bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequences of V kappa L subgroup light chains in Fanconi's syndrome. Light chain V region gene usage restriction and peculiarities in myeloma-associated Fanconi's syndrome.
Authors: Rocca A , Khamlichi A A , Touchard G , Mougenot B , Ronco P , Denoroy L , Deret S , Preud'homme J L , Aucouturier P , Cogné M 
Published: January 2023

Abstract
Certain monoclonal Ig light chains (LC) are responsible for marked disturbances of proximal tubule cell functions (Fanconi's syndrome, FS). In patients with FS, intracellular crystal-like inclusions containing LC determinants are commonly found in plasma cells, macrophages, and renal tubular cells. In an attempt at understanding the pathogenesis of myeloma-associated FS, we recently determined the first complete primary sequence of a kappa-LC (CHEB) responsible for the disease. We now report on the primary structure of three other kappa-LC of the V kappa l variability subgroup associated with FS (TRE, TRO, and DEL). After PCR amplification, cDNA encoding these LC were sequenced. CHEB, TRE, and TRO LC genes were found to be highly homologous to the same germline gene O2/O12. These patients had numerous intracellular crystals, whereas the fourth patient, DEL, had no detectable crystals. The LC from the latter patient was homologous to another germline gene, O8/O18. Comparison of these LC sequences to previously reported LC of the V kappa l subgroup allowed identification of a number of unusual amino acid substitutions in the V region that had rarely or never been previously described at the corresponding positions. Some of these unusual substitutions affect highly conserved amino acids located either in an external loop (residue 30) or in inner (residues 48 and 55) and outer (positions 63 and 72) beta-sheets that may be important for the structure and binding properties of the kappa-chains. These and several other substitutions, some of them shared with amyloidogenic kappa-LC, could induce conformational alterations and represent a determinant pathogenic factor.
Induction of antigen-specific T and B cell immunity in colon carcinoma patients by anti-idiotypic antibody.
Authors: Somasundaram R , Zaloudik J , Jacob L , Benden A , Sperlagh M , Hart E , Marks G , Kane M , Mastrangelo M , Herlyn D 
Published: January 2023

Abstract
Polyclonal goat anti-idiotypic Abs directed against anti-human gastrointestinal carcinoma mAb GA733 were administered to 13 colon cancer patients who had their primary tumor and lymph node metastases removed before immunotherapy. Patients received four s.c. doses (0.5 to 8 mg each) of alum-precipitated anti-idiotypic Ab. Seven of the 13 patients produced anti-anti-Ids that bound specifically to the GA733 epitope on tumor cells and shared idiotopes with mAb GA733. In four of the seven responding patients, anti-Id therapy specifically modulated T cell responses. In two patients who did not demonstrate GA733 Ag/anti-Id-reactive T cells before therapy, anti-Id administration induced CD4+, MHC class II-dependent T cells that specifically proliferated in culture in response to stimulation with either anti-Id or GA733 Ag. In two other patients who did demonstrate Ag/anti-Id-reactive T cells before therapy, anti-Id administration transiently induced lymphocytes that suppressed the proliferative responses of cultured pretherapy lymphocytes to stimulation with anti-Id or GA733 Ag. Nine of the 13 treated patients showed no evidence of disease after 39 to 86 mo of observation. Five of these patients developed Ag-specific Ab3 and one had, in addition, a T cell response.
Cytokine and chemokine expression in tumors of mice receiving systemic therapy with IL-12.
Authors: Tannenbaum C S , Wicker N , Armstrong D , Tubbs R , Finke J , Bukowski R M , Hamilton T A 
Published: January 2023

Abstract
The cellular and molecular mechanisms of IL-12-mediated anti-tumor activity have been examined. BALB/c mice bearing established s.c. RENCA or CT26 tumors that were treated daily with IL-12 showed essentially complete tumor regression while tumors in untreated animals grew progressively. Examination of inflammatory gene expression in tumor tissue from treated vs untreated mice revealed the selective expression of IFN-gamma and the IFN-gamma-inducible CXC chemokine IP-10. Immunohistologic analysis demonstrated that tumors from treated mice were heavily infiltrated with CD8+ T cells and Mac-1+ mononuclear cells. Tumor regression in IL-12-treated mice was associated with expression of the lytic effector molecules perforin and granzyme B. These findings support the hypothesis that the anti-tumor function of IL-12 treatment depends upon the induced expression of IFN-gamma by T cells and/or NK cells, the amplification of the immune response mediated by IFN-gamma-induced expression of chemoattractant cytokines, and the IL-12-dependent potentiation of the cytolytic effector function of recruited CD8+ T cells.
Adjuvant-free hsp70 fusion protein system elicits humoral and cellular immune responses to HIV-1 p24.
Authors: Suzue K , Young R A 
Published: January 2023

Abstract
Heat shock proteins are major targets of the immune response to bacterial and parasitic pathogens. Mycobacterium tuberculosis hsp70 is an especially powerful Ag containing multiple B and T cell epitopes. We investigated whether M. tuberculosis hsp70 can be used as an adjuvant-free carrier to stimulate the humoral and cellular immune response to an accompanying protein. A recombinant hsp70 protein expression vector was developed that permits the production of any protein fused to the amino terminus of mycobacterial hsp70. We found that a recombinant HIV p24-hsp70 fusion protein produced with this vector elicited both humoral and cellular immune responses against p24 in mice when administered in saline in the absence of adjuvant. Covalent linkage of hsp70 to p24 was essential to elicit immune responses to p24 under these conditions. The anti-p24 IgG1 Abs induced in p24-hsp70-immunized mice persisted at high levels for more than 1 yr after immunization. These results demonstrate that the antigenic properties of M. tuberculosis hsp70 can be exploited to enhance the humoral and cellular immune response to an attached protein.
Uncoupling IL-2 production from apoptosis and TNF production by changing the signal through the TCR.
Authors: Glickstein L , Macphail S , Stutman O 
Published: January 2023

Abstract
T cells may discriminate between stimuli in a variety of ways, including the presence of cytokines or other costimulatory signals, the type of Ag (peptide, superantigen, or allorecognition), or the magnitude of the signal through the TCR. We have used anti-CD3 stimulation of T hybridomas to examine signals generated through the TCR in the absence of exogenous APCs. Soluble whole anti-CD3, but not F(ab')2 anti-CD3, was able to stimulate the T hybridomas to produce IL-2. Plastic-bound anti-CD3, in contrast, stimulated TNF production, G1 arrest, and apoptosis by the T hybridoma. Engagement of the CD4 coreceptor on these cells had no effect on the overall pattern of signaling observed. Although TNF production was correlated with apoptosis, anti-TNF treatment did not prevent cell death or G1 arrest. The response of the T hybridoma to both forms of anti-CD3 included significant IL-2 production even at the lowest dose tested. However, soluble anti-CD3 at the highest dose tested elicited only minor apoptosis, while plastic-bound anti-CD3 elicited significant apoptosis even at the lowest dose. The difference in response was not evident at the level of phosphotyrosine proteins two min after cross-linking of the TCR.
Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival.
Authors: Qin L , Chavin K D , Ding Y , Tahara H , Favaro J P , Woodward J E , Suzuki T , Robbins P D , Lotze M T , Bromberg J S 
Published: January 2023

Abstract
A murine heterotopic, nonvascularized cardiac allograft model was used to examine the effects of the immunosuppressive cytokine, viral IL-10 (vIL-10), delivered by gene transfer on graft rejection. Retroviral-mediated gene transfer and expression of vIL-10 significantly prolonged allograft survival, without conventional systemic immunosuppression, from 12.1 +/- 0.8 days to 39.4 +/- 2.5 days (p &lt; 0.0001). The effect was specific, dose dependent, and restricted to the site of transplantation. PCR analysis demonstrated specific expression of the transferred gene within the allograft. Analysis of the cellular infiltrate in the allografts showed a reduction in T cells and alloantigen-specific cytotoxic T cells and IL-2 producing helper T cells. Thus, the transient local expression of a gene encoding an immunosuppressive protein within a graft can generate local immunosuppression, making gene therapy a viable approach for facilitating transplantation.
Localization of classical and alternative pathway regulatory activity within the decay-accelerating factor.
Authors: Brodbeck W G , Liu D , Sperry J , Mold C , Medof M E 
Published: January 2023

Abstract
Decay-accelerating factor (DAF) is a cell-associated C regulatory protein that protects host cells from autologous C attack. It functions intrinsically in host cell surface membranes to rapidly dissociate autologous classical and alternative pathway C3 convertases whenever these amplifying enzymes assemble on host cell surfaces. It is composed of four contiguous approximately 70 amino acid long regions termed short consensus repeats (SCRs) that share homology with similar units in other C3 convertase regulatory proteins. It is attached to the cell surface membrane by a glycoinositol phospholipid (GPI) anchor that is added posttranslationally. In this study, we prepared rGPI-anchored DAF proteins devoid of individual SCRs. We then incorporated the GPI-anchored products into sheep erythrocyte (Esh) hemolytic intermediates and examined their abilities to intrinsically regulate classical or alternative pathway activation. We found that classical pathway C3 convertase regulatory function resides within SCR-2 and SCR-3, while alternative pathway C3 convertase regulatory function resides within SCR-2, -3, and -4. Functional comparisons of the variant DAF proteins in fluid phase C3 activation assays established that the differences reflect domain-specific interactions rather than changes in the spatial arrangement of SCRs above the cell surface. In accordance with these findings, we found that variant DAF molecules containing SCR-1, -2, and -3, but not SCR-4, function to selectively inhibit classical pathway activation.
Di- and trinucleotide target preferences of somatic mutagenesis in normal and autoreactive B cells.
Authors: Smith D S , Creadon G , Jena P K , Portanova J P , Kotzin B L , Wysocki L J 
Published: January 2023

Abstract
During Ag-driven development of memory B cells, Ab V genes are modified by somatic mutagenesis. Although V gene somatic mutations have important biologic consequences in both physiologic and autoimmune Ab responses, little is known about the mechanism of mutation, or whether it operates normally in autoreactive B cells. To approach these issues, we analyzed somatic mutations in Ab genes for evidence of sequence-specific target preferences. Our analysis was confined to noncoding segments of V genes so that the intrinsic characteristics of the somatic mutation process could be reliably dissociated from the indirect but substantial influences of cellular selection. We consistently observed that some dinucleotides, GC and TA in particular, mutated at frequencies that were higher than expected based on their frequency of occurrence. Most of the dinucleotide mutation preferences could not be extrapolated directly from mononucleotide mutation preferences. Specific trinucleotides, including AGC, TAC, and their inverse repeats (GCT, GTA), also mutated more frequently than expected. These and other mutation characteristics were virtually indistinguishable in V genes of normal and autoreactive B cells. An analysis of mutations in published flanking sequences confirmed the target preferences, as did an examination of reported "hot spots" within coding V sequences. The shared preferences in coding and noncoding regions of V genes suggests that somatic mutations are generated de novo. Collectively, our findings indicate that the somatic mutation process exhibits sequence-specific preferences, consistent with an untemplated mechanism, and appears to operate similarly in normal and autoreactive B cells.
Mucosal IFN-gamma gene transfer inhibits pulmonary allergic responses in mice.
Authors: Li X M , Chopra R K , Chou T Y , Schofield B H , Wills-Karp M , Huang S K 
Published: January 2023

Abstract
Th2 cytokines are associated with the airway inflammation and hyperreactivity in allergic asthma and are potential targets for developing novel therapies. The efficacy of a mucosal cytokine-gene transfer approach was examined in a mouse model for allergic asthma. We showed first that mucosal IFN-gamma gene transfer results in a significant expression of IFN-gamma in the pulmonary epithelium. Significantly, this approach inhibits both Ag- and Th2-cell-induced pulmonary eosinophilia and airway hyperreactivity. These findings suggest that mucosal IFN-gamma gene transfer is effective in modulating pulmonary allergic responses and provides a basis for developing a novel therapeutic approach.
Residues critical for H-L disulfide bond formation in human IgA1 and IgA2.
Authors: Chintalacharuvu K R , Morrison S L 
Published: January 2023

Abstract
There are two subclasses of human IgA, IgA1 and IgA2. IgA2 exists as two known allotypes, IgA2 m(1) and IgA2 m(2) with a recently reported novel IgA2 (IgA2(n)) possibly representing a third allotype. The variants of human IgA differ in their H and L chain disulfide-bonding pattern; in IgA1, IgA2(n), and IgA2 m(2), a disulfide bond connects a cysteine residue in CH1 of the H chain with the L chains while human IgA2 m(1) has been reported to lack a covalent bond between the H and L chains. Here we have used site-directed mutagenesis to demonstrate that Cys133 is essential for the formation of the H-L disulfide bond in IgA1. However, IgA2 m(2) and the IgA2(n) but not IgA2 m(1) form an H-L disulfide in the absence of Cys133. IgA2 m(1) differs from IgA2 m(2) and the IgA2(n) at two positions in CH1; IgA2 m(1) has Pro212 and Pro221 whereas IgA2 m(2) and the IgA2(n) have Ser212 and Arg221. Our studies demonstrate that it is the presence of Pro221 in IgA2 m(1) that interferes with the H-L disulfide in the absence of Cys133. Contrary to what has been previously reported, protein purified from culture supernatants of IgA2 m(1) show some HL, H2L2, and H4L4J, suggesting that IgA2 m(1) can exist either as a form lacking H-L disulfide bonds or as a form with H-L disulfides.
HMG box-activating factors 1 and 2, two HMG box transcription factors that bind the human Ig heavy chain enhancer.
Authors: Stevens S , Ordentlich P , Sen R , Kadesch T 
Published: January 2023

Abstract
We present the isolation of two cDNAs that encode distinct, yet related, proteins that bind the HE2 region of the human Ig heavy chain (IgH) enhancer. Designated HMG box-activating factors (HAF) 1 and 2, the two proteins are new members of the HMG box family of DNA binding proteins. Both are potent transcription activators when expressed 1) as GAL4 fusions targeted to promoters containing GAL4 operators, or 2) as intact proteins targeted to minimal promoters containing binding sites derived from the IgH enhancer. HAF-1 and HAF-2 mRNAs are apparently expressed in both B cells and non-B cells. However, activity generated by the isolated HE2 region in B cells is dependent on both an intact HAF-1/HAF-2 binding site and at least one additional site that has been reported previously to bind a B cell-restricted protein. Our results suggest a collaborative role for either or both HAF-1 and HAF-2 in establishing the B cell activity of the human IgH enhancer.
Induction of antigen-specific tolerance for the treatment of ongoing, relapsing autoimmune encephalomyelitis: a comparison between oral and peripheral tolerance.
Authors: Kennedy K J , Smith W S , Miller S D , Karpus W J 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune demyelinating disease of the central nervous system that serves as an animal model for multiple sclerosis. Various forms of Ag-specific tolerance have been used prophylactically to prevent development of acute EAE. Here we compare the induction of Ag-specific tolerance using two regimens, proteolipid protein 139-151 (PLP139-151) peptide-coupled splenocytes and oral administration of PLP139-151, for efficacy in the reduction of established, chronic clinical EAE. PLP139-151-coupled splenocytes and not oral administration of PLP139-151 was able to down-regulate established EAE, including subsequent relapses. PLP139-151 peptide-coupled splenocytes were effective at reducing Ag-specific T cell proliferation and IL-2 and IFN-gamma production, while concomitantly increasing IL-4 production. Oral administration of PLP139-151 did not reduce IL-2 or IFN-gamma production and appeared to increase Ag-specific T cell proliferation. Neither multiple high nor low doses of PLP139-151 were effective at decreasing ongoing clinical EAE or PLP139-151-specific IL-2 and IFN-gamma production. These results suggest that PLP139-151 peptide-induced tolerance is an efficacious treatment for ongoing, R-EAE when the peptide is coupled to chemically fixed splenocytes and not when given orally.
Role of adhesion molecules of the selectin-carbohydrate families in antibody-dependent cell-mediated cytoxicity to schistosome targets.
Authors: Trottein F , Nutten S , Papin J P , Leportier C , Poulain-Godefroy O , Capron A , Capron M 
Published: January 2023

Abstract
The role of adhesion molecules in antibody-dependent cell-mediated cytotoxicity (ADCC) of macrophages toward the extracellular parasite Schistosoma mansoni was investigated by using 1) a panel of blocking mAbs directed against adhesion molecules and 2) different soluble ligands as candidate inhibitors of ADCC. The results show that the beta2-integrin Mac-1 (CD11b/CD18), L-selectin (CD62-L), and the carbohydrate determinant sialyl Lewis(x) (sLe(x); sCD15) are required for macrophage effector function toward schistosomula targets. On the other hand, the parasite counter-receptors involved in ADCC were found to share common motifs with the mammalian selectin-carbohydrate families. One family of parasite receptor(s) involved in ADCC carries the Lewis(x) (Le(x); CD15) carbohydrate structure, whereas a second family of receptor(s) appears to display selectin-like properties with affinity for the sLe(x) tetrasaccharide. Immunostaining experiments confirmed that schistosomula express on their surface hostlike molecules recognized by anti-Le(x) (CD15) and by anti-human E-selectin (CD62-E) mAbs. The double receptor-ligand interaction between macrophages and parasite targets provides new insights into the biologic roles of selectins and Le(x)-related structures in immunity against helminthic parasites.
Activation and migration of CD8 T cells in the intestinal mucosa.
Authors: Kim S K , Reed D S , Heath W R , Carbone F , Lefrançois L 
Published: January 2023

Abstract
The activation of CD8 T cells was studied using transgenic mice expressing an MHC class I-restricted OVA-specific TCR (OT-I). Immunization of OT-I mice resulted in activation of lymph node T cells and up-regulation of expression of B220, CD11a, and CD44 and caused a preferential loss of mucosal-type T cells from the periphery. Immunization induced dramatic changes in intestinal lymphocytes, including the appearance of a CD11a high population that resembled peripheral T cells and induced a primary cytolytic response. Activation of adoptively transferred OT-I cells induced migration of CD8 T cells into the lamina propria and intraepithelial lymphocyte compartments. The results suggest that Ag presentation in the intestinal epithelium occurs, and that CD8 cells activated in the periphery can readily enter the mucosa during an ongoing immune response.
The orientation of a T cell receptor to its MHC class II:peptide ligands.
Authors: Hong S C , Sant'Angelo D B , Dittel B N , Medzhitov R , Yoon S T , Waterbury P G , Janeway C A 
Published: January 2023

Abstract
The TCR found on CD4 T cells recognizes peptides bound to self MHC class II molecules as well as non-self MHC class II molecules. We have used the receptor on a cloned T cell line called D10.G4.1 (D10) to perform a structure-function analysis of this interaction. The D10 T cell clone recognizes not only a peptide from conalbumin (CA-wt) bound to syngeneic I-Ak against which it was raised, but also the allogeneic MHC molecules I-A(b,v,p,q,d). In the present study, we show that residue 30 in complementarity-determining region 1 (CDR1) of the TCR alpha-chain interacts with the I-A alpha-chain at hvr2 (residues 52, 53, and 55). We also show that residue 51 in CDR2 of the TCR alpha-chain interacts with the peptide at peptide residue 2. Finally, we show that residue 29 in CDR1 of the TCR beta-chain affects recognition of the glutamic acid at residue 66 in the I-A beta-chain. These data suggest an orientation of TCR relative to its peptide:MHC class II ligands. We argue that this orientation will be shared by all CD4 TCRs, and that it is only subtly different from the common orientation proposed for receptors binding to MHC class I.
Syk-independent tyrosine phosphorylation and association of the protein tyrosine phosphatases SHP-1 and SHP-2 with the high affinity IgE receptor.
Authors: Kimura T , Zhang J , Sagawa K , Sakaguchi K , Appella E , Siraganian R P 
Published: January 2023

Abstract
Aggregation of the high affinity IgE receptor (Fc epsilonRI), a member of the immune receptor family, results in the activation of protein tyrosine kinases and downstream signaling pathways. The two cytoplasmic Src homology 2 domain-containing protein tyrosine phosphatases, SHP-1 (also called SH-PTP1, PTP1C or HCP) and SHP-2 (also known as SH-PTP2, PTP1D, PTP2C, or Syp), are expressed in the RBL-2H3 rat mast cell line. Here we report that aggregation of Fc epsilonRI induced the tyrosine phosphorylation of both SHP-1 and SHP-2. This phosphorylation was independent of the presence of the protein tyrosine kinase Syk. Both SHP-1 and SHP-2 associated with Fc epsilonRI. Whereas SHP-1 was constitutively associated with the receptor, SHP-2 coprecipitated with Fc epsilonRI only after receptor aggregation. Fusion proteins containing either the full-length or the Src homology 2 domains of SHP-2 directly bound to the tyrosine-phosphorylated beta, but not the gamma, subunit of Fc epsilonRI. In the reciprocal experiments, synthetic phosphorylated peptides based on the immunoreceptor tyrosine-based activation motif of the beta, but not the gamma, subunit precipitated SHP-2. In contrast, neither fusion proteins nor synthetic peptides detected interaction between SHP-1 and Fc epsilonRI. In vitro, both SHP-1 and SHP-2 dephosphorylated tyrosine-phosphorylated beta and gamma subunits of Fc epsilonRI. Therefore, SHP-1 and SHP-2 associate with Fc epsilonRI by different mechanisms and can regulate the extent of the tyrosine phosphorylation of the receptor subunits. Thus, unlike other immune cells in which inhibitory molecules are recruited by accessory proteins, Fc epsilonRI bind molecules that both activate and inhibit signal transduction.