not show any QTLs. In contrast, genetic analysis using CSSLs carrying Koshihikari chromosome segments in the Takanari genetic background revealed some QTLs, including chromosomes 4 and 9. These results suggest that the expression of QTLs may depend on genetic background. The two CSSLs, SL1313 and SL1330, which carried the QTLs on chromosomes 4 and 9, respectively, exhibited a spikelet fertility of over 80% and relatively large anther dehiscence compared with Takanari. These results suggest that the Koshihikari allele of QTLs may be related to improved anther dehiscence, which may lead to successful pollination and ultimately increased spikelet fertility under heat stress conditions. The findings in the present study should be useful to enhance heat stress tolerance at anthesis in rice in future breeding programs.

ABSTRACTA new rice (Oryza sativaL.) cultivar, ‘Oonari’, was developed to reduce the shattering habit of the high-yielding cultivar ‘Takanari’. To evaluate the effects of environment on its yield and related traits, Oonari and Takanari were grown in multiple environmental conditions at three locations in Japan. The whole and filled brown rice yields of Oonari were around 1000 g m−2, similar to those of Takanari. But the panicle number m−2of Oonari was slightly but significantly higher than that of Takanari and the spikelet number per panicle was slightly but significantly lower. With respect to the effect of environment on yield of Oonari, cumulative radiation during 40 days after heading was positively related to whole brown rice yield of Oonari. Yield tended to be higher under increased atmospheric CO2concentration than under ambient. Oonari was confirmed to exhibit high yield in various environmental conditions.

ABSTRACTEnhancing crop traits that increase grain yield under elevated CO2concentrations is an important option for increasing the future productivity of rice. Here, we compared the growth and yield of five varieties with different genetic background under Free-Air CO2Enrichment (FACE) conditions to identify traits responsible for varietal differences in yield increase under elevated CO2. Three high-yielding and two standard rice varieties grown under FACE conditions commonly had (1) shorter growth periods, (2) higher dry matter production, (3) higher numbers of spikelets (sink capacity) and panicles; and (4) higher yield than those grown under ambient CO2. Yield enhancement by elevated CO2(FACE/Ambient), however, differed significantly among varieties, ranging from 1.10 to 1.25. The greater response of the sink capacity, defined as the product of spikelet number and single grain mass, was the main factor involved in yield increase. Three high-yielding varieties (Momiroman, Takanari, and Hokuriku 193) had greater sink capacity than two standard varieties and the sink capacity of these varieties significantly increased under FACE condition. However, yield enhancement in elevated CO2was lower in Hokuriku 193 than in Momiroman and Takanari. In Hokuriku 193, sink production was relatively low while dry matter production was similar to the others. Therefore, larger increase in sink production efficiency per unit of dry matter production under FACE was found to be a particularly important varietal trait, suggesting that efforts to develop varieties suited to the predicted elevated CO2condition should focus on this and the related traits.

ABSTRACTTo enhance the yield potential of rice by breeding, it is important to reveal the genetic factors affecting yield components in high-yielding cultivars. Quantitative trait loci (QTL) analysis for panicle structure and spikelet weight as an index of grain filling was conducted using recombinant inbred lines (RILs) derived from a cross between an indica-dominant high-yielding cultivar, Takanari, and a japonica-dominant high-yielding cultivar, Momiroman in 2012 and 2013 in eastern Japan. The grain-filling ability of Takanari is reported to be better than that of Momiroman. Since grain filling is generally better near the tip of the panicle and decreases as the number of branches from the rachis increases, we classified whole panicles into upper and lower side panicles and spikelets into primary, secondary, and tertiary spikelets according to the number of branches from the rachis. On chromosomes 1, 4, and 6, QTLs regulating the number of spikelets per panicle and panicle structure were detected and were most likely identical to GN1a, SPIKE, and APO1, respectively, which has been previously reported as QTLs regulating the number of spikelets per panicle. Takanari produced much heavier secondary and tertiary spikelets than Momiroman on the lower side panicle. On chromosome 5, novel QTLs regulating spikelet weight were detected. The Takanari allele enhanced secondary and tertiary spikelet weight on the lower side panicle. These results indicate that it may be possible to enhance sink capacity and translocation of source with a combination of novel QTLs detected on chromosome 5 and GN1, APO1, and SPIKE.

Increasing rice yield potential is a continuous challenge posed by world population growth. To increase yield potential, favorable alleles of valuable genes need to be accumulated in promising germplasm. We conducted comparative yield trials for two years in Tsukuba, Japan, in a temperate region and at the International Rice Research Institute (IRRI), Philippines, in a tropical region using five high-yielding rice cultivars: Takanari and Hokuriku193, developed in Japan, and IR64, NSIC Rc158, and YTH183, developed in the Philippines. Genotype plus genotype × environment interaction (GGE) biplot analysis across four environments (two regions × two seasons) classified the five cultivars into four categories: Takanari and YTH183 showed high adaptability to both tropical and temperate regions, Hokuriku193 was suitable for temperate regions, NSIC Rc158 was suitable for the tropics, and IR64 was inferior to the other cultivars in both regions. The high yield and adaptability in Takanari and YTH183 were attributed to their large sink capacity with good grain filling. The plant type for high yield was different, however, between the two cultivars; Takanari was a panicle-weight type, whereas YTH183 was a panicle-number type. Evaluations of F2progeny of a cross between Takanari and YTH183 showed transgressive segregation for number of panicles per plant as well as number of spikelets per panicle, leading some F2plants to produce more spikelets per plant (corresponding to larger sink size) than the parental cultivars in both regions. These results suggest the possibility of developing rice cultivars with high yield potential in both temperate and tropical regions by crossing temperate with tropical high-yielding cultivars.

In this study, Horiguchi et al. set out to examine the previously reported tumor-promoting function of Angiopoietin-like protein 2 (ANGPTL2). The authors compare ANGPTL2 function in cancer progression in a mouse models of melanoma and renal cell carcinoma, and show that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.

Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3−/− mice was shown to depend on Toll-like receptor 7 (TLR7), which senses a combination of nucleosides and oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving the proliferation of Ly6Chi immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3−/− mice. Downstream of TLR7, FcRγ and DAP10 were required for monocyte proliferation. Histiocytosis is accompanied by inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden splenic monocytes failed to activate inflammatory responses. Enhanced production of proinflammatory cytokines was observed only after stimulation with ssRNAs, which would increase lysosomal ORNs. Patient-derived monocytes harboring the G208R SLC29A3 mutation showed enhanced survival and proliferation in a TLR8-antagonist-sensitive manner. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.

γ‐Oryzanol and its major components, 24‐methylenecycloartanyl ferulate and cycloartenyl ferulate, which are distributed in the rice bran layer, exert biomedical effects. The objective of the present study was to detect QTLs regulating the concentrations of 24‐methylenecycloartanyl ferulate and cycloartenyl ferulate by using the reciprocal CSSLs derived from a cross between an indica‐type cultivar Takanari and a japonica‐type cultivar Koshihikari, having low and high concentrations, respectively. We detected QTLs for the concentrations of γ‐oryzanol and 24‐methylenecycloartanyl ferulate (μg/grain and/or mg/kg) on chromosome 5 and the concentrations of cycloartenyl ferulate (μg/grain and/or mg/kg) on chromosomes 4 and 11 in reciprocal genetic backgrounds. The concentrations were increased by the Koshihikari allele but decreased by the Takanari allele. In addition, we found a QTL for cycloartenyl ferulate concentration (mg/kg) on chromosome 2 in reciprocal genetic backgrounds. Interestingly, unlike the QTLs on chromosomes 4, 5, and 11, the concentrations were decreased by the Koshihikari allele but increased by the Takanari allele. The favorable alleles from japonica‐type cultivars can be used to improve the lower concentrations of γ‐oryzanol, 24‐methylenecycloartanyl ferulate, and cycloartenyl ferulate in indica‐type cultivars. In addition, the favorable alleles from indica‐type cultivars can be used to further increase the higher concentrations of cycloartenyl ferulate in japonica‐type cultivars. The QTLs detected in this study should contribute to future‐breeding programs can enhance the health benefits conferred by rice.

AbstractRecent progress in rice genomics has promoted the identification of quantitative trait loci (QTLs) associated with yield and its related traits. SPIKE, a QTL controlling spikelet number per panicle, and GPS, a QTL controlling leaf photosynthesis rate, were identical to NAL1. To assess the effect of SPIKE/GPSon yield potential, we compared DNA sequences of these alleles and conducted yield experiments in the field of Japan using the near-isogenic lines NIL-SPIKE(allele from Daringan in IR 64 genetic background), NIL-GPS(allele from Koshihikari in Takanari genetic background), and a chromosome segment substitution line, SL2115 (allele from Koshihikari in IR 64 genetic background). Despite the two SNPs in the promoter regions between Koshihikari and Daringan, both alleles were effective to increase the number of spikelets per panicle both in Takanari and IR 64 backgrounds. However, the extent of the increase was smaller and unstable in Takanari background than that in IR 64 background. In addition, SPIKE/GPSimproved percentage of filled spikelets only in the IR 64 background. These results suggest that the effects of SPIKE/GPSalleles are similar but are affected by the difference of the genetic backgrounds. Because the increasing effect of spikelets number per panicle was canceled by the decrease of the number of panicles, which seems to be affected by environmental factors, none of NIL-SPIKE, SL2115, or NIL-GPSsignificantly out-yielded their parental cultivars. These results indicate the importance to consider genetic backgrounds and QTL-environment interaction toward the future use of SPIKE/GPS.

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are a population of immune suppressive cells that are involved in tumor-associated immunosuppression, and dominate tumor progression and metastasis. In this study, we report that the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4, murine ortholog gp49B) orchestrates the polarization of MDSCs to exhibit pro-tumor phenotypes. We found that gp49B deficiency inhibited tumor metastases of cancer cells, and reduced tumor-infiltration of monocytic MDSCs (M-MDSCs) in tumor-bearing mice. Gp49B−/−MDSCs inhibited pro-tumor immune responses, such as activation of Treg cells, promotion of cancer cell migration, and stimulation of tumor angiogenesis. Treatment of wild-type tumor-bearing mice with gp49B−/−M-MDSCs reduced cancer metastasis. Furthermore, gp49B knockout affected plasma exosome composition in terms of increased miR-1 family microRNAs (miRNAs) expression, which correlates with the upregulation of gp49B−/−MDSC-derived anti-tumor miRNAs. Collectively, our findings reveal that LILRB4/gp49B promotes MDSC-mediated tumor metastasis by regulating the M2-polarization of MDSCs and suppressing the secretion of miR-1 family miRNAs, which facilitate tumor migration and invasion.AbbreviationsCTLA-4: cytotoxic T-lymphocyte-associated protein-4; FBS: fetal bovine serum; G-MDSCs: granulocytic-MDSCs; GP49B: glycoprotein 49B; HE: hematoxylin-eosin; ICI: immune checkpoint inhibitor; ITIM: immunoreceptor tyrosine-based inhibition motif; LILRB4: leukocyte immunoglobulin-like receptor B4; M-CSF: macrophage colony stimulating factor; MDSC: myeloid-derived suppressor cell; M-MDSC: monocytic MDSC; MMP-9: metallopeptidase-9; mAb: monoclonal antibody; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PD-1: programmed death-1; PD-L1: programmed death ligand-1; PMN-MDSC: polymorphonuclear-MDSC; qRT-PCR: quantitative reverse transcription PCR; TAM: tumor associated macrophage; TME: tumor microenvironment; TMM: trimmed mean of M value; VEGFA: vascular endothelial growth factor A

ABSTRACTThe host deploys a subset of immune responses to expel helminths, which differs depending on the nature of the helminth. Strongyloides venezuelensis, a counterpart of the human pathogen S. stercoralis, naturally infects rodents and has been used as an experimental model. Here we show that induction of immunoglobulin G (IgG) and IgE is a prerequisite for rapid expulsion of S. venezuelensisduring a primary infection. Activation-induced cytidine deaminase-deficient (AID-/-) mice, which lack the ability to switch IgM to other isotypes, normally developed T-helper 2 (Th2) cells and intestinal mastocytosis after infection with S. venezuelensis. Although AID-/-mice expelled Nippostrongylus brasiliensisnormally, they required a much longer period to expel S. venezuelensisthan wild-type (WT) mice. Adoptive transfers of immune sera from S. venezuelensis-infected but not N. brasiliensis-infected mice restored the ability of AID-/-mice to promptly expel S. venezuelensis. Immune serum-derived IgG and IgE induced worm expulsion via Fc ? receptor III (Fc?RIII) and Fc e receptor I (FceRI), respectively, and a mixture of IgG and IgE showed collaborative effects. Whereas Fc?RIII-/-mice or FceRIa-/-mice normally could expel S. venezuelensis, Fc?RIII-/-mice, when their IgE was neutralized by anti-IgE, or FceRIa-/-mice, when their IgG binding to Fc?RIII was blocked by anti-Fc?RIII, showed a markedly reduced ability to expel S. venezuelensis. These data reveal that IgG and IgE play redundant roles but act in concert to accelerate S. venezuelensisexpulsion. Mast cell-deficient mice, even those equipped with immune serum-derived IgG or IgE, failed to expel S. venezuelensispromptly, suggesting that mast cells are cellular targets of IgG and IgE.

AbstractThe contribution of cell wall components and nonstructural carbohydrate (NSC) to grain filling in rice (Oryza sativaL.) was clarified by investigating the differences in the dynamics of hemicellulose, sugar composition of hemicellulose,β-(1→3),(1→4)-glucan, and NSC among cultivars with different grain filling capacities. This investigation was performed using the stems of standard, high yield and low harvest index (HI) cultivars. Hemicellulose concentration in stems tended to decrease slightly during the grain filling stage. This decrease was attributed to a decrease inβ-(1→3),(1→4)-glucan concentration, which was detected as a decrease in glucose composition of hemicellulose in the stems during the grain filling stage. The rate of decrease and decrease in the amount ofβ-(1→3),(1→4)-glucan in the stems differed among the cultivars. These were higher in high yield and high HI cultivars than in relatively low yield and low HI cultivars. Moreover, a positive correlation was observed between the rate of decrease inβ-(1→3),(1→4)-glucan and NSC, indicating similarities in the dynamics ofβ-(1→3),(1→4)-glucan and NSC among the cultivars. When the top half of panicle was removed,β-(1→3),(1→4)-glucan and NSC concentrations in the culm and leaf sheath did not decrease during the grain filling stage. Therefore, theβ-(1→3),(1→4)-glucan in stems might be one of the sources that supply substrate to panicle as well as NSC.

Rice (Oryza sativaL.) yield is determined by the relationship between sink, source, and plant architecture. ‘Takanari’, a high‐yielding rice variety descended from ‘IR8’ and ‘Tongil’, shows a semidwarf plant stature and has a large sink size and high photosynthesis rate. Previous studies have revealed that alleles of semi‐dwarf1(sd1) and GRAIN NUMBER1A(GN1A), which confer a semidwarf plant type and large panicles, respectively, have been selected repeatedly in breeding programs during the process of breeding for high yield. Until now, however, no genetic factors related to photosynthesis have been identified as having been selected in breeding programs. In this study, we conducted comparative mapping of quantitative trait loci (QTLs) for photosynthesis‐related traits using three F2populations: ‘Koshihikari’ × Takanari, Koshihikari × Tongil, and Koshihikari × IR8. Comparison of QTL locations in the three populations revealed a QTL in the same location on the long arm of chromosome 4 in each one, with the allele for higher photosynthesis‐related traits coming from the higher‐yielding parent of each population. Further genotypic analysis of the Takanari pedigree revealed the same genotype on the long arm of chromosome 4 in varieties related to IR8 and Takanari. These results suggest that breeders have selected the favorable allele of the QTL for photosynthesis on chromosome 4 in several breeding programs for high yield.

Plasmacytoid dendritic cells (PDCs) produce type I interferons (IFNs) in response to viral nucleic acids to exert antiviral immunity. However, PDCs are related to the progress and severity of autoimmune diseases, such as systemic lupus erythematosus, because they respond to host DNA. Therefore, the regulation of PDC activation is critical for maintaining adequate immune responses. Here we show that an inhibitory major histocompatibility complex class I receptor, paired immunoglobulin-like receptor B (PIR-B), suppressed Fms-like tyrosine kinase 3 ligand-induced PDC differentiation in BM cells, as well as Toll-like receptor 9-mediated IFN-α production by PDCs, through the dephosphorylation of STAT1/STAT2. In particular, PIR-B inhibited IFN-α–mediated STAT phosphorylation, suggesting that PIR-B negatively regulates the positive feedback mechanism of IFN-α secretion triggered by Toll-like receptor 9. These results demonstrate a novel regulatory role for PIR-B in PDCs.

Plasmacytoid dendritic cells (PDCs) produce type I interferons (IFNs) in response to viral nucleic acids to exert antiviral immunity. However, PDCs are related to the progress and severity of autoimmune diseases, such as systemic lupus erythematosus, because they respond to host DNA. Therefore, the regulation of PDC activation is critical for maintaining adequate immune responses. Here we show that an inhibitory major histocompatibility complex class I receptor, paired immunoglobulin-like receptor B (PIR-B), suppressed Fms-like tyrosine kinase 3 ligand-induced PDC differentiation in BM cells, as well as Toll-like receptor 9-mediated IFN-α production by PDCs, through the dephosphorylation of STAT1/STAT2. In particular, PIR-B inhibited IFN-α–mediated STAT phosphorylation, suggesting that PIR-B negatively regulates the positive feedback mechanism of IFN-α secretion triggered by Toll-like receptor 9. These results demonstrate a novel regulatory role for PIR-B in PDCs.

Immature dendritic cells (imDCs) can have a tolerizing effect under normal conditions or after transplantation. However, because of the significant heterogeneity of this cell population, it is extremely difficult to study the mechanisms that mediate the tolerance induced or to harness the application of imDCs for clinical use. In the present study, we describe the generation of a highly defined population of imDCs from hematopoietic progenitors and the direct visualization of the fate of TCR-transgenic alloreactive CD4+ and CD8+ T cells after encountering cognate or noncognate imDCs. Whereas CD4+ T cells were deleted via an MHC-independent mechanism through the NO system, CD8+ T-cell deletion was found to occur through a unique MHC-dependent, perforin-based killing mechanism involving activation of TLR7 and signaling through Triggering Receptor-1 Expressed on Myeloid cells (TREM-1). This novel subpopulation of perforin-expressing imDCs was also detected in various lymphoid tissues in normal animals and its frequency was markedly enhanced after GM-CSF administration.

Immature dendritic cells (imDCs) can have a tolerizing effect under normal conditions or after transplantation. However, because of the significant heterogeneity of this cell population, it is extremely difficult to study the mechanisms that mediate the tolerance induced or to harness the application of imDCs for clinical use. In the present study, we describe the generation of a highly defined population of imDCs from hematopoietic progenitors and the direct visualization of the fate of TCR-transgenic alloreactive CD4+and CD8+T cells after encountering cognate or noncognate imDCs. Whereas CD4+T cells were deleted via an MHC-independent mechanism through the NO system, CD8+T-cell deletion was found to occur through a unique MHC-dependent, perforin-based killing mechanism involving activation of TLR7 and signaling through Triggering Receptor-1 Expressed on Myeloid cells (TREM-1). This novel subpopulation of perforin-expressing imDCs was also detected in various lymphoid tissues in normal animals and its frequency was markedly enhanced after GM-CSF administration.

We evaluated genetic variations in the non-structural carbohydrate (NSC) and the cell-wall components of stem in rice, sorghum, and sugar cane to assess the potential suitability of these gramineous crops for bioethanol production. For NSC, the maximum soluble sugar concentration was highest in sugar cane, followed by sorghum with sucrose. The major NSC in rice was starch, but there were wide variations in the starch to soluble sugar ratios among the cultivars. The total concentration of cell-wall components was negatively correlated with the NSC concentration, indicating competition for carbon sources. Among the cell-wall components, lignin was relatively stable within each group. The major sugar species composing hemicellulose was xylose in all crop groups, but there were differences in composition, with a higher fraction of arabinose and glucose in rice as compared to the other crops. In rice, there was less lignin than in sorghum or sugar cane; this might be advantageous for the efficient saccharification of cellulose.

Leaf photosynthesis, an important determinant of yield potential in rice, can be estimated from measurements of chlorophyll content. We searched for quantitative trait loci (QTLs) for Soil and Plant Analyzer Development (SPAD) value, an index of leaf chlorophyll content, and assessed their association with leaf photosynthesis. QTL analysis derived from a cross between japonicacultivar Sasanishiki and high-yielding indicacultivar Habataki detected a QTL for SPAD value on chromosome 4. This QTL explained 31% of the total phenotypic variance, and the Habataki allele increased the SPAD value. Chromosomal segment substitution line (CSSL) with the corresponding segment from Habataki had a higher leaf photosynthetic rate and SPAD value than Sasanishiki, suggesting an association between SPAD value and leaf photosynthesis. The CSSL also had a lower specific leaf area (SLA) than Sasanishiki, reflecting its thicker leaves. Substitution mapping under Sasanishiki genetic background demonstrated that QTLs for SPAD value and SLA were co-localized in the 1,798-kb interval. The results suggest that the phenotypes for SPAD value and SLA are controlled by a single locus or two tightly linked loci, and may play an important role in increasing leaf photosynthesis by increasing chlorophyll content or leaf thickness, or both.

It has been forty years since the discovery of Fc Receptors and their function. Fc Receptors include the IgG receptors (FcγR), high-affinity IgE receptor (FcηRI), IgA and IgA/IgM receptors, and neonatal Fc receptor for IgG (FcRn). In particular, the FcγRs have been well known to play an important role in many biologic processes including those associated with the response to infection and cancer as well as in the pathogenesis of immune-mediated diseases. Both positive and negative regulatory function has ascribed to Fc receptors and FcγRs in particular which serve to establish a threshold for immune cell activation. In other cases, Fc receptors such as FcRn possess a novel structure and function by playing a major role in the transport of IgG across polarized epithelial barriers at mucosal surfaces and in the regulation of IgG halflife. These diverse functions highlight the potential effectiveness of targeting Fc receptors for therapeutic purposes. This review summarizes new information available in the therapeutic applications of this biology.

Inhibitory MHC class I receptors are mainly expressed on NK cells. NK cells bear various kinds of inhibitory MHC class I receptors, Killer cell immunoglobulin (Ig)-like receptors, CD94/NKG2A hetrodimer, and murine Ly49 receptor family for monitoring the expression of MHC class I on surrounding cells. Leukocyte Ig-like receptors (LILRs), which bind MHC class I molecules, are expressed on other immune cells, such as B cells, macrophages, dendritic cells (DCs) and mast cells. A murine LILR relative, paired Ig-like receptor (PIR), which is expressed on B cells and myeloid cells but not on NK and T cells, also recognizes MHC class I molecules as its ligand. Recent studies have revealed that some of these inhibitory receptors associate with MHC class I on the same cell surface (in cis). Moreover, the cisinteraction has been verified to regulate effector functions of NK cells or myeloid cells. In this review, we summarize recent discoveries on the functions of inhibitory MHC class I receptors, and discuss their regulatory roles in immune responses.

ABSTRACTCitrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the colon utilizing attaching and effacing lesions to adhere specifically to the surfaces of intestinal epithelial cells and cause mucosal inflammation. CD4+T cells, B cells, and immunoglobulin G (IgG), but not secretory IgA or IgM, play a critical role in eradicating this pathogen. Consistent with the importance of IgG in C. rodentiumeradication, IgG transport by the neonatal Fc receptor for IgG within the intestinal epithelium also has a critical role in the regulation of C. rodentiuminfection. It remains to be determined, however, whether Fcγ receptors (FcγRs), the receptors for the Fc portion of IgG, regulate this bacterial infection within mucosal tissues. Therefore, we investigated the roles of FcγRs during C. rodentiuminfection. Fc receptor common gamma chain (FcRγ)-deficient mice were more susceptible to C. rodentium-induced colitis. This occurred through decreased efficiency of FcR-mediated endocytosis and maturation of dendritic cells and consequently T-cell activation of antigen-specific T cells. Moreover, in the absence of FcγRs, phagocytosis by macrophages was significantly diminished. Therefore, activating FcγRs play an important role in defending against C. rodentiuminfection, indicating that the critical role played by IgG in this infection is not mediated by IgG alone but is dependent upon this class of receptors.

Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the colon utilizing attaching and effacing lesions to adhere specifically to the surfaces of intestinal epithelial cells and cause mucosal inflammation. CD4+T cells, B cells, and immunoglobulin G (IgG), but not secretory IgA or IgM, play a critical role in eradicating this pathogen. Consistent with the importance of IgG in C. rodentium eradication, IgG transport by the neonatal Fc receptor for IgG within the intestinal epithelium also has a critical role in the regulation of C. rodentium infection. It remains to be determined, however, whether Fc receptors (FcRs), the receptors for the Fc portion of IgG, regulate this bacterial infection within mucosal tissues. Therefore, we investigated the roles of FcRs during C. rodentium infection. Fc receptor common gamma chain (FcR)-deficient mice were more susceptible to C. rodentium-induced colitis. This occurred through decreased efficiency of FcR-mediated endocytosis and maturation of dendritic cells and consequently T-cell activation of antigen-specific T cells. Moreover, in the absence of FcRs, phagocytosis by macrophages was significantly diminished. Therefore, activating FcRs play an important role in defending against C. rodentium infection, indicating that the critical role played by IgG in this infection is not mediated by IgG alone but is dependent upon this class of receptors.

We have analyzed leukocyte mono-Ig–like receptor 5 (LMIR5) as an activating receptor among paired LMIRs. Mouse LMIR5 (mLMIR5) is expressed in myeloid cells such as mast cells, granulocytes, macrophages, and dendritic cells. Cross-linking of transduced mLMIR5 in bone marrow–derived mast cells (BMMCs) caused activation events, including cytokine production, cell survival, degranulation, and adhesion to the extracellular matrix. mLMIR5 associated with DAP12 and to a lesser extent with DAP10, and mLMIR5-mediated functions of BMMCs were strongly inhibited by DAP12 deficiency. Importantly, cross-linking of endogenous mLMIR5 induced Syk-dependent activation of fetal liver–derived mast cells. Unlike mLMIR5, cross-linking of human LMIR5 (hLMIR5) induced cytokine production of BMMCs even in the absence of both DAP12 and DAP10, suggesting the existence of unidentified adaptors. Interestingly, hLMIR5 possessed a tyrosine residue (Y188) in the cytoplasmic region. Signaling via Y188 phosphorylation played a predominant role in hLMIR5-mediated cytokine production in DAP12-deficient, but not wild-type BMMCs. In addition, experiments using DAP10/DAP12 double-deficient BMMCs suggested the existence of Y188 phoshorylation-dependent and -independent signals from unidentified adaptors. Collectively, although both mouse and human LMIR5 play activatory roles in innate immunity cells, the functions of LMIR5 were differentially regulated in mouse versus human cells.

We have analyzed leukocyte mono-Ig–like receptor 5 (LMIR5) as an activating receptor among paired LMIRs. Mouse LMIR5 (mLMIR5) is expressed in myeloid cells such as mast cells, granulocytes, macrophages, and dendritic cells. Cross-linking of transduced mLMIR5 in bone marrow–derived mast cells (BMMCs) caused activation events, including cytokine production, cell survival, degranulation, and adhesion to the extracellular matrix. mLMIR5 associated with DAP12 and to a lesser extent with DAP10, and mLMIR5-mediated functions of BMMCs were strongly inhibited by DAP12 deficiency. Importantly, cross-linking of endogenous mLMIR5 induced Syk-dependent activation of fetal liver–derived mast cells. Unlike mLMIR5, cross-linking of human LMIR5 (hLMIR5) induced cytokine production of BMMCs even in the absence of both DAP12 and DAP10, suggesting the existence of unidentified adaptors. Interestingly, hLMIR5 possessed a tyrosine residue (Y188) in the cytoplasmic region. Signaling via Y188 phosphorylation played a predominant role in hLMIR5-mediated cytokine production in DAP12-deficient, but not wild-type BMMCs. In addition, experiments using DAP10/DAP12 double-deficient BMMCs suggested the existence of Y188 phoshorylation-dependent and -independent signals from unidentified adaptors. Collectively, although both mouse and human LMIR5 play activatory roles in innate immunity cells, the functions of LMIR5 were differentially regulated in mouse versus human cells.

AbstractCarbon isotope discrimination (Ċ) occuring in the process of photosynthesis, shows variation among rice (Oryza sativaL.) cultivars. Elucidation of specific traits associated with the extent of this discrimination under irrigated conditions may be useful to improve photosynthetic ability in rice plants. We measured leaf photosynthesis and Ċ in Milyang 23 and Akihikari, and conducted quantitative trait loci (QTL) analysis on Ċ at heading stage using a population of 126 recombinant inbred lines (RILs), derived from a cross between the two cultivars. While the two parental cultivars showed a similar Ċ, the RILs showed a wide variation in Ċ including transgressive segregation. Seven QTLs were detected for Ċ; four on chromosomes 2 (two regions), 7, and 11 were those for Ċ that is increased by the Milyang 23 allele, whereas the other three on chromosomes 1, 2, and 6 were those for Ċ that is increased by the Akihikari allele. These results suggest that 13C in Milyang 23 may be discriminated through a photosynthetic process different from that in Akihikari. Milyang 23 showed a higher stomatal conductance and a higher ratio of intercellular to ambient CO2concentration (Ci/Ca), while Akihikari showed a higher carboxylation efficiency but a lower Ci/Ca. According to the theory that a higher Ci/Ca leads to a higher Ċ, the QTLs for Ċ that is increased by the Milyang 23 allele might be related to a higher stomatal conductance. However, the theory provided no persuasive factors to explain the QTLs for Ċ that is increased by the Akihikari allele. Plausible factors associated with these QTLs are discussed.

Activated natural killer (NK) cells proliferate in large numbers in murine mesometrial endometrium from Day 6 to Day 12 of gestation (term = 19 gestation days) to become the most abundant uterine lymphocytes. Early human decidua contains analogous CD56+/CD16−cells. Murine uterine (u)NK cells localize to decidua basalis and mesometrial lymphoid aggregate of pregnancy (MLAp). Decidua and MLAp are transient, pregnancy-associated tissues traversed by maternal arteries to the placentas. Uterine NK cells sensitize these arteries, facilitating their structural changes into high-volume conduits by Gestation Day 10 through release of interleukin (IL)-18, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), and other molecules. Little information exists concerning where, when, or how murine or human uNK cells become activated. In murine lymphoid tissue, three NK cell adaptor-mediated activation pathways are known: FcRγ/CD3ζ, DNAX-activating protein (DAP) 10, and DAP12 (genes Fcgr3/Cd3z, Hcst,and Tyrobp, respectively). Expression of ligands for these receptors was demonstrated in implantation sites of normal C57BL/6J mice. Then, histological and morphometric analyses of implantation sites in mice with genetic inactivation of each pathway were undertaken. Implantation sites in DAP10−/−(Hcstdeleted) mice appeared normal, spiral artery modification occurred, and concentrations of IFN-γ in MLAp and decidua basalis were similar to those in time-matched C57BL/6J. Implantation sites of FcRγ−/−/CD3ζ−/−(Fcgr3/Cd3zdouble knockout), DAP12 (Tyrobp)-loss-of-function-mutant, and FcRγ−/−/DAP12−/−(Fcgr3/Tyrobpdouble knockout) mice differentiated abundant but functionally impaired uNK cells that could not modify spiral arteries. These data reveal key importance of FcRγ−/−/CD3ζ−/−and thus maternal IgG during activation of mouse uNK cells and assign DAP12 but not DAP10 signaling contributions.

Immune activation and inhibitory receptors play an important role in the maintenance of an adequate activation threshold of various cells in our immune system. Analyses of murine models show that the inhibitory Fcreceptor, FcγRIIB plays an indispensable role in the suppression of anti-body-mediated allergy and autoimmunity. In contrast, the activating-type Fcreceptors (FcRs) are essential for the development of these diseases, suggesting that regulation of inhibitory or activating FcR is an ideal target as a therapeutic agent. In addition, recent crystal structural analyses of FcR-Ig-Fc fragment complexes provide an effective approach for developing FcR-targeting drugs. This review summarises recent advances of FcR, which were mainly obtained by murine studies, and highlights novel antibodies as possible FcR-targeting therapies for allergy, autoimmune diseases and cancer.

Abstract The activation threshold of cells in the immune system is often tuned by cell surface molecules. The Fc receptors expressed on various hematopoietic cells constitute critical elements for activating or downmodulating immune responses and combines humoral and cell-mediated immunity. Thus, Fc receptors are the intelligent sensors of the immune status in the individual. However, impaired regulation by Fc receptors will lead to unresponsiveness or hyperreactivity to foreign as well as self-antigens. Murine models for autoimmune disease indicate the indispensable roles of the inhibitory Fc receptor in the suppression of such disorders, whereas activating-type FcRs are crucial for the onset and exacerbation of the disease. The development of many autoimmune diseases in humans may be caused by impairment of the human Fc receptor regulatory system. This review is aimed at providing a current overview of the mechanism of Fc receptor-based immune regulation and the possible scenario of how autoimmune disease might result from their dysfunction.

The Ig-like receptors provide positive and negative regulation of immune cells upon recognition of various ligands, thus enabling those cells to respond adequately to extrinsic stimuli. Murine paired Ig-like receptor (PIR)-A and PIR-B, a typical receptor pair of the Ig-like receptor family, are expressed on a wide range of cells in the immune system, such as B cells, mast cells, macrophages and dendritic cells, mostly in a pair-wise fashion. The PIR-A requires the homodimeric Fc receptor common y chain for its efficient cell-surface expression and for the delivery of activation signaling. In contrast, PIR-B inhibits receptor-mediated activation signaling in vitroupon engagement with other activating-type receptors, such as the antigen receptor on B cells and the high-affinity Fc receptor for IgE on mast cells. Although the ligands for PIR-A and PIR-B remain unknown, recent studies on PIR-B-deficient mice have provided us with valuable insight into the physiological significance of PIR-B, particularly in its regulatory role in balancing the humoral immune response.

The activation threshold of various cells in the immune system is tuned by immune inhibitory receptors. The inhibitory Fc receptor, FcRIIB, is one of the critical elements for keeping immune cells silent. Murine models for allergic responses and autoimmune diseases illustrate the indispensable roles of FcRIIB in the suppression of these immune disorders. On the contrary, activating-type Fc receptors are crucial for the onset and exacerbation of such diseases. In addition, recent reports have revealed the pivotal roles of Fc receptors in enhancing antigen presentation by dendritic cells, which leads to efficient major histocompatibility complex class I- and class II-restricted T cell activation. In this context, anti-cancer immunopotentiation could be augmented by targeting the tumor antigens to Fc receptors on dendritic cells. This review summarizes recent advances in Fc receptor biomedicine in light of exploiting them as potential therapeutic targets for allergy, autoimmune disease and cancer.

Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI−/− mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI−/− mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI−/− macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor κB activities after LPS treatment than do SLPI+/+ macrophages. SLPI also affects B cell function. SLPI−/− B cells show more proliferation and IgM production after LPS treatment than SLPI+/+ B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity.

Previous work on cellular destruction induced by several clinically relevant anti-platelet IgG antibodies suggested antigen-specific mechanisms in the development of immune thrombocytopenia in mice. mAb directed against mouse platelet GPIbalpha and integrin alpha(IIb)beta(3) were highly pathogenic, and mediated their effects via different Fc-dependent (alpha(IIb)beta(3)) and Fc-independent (GPIbalpha) pathways, indicating that clearance of IgG-bound platelets is only one event in the pathogenesis of murine thrombocytopenia. Here, we demonstrate that in addition to thrombocytopenia, targeting of platelet integrin alpha(IIb)beta(3) results in acute systemic reaction and bleeding that is regulated by activating IgG Fc receptors (FcgammaR) and the inhibitory FcgammaRII. As shown by electron microscopy, anti-alpha(IIb)beta(3) IgG mediated initial loss of alpha(IIb)beta(3) integrin from platelet surfaces followed by rapid accumulation of alpha(IIb)beta(3) antibody-containing immune complex (IC)-like structures in spleen and liver in vivo. In FcRgamma chain deficiency, mice resisted bleeding, but not platelet destruction, while genetic ablation of FcgammaRII resulted in uncontrolled systemic reaction and severe hemorrhage leading to enhanced mortality. Together, these results provide evidence that IC formation and engagement of FcgammaR on effector cells determines the alpha(IIb)beta(3)-specific part of the platelet pathology of the systemic reaction and bleeding in murine thrombocytopenia.

Background:The systemic anaphylaxis reaction comprises various symptoms, including hypotension, changes in respiration pattern, and hypothermia. Objective:To elucidate the role of histamine in each of these symptoms, we induced the passive systemic anaphylaxis reaction in histidine decarboxylase gene knockout (HDC [-/-]) mice, which lack histamine. Methods:HDC(-/-) mice were generated by knocking out the HDC gene, which codes for the unique histamine-synthesizing enzyme. Twenty-four hours after the injection of IgE, HDC(+/+) and HDC(-/-) mice were injected with allergen and body temperature, blood pressure, and respiratory function were monitored in each mouse. Results:Blood pressure dropped in both the HDC(-/-) mice and the HDC(+/+) mice. In contrast, respiratory frequency dropped and the expiratory respiration time was elongated only in the HDC(+/+) mice. Body temperature was decreased in the HDC(+/+) mice and was practically unchanged in the HDC(-/-) mice. Histamine receptor antagonists blocked the body temperature drop in the HDC(+/+) mice. Intravenous histamine induced similar patterns of body temperature decrease in the HDC(+/+) mice and the HDC(-/-) mice. Mast cell-deficient W/Wvmice did not show the decrease in body temperature; this suggests that the histamine that contributed to the decrease in body temperature was derived from mast cells. Conclusion:According to the results of this investigation, in the passive systemic anaphylaxis reaction, respiratory frequency, expiratory time, and body temperature are shown to be controlled by the activity of histamine, but its contribution to blood pressure is negligible. (J Allergy Clin Immunol 2002;110:298-303.)

The Src family kinase Lyn initiates intracellular signal transduction by associating with a variety of immune receptors such as antigen receptor on B cells and high-affinity Fc receptor (FcR) for immunoglobulin Ig(E) (FcεRI) on mast cells. Involvement of Lyn in the IgE-mediated immediate-type hypersensitivity is well documented, but the physiological significance of Lyn in IgG-dependent, type III low-affinity FcR for IgG (FcγRIII)-mediated responses is largely unknown. In this study, we generated a double-mutant mouse strain deficient in both type II FcR for IgG (FcγRIIB) and Lyn to exclude any involvement of inhibitory signaling by FcγRIIB, which otherwise downregulates FcγRIII-mediated cellular responses. FcγRIIB-deficient but Lyn-sufficient mice served as controls. The Lyn deficiency attenuated IgG-mediated systemic anaphylaxis in vivo, and significantly reduced calcium mobilization and degranulation responses of bone marrow–derived mast cells (BMMCs) in vitro. However, we found that either interleukin 4 or tumor necrosis factor α release by BMMCs was comparable to that from Lyn-deficient and control mice, and the reverse-passive Arthus reaction was equally induced in both mutant mice, indicating that Lyn is not involved in the onset of the IgG-mediated, FcγRIII-dependent late phase responses of mast cells. These findings provide us with insight into distinct signaling mechanisms in mast cells underlying the development of diverse pathologies as well as a therapeutic potential for selective treatment of allergic disorders.