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Biomedical subjects

E Möller

Publications and source records attributed to E Möller.

At least 37 records · Page 2Linked to original sources
PubMed1998

Autoantibody patterns in synovial fluids from patients with rheumatoid arthritis or other arthritic lesions.

Patients with rheumatoid arthritis (RA) produce a variety of autoantibodies, not only demonstrable in the circulation, but also locally in the inflamed joint. We investigated the local production of several autoantibodies in the synovial fluid (SF) of 24 patients with RA and of 26 patients with other arthritic lesions. RA patients had higher titres of immunoglobulin M (IgM) and immunoglobulin G (IgG) rheumatoid factors (RFs) and of collagen type II antibodies in SF, whereas there were no demonstrable differences between groups with regard to antibodies against double-stranded (ds) DNA, C1q or the hapten 2,4,6-trinitrobenzene sulfonic acid (TNP). No differences were observed for total synovial levels of IgM or IgG. There was no autoantibody pattern that was typical of RA patients, except for the local presence of RF, primarily in seropositive RA patients. Our findings therefore support the notion that RF and collagen type II antibodies are induced by immunogenic material present in the local inflamed environment. In the accompanying paper we studied various synovial fluid cytokines in the same patient groups. Here we correlated the level of these cytokines with autoantibody titres in SF, but no specific cytokine associated with the production of RF was found. Hence, we conclude that several different inflammatory mediators might contribute to the chronic inflammation and autoantibody production in the joint of RA patients. An inverse correlation was established between concentrations of tumour necrosis factor-alpha (TNF-alpha) and levels of total IgG.

Adult↗
PubMed1998

Cytomegalovirus DNA can be detected in peripheral blood mononuclear cells from all seropositive and most seronegative healthy blood donors over time.

BACKGROUND: A poor correlation between cytomegalovirus (CMV) seroreactivity and the risk of CMV transmission prompted an investigation of the presence of CMV DNA in peripheral blood mononuclear cells (PBMNCs) from seropositive and seronegative blood donors. Because latent CMV exists in monocytes, monocyte-enriched cells were analyzed separately. STUDY DESIGN AND METHODS: Samples from 270 blood donors were tested with a sensitive polymerase chain reaction (PCR) test that detects two CMV genes, and the results were correlated to CMV serology. Cross-reactivity with other herpesvirus genes was not recorded. RESULTS: PCR testing demonstrated that 71 percent of seropositive donors harbor CMV in PBMNCs. Thus, not all seropositive donors were CMV DNA positive when individual samples were tested. Tests repeated over a period of time showed that all seropositive individuals were positive. Increased sensitivity was obtained with enriched monocytes. Among seronegative donors, 55 percent harbored CMV DNA in monocyte-enriched PBMNCs, while 14 percent had CMV DNA in PBMNCs. CONCLUSION: All seropositive donors harbored latently infected PBMNCs, as demonstrated by the testing of samples collected over time. In addition, a substantial proportion of seronegative individuals are CMV carriers and might transfer infection. The findings concur with clinical evidence of CMV transmission by blood components from seronegative individuals and with in vitro reactivation of CMV in PBMNCs from seronegative donors.

Antibodies, Viral↗
PubMed1998

Human NK cell and ADCC reactivity against xenogeneic porcine target cells including fetal porcine islet cells.

In vitro studies of human NK cell-mediated cytotoxicity and ADCC against porcine target cells were performed. Stimulation of human PBMC responder cells with either allogeneic or xenogeneic porcine cells led to a marked increase in NK cell reactivity. Maximum reactivity was reached following 3-6 days of in vitro culture. The sensitivity of target cells ranked as follows: K562 > porcine PHA-induced lymphoblasts > resting porcine PBMC. Limiting dilution analysis showed that allo- and xeno-stimulation in vitro led to differentiation of similar frequencies of effector NK cells. Split culture experiments showed that single NK effector cells were cytotoxic against both K562 and porcine lymphoblasts, demonstrating that individual NK cells lack species specificity. NK effector cell generation stimulated by xenogeneic cells was cyclosporin A (CsA) sensitive and dependent on the presence of autologous responder T lymphocytes, a dependence that was completely reconstituted by the sole addition of human IL-2. Xenostimulation of enriched CD3+ cells also led to a preferential appearance of CD16+ or CD56+ lymphoblasts. Natural xenoreactive human anti-porcine antibodies are mainly of IgM and IgG2 subclasses, but antibodies in xenoimmunised patients reactive against porcine lymphocytes and fetal porcine islet cells were also of IgG1 and IgG3 subclasses. The same subclass distribution was found among antibodies specific for gal(alpha)1,3 gal epitopes as shown by tests performed with alpha1,3 galactosyltransferase-transfected Raji cells (human Burkitt lymphoma cells). Natural antibodies did not mediate ADCC, whereas gal(alpha)1,3 gal-specific antibodies in sera from xenoimmunised patients did. Fetal porcine islet cells were sensitive to human NK cell-mediated cytotoxicity and to ADCC mediated by xenoimmune sera.

Animals↗
PubMed1998

Mechanisms for induction of autoimmunity in humans.

The triggering or immunogenic stimulus for human autoimmune diseases is unknown. It is not even known whether the stimulus is endogenous, i.e. truly "self" or exogenous, "non-self". Many autoimmune diseases are human lymphocyte antigen (HLA)-associated and demonstrate linkage to the HLA chromosome in family investigations. For most of these diseases, evidence is strong that the association is directly dependent on specific HLA class I or II molecules rather than on other genes located in the HLA region. Since HLA polymorphic HLA molecules have so far only been shown to have two distinct functions, both of which are immunological, a HLA association supports the notion that a particular disease is autoimmune. Furthermore, an association to a specific HLA allele implies that the immunogenic stimulus for autoimmunity would be one specific HLA-binding peptide and that, at least initially, autoimmunity is dependent on the reactivity of one or a limited number of potentially autoaggressive T cell clones. These findings are encouraging and formin the basis for future preventive measures. One current theory is that autoimmune disease is precipitated by an environmental agent, such as a viral infection. Several different mechanisms to explain how a viral infection could induce autoimmune disease in humans are described and one specific example is presented for a virus-induced autoimmune disease in humans. The question of whether ITP could also be dependent on such a mechanism is briefly discussed.

Autoimmune Diseases↗
PubMed1997

In vitro effects of mercuric chloride (HgCl2) on human mononuclear cells.

Due to the release of the toxic compounds of mercury from amalgam fillings, dental amalgam has been questioned as an adequate restoration material for tooth fillings. HgCl2 has been found to be mitogenic for human blood lymphocytes in vitro. However, activation required much higher concentrations than are ever found in vivo. This study has been initiated to evaluate further the influence of HgCl2 on human immunocompetent cells in vitro. It is found that HgCl2 in a narrow concentration range has the ability to preferentially stimulate the CD4+ T cell subset to blast transformation and DNA synthesis. The reaction, when monitored during days 2-6, is maximal at day 6, and most blasts express the IL-2 receptor (IL-2R), indicating in vitro activation. The CD8+ T cell subset is not affected to the same extent. In addition, HgCl2-induced lymphocyte reactivity is dependent on accessory cells, i.e. CD14+ cells.

Cells, Cultured↗
PubMed1997

IgG2b inducing factor from rheumatoid arthritis synovial fluid synergizes with transforming growth factor-beta in promoting IgG2b antibody production in mouse B lymphocytes.

Rheumatoid arthritis synovial fluid (RA-SF) contains a distinct biological activity that selectively induces IgG2b production in LPS-activated murine B blasts. This IgG2b inducing factor (IgG2bIF) acts directly on purified LPS-activated B blasts from normal and Bruton's tyrosine kinase-defective CBA/N mice. In order to test the possibility that TGF-beta and IgG2bIF in RA-SF act in concert to induce IgG2b production, anti-TGF-beta monoclonal antibodies and RA-SF were added to LPS-activated CBA B blasts, which led to a marked reduction of IgG2b-producing cells. This result indicates that TGF-beta and IgG2bIF in RA-SF synergize in the induction of IgG2b production. TGF-beta antibodies do not inhibit IgG2b production in CBA/N B blasts, further substantiating our earlier notion that CBA/N B blasts have a higher endogenous production of TGF-beta after LPS stimulation, which might be responsible for the aberrant reactivity in btk deficient CBA/N mice. RA-SF is able to reconstitute the deficient IgG1 response in LPS- and IL-4-stimulated CBA/N B blasts. Addition of antibodies against TGF-beta had only a marginal effect on the IgG1 response, indicating that the reconstitution is mediated by another factor(s), which is present in RA-SF.

Animals↗
PubMed1997

IgG2b inducing factor from rheumatoid arthritis synovial fluid activates antibody production in highly purified mouse B lymphocytes.

Rheumatoid arthritis synovial fluid (RA-SF) contains a factor that induces IgG2b antibody production in LPS-stimulated murine B cells and therefore is called IgG2b inducing factor (IgG2bIF). When LPS, together with crude RA-SF or semi-purified IgG2bIF, was added to highly purified LPS-stimulated B cells, the number of IgG2b-producing cells was substantially enhanced. This shows that IgG2bIF acts directly on activated B cells, presumably by binding to a receptor expressed on LPS-activated B cells. In vivo LPS-activated B blasts were not able to respond to RA-SF unless LPS was present in vitro, showing that LPS is needed to maintain cell viability and responsiveness to the IgG2bIF. To elucidate the mechanism for the IgG2bIF effect on highly purified B cells, the IgG2b response of LPS-stimulated, Bruton's tyrosine kinase-defective, xidB blasts was studied. Purified B blasts from the btk-defective CBA/N mouse strain were sensitive to IgG2bIF. These findings show that IgG2bIF acts directly on B cells and activates cells through a btk-independent pathway.

Animals↗
PubMed1997

Primary lymphoma of the stomach: three-year results of a prospective multicenter study. The German Multicenter Study Group on GI-NHL.

BACKGROUND: In October 1992, an ongoing prospective study on primary gastrointestinal (GI) lymphoma was initiated to evaluate histological features, sites of involvement, and management. PATIENTS AND METHODS: Until May 1996, 352 patients were enrolled, with 279 being evaluable for clinical features (208 patients presented with primary gastric lymphoma). Standardized diagnostic workup included central histologic review and endoscopic and radiologic evaluation of the complete GI tract. Primary surgery or conservative management depended on the physician's decision, followed by radiotherapy with or without chemotherapy. Treatment outcome is evaluable in 122 patients with gastric lymphoma. RESULTS: In 279 evaluable patients, the distribution of NHL was as follows: stomach 74.6%, small bowel 8.6%, ileocoecal region 6.5%, multilocal GI involvement 6.8%. In gastric lymphoma, low-grade NHLs accounted for 39%. Of the remaining high-grade NHLs, 36.1% showed simultaneous low-grade components, thus being also of MALT origin. Of 208 patients with gastric NHL, 71.1% were classified as stage I and II1. CCR rate in stomach lymphoma is significantly higher compared to those of the small bowel, whereas involvement of multiple GI organs has the worst prognosis. So far only 7 patients with gastric NHL in stages I and II presented with progressive disease or relapse. Over all stages there seems to be no difference in therapeutic outcome in surgically or conservatively treated patients. Even after R0-resection in limited stages patients appear to have no better outcome. CONCLUSION: The value of surgery in treatment of primary gastric lymphoma--as favored by most authors--should be reexamined.

Adult↗
PubMed1996

Xenograft rejection of porcine islet-like cell clusters in normal and natural killer cell-depleted mice.

Fetal porcine islet-like cell clusters (ICC) were transplanted under the renal capsule of normoglycemic normal or athymic (nu/nu) C57BL/6 mice. Control animals were implanted with allogeneic minced kidney tissue from C57BL/Ks mice. The animals were killed 6 or 14 days after transplantation and the grafts were processed for flow cytometric analyses or immunohistochemistry. Xenograft destruction was evident in normal mice on day 6 after transplantation. The majority of infiltrating cells were macrophage-like cells expressing the F4/80 antigen. Lymphocytes expressing the CD3 antigen were in minority and mainly located in the peripheral parts of the ICC xenograft. The frequency and distribution of CD4+ cells were found to resemble those of the CD3+ cells. A large number of infiltrating cells, including several macrophage-like cells, expressed the Thy 1.2 antigen. Flow cytometry of infiltrating cells in the ICC xenograft revealed that approximately half of the cells expressing the F4/80 antigen also expressed Thy 1.2 and/or CD4. No cells were found expressing both the F4/80 and CD8 antigens. Both the F4/80 single-positive and the F4/80, CD4 double-positive cells were found to be larger and more granular than the CD4 single-positive cells. No co-expression of CD4 or Thy 1.2 with the F4/80 antigen was detected on cells infiltrating allogeneic tissue grafts. Moreover, a relative large number of cells (approximately 15%) in the xenograft expressed the NK 1.1 antigen as determined by flow cytometry. The role of natural killer (NK) cells in islet xenograft rejection was further evaluated in mice depleted of NK cells, using intraperitoneal injections of the monoclonal antibody NK 1.1. The simultaneous inoculation and subsequent growth of the NK cell-sensitive beta 2-microglobulin-deficient mutant, C4.4-25-, lymphoma cell line EL-4 served as an in vivo control of NK cell depletion. However, all NK cell-depleted mice rejected the ICC xenograft. In contrast, athymic mice permanently accepted the porcine ICC xenograft but, readily rejected the NK cell-sensitive lymphoma cell line. Taken together, ICC xenograft rejection in mice seems to be T cell dependent, as evidenced in the nude mice model, while the main effector cell appears to be a macrophage with a unique phenotype.

Animals↗
PubMed1996

Mercury induces polyclonal B cell activation, autoantibody production and renal immune complex deposits in young (NZB x NZW)F1 hybrids.

It is well established that in susceptible mouse strains, chronic treatment with subtoxic doses of mercuric chloride (HgCl2) induces a systemic autoimmune disease, which is characterized by increased serum levels of IgG1 and IgE antibodies, by the production of anti-nucleolar antibodies and by the development of immune complex-mediated glomerulonephritis. Susceptibility to mercury is partly under the control of major histocompatibility complex genes. To study the susceptibility to mercury further, we investigated the in vivo effects of mercury in young autoimmune disease prone (NZB x NZW)F1 (H-2d/z) mice prior to establishment of spontaneous autoimmune disease. Mercury-susceptible SJL (H-2s) mice and mercury low-responder BALB/c (H-2d) mice were used as positive and negative controls, respectively. In (NZB x NZW)F1 mice, treatment with mercury stimulated an intense antibody formation characterized by increased numbers of splenic IgG1 and IgG3 antibody-producing cells as well as by elevated serum IgE levels. Injection with mercury also induced an increased production of IgG1, IgG2b and IgE antibodies in SJL, but not in BALB/c mice. The mercury-induced IgG1 response in (NZB x NZW)F1 and SJL mice was found to be polyclonal and autoantibodies against double-stranded (ds)DNA, IgG, collagen, cardiolipin, phosphatidylethanolamine as well as antibodies against the hapten trinitrophenol were produced. In addition, SJL, but not (NZB x NZW)F1 or BALB/c mice, produced IgG1 anti-nucleolar antibodies after treatment with mercury. Further studies demonstrated that (NZB x NZW)F1 and SJL mice developed high titers of renal mesangial immune complex deposits containing IgG1 antibodies 3 weeks after injection with mercury. Thus, a mouse strain genetically prone to develop spontaneous autoimmune diseases is highly susceptible to mercury-induced immunopathological alterations.

Animals↗
PubMed1996

15-Deoxyspergualin inhibits interleukin 6 production in in vitro stimulated human lymphocytes.

Experimental data show that relatively low concentrations of 15-deoxyspergualin (DSG) inhibit the induction of cytotoxic T lymphocytes (CTL) and the generation of antibody-producing cells. Considerably higher concentrations of DSG are required to inhibit proliferative responses. In this in vitro study, the effects of DSG on CTL induction, on proliferative responses induced by different stimuli, and on the production of interleukins IL-1, IL-2 and IL-6 and IFN-gamma (gamma-interferon) were assessed and compared with the effects of CsA (cyclosporine A) and/or FK506. We confirmed the suppressive action of DSG on the generation of CTL. Quite unexpectedly, however, we found that, although DSG did not affect the proliferative response to allogeneic lymphocytes or a superantigen, it did inhibit proliferation of peripheral blood leucocytes (PBL) stimulated with Staphyloccus aureus. DSG was active even when added on day 2 of in vitro culture, suggesting that DSG does not inhibit early events. The fraction of CD3+ lymphoblasts and the CD4/CD8 ratio was lower in cells stimulated by S. aureus in the presence of DSG, showing a selective effect on CD3+CD4+ responder T lymphocytes. The proportion of IL-2 receptor (CD25) positive cells was also reduced by DSG treatment. Moreover, we found that DSG inhibited the proliferation induced by PHA (phytohaemagglutinin) but not by Con A (concanavalin A). This effect of DSG was time-dependent, since PHA induced proliferation was not affected until day 4 after stimulation, and indicated that DSG may inhibit proliferation induced via a CD2- but not via a CD3-mediated pathway. DSG did not influence the production of IL-2 or IFN-gamma or the lipopolysaccharide induced production of IL-2 or IL-6. In contrast, the production of IL-6 was inhibited when cells were stimulated by allogeneic lymphocytes, S. aureus, PHA or Con A. This suggested to us that the DSG-suppressed IL-6 production could be the basis for the other observed effects. We tried to mimic the DSG effects with antibodies and indeed found that the IL-6 specific antibodies had similar effects. Furthermore, recombinant IL-6 completely overcame the suppressive effects of DSG on S. aureus and PHA induced proliferation, whereas addition of IL-6 to DSG treated PBL only partly restored the cytotoxic activity of lymphoblasts induced by allogeneic cells. Thus, the inhibitory effect of DSG on de novo synthesis of IL-6 could explain some of its immunosuppressive effects, but additional DSG-sensitive steps are obviously involved in CTL induction and differentiation.

Antibodies, Monoclonal↗
PubMed1996

Acid treatment of lymphocytes selectively decreases the expression of HLA class I antigens: a method to confirm that a positive clinical crossmatch test was due to class I antibodies.

A rapid and reliable method for eliminating HLA class I antigens from the surface of lymphocytes without damaging the cells is described. Lymphocytes were exposed to an acid solution (pH 3.0) which selectively destroys the antigenicity of HLA class I antigens. Alloantisera containing multispecific HLA class I antibodies reacted with phosphate-buffered saline (PBS)-treated, but not with acid-treated, lymphocytes. Specificity controls included: antibodies against HLA class II antigens and CD3, CD4, CD8; markers expressed on T cells and CD19, CD23; markers expressed on B cells. No change in lymphocyte reactivity to any of these surface antigens or to autoantibodies was observed. The viability of acid-treated lymphocytes was regularly around 90%. We propose that acid-treated lymphocytes are suitable targets for determination of the sole presence of class I antibodies in crossmatch sera of patients awaiting organ transplants.

Acids↗
PubMed1996

Binding specificities of a polyreactive and a monoreactive human monoclonal IgG rheumatoid factor: role of oligosaccharides.

The immunological specificites of two human rheumatoid factor-reactive IgG monoclonal antibodies derived from unstimulated rheumatoid synovial lymphocytes have been analysed. A malaria antigen-reactive IgG monoclonal antibody from an immune donor served as a control. Purified IgG monoclonal antibody from one IgG-RF hybridoma (L1), but not from the other IgG-RF hybridoma (D1) or the anti-malaria monoclonal antibody, exhibited dose-dependent binding to multiple self and non-self antigens such as ds-DNA, cytochrome-c, bovine thyroglobulin, transferrin, cellulose and lipopolysaccharide and therefore was considered polyreactive. The immunological specificity was confirmed by inhibition experiments using the same soluble antigens as inhibitors. The polyreactivity of the IgG-RF MoAb was markedly inhibited by absorption with glycoproteins such as thyroglobulin, a commonly used target for xenoreactive natural antibodies, and cytochrome-c, indicating that the monoclonal antibody is reactive with epitopes expressed on these ligands. Since some naturally occurring antibodies are carbohydrate specific, the authors tested the IgG-RF MoAb for possible carbohydrate specificity. Absorption with certain polysaccharides containing only one or two different sugar moieties did not inhibit the binding reactivities to any of the tested antigens. Polyreactivity of the monoclonal antibody, unlike most xenoreactive natural antibodies, was not caused by reactivity with (gal alpha 1-3gal) as indicated by the remaining binding reactivity after alpha-galactosidase treatment of the antigen. Removal of the N-linked glycosylation sites within the Fc portion of target IgG markedly reduced the antibody binding. The findings suggest that the carbohydrate content of the antigen is necessary for binding of the polyreactive IgG-RF MoAb. Reactivity to carbohydrate antigens may readily explain the so-called multispecificity of certain antibodies.

Animals↗
PubMed1996

Neutralization of human cytomegalovirus by human CD13-specific antibodies.

The mechanisms of inhibition of cytomegalovirus (CMV) infection by human CD13 (aminopeptidase N)-specific antibodies were studied. These antibodies protect CD13-negative and -positive cells from CMV infection only if incubated with the virus inoculum, suggesting they bind to CMV virions. The association of a CD13-like molecule with virions was further supported by the transfer of CD13 immunoreactivity to the surface of CD13-negative cells upon binding of CMV; the binding of CD13-specific antibodies directly to the surface of CMV virions; and the presence of anti-CD13 immunoreactive bands, including one with mobility similar to that of native cellular CD13 on immunoblots of proteins of purified CMV particles. Importantly, CD13-specific antibodies neutralize CMV in urine of neonates with congenital CMV, indicating that the CD13-like molecule is associated with natural CMV and not acquired in vitro. These studies demonstrate that a CD13-like molecule is associated with CMV particles and may be important in CMV pathogenesis.

Animals↗
PubMed1996

A novel mechanism for virus-induced autoimmunity in humans.

A novel mechanism for virus-induced autoimmunity in humans is described. Infection of immunocompromised bone marrow-transplanted patients with human CMV results in the formation of autoantibodies specific for the cell-surface protein CD13 (aminopeptidase N). CD13 is present on all CMV-susceptible cells and infection can be specifically blocked by antibodies against CD13. CMV particles carry CD13, which is incorporated in the viral envelope during budding of viral nucleo-capsids into Golgi-derived vacuoles. Antibodies against CD13 are virus-neutralizing, in efficiency comparable to antibodies against viral envelope glycoproteins. Autoantibodies against CD13 are present in patients who develop chronic GVHD following allogeneic bone marrow transplantation. This lesion shows striking similarities to certain autoimmune diseases in humans, of which scleroderma is one example. In vivo binding of antibodies to tissue structures known to be targets for chronic GVHD has been demonstrated in patients with chronic GVHD. Finally, patient serum containing CD13-specific antibodies binds to skin and mucosa tissue sections in vitro, a binding which is inhibited by CD13-specific monoclonal antibodies. Thus a virus infection can activate an immune response against a specific autoantigen, providing possibilities for destruction of non-infected host cells, as originally proposed by Fujinami & Oldstone (1985), and also for the molecular mimicry model for induction of autoimmunity. Our findings lend support to the idea that inhibiting the transfer of CMV infection in bone marrow transplants will reduce morbidity and mortality from CMV infection but will also reduce the incidence of chronic GVHD. Elimination of CD13+ cells in bone marrow is not believed to interfere with the chance of recipient repopulation, and may be a way to decrease morbidity and mortality substantially following BMT. For all patients, every effort should be taken to prevent a post-BMT CMV infection in order to reduce the risk of the later development of chronic GVHD.

Animals↗