bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional studies of epidermal Langerhans cells and blood monocytes in HIV-infected persons.
Authors: Blauvelt A , Clerici M , Lucey D R , Steinberg S M , Yarchoan R , Walker R , Shearer G M , Katz S I 
Published: December 2022

Abstract
APC dysfunction may be important in immune dysregulation associated with HIV disease. Langerhans cells, epidermal APC, can be infected with HIV, although their function in HIV-infected persons has not been studied. Therefore, we studied the immunologic function of Langerhans cells, in parallel with blood APC (enriched for monocytes/macrophages (M phi) function, in 21 HIV-seropositive (HIV+) and 21 HIV-seronegative volunteers, including three monozygotic twin pairs discordant for HIV serology. Langerhans cells from HIV+ patients were quantitatively normal and expressed normal levels of HLA-DR. However, Langerhans cells from AIDS patients and M phi from both AIDS and HIV+ non-AIDS patients stimulated allogeneic T cells less well compared with control APC. In addition, decreased recall Ag- and mitogen-induced T cell responsiveness was observed in HIV+ patients using either autologous Langerhans cells or autologous M phi as APC/accessory cells. Interestingly, Langerhans cells and M phi isolated from HIV+ twins (CD4+ cell counts of 181, 271, and 562/mm3) were able to present recall Ag normally to HIV-uninfected syngeneic T cells. In summary, APC from HIV+ patients were impaired in their ability to generate a primary immune response (i.e., alloantigen-induced T cell stimulation), but they retained the ability to generate a secondary immune response (i.e., recall Ag-induced syngeneic T cell stimulation). Thus, these findings suggest that defects in secondary immune responses commonly observed in HIV disease are dependent on T cell dysfunction alone, whereas defective primary immune responses may be secondary to both T cell and APC dysfunction.
Self-peptides in the initiation of lupus autoimmunity.
Authors: Bockenstedt L K , Gee R J , Mamula M J 
Published: December 2022

Abstract
Systemic lupus erythematosus is characterized by high titers of autoantibodies directed at multiple proteins of the U1/Sm small nuclear ribonucleoproteins (snRNPs). The origin of this type of autoimmunity, that is, whether it is initiated by foreign molecular mimics or by the self-snRNPs, is not known. In this study using normal mice, we investigated the presence of autoreactive B and T cells to the D protein of murine snRNPs. Although neither B nor T cell responses could be detected after immunization with native self-snRNPs, two synthetic self-peptides corresponding to amino acids 26-40 and 56-70 of the snRNP D protein elicited strong autoreactive T cell proliferation as well as a limited Ab response that bound the self-protein in immunoblots. T cells elicited by these peptides did not respond to stimulation with native snRNPs, suggesting that the peptides are cryptic and are not processed from the native protein for presentation by APCs. After priming with either of these cryptic self-peptides, exposure of the immune system to native murine snRNPs resulted in a diversified response with Abs that immunoprecipitated snRNPs and that produced an antinuclear immunofluorescence pattern on murine cell substrates. These studies demonstrate that autoreactive B and T cells specific for self-snRNPs are components of the normal repertoire of mouse lymphocytes; they have been neither deleted nor irreversibly anergized. Furthermore, we show that a diverse autoimmune response to lupus autoantigens, snRNPs, can originate from self-peptides without the influence of foreign Ags or molecular mimics.
Experimental autoimmune encephalomyelitis. Qualitative and semiquantitative differences in heat shock protein 60 expression in the central nervous system.
Authors: Gao Y L , Brosnan C F , Raine C S 
Published: December 2022

Abstract
The factors that contribute to disease progression in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are not known. In this study, we have tested the hypothesis that inflammation in the central nervous system (CNS) is associated with altered expression of heat shock proteins (hsp) that may function as a target in the development of chronic disease. In normal mouse spinal cord, hsp 60 immunoreactivity was localized exclusively to its constitutive site in mitochondria. In animals with acute EAE, lesions were accentuated by increased expression of hsp 60, primarily by infiltrating cells. In chronic EAE, hsp 60 was found predominantly on CNS components, particularly oligodendrocytes, and astrocytes. In both acute and chronic lesions, hsp 60 was located in the cytoplasm of cells, but in non-lesion areas, it was mitochondrial. By semiquantitative Western blotting, hsp 60 in normal mouse spinal cord (n = 6) was 0.99 +/- 0.09% of total protein. In acute EAE (n = 6), the value was 1.08 +/- 0.1%, and in chronic EAE (n = 8), 1.39 +/- 0.39%. FACS analysis showed that a subpopulation of CD3+ cells expressed hsp 60 on the cell surface, an observation confirmed by cell surface labeling and immunoprecipitation. In chronic EAE lesions, gamma delta T cells colocalized with areas of increased hsp 60 immunoreactivity. The results support the conclusion that development of autoimmune-directed inflammation in the CNS is associated with differences in hsp 60 expression that may act as an additional target and/or modulator of the immune response.
Phenothiazine induces de novo MHC class II antigen expression on thyroid epithelial cells. A new mechanism for drug-induced autoimmunity.
Authors: Takorabet L , Ropars A , Raby C , Charreire J 
Published: December 2022

Abstract
Autoimmune responses are initiated by MHC class II-restricted T cell responses directed against tissue-specific autoantigens. Furthermore, HLA-DR expression in thyroid epithelial cells is a prominent feature of autoimmune thyroid disease. In the present work, we were particularly interested in a phenothiazine, a neuroleptic and anti-depressant drug of pharmacologic importance named alimemazine. Our interest in this compound stems from previous findings of immune effects of this and other phenothiazines. We demonstrate that MHC class II Ags can be experimentally induced on thyroid cells by pharmacologic concentrations of alimemazine, a drug commonly used in psychiatry. In contrast, MHC class II Ags were not induced on the lymphoid cell lines Raji and Jurkat. Expression of MHC class II Ag on the surface of the cloned human thyroid cell hybridoma, GEJ, was demonstrated by flow cytometry. Moreover, by using Northern blot and Southern blot analyses, this finding was confirmed at the molecular level in GEJ and in murine thyroid epithelial cell cultures, respectively. The functional role of phenothiazine-, de novo-induced MHC class II Ags on thyroid cells was assessed by both syngeneic murine thyroglobulin-specific and allogeneic proliferative T cell responses. These results suggest that antidepressant drugs of the phenothiazine type could play a role in the induction and the perpetuation of thyroid autoimmune disorders, through induction of class II restriction elements on normally class II-negative thyroid epithelial cells.
Mucosal immunization with a bacterial protein antigen genetically coupled to cholera toxin A2/B subunits.
Authors: Hajishengallis G , Hollingshead S K , Koga T , Russell M W 
Published: December 2022

Abstract
The generation of secretory IgA Abs for specific immune protection of mucosal surfaces depends on stimulation of the mucosal immune system, but this is not effectively achieved by parenteral or even oral administration of most soluble Ags. To harness the exceptional mucosal immunogenicity of cholera toxin (CT), which is largely attributed to the cell-binding property of its B subunit, for the generation of other oral vaccines, we have genetically replaced the toxic A1 subunit of CT with a 42-kDa segment of a streptococcal protein adhesin. This construct was expressed in Escherichia coli as a chimeric protein that retained the GM1 ganglioside-binding activity of CT subunit B and the antigenicity of the streptococcal adhesin, as shown by GM1-ELISA developed with Abs to the steptococcal segment. The protein composition of chromatographically purified chimeric protein was verified by SDS-PAGE and Western blotting with Abs to both antigenic components of the construct. Peroral administration of this chimeric immunogen in mice elicited high levels of mucosal IgA and serum IgG Abs to the streptococcal adhesin, which persisted for at least 6 mo. This strategy allows the development of similar constructs from other candidate Ags for oral immunization against a variety of mucosally acquired infections.
The role of IL-10 in human B cell activation, proliferation, and differentiation.
Authors: Itoh K , Hirohata S 
Published: December 2022

Abstract
Recent studies have disclosed variable effects of IL-10 on viabilities of human B lineage cells. Thus, IL-10 has been shown to prevent apoptosis of germinal center B cells, whereas IL-10 has been found to induce apoptosis of B-chronic lymphocytic leukemia cells, suggesting the possibility that the effects of IL-10 might be different depending on the state of activation of B cells. The current studies therefore examined in detail the regulation of the survival of human peripheral blood B cells by IL-10 and its relevance to Ig production. Highly purified B cells from healthy adult individuals were cultured with Staphylococcus aureus (SA) Cowan I in the presence or absence of IL-10. When IL-10 was present during the initial activation of B cells with SA, IL-10 facilitated the apoptosis of SA-activated B cells, as determined by staining with propidium iodide, followed by analysis with flow cytometry, thus resulting in very modest IgM production. IL-2 prevented the IL-10-mediated progression of the apoptosis of SA-activated B cells during the initial activation, and thus restored the further differentiation of these B cells into Ig secreting cells. By contrast, IL-10 rather rescued SA-activated B cells from apoptosis and thus supported the differentiation of these B cells without any influences of IL-2, when it was added after 72 h of culture. Of note, cyclosporin A prevented the IL-10-mediated promotion of the apoptosis of SA-activated B cells, thus resulting in the marked enhancement of IgM production of B cells stimulated with SA + IL-10. Finally, the promotion or prevention of the IL-10-mediated apoptosis was correlated with the expression of Bcl-2 oncoprotein in SA-activated B cells. These results indicate that the effects of IL-10 are different depending on the state of activation of B cells after ligation of Ag receptors. Thus, the data have demonstrated that IL-10 during the initial activation delivers negative signals that promote the apoptosis of B cells, whereas IL-10 supports the differentiation of B cells in the complete absence of IL-2 during the subsequent responses following activation. These results therefore emphasize unique biphasic effects of IL-10 on human B cell responsiveness in determining the outcome of humoral immune responses.
T cell gelatinases mediate basement membrane transmigration in vitro.
Authors: Leppert D , Waubant E , Galardy R , Bunnett N W , Hauser S L 
Published: December 2022

Abstract
T cell homing into extravascular sites requires penetration across the subendothelial basal lamina, a specialized nonfibrillar connective tissue structure that anchors endothelial cells to parenchymal surfaces. Herein, we show that normal human T cells express gelatinases A and B, two matrix metalloproteinases active against the major basal lamina constituents, collagen types IV and V. Expression is confirmed at both the mRNA and protein levels. Gelatinase B is expressed constitutively, whereas gelatinases A and B expression is induced by T cell activation. In vitro migration of resting T cells across a basal lamina equivalent is mediated by gelatinase B, because it is specifically blocked by GM6001, a hydroxamic acid inhibitor of matrix metalloproteinases. Inhibition of T cell homing by interference with gelatinase function may represent a useful approach to the treatment of T cell-mediated autoimmune diseases.
Gamma delta T cells down-regulate primary IgE responses in rats to inhaled soluble protein antigens.
Authors: McMenamin C , McKersey M , Kühnlein P , Hünig T , Holt P G 
Published: December 2022

Abstract
The biologic role and repertoire of cells bearing the gamma delta T cell receptor has not been fully defined. However, their tropism for epithelial microenvironments is recognized and suggests an important role for these cells in immune defense at mucosal tissue surfaces. The study presented below utilizes an experimental model in which repeated exposure of Brown Norway rats to OVA by inhalation induces a state of Ag-specific, IgE isotype-specific "tolerance" via immune deviation. This process seems similar to oral tolerance in the gut. This form of tolerance was adoptively transferred to naive syngeneic recipients by i.p. injection of as few as 10(3) positively selected TCR-gamma delta+ cells from OVA-exposed rats. These TCR-gamma delta+ T-cells are demonstrated to produce high levels of INF-gamma in response to OVA stimulation, and this provides a potential mechanism for the inhibition of Th2 cell proliferation, resulting in suppression of IgE production. The unique potency of these cells in selective suppression of IgE Ab production in response to natural "mucosal" Ag exposure suggests a potentially important role in protection against primary allergic sensitization in vivo.
V7, a novel leukocyte surface protein that participates in T cell activation. I. Tissue distribution and functional studies.
Authors: Rivas A , Ruegg C L , Zeitung J , Laus R , Warnke R , Benike C , Engleman E G 
Published: December 2022

Abstract
Among a panel of mouse mAbs generated to a human T cell clone, one mAb, V7.1, inhibited T cell activation in the mixed lymphocyte reaction and was studied further. V7.1 reacted strongly with Ag-specific T cell clones, in addition to freshly isolated monocytes and granulocytes. However, the mAb reacted weakly with freshly isolated PBLs (T cells, B cells, and NK cells), T cells stimulated with phytohemagglutinin, or Con A, and did not stain the vast majority of transformed cell lines of hemopoietic origin. Stimulation of T cells with anti-CD3, or the combination of anti-CD3 and PMA, or anti-CD3, PMA and ionomycin, markedly increased V7.1 surface staining. The mAb precipitated a single polypeptide chain of approximately 135 kDa from alloactivated T cells or monocytes, which was reduced to approximately 110 kDa after treatment with N-glycanase. The proliferative response of T cells to allogeneic monocytes or B lymphoblastoid cells was inhibited by V7.1, and inhibition was maximal when the mAb was present at the initiation of culture. V7.1 also exhibited dose-dependent inhibition of the T cell response to immobilized anti-CD3 Ab in the absence of APCs, indicating that the inhibitory effect of this Ab occurs at the T cell level. Expression of CD25 (IL-2R) on anti-CD3-activated T cells and secretion of IL-2 induced with anti-CD3 and PMA were inhibited by V7.1, whereas the Ab had no effect on T cell proliferation induced by PHA or Con A or on T cell-mediated cytotoxicity. These results indicate that V7.1 recognizes a novel leukocyte surface glycoprotein, designated V7, that is up-regulated on Ag but not lectin-activated T cells, and appears to play a role in TCR/CD3-dependent T cell activation. In an accompanying study, the gene encoding the V7 Ag is described and the molecule is shown to be a novel member of the Ig superfamily.
Identification of a unique costimulatory activity for murine T helper 1 T cell clones.
Authors: Zuckerman L A , Sant A J , Miller J 
Published: December 2022

Abstract
We have examined the ability of several class II-positive tumor cell transfectants to stimulate murine Th1 clones. Most of the transfectants failed to activate the Th1 clones and, in fact, induced Ag-specific anergy. However, we found that one tumor, a UV-induced fibrosarcoma (6130-VAR1), was capable of stimulating both cytokine production and proliferation in Th1 clones. We believe that 6130-VAR1 cells possess a unique costimulatory activity for the following reasons. First, these cells fail to express known costimulatory molecules including B7-1 and B7-2. Second, 6130-VAR1-mediated stimulation of Th1 clones was not blocked by anti-CD28 Fab or by CTLA4Ig, which suggests that members of the B7 family were not up-regulated during the course of stimulation and that activation does not occur via a CD28-dependent pathway. Third, 6130-VAR1 could provide costimulation when presented on a different surface than the class II/peptide ligand for the TCR. This last finding suggested that the activity on these cells was not simply an adhesion molecule that facilitated increased efficiency of T cell:MHC interactions. Finally, like B7-1 transfectants, stimulation by class II-positive 6130-VAR1 cells prevented the induction of anergy in the Th1 clones. Taken together, these results strongly suggest that 6130-VAR1 expresses a unique costimulatory activity (VAM-1) that, like B7-1, can promote T cell activation and prevent anergy induction.
IL-4 activates a latent DNA-binding factor that binds a shared IFN-gamma and IL-4 response element present in the germ-line gamma 1 Ig promoter.
Authors: Berton M T , Linehan L A 
Published: December 2022

Abstract
IL-4 regulates transcription of the germ-line gamma 1 Ig gene in murine B cells and by doing so targets this isotype for switch recombination by an unknown mechanism. In this study, we have identified an IL-4-induced DNA-binding protein factor in murine B cells designated NF-IL-4-gamma 1. This factor binds specifically to a site within a 13-bp DNA sequence extending from -125 to -113 (5' CATTCACATGAAG 3') in the germ-line gamma 1 promoter and shown previously to be important for IL-4-responsive transcription. This sequence is highly homologous to the IFN-gamma activation site or GAS, and competitive binding studies demonstrate that NF-IL-4-gamma 1 can also bind to GAS elements in the promoters of two IFN-gamma-responsive genes and to an IL-4-responsive element in the germ-line epsilon Ig promoter. NF-IL-4-gamma 1 is rapidly induced in the absence of de novo protein synthesis and expression is sustained through day 4 of in vitro culture with IL-4 and LPS. Induction of NF-IL-4-gamma 1 is inhibited by the kinase inhibitor staurosporine and the factor itself requires phosphorylation for binding activity. The binding specificity and expression characteristics of NF-IL-4-gamma 1 suggest identity with other recently described IL-4-activated, GAS-binding factors that are members of the signal transducers and activators of transcription (STAT) family of cytokine-responsive transcription factors.
Characterization of the constitutive and inducible components of a T cell IL-4 activation responsive element.
Authors: Tara D , Weiss D L , Brown M A 
Published: December 2022

Abstract
An Il-4 regulatory element, activation responsive element (ARE), located between -88 and -60, contributes to activation-dependent transcription of IL-4/CAT reporter gene constructs in T cells. It was previously demonstrated that nuclear proteins present in both unstimulated and stimulated T cells specifically interact with the ARE. In this study, these proteins were further characterized. UV cross-linking experiments established that multiple proteins are associated with the ARE in both the constitutive and activation-dependent complexes and several of these have identical apparent m.w. The formation of both complexes is dependent on the same ARE subsequence. In addition, activator protein 1 family members are uniquely associated with the activation-dependent complex. These results support a model in which activation-dependent proteins, including jun/fos family members, associate with a preexisting transcription complex to influence inducible IL-4 gene transcription. The ARE shares 9 bp of sequence identity with the IL-2 nuclear factor of activated T cell (NF-AT) binding site within the critical protein binding region, and several features of ARE-protein interactions are similar to the NF-AT transcription complex. However, we demonstrate that the constitutive nuclear ARE-associated factors react with Abs, raised to NF-ATp and NF-ATc, preferentially bind to the ARE but not to the NF-AT binding site and are cyclosporin A sensitive. Taken together, these data indicate that there are IL-4 gene-specific factors associated with the ARE and that the formation of the ARE and NF-AT complexes are regulated differently.
IL-12 modulation of T helper responses to the filarial helminth, Brugia malayi.
Authors: Pearlman E , Heinzel F P , Hazlett F E , Kazura J W 
Published: December 2022

Abstract
The purpose of the current study was to evaluate the effects of exogenous IL-12 on: 1) development of the Th cell response to Brugia malayi microfilariae (mf); 2) established B. malayi-specific Th2 responses; and 3) resistance to mf. IL-12 given at the time of inoculation with live mf resulted in a switch in development from a dominant Th2 (IL-4, IL-5 &gt; IFN-gamma) to a dominant Th1 response (IFN-gamma &gt; IL-4, IL-5). Induction of Th1 activity by IL-12 was dependent on IFN-gamma in vivo. When mice were given IL-12 (0.5 microgram daily for 4 days) after mf Ag-specific Th2 responses had been established, Ag-driven IL-4 and IL-5 production by spleen and peritoneal cells were reduced respectively by approximately 75 to 90% and approximately 30 to 40%, IFN-gamma production was elevated, and 68% fewer eosinophils were recovered from the peritoneal cavity. In vivo depletion of IFN-gamma ablated the effects of IL-12 on both cytokine production and eosinophil recovery. IL-12 treatment of either naive or previously sensitized mice challenged intravenously with live B. malayi did not alter the rate of clearance of mf from the blood. These data indicate that IL-12 treatment suppresses induction of filarial driven Th2 responses and modulates recall responses of established Th2 cells, but does not alter elimination of blood-borne mf in nonimmune or immune mice.
Mapping of T cell epitopes of the 30-kDa alpha antigen of Mycobacterium bovis strain bacillus Calmette-Guérin in purified protein derivative (PPD)-positive individuals.
Authors: Silver R F , Wallis R S , Ellner J J 
Published: December 2022

Abstract
The fibronectin-binding 30-kDa alpha Ag is a major secretory protein of growing mycobacteria that stimulates in vitro lymphocyte blastogenesis in most healthy purified protein derivative-positive individuals, but only a minority of patients with active tuberculosis. T cell epitopes of the alpha Ag were assessed using blastogenic responses of PBMC from 12 healthy purified protein derivative-positive subjects to a set of synthetic peptides based on the 325-amino acid sequence of the alpha Ag of Mycobacterium bovis BCG. Because epitope-specific precursor cells are infrequent and randomly distributed, we used Poisson analysis to determine positive responses to 10 micrograms/ml of each peptide in 12 replicate culture wells. Seven immunodominant regions of the alpha Ag were identified. Each subjects responded to at least one of the two most dominant epitopes, which correspond to amino acids 131-155 and 233-257 (from N terminus). Peptides of these two epitopes induced production of IFN-gamma by sorted CD4+ T cells. The immunodominant peptides may have use a components of a vaccine and as tools to study the evolution of the immune response to M. tuberculosis. The two most dominant epitopes both occur in regions of the alpha Ag that differ from those of the atypical pathogens M. avium and M. kansasii. In addition, the M. bovis epitope of amino acids 133-155 differs from that of M. tuberculosis by a single amino acid. It may be possible to exploit the sequence differences for development of diagnostic tests with increased specificity.