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PubMed1987

Potentiation of autoimmune response in rats infected with Toxoplasma gondii.

The influence that an infection with Toxoplasma gondii in thymus proximity produces on the autoimmune response was studied. Rats infected with 3 X 10(3) trophozoites of T. gondii in thymus proximity were immunized with 5 mg/ml of chemically modified rat male accessory glands saline extract (MRAG) and/or human serum albumin (HSA) emulsified in complete Freund's adjuvant (CFA) at 6 days after infection. A second immunization was performed 30 days later. Four experimental groups were made: group 1-rats were immunized with MRAG-CFA and HSA-CFA; group 2-rats were infected and immunized with MRAG-CFA and HSA-CFA; group 3-rats were infected and immunized with MRAG-CFA; group 4-rats were infected and immunized with HSA-CFA. The cellular immune response was evaluated at 15 days after first immunization by delayed type hypersensitivity (DTH) test and the humoral response was studied by passive haemagglutination test at 45 days after first immunization. The results indicate that the cellular and humoral immune response against MRAG were significantly potentiated in infected rats (p less than 0.02, p less than 0.05, respectively). The response to HSA did not show significant differences between the infected and uninfected groups. Concomitantly, the histopathological alterations produced by T. gondii in thymus gland were studied at 6 and 52 days after infection. Cortical depletion and presence of parasites in the thymic cortex were detected in both cases. Involution thymic was demonstrated in infected rats killed at 52 days after infection. The possible participation of the thymus gland in the enhancement of the autoimmune response to MRAG is discussed.

Animals↗
PubMed1984

Study of autoimmune response to rat male accessory glands in rats born to immune mothers.

Passive transfer of antibody across the placenta or in milk has been thought to have a regulatory effect on the immune responsiveness of young animals. The effect of maternal antibody against rat male accessory glands (MRAG) on the systemic autoimmune responses of rat kits was studied. Serum obtained during the nursing period from female rats immunized with 5 mg/0.5 ml of MRAG or human serum albumin (HSA) emulsified in Freund's complete adjuvant before and during pregnancy contained anti-MRAG or anti-HSA, respectively. Kits born to MRAG-immunized dams were intradermally immunized with 5 mg/0.5 ml of MRAG-CFA at 21 and 51 days of age. Control kits from dams immunized with 5 mg/0.5 ml of human serum albumin emulsified in Freund's complete adjuvant (HSA-FCA) were similarly immunized with MRAG-FCA. Delayed-type hypersensitivity (DTH) studied 13 days after immunization with MRAG given at 21 days of age was significantly reduced only in the male kits born to MRAG-immunized dams compared with that of male kits from HSA-immunized dams (P less than 0.005). This hyporesponsiveness was not found in female kits from dams immunized with MRAG-FCA. The titre of circulating anti-MRAG studied at 65 days of age in kits born to MRAG-immunized dams approximated that in control kits. Antibodies against MRAG passively acquired from MRAG-immunized mothers did not alter the humoral autoimmune response of their kits.

Animals↗
PubMed2005

Provision of granulocyte-macrophage colony-stimulating factor converts an autoimmune response to a self-antigen into an antitumor response.

Many tumor Ags recognized by T cells are self-Ags. Because high avidity, self-reactive T cells are deleted in the thymus, any residual self-reactive T cells existing in the periphery are likely to be low avidity and nonresponsive due to peripheral tolerance mechanisms. Activation of these residual T cells is critical for targeting tumors for immunotherapy. In this study, we studied immune responses against the murine B16 melanoma using a tyrosinase-related protein 2 (TRP-2) peptide as a model tumor/self-Ag. Our results showed that TRP-2 peptide vaccination alone elicited a weak T cell response and modestly decreased B16 lung tumor nodules. The combination of peptide vaccination and treatment with an Ab directed against the inhibitory receptor CTLA-4 enhanced the immune response against TRP-2 peptide, inducing autoimmune depigmentation and further decreasing lung tumor nodules. However, both vaccination methods failed to protect against orthotopic (s.c.) B16 tumor challenge. The addition of an irradiated GM-CSF-expressing, amelanotic tumor cell vaccine significantly delayed s.c. B16 tumor growth. Subsequent studies revealed that provision of GM-CSF increased dendritic cell numbers in lymph nodes and spleen. Furthermore, addition of CTLA-4 blockade increased the frequency of TRP-2-specific, IFN-secreting T cells in spleen and lymph nodes. Overall, our results indicate that combining enhancement of Ag presentation with removal of CTLA-4-mediated inhibition can convert a "weaker" autoimmune response into a more potent antitumor immune response.

Animals↗
PubMed2006

Natural antibody mediated innate autoimmune response.

Recent advance in autoimmunity research reveals that the innate immune system is able to recognize self-targets and initiate inflammatory response in a similar way as with pathogens. This review describes one novel example of this innate autoimmunity, ischemia-reperfusion (I/R) injury. Studies of intestinal, skeletal muscle, and heart I/R models showed that reperfusion of ischemic tissues elicits an acute inflammatory response involving serum complement system which is activated by natural IgM. The recent identification of a monoclonal natural IgM that initiates I/R led to the identification of non-muscle myosin heavy chain type II A and C as the self-targets in two different tissues. New evidence further suggests that IgM binds initially to ischemic antigen providing a binding site for mannan binding lectin (MBL) which subsequently leads to activation of complement and results in tissue injury. Therefore, natural IgM mediated innate autoimmunity is likely responsible for the detrimental consequences in ischemic diseases.

Animals↗
PubMed1992

Antigen-induced inhibition of the autoimmune response to rat male accessory glands: bone marrow dependence of the enhancement of IA+ but not IE+ antigen-presenting cells.

IE+ peritoneal cells (PC), involved in the induction of suppression of autoimmune response to rat male accessory glands (RAG), are obtained from rats 2 h after i.p. injection of a purified fraction (FI) of RAG (FI-PC2h). In contrast, IA+ PC, involved in the induction of autoimmune response to RAG, are obtained from rats 24 h after FI of RAG injection (FI-PC24h). The present report analyzes the effect of irradiation or irradiation/bone marrow reconstitution on the induction of both populations of PC. Peritoneal cell donor rats were irradiated in a telegamma therapeutic Cs137. Twenty hours later half of them were i.v. reconstituted with 40 x 10(7) bone marrow cells. Six days later rats were i.p. injected with 200 micrograms of FI of RAG and 10(7) resident PC. The PC were harvested 2 h or 24 h later. The ability of resident PC to yield IE+ FI-PC2h involved in the induction of suppression is not impaired by irradiation, but the ability of resident PC to yield IA+ FI-PC24h involved in the induction of a positive response is impaired by irradiation and restored by bone marrow reconstitution of irradiated rats. Culture of normal PC with FI of RAG for 2 h or 24 h shows a selective increase in IE+ cells able to induce suppression to RAG.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Autoimmune response to the Ro/SSA particle is directed to the human antigen.

Autoantibodies to defined cellular antigens in systemic lupus erythematosus (SLE) are usually directed to conserved epitopes on ubiquitous macromolecules including histone, Sm + nRNP (URNP particles), DNA, and La(SSB). We report here that the autoimmune response to the Ro(SSA) RNA protein particle is directed to epitopes on the human antigen which are not conserved in evolution. Ro(SSA) from bovine, rat, and mouse Ro(SSA) particles cross-react with human autoantibodies less effectively than does human Ro(SSA), and antigenically active Ro(SSA) is not detectable in chicken thymus extracts with the assays employed. These data suggest a special role for the Ro(SSA) antigen in the initiation and/or perpetuation of the anti-Ro(SSA) response in autoimmune disease.

Absorption↗
PubMed1994

Effect of aging on autoimmune response to rat male accessory glands: young, but not aged, antigen-presenting cells efficiently induce suppression in aged rats.

The present report analyzes the suppressor cell system of aged rats in an experimental model of autoimmunity to rat male accessory glands (RAG). A state of specific suppression to RAG was induced when young rats are pretreated with peritoneal cells (PC) obtained from syngeneic young rats i.p. injected 2 h previously with chromatographic fraction I (Sephadex G-100) (FI) of RAG (yFI-PC). Although the yFI-PC injection diminished the DTH in aged rats the autoimmune response remained positive. Peritoneal cells obtained from aged rats injected with FI of RAG (oFI-PC) did not suppress the DTH response in either aged or young rats. In both young and aged, pretreatment with yFI-PC stimulates spleen cells capable of inducing suppression (inductor-phase suppressor cells) when they are transferred to young recipients. However, the spleen inductor-phase suppressor cells of 12-month-old rats are unable to suppress the autoimmune response in their own aged environment. To obtain effective suppression in 12-month-old rats, the injection of yFI-PC was necessary prior to and subsequent to immunization. In this work we observe that 12-month-old rats could efficiently induce inducer phase and effector-phase suppressor cells when the adequate young antigen-presenting cells were present to stimulate them.

Aging↗
PubMed1994

Sex as a determining factor in the effect of exercise on in vivo autoimmune response adjuvant arthritis.

The present study was conducted to examine the effect of physical exercise on the development of adjuvant arthritis (AA), an animal model of the human rheumatoid arthritis, which is a T-cell-dependent autoimmune response. AA was inducted on day 0 in 8-wk-old Lewis rats of both sexes. Between postinjection days 1 and 12, two groups of rats (male and female) were trained on a treadmill every day (45-120 min/day and 15-30 m/min) before the onset of arthritic disease. Trained female (n = 27) and male (n = 22) rats and control female (n = 29) and male (n = 17) rats were observed every 2 days for the following clinical signs of AA: number of arthritic joints (swelling and redness), paw thickness, and weight gain during the disease. The results show that the incidence of arthritis (% of arthritic rats) was significantly higher in trained female rats (74%; P < 0.03) and significantly lower in trained male rats (27%; P < 0.05) compared with control rats of both sexes (female, 45%; male, 59%). There was no difference in the severity and development of the disease between trained rats and control rats of both sexes (P > 0.05). The present study indicates that the effect of exercise on the incidence of AA, an in vivo autoimmune response, depends on the sex of the animal.

Animals↗
PubMed1988

Participation of different cellular types in the enhancement of autoimmune response of old animals to sex accessory glands in male rats: importance of macrophages.

In a previous work, we showed that the immunization of male rats, 3 and 12 months old, with saline extract of rat male accessory glands chemically modified (MRAG) and human serum albumin (HSA) induced a higher humoral and cellular autoimmune response in old animals than in young ones. We have also demonstrated that the facilitation of the autoimmune response is transferred by spleen total cells of 12-month-old animals. The immune response to HSA was not modified. In this work, the cellular type involved in such facilitation was analyzed. For this transference experiment, cells enriched in T and B lymphocytes and macrophages were used. The results showed that the macrophage is the main cellular type involved. However, the transference was only total with the three cellular types together. The study, performed with macrophages pulsed in vivo with MRAG-HSA and then transferred to normal recipients, indicated that although the macrophages from young and old animals were capable of presenting the antigens, the latter did this with significantly greater efficiency for the autoantigen.

Aging↗
PubMed2004

Autoimmune responses to amyloid structures of Abeta(25-35) peptide and human lysozyme in the serum of patients with progressive Alzheimer's disease.

We have found an increased level of serum antibodies to the prefibrillar structures of both Abeta(25-35) peptide and human lysozyme in Alzheimer's disease (AD) patients compared to age-matched controls, indicating that autoimmunity is implicated in AD. In the serum of AD patients with a long-term duration (>15 years) the titer of serum antibodies to aggregates of Abeta(25-35) peptide increased by approximately 5-fold, whilst the antibody titer to lysozyme protofilaments decreased by approximately 8-fold compared to patients with AD duration of <5 years. The content of immunoglobulins of the A, G and M types declined, particularly in AD duration of >15 years. An increase in the concentration of immune complexes and higher lysozyme activity was detected in the serum of all patients and this was suggestive of an inflammatory reaction. We propose that the autoimmune response to different amyloid structures in AD can be viewed as a clearance pathway targeting amyloid development. Autoimmune response can be exploited as a marker of ongoing protein aggregation and hence be used as a diagnostic feature of AD.

Aged↗
PubMed2005

The autoimmune response to vimentin after renal transplantation in nonhuman primates is immunosuppression dependent.

BACKGROUND: Chronic allograft nephropathy (CAN) is a common late complication of kidney transplantation. Antibodies to both human leukocyte antigen and nonhuman leukocyte antigen antigens have been implicated in the development of this condition. Here we investigated the presence of antivimentin antibodies in nonhuman primate recipients of kidney allografts as a possible predictor of CAN and the effects of immunosuppression. METHODS: Thirty seven rhesus monkeys received a kidney allograft to study the potency of several different immunosuppressive regimens (conventional immunosuppression, n=19, vs. costimulatory blockade, n=18). Monkeys were tested for antivimentin antibody by enzyme-linked immunosorbent assay and for anti-donor antibody by staining donor spleen cells with recipient serum. The appearance of antibodies was correlated with the graft pathology in biopsy and necropsy material. RESULTS: Antivimentin antibodies were found in 31 of 37 animals, whereas only 15 of 32 animals made anti-donor antibodies. Conventional immunosuppression did not prevent antivimentin antibody formation. Costimulation blockade, in particular blocking CD40 and CD86, significantly delayed or prevented antivimentin antibody formation, but did not prevent CAN. Antivimentin antibodies were not significantly associated with development of CAN. CONCLUSIONS: We postulate that vimentin acts as an autoantigen after renal transplantation; it elicits an autoimmune response that is not regulated by cyclosporine. This autoimmune response may be part of the complex immunologic events occurring posttransplantation and may contribute to the development of CAN, but cannot be considered as a major cause of CAN because this condition also develops without antivimentin antibodies.

Animals↗
PubMedDate not supplied

Potentiation of autoimmune response in rats infected with Toxoplasma gondii. Effect of the infection route.

The aim of this report is to describe the influence of the way of infection with 3 X 10(3) trophozoites of Toxoplasma gondii on the auto- and heteroimmune responses of rats immunized with chemically modified rat male accessory glands (MRAG) and human serum albumin (HSA) 6 and 36 days after infection. The delayed hypersensitivity (DTH) response to MRAG was potentiated in rats infected in thymus proximity (p less than 0.02) when compared with rats only immunized. The parasites introduced intraperitoneally did not modify the cellular autoimmune response. The titers of hemagglutinating antibodies to MRAG were increased in animals infected by both ways (p less than 0.05). The response to HSA did not show significant difference between the infected and uninfected rats. Thymic involution and proliferation of lymphocytes and plasma cells were observed at 6 and 52 days post-infection only in rats infected in thymus proximity (p less than 0.05). A correlation between the potentiation of cellular autoimmune response and the injection of parasites in thymus proximity was observed.

Animals↗
PubMed1995

Maternal autoimmune response to recombinant Ro/SSA and La/SSB proteins in Japanese neonatal lupus erythem atosus.

BACKGROUND: Neonatal lupus erythematosus (NLE) is a syndrome characterized by dermatitis and congenital heart block (CHB). The disease is mostly associated with transplacental passage of maternal anti-Ro/SSA and/or La/SSB antibodies. OBJECTIVE: To examine maternal autoimmune response to recombinant Ro/SSA and La/SSB proteins in NLE with a single ethnic background. METHODS: This study examined 12 NLE infants and their mothers. Serum samples were tested by enzyme-linked immunosorbent assay for reactivity with full-length recombinant human 60-kd Ro/SSA, 52-kd Ro/SSA, and 48-kd La/SSB proteins. RESULTS: All 10 infants with skin lesions and/or CHB had maternal antibodies reactive to both the 60- and 52-kd Ro/SSA polypeptide components of the Ro/SSA particle. Anti-60-kd Ro/SSA without anti-52-kd Ro/SSA, or vice versa, was found in mothers of infants who had only hepatic manifestation of NLE. Nine of 12 NLE infants had anti-48-kd La/SSB. CONCLUSION: In the majority of Japanese infants with NLE, maternal anti-Ro/SSA autoimmune response was directed against both of 60-kd and 52-kd recombinant Ro/SSA proteins. There was no profile of anti-Ro/SSA and La/SSB response unique to mothers of children with CHB or cutaneous manifestations of NLE.

Adenosine Triphosphatases↗
PubMed2005

Initiation of an autoimmune response: insights from a transgenic model of rheumatoid arthritis.

K/BxN mice develop an inflammatory joint disease with many features characteristic of rheumatoid arthritis. This model is based on a T-cell receptor transgene, KRN, that has been shown to recognize both the foreign antigen bovine RNase, and the ubiquitously expressed self antigen, glucose-6-phosphate isomerase (GPI). We have used this model to investigate the initial events that occur during the autoimmune response to GPI. We and others have identified key mediators in the inflammatory response: Fc receptors (FcRs) (in particular FcRIII), the alternative pathway of complement, neutrophils, and mast cells. Using micro position emission tomography, we demonstrated that anti-GPI Immunoglobulin G (IgG) localizes specifically to the joints where arthritis occurs and that this localization is dependent on mast cells, neutrophils, FcRs, and immune complexes. The trigger of arthritis in this model is the KRN T-cell inducing the production of anti-GPI Ig. By overexpressing the ligand for the KRN T-cells in major histocompatibility complex class II-expressing cells, we demonstrated that KRN T-cells were able to escape tolerance induction in the thymus owing to insufficient levels of antigen in the thymus antigen-presenting cells. This allows the KRN T-cells to exit to the periphery, where they provide help to anti-GPI B-cells, inducing the production of arthritogenic Ig. To understand the joint specificity of the disease, we followed the anti-GPI B-cell response that naturally arises in K/BxN mice and showed that, although the GPI antigen is ubiquitously expressed, the anti-GPI B-cell response is focused on the lymph nodes draining the affected joints. Together, these studies have given us a greater understanding of how an autoimmune response is initiated at the level of both the adaptive and innate immune systems and demonstrate the versatility of the K/BxN arthritis model for studying human disease.

Amino Acid Sequence↗
PubMedDate not supplied

Allergic manifestations as the results of a conditional autoimmune response.

By means of repertoire cloning we have isolated human anti-IgE antibodies as well as human anti-FcepsilonRI antibodies. Whether the naturally occurring anti-IgE autoantibodies play a pathophysiological role may be disputed, but the beneficial role of recombinant anti-IgE antibodies as a therapeutic agent has been shown. On the other hand, the natural antibodies isolated from an antibody library of a nonallergic individual against the FcepsilonRI alpha-chain are anaphylactogenic, if FcepsilonRI was not occupied. Thus, anti-FcepsilonRI autoantibodies may be part of a conditional autoimmune reaction, leading to urticaria if local IgE is consumed, e.g. after an immediate reaction. Thus, anti-FcepsilonRI antibodies may represent an amplification arm of the late reaction. The normal occurrence of anti-IgE and anti-IgE receptor autoantibodies may suggest that it might also be feasible to induce such autoantibodies by vaccination. In a monkey model using a mimotope of human IgE it was possible to induce a beneficial anti- IgE autoimmune response. The actual epitope of the IgE molecule was then also molecularly reconstructed by generating recombinant anti-idiotypic antibodies. These antibodies also induced effectively an anti-IgE response in monkeys, suggesting that not only mimotopes but also anti-idiotypic antibodies may be used to generate an autoimmune response. Both of our projects suggest that active immunization may be a new form of immunomodulation for the treatment of allergic disease.

Animals↗
PubMed1994

Chronic modulation of the autoimmune response following parvovirus B19 infection.

We describe 2 patients with prolonged autoimmune alterations following parvovirus B19 infection. B19 induced aplastic crises were the revealing manifestations of asymptomatic hemolytic conditions in the 2 patients: a Coombs' positive hemolytic anemia induced by D-penicillamine in the first and congenital spherocytosis in the second. Both patients had transient clinical and serological manifestations highly suggestive of systemic lupus erythematosus. In addition, prolonged clinical and serological remission of rheumatoid arthritis was observed in the first patient, while arthralgias, FANA, and anti-Ro antibodies persisted in the second, previously healthy patient. Our data suggest that parvovirus B19 infection may lead to chronic modulation of the autoimmune response in predisposed individuals.

Adult↗
PubMed2005

Evidence for multiple shared antigenic determinants within Ro60 and other lupus-related ribonucleoprotein autoantigens in human autoimmune responses.

Ab responses directed against several ribonucleoprotein (RNP) Ags are a characteristic feature of systemic lupus erythematosus (SLE). Previous work in our laboratory using mouse model systems had revealed that both epitope spreading and inherent cross-reactivity between ribonucleoproteins contributes to the observed multiple specificities in autoimmune sera. We have now extended these studies to human autoimmune responses. Using purified polyclonal and mAbs derived from SLE patients, cross-reactivity between Ro60 and SmD was demonstrated. The cross-reactive epitope was mapped to nonhomologous regions on Ro60(481-505) and SmD(88-102). Five mAbs specifically recognized apoptotic cells, demonstrated variable levels of cross-reactivity toward other nonhomologous ribonucleoprotein targets and bound multiple, nonoverlapping and nonhomologous epitopes on Ro60. Our study demonstrates that cross-reactivity between frequently targeted autoantigens is an important aspect of human systemic autoimmune responses. The presence of multiple cross-reactive epitopes on Ro60 might be important for the generation of anti-Ro60 Ab in SLE patients and in normal individuals displaying no evidence of clinical disease.

Amino Acid Sequence↗
PubMed1985

The autoimmune response in active Heymann's nephritis in Lewis rats is regulated by T-lymphocyte subsets.

In this study the cellular events which are responsible for the induction and suppression of active Heymann's nephritis (HN) in Lewis rats were investigated. Using an enzyme-linked short-term culture assay specific autoantibody production in vitro by lymphoid cells directed against the nephritogenic renal tubular epithelial glycoprotein (RTE-Gp) was measured. By this method it was shown that only the lymph nodes that drain the site of immunization contained autoreactive B cells. Pretreatment with cyclosporine A (Cy-A) or with multiple injections of high doses of antigen in Freund's incomplete adjuvant markedly inhibited the development of disease to a subsequent nephritogenic challenge. In challenged high-dose-tolerant (HDT) rats the autoimmune response was only 5-10% of immunized nontolerant rats. This tolerance could not be transferred by lymphoid cells from Cy-A-treated rats, but could be transferred by lymphoid cells derived from the thymus or spleen of HDT rats. Thus a suppressor cell of thymic origin may be responsible for HDT. Transfer of affinity column-fractionated splenic T cells from HDT rats demonstrated that OX8- helper and OX8+ suppressor T cells are involved in the induction and suppression, respectively, of the autoimmune response in this experimental nephropathy.

Animals↗