bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of thyroiditis in mice with thyrotropin receptor lacking serologically dominant regions
Authors: Wang S H , Carayanniotis G , Zhang Y , Gupta M , Mcgregor A M , Banga J P 
Published: March 2003

Abstract
Grave's disease (GD) is characterized by pathogenic autoantibodies to the human thyrotropin receptor (hTSH-R), and is frequently associated with a lymphocytic infiltrate of the thyroid gland. In attempts to establish a murine model of GD, we and others have previously shown that immunization of mice with recombinant preparations of the hTSH-R ectodomain induces high titres of specific antibodies, which, however, are not pathogenic, nor is the response accompanied by the development of thyroiditis. Since earlier reports identified the serological immunodominant determinants within the N- and C-terminal regions of hTSH-R ectodomain, we reasoned that immunization of mice with truncated fragments of ectodomain lacking these dominant regions might result in skewing of the response to other determinants of the molecule, with consequent induction of immunopathological features present in GD. We show here that multiple challenge of BALB/c mice with an amino acid fragment of residues 43–282 generates antibodies directed at hTSH-R peptides 37–56, 157–176, 217–236 and 232–251. This reactivity pattern is distinct from that induced previously with the whole ectodomain of hTSH-R in BALB/c animals. Thyroid function remained unaffected in these mice, suggesting that pathogenic antibodies were not being induced. Interestingly, some animals developed lymphocytic infiltration of the thyroid gland, clearly indicating the presence of pathogenic T cell determinants within the 43–282 fragment. Challenge with the related fragment 43–316 produced the same pattern of serological response to the synthetic peptides as fragment 43–282, but was not accompanied by thyroiditis. The results demonstrate: (i) the presence of thyroiditogenic determinants within hTSH-R, and (ii) that these pathogenic determinants are likely to be cryptic, as their effect is exhibited only when the hierarchy of immunodominance within hTSH-R is drastically altered.
Cytokine-stimulated release of decay-accelerating factor (DAF; CD55) from HT-29 human intestinal epithelial cells
Authors: Nasu J , Mizuno M , Uesu T , Takeuchi K , Inaba T , Ohya S , Kawada M , Shimo K , Okada H , Fujita T , Tsuji T 
Published: March 2003

SUMMARYExpression of DAF (CD55) is enhanced on colonic epithelial cells of patients with ulcerative colitis (UC), and stool DAF concentrations are increased in patients with active disease. Cytokines are known to modulate DAF expression in various human cells, and lesions of UC reveal altered profiles of cytokine production. In this study, we evaluate the effects of various cytokines, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, and interferon-gamma (IFN-γ), on the synthesis and kinetics of DAF protein in HT-29 human intestinal epithelial cells. Using flow cytometry and an ELISA, we found that HT-29 cells constitutively express DAF on the cell surface and spontaneously release DAF into the culture supernatant under standard culture conditions. When the culture supernatant was centrifuged at 100 000 g, nearly a half of DAF was precipitated, indicating that one half of the released DAF was present as a membrane-bound form and the other half as a soluble form. Analysis of the culture supernatant of biotin surface-labelled HT-29 cells suggested that the soluble form DAF was derived by secretion from within the cell or by cleavage from the cell surface. Among the cytokines, IL-4 markedly, and IL-1β moderately, enhanced the expression and the release of DAF. Actinomycin D, cycloheximide, and brefeldin A inhibited the increase in DAF release induced by IL-4 and IL-1β stimulation. These results suggest that DAF is released from intestinal epithelial cells in response to cytokine stimulation and that IL-4 and IL-1β are possible cytokines involved in DAF release into the colonic lumen of patients with UC.
Cytokine production by CD4 and CD8 T cells during the growth ofMycobacterium tuberculosisin mice
Authors: Howard A D , Zwilling B S 
Published: March 2003

SUMMARYChanges in the pattern of cytokines found in CD4 and CD8 T cells during the growth of Mycobacterium tuberculosis that resulted in the establishment of a latent infection were monitored. Subsets of T cells were identified based on their differential expression of CD45 and CD44 which allowed them to be classified as naive, activated or memory. We found that the T cells in the lung produced a predominantly type 1 cytokine response. The appearance of large numbers of Th1 cells coincided with the establishment of latency. In contrast, the predominant response in the mediastinal lymph node and spleen was a Th2-type response.
Evidence of idiotypic modulation in the immune response to gp43, the major antigenic component ofParacoccidioides brasiliensisin both mice and humans
Authors: Souza A R , Gesztesi J-L , Moraes J Z , Cruz C R B , Sato J , Mariano M , Lopes J D 
Published: March 2003

SUMMARYParacoccidioidomycosis (PCM) is a systemic mycosis endemic in Latin America, with a high prevalence in Brazil, Argentina, Colombia and Venezuela. The aetiologic agent of disease is a thermal dimorphic fungus, Paracoccidioides brasiliensis. A glycoprotein of 43 000 D (gp43) is the major antigen of P. brasiliensis. Antibodies directed to this antigen are detected in the sera of all patients with PCM. Gp43 binds to laminin, thus participating in adhesion, invasion and pathogenesis of the fungus. As the role of antibodies in PCM is not fully understood, we decided to investigate the outcome of mice immunization with three distinct anti-gp43 MoAbs (17c, 8a and 24a) coupled with keyhole limpet haemocyanin (KLH). Results show not only the expected presence of anti-Id (AB2) antibodies in the sera of these animals but also a spontaneous and increasing amount of anti-anti-Id (AB3) antibodies after the third course of immunization. Hybridomas producing both AB2 and AB3 MoAbs were obtained using spleen cells from mice immunized with MoAb 17c. AB3 MoAbs were also obtained with spleen cells of mice immunized with MoAbs 8a and 24a. It was also shown that human PCM patients' sera with high titres of anti-gp43 antibodies generate anti-Id antibodies. These data suggest that the immune response to P. brasiliensis can be spontaneously modulated by the idiotypic network.
Differential production of IL-10 by T cells and monocytes of HIV-infected individuals: association of IL-10 production with CD28-mediated immune responsiveness
Authors: Kumar A , Angel J B , Daftarian M P , Parato K , Cameron W D , Filion L , Diaz-Mitoma F 
Published: March 2003

SUMMARYImmune unresponsiveness in HIV-1 infection can result from impaired signals delivered by the costimulatory CD28-B7 pathway and the altered production of immunoregulatory cytokines, in particular IL-10, whose production is altered in HIV-1 infection. In this study we investigate IL-10 regulation in T cells and monocytes from HIV+ individuals, and its association with CD28-mediated T cell proliferation. IL-10 production as analysed in T cell- and monocyte-depleted peripheral blood mononuclear cells (PBMC), and by intracellular staining at the single-cell level, reveals a defect in IL-10 production by CD4+ and CD8+ T cells, whereas monocytes constitute the major IL-10-producing cell type. To investigate the impact of IL-10 on immune responsiveness, CD28-mediated proliferative responses in HIV+ individuals were correlated with PHA-induced IL-10 production. CD4+ T cells expressed CD28, yet exhibited markedly reduced CD28-mediated cell proliferation. This CD28-mediated CD4+ T cell proliferation was found to be inversely associated with the levels of PHA-induced IL-10 production and could be restored, at least in part, by anti-IL-10 antibodies. These results suggest that IL-10 production is differentially regulated in T cells and monocytes of HIV+ individuals, and that IL-10 may have a role in inducing immune unresponsiveness by modulating the CD28-B7 pathway.
T lymphocytes are not the target for estradiol-mediated suppression of DTH in reconstituted female severe combined immunodeficient (SCID) mice
Authors: Taube M , Svensson L , Carlsten H 
Published: March 2003

SUMMARYOestrogen has the capacity to suppress T cell-dependent DTH. To explore the mechanisms whereby oestrogen exerts its effects on the immune system we have used SCID mice which are largely devoid of functional T and B lymphocytes, hence being unable to raise DTH, but display intact antigen-presenting capacity. Transfer of lymphocytes to SCID mice restores the DTH capacity. In order to analyse if oestrogen down-regulates DTH by a direct action on T cells we reconstituted SCID mice with either splenocytes or thymocytes from congenic C.B-17 or allogeneic B6 donor mice. Either donor or recipient mice were exposed to estradiol before cell transfer. DTH response was registered in recipient SCID mice 1 and 3 weeks after challenge with oxazolone (OXA). SCID mice receiving estradiol-exposed spleen cells from congenic or allogeneic donor mice displayed lower DTH responses compared with control mice. In contrast, SCID mice receiving estradiol-exposed thymocytes from congenic donor mice showed no significant difference in DTH response compared with control mice. Estradiol-treated SCID mice, transferred with either spleen cells or thymocytes from congenic, hormonally non-treated donors, displayed a significantly lower DTH response compared with control mice. In contrast, estradiol-treated SCID mice receiving hormonally non-treated allogeneic spleen cells showed no difference in DTH response compared with control mice. The results show that T lymphocytes are not the target cell population for estradiol-mediated suppression of DTH in reconstituted female SCID mice.
Sequence analysis of V4–34-encoded antibodies from single B cells of two patients with systemic lupus erythematosus (SLE)
Authors: Mockridge C I , Chapman C J , Spellerberg M B , Sheth B , Fleming T P , Isenberg D A , Stevenson F K 
Published: March 2003

SUMMARYSLE is an autoimmune disease characterized by the presence of autoantibodies against double-stranded (ds)DNA. A large proportion (approx. 40%) of patients with lupus also have increased levels of serum immunoglobulin encoded by the V4–34 heavy chain gene, which often fluctuate with disease activity, and this gene is utilized by a subset of anti-dsDNA antibodies. In order to probe the nature of the V4–34-encoded immunoglobulin, B cells were isolated from the blood of two patients with active disease, using the 9G4 MoAb specific for the immunoglobulin gene product. Following cell picking, single-cell polymerase chain reaction (PCR) amplification of cDNA was used to investigate both VH and VL genes. Sequences were obtained from B cells synthesizing IgM (n = 10), IgG (n = 4) and IgA (n = 1). For VH, all were derived from V4–34 as expected, and the isotype-switched sequences and 2/6 IgM sequences were somatically mutated. In contrast, VL (12 κ and 3 λ) showed a low level of mutation, possibly indicating secondary rearrangements. The three most highly mutated VH sequences were associated with unmutated VL sequences. Analysis of the distribution of mutations revealed only minor clustering in complementarity-determining regions (CDRs) characteristic of antigen selection. The CDR3 lengths of VH ranged from five to 19 amino acids, and in 3/15 there was evidence of an excess of positively charged amino acids, compared with the normal expressed repertoire. Basic amino acids were also found at the VL–JL junctions in 4/15. These findings provide insight into the V4–34–VL gene combinations used by B cells in patients with SLE which might have clinical relevance.
Mercury-induced autoimmunity in the absence of IL-4
Authors: Bagenstose L M , Salgame P , Monestier M 
Published: March 2003

SUMMARYIn susceptible H-2s mice, mercuric chloride (HgCl2) induces an autoimmune syndrome characterized by production of anti-nucleolar antibodies (ANoA) and increased serum levels of IgG1 and IgE antibodies. The increase in serum IgG1 and IgE, which are under IL-4 control, suggests a role for the Th2 subset in the induction of this syndrome. We have previously shown that administration of IL-12, a potent Th1-promoting cytokine, resulted in a dramatic reduction of the HgCl2-induced anti-nucleolar antibody titres and inhibited serum IgG1 increase. These results suggest that Th1 T cells can down-regulate ANoA, and support a role for the Th2 subset in ANoA production, possibly via IL-4. To examine the role of IL-4 in this syndrome, C57Bl/6 mice (H-2b) with a targeted deletion of the IL-4 gene were mated with A.SW mice (H-2s) to yield H-2s mice lacking IL-4. We then analysed ANoA and serum immunoglobulin levels in these mice after HgCl2 treatment. While mercury-treated IL-4−/− H-2s mice had virtually no detectable serum IgG1 or IgE, and very low levels of IgG1 ANoA, these mice had levels of IgG2a and IgG2b class ANoA comparable to mercury-treated IL-4+ H-2s mice, indicating that IL-4 is not required for the ANoA response in mercury-induced autoimmunity.
Whole virus influenza vaccine activates dendritic cells (DC) and stimulates cytokine production by peripheral blood mononuclear cells (PBMC) while subunit vaccines support T cell proliferation
Authors: Saurwein-Teissl M , Zisterer K , Schmitt T L , GLÜck R , Cryz S , Grubeck-Loebenstein B 
Published: March 2003

SUMMARYThree types of trivalent influenza vaccines were analysed for their in vitro stimulatory properties on immune cells from young healthy volunteers. A whole inactivated virus (WV) vaccine, a conventional subunit (c-SU) preparation and a new virosomal subunit (v-SU) vaccine were used. Blood-derived DC up-regulated MHC class II, CD54, CD80 and CD86 after exposure to WV vaccine, indicating their functional maturation, but were only moderately affected by subunit (SU) vaccines. In addition, IL-12 and tumour necrosis factor-alpha (TNF-α) secretion by DC were markedly enhanced by WV, but not by SU vaccines. The production of IL-2 and interferon-gamma (IFN-γ) by PBMC was also strongly stimulated by WV, but much less by SU vaccines, among which the v-SU vaccine was a better stimulator of IL-2 secretion. In contrast to WV vaccine both SU vaccines were powerful stimulators of PBMC proliferation. Our results suggest that the presence of influenza core components leads to the activation of DC and triggers the production of cytokines by PBMC. SU vaccines are in contrast excellent stimulators of T cell growth. A combination of WV and SU vaccines in immunization regimes might allow optimal T cell priming as well as the efficient generation and maintenance of memory cells.
The immunosuppressive activity ofAscaris suumis due to high molecular weight components
Authors: Faquim-Mauro E L , Macedo M S 
Published: March 2003

SUMMARYThe role of isolated components obtained by gel filtration chromatography of Ascaris suum body extract (Asc) on the modulation of the immune response to ovalbumin (OvA) was evaluated and correlated with the immunogenic properties of such components. We showed that high (PI), but not low (PIII), molecular weight components have the ability to inhibit OvA-induced immediate and DTH reactions, lymph node (LN) cell proliferation, cytokine (IL-2, interferon-gamma (IFN-γ), IL-4 and IL-10) and antibody (IgG1, IgG2a, IgM and IgE) production in mice concomitantly immunized with OvA and these high mol. wt components. The pattern of cytokines synthesized in response to PI or PIII was totally different: the former induced more IL-4 and IL-10 and the latter more IL-2 and IFN-γ. The levels of Asc-specific IgG1 antibodies were higher in mice immunized with OvA plus PI and IgG2a anti-Asc antibodies predominated in those immunized with PIII. IgE antibody production, however, was low in the former group of mice. These results indicate that the high mol. wt components present in the body extract from the helminth A. suum are responsible for its suppressive effect upon Th1- and Th2-dependent immune responses to an unrelated antigen. The suppression of the Th1-dependent parameters could be related to high-level expression of IL-4 and IL-10 induced by such components.
Ro/SS-A-reactive B lymphocytes in salivary glands and peripheral blood of patients with Sjögren's syndrome
Authors: HALSE A-K , HARLEY J B , KRONELD U , JONSSON R 
Published: March 2003

SUMMARYThe aim of this study was to investigate the production of anti-Ro/SS-A antibodies in labial salivary glands (LSG) and peripheral blood (PB) of Sjögren's syndrome (SS) patients. The ELISPOT method was performed to quantify the frequency of LSG lymphocytes and PB lymphocytes spontaneously secreting anti-Ro/SS-A antibodies. The total number of IgG-, IgA- and IgM-producing cells was also quantified. The bovine Ro 60-kD protein was used as target antigen. Six of six primary SS patients had LSG B cells producing anti-bovine Ro 60 kD of the IgG isotype, and two of two primary SS patients had in addition PB lymphocytes producing anti-bovine Ro 60 kD of the IgG isotype. The six patients who had IgG antibodies against the Ro/SS-A antigen in LSG all had focus scores of ≥ 7 in biopsies of LSG. The results indicate that SS patients with a high degree of local inflammation in LSG have B cells producing anti-Ro/SS-A antibodies in both LSG and PB. Thus, the anti-Ro/SS-A antibodies may have pathogenic importance in the progression of the exocrinopathy of SS.
Molecular chaperones are targets of autoimmunity in Ro(SS-A) immune mice
Authors: KINOSHITA G , PURCELL A W , KEECH C L , FARRIS A D , McCLUSKEY J , GORDON T P 
Published: March 2003

SUMMARYWe have used a murine model of experimental anti-Ro(SS-A) autoimmunity to dissect additional intermolecular interactions between the 52-kD Ro (Ro52) and 60-kD Ro (Ro60) autoantigens and molecular chaperones. Immune responses to members of the heat shock protein hsp70 and hsp90 families were measured by immunoblotting and ELISA in sera from mice immunized and boosted with purified recombinant Ro52, Ro60 and La (SS-B). All Ro52 and Ro60 immune sera immunoblotted the inducible glucose-regulated protein grp78 and hsp70 species but not constitutive hsc70 or hsp90. The kinetics of antibody production and reciprocal affinity purification experiments indicated that the grp78 and hsp70 responses were cross-reactive but distinct from immune responses to the primary Ro52 and Ro60 immunogens and the endoplasmic reticulum (ER)-resident chaperone calreticulin. No responses to molecular chaperones were detected in the La-immunized mice. Control immunizations indicated that the recruited grp78 and hsp70 responses were specific for the Ro proteins and not due to immunization with denatured protein. The rapid spreading of immunity to the inducible grp78 and hsp70 in Ro52- and Ro60-immunized mice suggests that these components may co-localize and physically associate under certain physiological conditions which may promote autoimmunization. The potential importance of the ER-resident chaperones grp78 and calreticulin is further supported by their co-localization with Ro in small apoptotic membrane blebs and the finding of a novel putative grp78 binding motif in the carboxyl-terminal region of Ro52.
HLA-DMB expression by thyrocytes: indication of the antigen-processing and possible presenting capability of thyroid cells
Authors: WU Z , BIRO P A , MIRAKIAN R , HAMMOND L , CURCIO F , AMBESI-IMPIOMBATO F S , BOTTAZZO G F 
Published: March 2003

SUMMARYExpression of HLA class II molecules on thyrocytes is a characteristic feature of autoimmune thyroid disease and may lead the thyroid cells to present autoantigens to CD4+ T lymphocytes. Since HLA-DM is a critical molecule in class II-restricted antigen processing and presentation, we assessed the expression of HLA-DMB, -invariant chain (Ii), class II transactivator (CIITA) and DRA in an untransformed, pure thyrocyte strain HTV-59A. Here we report that both HLA-DMB mRNA and the protein are expressed in thyrocytes and that CIITA expression is enhanced by interferon-gamma (IFN-γ) treatment and occurs before DMB, Ii and DRA up-regulation, suggesting CIITA expression is a requirement for antigen processing in thyrocytes. These results indicate that thyrocytes are capable of antigen processing and possibly antigen presentation to T cells.
Active suppression in orally tolerized rats coincides within situtransforming growth factor-beta (TGF-β) expression in the draining lymph nodes
Authors: LUNDIN B S , KARLSSON M R , SVENSSON L A , HANSON L Å , DAHLGREN U I H , TELEMO E 
Published: March 2003

SUMMARYAdult rats were fed pellets containing ovalbumin (OvA) during 4 weeks, and were 2 weeks thereafter immunized subcutaneously with a mixture of OvA and human serum albumin (HSA) in Freund's complete adjuvant (day 0). As a result of the immunization, the draining lymph nodes of the non-tolerized (control) rats were heavily enlarged from day 10 to day 18; however, this size increase was absent in the OvA-fed rats. This manifestation of active suppression in the tolerized rats was preceded by the appearance of scattered CD4+ TGF-β-expressing T cells in the T cell area of their lymph nodes (days 5–8); correspondingly, the levels of TGF-β mRNA in the nodes were elevated in the tolerant rats compared with the control rats. The anti-OvA antibody levels in sera from the rats revealed that there was an initial B cell priming in the OvA-fed group, with levels higher than in the control group during the first week. Thereafter, suppression governed the response, and from day 10 onwards the anti-OvA levels were considerably lower than in the controls. When other groups of animals were pretreated with neutralizing anti-TGF-β antibodies 1 day before the immunization, the anti-OvA response of the OvA-fed rats was restored to the levels of the control group, demonstrating the importance of TGF-β in the maintenance of suppression. In conclusion, we demonstrate that TGF-β-producing cells appear in the draining lymph nodes shortly after immunization in rats made orally tolerant using a relatively high-dose feeding regime; these cells are probably responsible for the down-regulation of the immune response observed in the OvA-fed rats.
AsymptomaticBorrelia-seropositive individuals display the same incidence ofBorrelia-specific interferon-gamma (IFN-γ)-secreting cells in blood as patients with clinicalBorreliainfection
Authors: EKERFELT C , FORSBERG P , SVENVIK M , ROBERG M , BERGSTRÖM S , ERNERUDH J 
Published: March 2003

SUMMARYBorrelia Lyme disease is a complex disorder that sometimes becomes chronic. There are contradictory reports of experimental Borrelia infections regarding which type of T cell cytokine responses, i.e. Th1 or Th2, are needed to eradicate the Borrelia spirochaetes. In human borreliosis a predominance of Borrelia-specific Th1-like responses has been shown. In this study, spontaneous, as well as Borrelia-specific, secretion of IFN-γ (Th1) and IL-4 (Th2) in Borrelia-seropositive healthy asymptomatic individuals (n = 17) was investigated in peripheral blood by a sensitive ELISPOT assay, and compared with previously reported responses in patients with clinical Borrelia infection (n = 25). The seropositive asymptomatic individuals displayed the same predominance of Borrelia-specific IFN-γ-secreting cells as the patients with clinical Borrelia infection. Interestingly, the proportion of spontaneously IL-4-secreting cells, reflecting the unstimulated in vivo secretion, was lower in the seropositive asymptomatic individuals compared with patients with chronic Borrelia infections (n = 13, P = 0.02), whereas no such difference was found compared with subacute Borrelia infections (n = 12). These findings indicate that IFN-γ secretion alone is not sufficient to eliminate Borrelia spirochaetes in humans, although IFN-γ may still have a beneficial role in borreliosis acting in concert with other mechanisms.