bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isolation of the Xenopus complement factor B complementary DNA and linkage of the gene to the frog MHC.
Authors: Kato Y , Salter-Cid L , Flajnik M F , Kasahara M , Namikawa C , Sasaki M , Nonaka M 
Published: December 2022

Abstract
C factor B (Bf) is the key component of the C3 convertase of the alternative C pathway, and its gene resides in the class III region of the mammalian MHC. To elucidate the evolution of both the C system and the MHC, we isolated Bf cDNA clones from Xenopus laevis, an ectothermic vertebrate in which the MHC has been well defined at both the biochemical and functional levels. A part of the serine protease domain of the Xenopus Bf mRNA was amplified by reverse transcriptase-PCR, using degenerate primers corresponding to regions encoding the perfectly conserved amino acid sequences found in both the mouse Bf and C2 proteins. A full length Xenopus Bf cDNA clone was isolated from a Xenopus liver cDNA library. The deduced amino acid sequence of 747 residues showed the same domain structure as mammalian Bf and C2: three short consensus repeat domains, a von Willebrand domain and a serine protease domain. Xenopus Bf has 40% and 30% overall amino acid identity to mouse Bf and mouse C2, respectively. Because the amino acid identity between mouse Bf and mouse C2 is 38%, the gene duplication of Bf/C2 probably occurred before the divergence of amphibians and mammals. Southern blotting analysis of the Xenopus Bf gene showed a close linkage to the MHC, indicating that the Bf gene was linked to the class I and class II genes at the time Xenopus shared a common ancestor with mouse and man, 350 x 10(6) yr ago.
Characterization of astrocyte nuclear proteins involved in IFN-gamma- and TNF-alpha-mediated class II MHC gene expression.
Authors: Panek R B , Lee Y J , Itoh-Lindstrom Y , Ting J P , Benveniste E N 
Published: December 2022

Abstract
IFN-gamma is a potent inducer of class II MHC Ags on different cell types, including the astrocyte. TNF-alpha alone has no effect on class II MHC expression, but enhances IFN-gamma-induced class II expression. IFN-gamma acts by inducing transcription of the class II gene, and TNF-alpha enhances the rate of IFN-gamma-induced transcription. We have previously described two factors, IFN-gamma-enhanced factor X (IFNEX) and TNF-alpha induced complex X (TIC-X), whose expression is induced by IFN-gamma and IFN-gamma/TNF-alpha, respectively, which interacted with the X box of the DRA promoter. In this study, we show that IFNEX and TIC-X bind to the X2 core, with contacts extending into the 3' end of X1 and into the spacer region of the DRA promoter. We also show a functional correlation between binding activity and transcriptional activity of the DRA promoter. These results strongly suggest that both IFNEX and TIC-X play important roles in the regulation of class II MHC gene expression in the astrocyte.
E1A repression of IL-6-induced gene activation by blocking the assembly of IL-6 response element binding complexes.
Authors: Takeda T , Nakajima K , Kojima H , Hirano T 
Published: December 2022

Abstract
Some viral products interfere with host antiviral defense mechanisms. Adenovirus E1A represses IFN signal transduction pathways which induces gene activation and an antiviral state. Both IFN and IL-6 activate Jak/Tyk protein tyrosine kinases and the STAT (signal transducer and activator of transcription) family proteins. We showed that 12S E1A repressed IL-6 signals activating the junB promoter and the two IL-6 response elements (REs), JRE-IL6 and type II IL-6 RE (also called acute phase response element), required for IL-6-induced activation of the junB promoter and the type II acute phase reactant genes, respectively, in hepatocytes. Conserved region 1 of the 12S E1A was responsible for the repression. Target molecules of the repression by E1A appeared to be IL-6-inducible DNA-binding proteins acting on the IL-6 REs. In a rat 3Y1 cell line stably expressing E1A, the levels of IL-6-induced IL-6 RE binding proteins were severely reduced compared with those in a parental 3Y1 cell line. Moreover, we found that the levels of the STAT family proteins including Stat1-alpha (p91), Stat1-beta (p84), Stat2 (p113), and Stat3 were decreased by the stable expression of adenovirus E1A. The E1A-induced reduction in the amount of DNA-binding proteins seemed to be partly responsible for the decreased transcriptional activity of the IL-6 RE-driven gene expression in response to IL-6. This repression mechanism may be applicable to the E1A repression of IFN-gamma-induced gene activation.
Influenza and vaccinia viruses expressing malaria CD8+ T and B cell epitopes. Comparison of their immunogenicity and capacity to induce protective immunity.
Authors: Rodrigues M , Li S , Murata K , Rodriguez D , Rodriguez J R , Bacik I , Bennink J R , Yewdell J W , Garcia-Sastre A , Nussenzweig R S 
Published: December 2022

Abstract
We compared the effectiveness of several recombinant influenza and vaccinia viruses to induce a malaria-specific immune response. The CD8+ T cell epitope of the circumsporozoite (CS) protein of Plasmodium yoelii, a rodent malaria parasite, was expressed in two distinct influenza virus proteins, the hemagglutinin and the neuraminidase. These recombinant viruses were found to be equally efficient at inducing CS-specific CD8+ T cells in mice. A third recombinant virus, which expresses a B cell epitope of the CS protein, induced neutralizing anti-sporozoite Abs. Expression in the same recombinant virus of the CD8+ T cell epitope and of the B cell epitope did not impair the capacity of this recombinant virus to induce malaria-specific CD8+ T cells and neutralizing Abs. The immunogenicity of a vaccinia virus, expressing the entire CS protein, was compared with that of a highly attenuated vaccinia strain expressing the same protein and with that of another vaccinia virus expressing only the CD8+ T cell epitope. All three vaccinia virus recombinants elicited CS-specific CD8+ cells and a potent inhibitory response against pre-erythrocytic stages of malaria parasites. Optimal levels of anti-sporozoite Abs, inhibition of liver stage development, and protection against malaria infection resulted from repeatedly immunizing the animals with recombinant influenza viruses followed by boosters with a recombinant vaccinia virus. These findings support the concept that live viral vectors expressing the appropriate proteins and/or epitopes can be used as promising vaccine candidates.
MHC class I gene(s) in the D/L region but not the TNF-alpha gene determines development of toxoplasmic encephalitis in mice.
Authors: Suzuki Y , Joh K , Kwon O C , Yang Q , Conley F K , Remington J S 
Published: December 2022

Abstract
Previous studies revealed that mice with the b or k allele at the H-2D region are susceptible to toxoplasmic encephalitis (TE); those with the d allele are resistant. To determine whether the b or d allele is dominant, F1 hybrids between susceptible C57BL/6 (H-2b) and resistant BALB/c (H-2d) mice were infected with T. gondii. TE was not observed in the F1 hybrids, indicating that the d allele is dominant for protection against development of TE. Mice with a mutation in the D/L region were used to determine whether the D gene or the L gene of MHC class I Ags of the H-2D region is most critical for resistance against development of TE. B10.D2-H2dm1 (dm1) mice that have the mutant D/L hybrid gene formed by fusion of the 5' part of the Dd gene and the 3' part of the Ld gene developed TE in contrast to their background B10.D2 mice. BALB/c-H-2dm2 (dm2) mice, which have a complete deletion of the Ld gene, had significantly more T. gondii cysts in their brains than did dm1 mice and developed large areas of necrosis in their brains that were not observed in dm1 mice. These results indicate that a gene(s) in the D/L region determines whether TE will occur and that the Ld gene plays a critical role in the resistance against development of TE. Polymorphisms in the TNF-alpha gene (located in the H-2D region) have been reported to correlate with resistance against the development of TE. When development of TE was studied in BALB/c and dm2 mice that have the same TNF-alpha gene, only dm2 mice developed TE. This indicates that the TNF-alpha gene is not a determining factor for the development of TE. Transcripts for TNF-alpha were detected in brains of infected dm2 mice but not in BALB/c mice. Injection of neutralizing Abs against TNF-alpha resulted in worsening of the TE in infected dm2 mice but did not induce TE in infected BALB/c mice. Thus, TNF-alpha appears to be produced in the brain after TE has developed and is responsible for preventing the progression of TE.
Epitope mapping of the branched chain alpha-ketoacid dehydrogenase dihydrolipoyl transacylase (BCKD-E2) protein that reacts with sera from patients with idiopathic dilated cardiomyopathy.
Authors: Ansari A A , Neckelmann N , Villinger F , Leung P , Danner D J , Brar S S , Zhao S , Gravanis M B , Mayne A , Gershwin M E 
Published: December 2022

Abstract
Sera from 29 of 48 patients with idiopathic dilated cardiomyopathy (IDCM) and six of six patients with dilated cardiomyopathy (DCM) secondary to suspected viral myocarditis were shown to react with the branched chain alpha-ketoacid dehydrogenase (BCKD) complex mitochondrial proteins. Whereas sera from only 1 of 26 patients with ischemic heart disease showed reactivity against the BCKD complex protein, 0 of 30 sera from normal human volunteers, 0 of 64 sera from patients with lupus, and 0 of 34 sera from patients with rheumatoid arthritis showed detectable reactivity, denoting an element of specificity for the reactivity of sera from IDCM patients. The major reactivity was localized to the dihydrolipoyl transacylase (E2) component of BCKD complex. By using recombinant techniques, the immunodominant BCKD-E2 epitope recognized by sera from IDCM patients was localized to amino acid (aa) sequences 116 to 134. Each of the IDCM sera that reacted with the native BCKD complex was shown to react with the immunodominant peptide, as defined by a peptide inhibition ELISA and by an ELISA using the reactive peptide conjugated to BSA. Sera from IDCM patients that reacted with the native BCKD complex and the reactive peptide also showed inhibition of BCKD enzyme activity. The possible mechanisms for the induction of the Abs and the implications of these findings for the pathogenesis of IDCM are discussed.
Idiotype-cytokine fusion proteins as cancer vaccines. Relative efficacy of IL-2, IL-4, and granulocyte-macrophage colony-stimulating factor.
Authors: Chen T T , Tao M H , Levy R 
Published: December 2022

Abstract
Idiotypic determinants, antigenic sites expressed on the variable region of Ig molecules of malignant B cells, represent tumor-specific Ags but are weak immunogens. We have previously shown that the immunogenicity can be dramatically increased by fusing tumor Id to granulocyte macrophage (GM)-CSF. Here, we demonstrate that fusion proteins with IL-2 or IL-4 can also be highly immunogenic. Co-immunization of these fusion proteins with another Id demonstrated the importance of physical linkage between the cytokine and relevant Ag for this enhancement. All three fusion proteins are capable of eliciting significant levels of specific Abs against the Id without the use of carrier proteins or adjuvants, although the GM-CSF fusion protein appeared to be unique in its ability to induce higher titers of anti-Id Abs in the primary response. Furthermore, the Id-IL-2 fusion protein induced high titers of IgG2a and IgG3 anti-Id Abs, whereas the Id-IL-4 and Id-GM-CSF fusion proteins did not. Despite the differences, tumor protection was comparable in all mice having significant titers of anti-Id Abs, regardless of the fusion protein used. We concluded that Id-cytokine fusion proteins are potent immunogens that can elicit significant antitumor immunity. The general approach of fusing a cytokine to a potential Ag may be applicable to the design of vaccines for immunotherapy of other types of tumors as well as for other pathogens and disease states.
The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes.
Authors: Sette A , Vitiello A , Reherman B , Fowler P , Nayersina R , Kast W M , Melief C J , Oseroff C , Yuan L , Ruppert J , Sidney J , del Guercio M F , Southwood S , Kubo R T , Chesnut R W , Grey H M , Chisari F V 
Published: December 2022

Abstract
The relationship between binding affinity for HLA class I molecules and immunogenicity of discrete peptide epitopes has been analyzed in two different experimental approaches. In the first approach, the immunogenicity of potential epitopes ranging in MHC binding affinity over a 10,000-fold range was analyzed in HLA-A*0201 transgenic mice. In the second approach, the antigenicity of approximately 100 different hepatitis B virus (HBV)-derived potential epitopes, all carrying A*0201 binding motifs, was assessed by using PBL of acute hepatitis patients. In both cases, it was found that an affinity threshold of approximately 500 nM (preferably 50 nM or less) apparently determines the capacity of a peptide epitope to elicit a CTL response. These data correlate well with class I binding affinity measurements of either naturally processed peptides or previously described T cell epitopes. Taken together, these data have important implications for the selection of epitopes for peptide-based vaccines, and also formally demonstrate the crucial role of determinant selection in the shaping of T cell responses. Because in most (but not all) cases, high affinity peptides seem to be immunogenic, our data also suggest that holes in the functional T cell repertoire, if they exist, may be relatively rare.
Neutrophils migrate to delayed-type hypersensitivity reactions in joints, but not in skin. Mechanism is leukocyte function-associated antigen-1-/Mac-1-independent.
Authors: Gao J X , Issekutz A C , Issekutz T B 
Published: December 2022

Abstract
We have previously found that polymorphonuclear leukocyte (PMNL) migration to adjuvant arthritic joints of rats was only partially inhibited by mAbs to the adhesion molecules LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18), suggesting that there is a CD11/CD18-independent mechanism for PMNL migration to inflamed joints. Adjuvant arthritis in rats is believed to be initiated by a T lymphocyte-dependent immune response and maintained by proinflammatory cytokines such as IL-1 and TNF-alpha. Here we studied two types of joint inflammation: that induced by a delayed-type hypersensitivity (DTH) reaction in the joint and that induced by intra-articular (i.a.) injection of cytokines, to explore PMNL migration to inflamed joints and examine the role of CD18. 51Cr-labeled blood PMNL were used to measure PMNL migration in rats to inflammatory reactions in joints and compared with reactions in skin. A large number of PMNL migrated to the carpal and talar joints after i.a. injection of Mycobacterium purified protein derivative in sensitized animals to induce DTH, but there was minimal PMNL migration to this DTH reaction in the skin. This migration to the joints was not inhibited by mAbs to LFA-1 alone or mAbs to LFA-1 plus Mac-1 that almost completely inhibited PMNL accumulation in dermal inflammatory reactions induced by zymosan-activated serum (C5adesArg), endotoxin, IL-1 alpha, or TNF-alpha in the same rats. Intra-articular injection of the cytokines IL-1 alpha and TNF-alpha, but not IFN-gamma, induced marked PMNL accumulation in the joints; this was strongly inhibited by the treatment of rats with anti-LFA-1 and anti-Mac-1. Thus, PMNL migrate to DTH induced in joints but not in skin, and this migration is CD18-independent, but migration to i.a. IL-1 alpha and TNF-alpha is largely CD18 dependent in both joints and skin. This suggests that both the joint microenvironment and the T cell dependence of the inflammatory reaction in the joint governs the mechanism of PMNL recruitment.
Elevated levels of shed type II IL-1 receptor in sepsis. Potential role for type II receptor in regulation of IL-1 responses.
Authors: Giri J G , Wells J , Dower S K , McCall C E , Guzman R N , Slack J , Bird T A , Shanebeck K , Grabstein K H , Sims J E 
Published: December 2022

Abstract
Two types of cellular IL-1Rs have been characterized and cloned from both human and murine sources. The type II IL-1R has a very short cytoplasmic domain and does not seem to participate in IL-1 signaling. We demonstrate that type II IL-1Rs are released from the surface of neutrophils in response to treatment with TNF or endotoxin. In addition, serum from patients with sepsis syndrome contains elevated levels of soluble type II IL-1Rs. Neutrophils isolated from patients with sepsis have greatly enhanced expression of type II IL-1R mRNA and cell surface receptors and are therefore a likely source for the shed receptors in serum. Of the three forms of IL-1, soluble type II IL-1R binds IL-1 beta with highest affinity and also selectively inhibits IL-1 beta activity. We propose that increased cell surface expression and rapid release of preformed type II IL-1R from neutrophils, as a soluble IL-1 beta binding protein, represents a mechanism that has evolved for regulating IL-1 activity in sepsis.
Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor.
Authors: Taylor A W , Streilein J W , Cousins S W 
Published: December 2022

Abstract
Suppression of immune-mediated inflammation within the normal anterior chamber (AC) of the eye is in part the result of active suppression of effector T cell activities by immunosuppressive cytokines found in aqueous humor (AqH), the fluid filling the AC. There are immunosuppressive factors found in the low m.w. fraction (&lt; 5 kDa) of AqH, including the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH). In seeking other factors, we now report that the neuropeptide vasoactive intestinal peptide (VIP) is also present in normal AqH. VIP immunoreactivity was found in normal rabbit eyes at a concentration of 12 +/- 1 nM. At this intraocular concentration, VIP suppressed Ag-stimulated lymph node cell (LNC) proliferation and IFN-gamma production in vitro. Although suppression of LNC proliferation was not neutralized by absorption of VIP from the low m.w. fraction of AqH, removal of VIP did neutralize suppression of IFN-gamma production by this fraction of AqH. Absorption of both VIP and alpha-MSH from this fraction of AqH permitted production of IFN-gamma by Ag-stimulated LNC that was no different than absorbing VIP alone. The low m.w. fraction of AqH absorbed of either alpha-MSH and VIP lost its ability to suppress local adoptive transfer of delayed-type hypersensitivity. The results suggest that VIP is an important immunosuppressive neuropeptide in AqH. Neuropeptides play an important role in ocular immune privilege and creation of an intraocular immunosuppressive microenvironment.
Inhibition of Plasmodium falciparum in vitro by human gamma delta T cells.
Authors: Elloso M M , van der Heyde H C , vande Waa J A , Manning D D , Weidanz W P 
Published: December 2022

Abstract
As assessed by flow cytometry, human gamma delta T cells were shown here to inhibit replication of blood-stage Plasmodium falciparum in vitro in a dose-dependent fashion; no other leukocyte population tested was suppressive. Replication of intraerythrocytic stages of the parasite (rings, trophozoites, and schizonts) was not affected by coculture with gamma delta T cells nor were erythrocytes damaged by this coculture, indicating that the targets recognized by gamma delta T cells are extracellular merozoites in transit to new host erythrocytes. Moreover, parasite inhibition requires contact between gamma delta T cells and merozoites. These findings suggest that gamma delta T cells may exert a protective effect in immunity to malaria.
Induction of antibodies to the Plasmodium falciparum merozoite surface protein-1 (MSP1) by cross-priming with heterologous MSP1s.
Authors: Hui G S , Hashimoto A C , Nikaido C M , Choi J , Chang S P 
Published: December 2022

Abstract
The merozoite surface protein-1 (MSP1) of Plasmodium falciparum possesses intervening conserved and nonconserved sequences. The relative importance of these sequences in providing T cell help for Ab production was investigated in a series of cross-priming studies using homologous and heterologous parasite MSP1 proteins. Cross-priming with heterologous MSP1s was as efficient as homologous immunizations in inducing anti-MSP1 Abs. Similar to homologous immunization, cross-priming with heterologous MSP1s induced primarily Abs to conserved epitopes. The specificities of the Abs were also similar for the two immunization regimens. Studies were also performed with use of the C-terminal p42 fragment of MSP1 expressed in baculovirus (BVp42). When BVp42 was used either as the priming Ag followed by boosting with homologous (or heterologous) MSP1 or as the booster Ag after priming with homologous (or heterologous) MSP1, much lower anti-BVp42 Ab titers were produced compared with priming/boosting with homologous or heterologous MSP1s or BVp42 alone. Thus, immunization with the complete parasite MSP1 induced a dominant, conserved Th epitope(s) specific for anti-p42 Ab production, and such determinant(s) was either located outside the p42 region or was not provided by the BVp42 because of possible differences in the processing of parasite MSP1 vs BVp42. Our data provided a strong rationale to identify and include conserved Th epitope(s) in MSP1 vaccines. Furthermore, a MSP1 vaccine on the basis of the C-terminal p42 fragment may benefit by the inclusion of additional Th epitopes to achieve effective boosting in the field.
Nitric oxide-independent killing of Francisella tularensis by IFN-gamma-stimulated murine alveolar macrophages.
Authors: Polsinelli T , Meltzer M S , Fortier A H 
Published: December 2022

Abstract
Alveolar macrophages (AMs) were analyzed for ability to support replication of the intracellular bacterium Francisella tularensis live vaccine strain (LVS). AM supported in vitro growth (2 to 3 logs over 5 days) of LVS with a doubling time of 8 +/- 0.8 h. AMs were analyzed for responsiveness to rIFN-gamma for destruction of this lung pathogen. AM treated with 50 U/ml rIFN-gamma allowed early growth of bacteria (six doublings over 48 h) but between 48 and 96 h rIFN-gamma-treated AM eliminated 1.5 logs of LVS. AMs were sensitive to effects of rIFN-gamma; as little as 5 U/ml rIFN-gamma stimulated AM antimicrobial activity, with half-maximal activity 0.3 U/ml. rIFN-gamma-induced antimicrobial effects in AM correlated with amount of nitrites produced, but nitric oxide played only a minimal role in antibacterial effects induced in AM, because NG-MMLA (specific inhibitor of L-arginine-dependent nitric oxide production) failed to block antimicrobial activity of IFN-gamma-stimulated AM. IL-10, TGF-beta 1, and IFN-alpha (cytokines known to regulate effector functions of activated macrophages) also did not block anti-F. tularensis activity of IFN-gamma-stimulated AM. Reactive oxygen metabolites, depletion of tryptophan, and sequestration of iron did not contribute to anti-F. tularensis activity because addition of superoxide dismutase or catalase, excess iron, or tryptophan to IFN-gamma-treated AM did not reverse the anti-F. tularensis activity observed in these cells. Regulation of AM effector activity differed from that of other macrophage populations, in that while rIFN-gamma-stimulated AM produced TNF-alpha (100 U/ml at 72 h), TNF-alpha was not required as a costimulator for induction of antimicrobial activities by rIFN-gamma because anti-TNF-alpha treatment of rIFN-gamma-stimulated AM blocked TNF-alpha but had no effect on either production of nitrites or anti-F. tularensis activity.