Search PubMedSearch

Biomedical subjects

T Ternynck

Publications and source records attributed to T Ternynck.

At least 19 recordsLinked to original sources

Defects in the regulation of anti-DNA antibody production in aged lupus-prone (NZB x NZW)F1 mice: analysis of T-cell lymphokine synthesis.

(NZB x NZW)F1 (B/W) mice spontaneously develop a lupus-like syndrome characterized by an increased level of autoantibodies in old mice. We analysed the role of T cells in the regulation of anti-DNA antibody production by B cells in vitro as a function of age. In cultures of old mouse T and B cells, IgG and IgM anti-DNA antibodies were synthesized at high levels, in contrast to consistently lower amounts, particularly of IgG, measured in cultures of young mouse cells. Addition of young mouse T cells to old B cells inhibited IgG, but not IgM, anti-DNA production, whereas T cells from old mice stimulated IgG synthesis by young mouse B cells. Addition of supernatants harvested from concanavalin A (Con A)-stimulated T cells to B-cell cultures induced similar effects. Therefore, we evaluated possible modifications of lymphokine synthesis compared to that of the healthy NZW parent. T cells from old mice were able to secrete normal levels of interferon-gamma (IFN-gamma) and interleukin (IL)-10; however, secretion of IL-2 and IL-4 was dramatically decreased. Semi-quantitative polymerase chain reaction analysis of constitutive RNA messengers showed increased IFN-gamma levels in young and old B/W mice, and normal IL-10 mRNA levels in young and higher levels in old mice. Constitutive IL-2 and IL-4 mRNA were detected only after Con A stimulation and their levels decreased in old compared to young B/W mice; in particular IL-2 mRNA was considerably lower in old B/W than in control NZW mice. Taken together, these results suggest that, despite constitutive T-cell abnormalities, young B/W mice are able partially to control their lymphokine production, whereas aged mice exhibit a deficient synthesis, associated with an increased capacity to produce IFN-gamma.

Aging

[Physiological autoimmunity].

The serum of normal individuals contains antibodies directed against their own antigens (autoantigens). These autoantibodies are the main and the best known component of normal autoimmunity. They mostly involve polyreactive (one antibody recognising several antigens) IgM, but also IgG, usually having low affinity for antigens. The role of natural autoimmunity is becoming better understood. It participates in the equilibrium of the immune system, contributing to controlled production of antibodies, accelerated elimination of external antigens or aged autoantigens, and to triggering of a specific immune response. Some data suggest that the action of autoantibodies in homeostasis can extend beyond the immune system. Many pathological states, of immune nature or not, are associated with an increase or diminution of the titre of natural autoantibodies. The mechanisms and consequences of these changes remain to be elucidated.

Animals

Beneficial effect of polyclonal immunoglobulins from malaria-infected BALB/c mice on the lupus-like syndrome of (NZB x NZW)F1 mice.

We previously reported that infection of BALB/c mice with the parasite Plasmodium chabaudi induces high production of natural autoantibodies. Here we demonstrate that such an infection of lupus-prone (NZB x NZW)F1 (B/W) mice retards the development of their autoimmune disease. Survival and disease hallmarks (high-grade proteinuria and IgG anti-DNA antibodies) were delayed for 6 months when parasite inoculation was given at either 3 or 7 months of age, i.e. before or after the onset of the clinical symptoms. Similar beneficial effects, although less pronounced, were obtained when mice were treated with a total of 800 micrograms of IgG (P-IgG) or IgM (P-IgM) or 300 micrograms of cryoglobulin preparations isolated from P. chabaudi-infected BALB/c mice while similarly prepared fractions from uninfected mice had little effect. Compared to these fractions, P-IgG and P-IgM contained higher levels of natural antibodies bearing the D23 idiotype characteristic of polyreactive natural autoantibodies with enhanced activity against Fab and Fc fragments of IgG. In surviving mice, the level of anti-DNA antibodies, particularly those of IgG1 isotype, were significantly decreased. Flow cytometric analysis of various T cell subsets showed that the number of cells expressing gamma delta T cell receptor (TcR) antigens which did not vary with age was not modified after P-IgG or P-IgM treatment. In contrast, the number of T cells expressing V beta 8.1,2,V beta 10 and V beta 14 TcR antigens, which increased with age, were significantly reduced. Taken together, these results indicate that parasite infection of mice induces the synthesis of populations of IgM and IgG natural autoantibodies with immunoregulatory properties and that these antibodies attempt, at least transitorily, to rescue a natural autoantibody network that is deficient in B/W mice.

Animals

Natural autoantibodies are involved in the haemolytic anaemia of NZB mice.

NZB is a mouse strain that spontaneously develops autoimmune haemolytic anaemia at 10-12 months of age. We analysed the autoantibodies present throughout their life and compared them to natural autoantibodies found in the normal mouse. Sera and Coombs' antibodies eluted from red blood cells (RBC) were tested for their activities against RBC and a panel of antigens: actin, myoglobin, myosin, tubulin, spectrin, DNA and trinitrophenyl bovine serum albumin (TNP-BSA), F(ab')2 and Fc fragments of IgG by using enzyme immunoassays (EIA) and Western blotting analysis of RBC membrane extracts. In NZB mouse sera, activities of IgM and IgG against the whole panel, compared to those of sera from age-matched BALB/c mice, increased progressively throughout life with oscillating values in parallel with the anti-RBC activity. Two periods of autoantibody production seem to exist: the first is characterized by a fluctuating high level of IgM and stable level of IgG natural autoantibodies, and the second by a rise of IgG natural autoantibodies in parallel with IgG anti-RBC antibodies. The presence of idiotype D23 (IdD23), which is characteristic of natural polyspecific autoantibodies, was high on serum IgM and low on IgG autoantibodies throughout life. To further analyse autoantibody level oscillations, we tested IgM and IgG fractions after their separation from whole serum and observed highly enhanced autoantibody activities of both IgM and IgG. These autoreactivities markedly diminished when the separated IgM and IgG fractions were recombined, suggesting humoral control of the autoreactivity as we had already noted for IgG in normal animals. During the first period of autoantibody production, IgM and IgG antibodies eluted from RBC (Combs' antibodies) and those eluted from serum using an RBC-immunoadsorbent (circulating antibodies) reacted with all RBC membrane components, with all antigens of the panel and with F(ab')2 and Fc. Some of these reactivities were comparable to those exhibited by a monoclonal antibody recognizing bromelain-treated RBC. In the second period, both IgM and IgG Coombs' antibodies reacted more strongly with spectrin, and exhibited new specificities, for example against the band 3 polypeptide. IdD23 was abundant on Combs' IgG antibodies in the second period. Taken together, these data suggest that IgM and IgG natural autoantibodies, able to recognize not only RBC antigens but also other antigens, particularly F(ab')2 and Fc fragment of IgG, predominate in Coomb's antibody population.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors

Autoantibodies in the sera of Trypanosoma cruzi-infected individuals with or without clinical Chagas disease.

Variations in the levels and the specificities of autoantibodies directed against a panel of antigens (cytoskeleton proteins, DNA, laminin) were analyzed in the sera from two groups of humans infected with Trypanosoma cruzi. One group was constituted of apparently healthy blood donors (BD) and the other of patients with clinically confirmed Chagas disease (CCH). In both infected groups, a high proportion but not all sera exhibited dramatic enhancement of IgM and IgG autoantibodies directed against all antigens tested. Sera positive for IgG autoantibodies were generally found more frequently in the CCH than in the BD group, except for anti-actin antibodies more often present in BD sera. Anti-laminin IgG antibodies were present in a similar number of individuals in both groups. Although the titers of anti-laminin IgG antibodies were in general higher in CCH, their dissociation constants were in the same range (7 x 10(-8) - 10(-7) M) in both groups. IgG autoantibodies were demonstrated to be polyreactive with laminin and other self antigens as well. Circulating immune complexes were present in sera from both groups and the activity of the antibodies dissociated from these complexes was directed against all the antigens of the panel. Although the IgE concentration was significantly enhanced in several subjects from both groups, the incidence of positive sera was higher in the CCH (60%) than in the BD (39%) group. Our results demonstrate that autoantibodies with the characteristics of natural autoantibodies are found in both T. cruzi-infected apparently healthy individuals and patients.

Antibody Affinity

Monoclonal IgG and IgM autoantibodies obtained after polyclonal activation, show reactivities similar to those of polyclonal natural autoantibodies.

In this study, we described the properties of two groups of polyreactive IgG monoclonal antibodies (mAb) derived from splenocytes of a Plasmodium chabaudi-infected BALB/c mouse. These IgG mAb reacted with self antigens, but not with the parasite. Depending upon the antigen under study, they showed low (10(-5) M) to high (10(-8) M) affinities. When examined by immunoblotting using mouse organ extracts as the antigen source, each IgG mAb had a different reactivity profile. The IgG2b, but not the IgG2a mAb group, reacted with F(ab')2 fragments of IgG from normal mouse sera, as well as with F(ab')2 fragments of other mAb from the same fusion. Their anti-F(ab')2 activity was inhibited by various antigens, suggesting that the binding sites for these antigens and F(ab')2 fragments were close or overlapping. We also characterized two monoclonal IgM that were strongly and almost exclusively reactive with polyclonal F(ab')2 fragments of normal IgG, and that inhibited the binding of normal polyclonal IgG to self antigens. We previously described such properties for polyclonal IgM from normal mouse sera. The binding of the F(ab')2-reactive IgG mAb to self antigens was also inhibited by normal polyclonal IgM. These results indicate that the IgG and IgM obtained after polyclonal stimulation, exhibit characteristics similar to those of autoantibodies present in normal mouse sera. Furthermore, they confirm our previous studies showing the polyreactivity of polyclonal IgG. Finally, they also show that such IgG mAb exhibit properties similar to those of natural IgM, namely polyreactivity, affinity and connectivity.

Animals

Natural mouse IgG reacts with self antigens including molecules involved in the immune response.

IgG isolated on protein A-Sepharose from pools of normal sera from various mouse strains were examined by immunoblotting for reaction with self antigens. Homogenates of the major mouse organs, i.e. brain, skin, spleen, kidney, adrenals, thymus, heart, muscle and liver were used as the source of autoantigens. IgG stained at least 220 bands on the immunoblots. The antigens corresponding to these bands were tentatively identified by molecular mass estimation and referenced to computerized mouse protein data banks. IgG mainly recognized enzymes but it also stained intracellular structural constituents and surface molecules implicated in the functioning of the immune system. The validity of this identification was confirmed by analyzing purified antigens from mouse or other animal species by immunoblotting and enzyme immunoassays. Furthermore, extracts of 125I-surface-labeled cells were immunoprecipitated with IgG in the liquid phase or immobilized on beads. The proteins precipitated migrated to the same positions as those precipitated by specific monoclonal antibodies (mAb), such as class I alpha chain and beta 2-microglobulin, class II alpha and beta chains, CD3, CD4 and CD8 antigens. The results obtained with several enzyme immunoassay procedures using cell membrane extracts, specific mAb and normal IgG further supported the specific interaction of IgG with Ia, CD4 and CD8 molecules. Affinity chromatography indicated that at least 20% of normal mouse IgG possess polyreactive autoantibody function. Dissociation constants of these IgG were calculated for some autoantigens and found to be in the range of 2 x 10(-6)-7 x 10(-6) M. It is concluded that normal mouse IgG exhibit autoreactivities similar to those previously described for IgM.

Animals

Autoantibodies and circulating immune complexes in sera from patients with hepatitis B virus-related chronic liver disease.

Sera from 56 patients with hepatitis B virus-related chronic liver disease (CLD) and 30 normal individuals as controls were examined by enzyme immunoassay (EIA) for the presence of autoantibodies directed against actin, tubulin, myosin, double-stranded (ds) DNA, polymerized human albumin, thyroglobulin, and trinitrophenyl coupled to bovine serum albumin (TNP-BSA). Patients with CLD had consistently elevated levels of IgG, IgA, and IgM antibodies directed against all the panel antigens. The percentage of patients with autoantibodies of the IgA class was particularly high: respectively, 88 and 78% of the patients had strikingly high levels of anti-actin and anti-TNP-BSA IgA autoantibodies. High amounts of IgA and IgG antibodies to polymerized albumin as well as IgG to thyroglobulin were also detected. Circulating immune complexes (CIC) were isolated from patients' sera and their autoantibody activities were tested on the same antigen panel. The autoantibodies thus detected were of the same class and possessed the same activities, although at higher values than those present in the homologous sera. These results indicate that, regardless of their origin, autoantibodies are present in high amounts in the sera of these patients. Moreover, autoantibodies participating in the formation of CIC might play a pathological role.

Actins

Comparison of natural antibodies to autoantibodies arising during lupus in (NZB x NZW)F1 mice.

Autoantibodies arising in (NZB x NZW)F1 (B/W) mice during the lupus-like syndrome were studied and compared to natural antibodies present in normal mice. The antibody activities were tested in sera, circulating immune complexes (CIC) and kidney eluates, using an enzyme immunoassay against a panel of self and non-self antigens: actin, myosin, tubulin, DNA, myoglobin, spectrin and trinitrophenylated bovine serum albumin (TNP/BSA). In the B/M mouse sera, IgM antibodies reacting with all the panel of antigens (PAg) and comparable to those of normal mice, increased moderately from 5 to 9 months and markedly during the last stage preceding death (10 months), when particularly high levels of anti-DNA, anti-tubulin and anti-myoglobin antibodies were noted. Polyreactive IgM antibodies present in CIC were moderately increased while those present in complexes deposited in kidneys were strongly enhanced after the 8th month. IgG antibodies showed an early increase (2 months) in B/W sera for anti-TNP activity, which remained more or less constant until death, while a later (5-6 months) and greater increase of activity, mainly directed against DNA but also against the other antigens of the panel, was observed. In CIC, IgG, mainly anti-DNA but also anti-TNP, were enhanced at the end of the disease while at the same time IgG reacting with all the PAg were found in kidney deposits. Isolation of antibodies from sera on a DNA-immunoadsorbent demonstrated that eluted IgM reacted with all the PAg but mainly with DNA, while IgG reactivity was more restricted to DNA and to a lesser degree to TNP. The D23 idiotype, characteristics of natural polyspecific antibodies, was expressed on IgM and IgG autoantibodies from B/W mice and was enhanced, particularly in kidneys, at the end of the disease. These results demonstrate that natural antibodies are a part of the population of increased autoantibodies in this disease and could participate with IgG anti-DNA antibodies in lupus.

Animals

Induction of high levels of IgG autoantibodies in mice infected with Plasmodium chabaudi.

This study analyzed the effect of infection of mice with a virulent strain of Plasmodium chabaudi on natural autoantibodies. Mice received appropriate treatments in order to survive and the serum autoantibodies were characterized either by enzyme immunoassays against a panel of self and non-self antigens or by Western immunoblots using fibroblast or red blood cell (RBC) extracts. IgM and mainly IgG antibodies directed against actin, myoglobin, myosin, spectrin, tubulin, and trinitrophenylated-ovalbumin were found a few days after the parasitemia peak, persisted for several weeks after parasite clearance, and returned to almost normal levels after 2 months. Following a challenge with parasitized RBCs, a similar increase in all antibodies was observed, their levels remaining high 20 days post-injection and still remaining at twice the normal level 1 month later. Western blotting detected autoantibodies to many membrane RBC proteins, e.g. spectrin, and band 3 and its related polypeptides, as well as against fibroblast constituents, such as tubulin, actin, and the 70 kd heat shock protein. Autoantibodies seemed to be polyspecific, since those eluted from infected mouse RBCs and the IgG antibodies from infected mouse sera affinity-purified on a mouse tubulin immunoadsorbent reacted with all antigens of the panel, including parasite extracts. Surprisingly, in mice which had recovered from infection, autoantibody levels, particularly anti-spectrin and anti-band 3, rose after the injection of a high dose of normal instead of parasitized RBCs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Polyreactivity of human monoclonal antibodies: human anti-Rh monoclonal antibodies of IgM isotype are frequently polyreactive.

The specific aim of this study was to characterize human anti-Rh monoclonal antibodies cross-reacting with self-antigens. We studied supernatants from man-mouse hybridomas and from lymphoblastoid cell lines. Man-mouse hybridomas were established by fusion of peripheral blood lymphocytes from healthy individuals recently immunized against Rh alloantigens, with mouse myeloma (or man-mouse heteromyeloma) cell lines. Lymphoblastoid cell lines were produced by Epstein-Barr virus induction of lymphocytes from identical sources. Of the 55 monoclonal alloantibodies studied, 11 also reacted with intracellular self-antigens as demonstrated by immunofluorescence assay on cryostat sections of human tissues. This cross-reactivity was mainly a property of monoclonal alloantibodies belonging to the IgM isotype (among the 11 cross-reacting mAbs 10 were IgM). The cross-reactivities of these monoclonal antibodies were ascertained by absorption of alloreacting antibodies with red blood cells. Similar results were obtained on a panel of purified cellular antigens by ELISA. The results confirm that during an immune response against a foreign antigen (alloantigen), B cells that produce polyreactive antibodies are not excluded from the pool of responding cells. Therefore, polyreactive autoantibodies present in sera from healthy individuals may be the result of an immune response against foreign antigens.

Antibodies, Monoclonal

IgG autoantibody activity in normal mouse serum is controlled by IgM.

In the serum of normal BALB/c mice, IgG antibody reactivity to mouse actin and tubulin, DNA, and TNP groups was very low compared to that of the IgM. This activity was considerably increased when IgG was separated, by affinity chromatography on protein A-Sepharose, whereas no difference in the IgM activity was observed. Addition of IgM to IgG isolated from the same serum resulted in the inhibition of IgG binding to these Ag. Isolation of IgG antibodies on actin, TNP, and tubulin immunoadsorbents has indicated that at least part of the IgG antibodies is polyreactive. In order to understand this inhibition better, experiments with F(ab')2 fragments of IgG were performed. IgM inhibited the binding of F(ab')2 to the antigens in a dose-dependent manner and reacted with immobilized F(ab')2. IgM isolated on F(ab')2 immunoadsorbent, as compared to the initial IgM preparation, were less active toward the Ag but more inhibitory for IgG binding to the Ag. In some pathologic situations, IgM failed to inhibit some IgG antibody activities. The anti-DNA IgG activity from (NZB x NZW)F1 mice was not affected by autologous IgM. Similarly the anti-tubulin IgG from mice infected with Trypanosoma cruzi were less inhibited by IgM from autologous serum than antitubulin IgG from normal mice. These results are compatible with the existence in normal mice of an idiotypic-like network, regulating via an IgM population in the serum, the binding of IgG autoantibodies to self Ag. Modifications of this idiotype-anti-idiotype system might lead to the expression and/or expansion of autoreactive IgG-producing clones.

Actins

Comparison between autoantibodies arising during Trypanosoma cruzi infection in mice and natural autoantibodies.

The autoantibodies induced in (C57BL/6 x BALB/c)F1 mice during Trypanosoma cruzi (CL strain) infection were analyzed and compared with natural autoantibodies present in healthy mice. Mice were killed at intervals after infection and their sera were tested by enzyme immunoassay against a panel of self- and non-self-Ag: actin, myoglobin, myosin, tubulin, DNA, and TNP-OVA. The level of IgM and IgG autoantibodies against all Ag started to increase from day 15 until 6 wk after the parasite infection. The high level of all autoantibodies persisted 3 mo postinfection, and 1 yr later, half of the mice still had elevated levels of IgM and IgG autoantibodies, particularly antitubulin IgG antibodies. IgM and IgG were isolated from pools of normal and infected mouse sera and their binding capacity to all Ag was compared. The titers of infected mouse sera were increased and the slopes of both IgM and IgG binding curves of autoantibodies to actin, myosin, and tubulin were greater than those of control mouse sera, indicating higher affinities. The average dissociation constant of the IgG2a autoantibody to mouse tubulin was 5 times lower than that of natural antitubulin IgG2a antibodies. Furthermore, absorption of the IgG from infected mouse sera onto a tubulin immunoadsorbent removed half the reactivity with tubulin and also with myosin, actin and parasite extracts. The eluted antibodies bound the same Ag. When IgG were further analyzed by Western blot on proteolytic fragments of tubulin, we found that antibodies from both groups bound to the same broad spectrum of polypeptide bands. However, additional fragments were recognized by antibodies from infected mice. All these results indicate that the autoantibodies naturally present in mice are significantly affected after infection with T. cruzi, in quantity as well as in specificity and affinity.

Animals

Idiotypic interactions between normal human polyspecific IgG and natural IgM antibodies.

Pooled normal human polyspecific IgG (IVIg) contain anti-idiotypes against a variety of autoantibodies from patients with autoimmune diseases and IgG autoantibodies present in IVIg. The present study indicates that IVIg may also react through idiotypic/anti-idiotypic interactions with human natural IgM antibodies. Sixty-four percent of IgM secreted by B lymphoid cell lines derived from B cells of healthy elderly donors and 18% of IgM secreted by cloned EBV-transformed cord B cells that were tested, bound through their variable region to F(ab')2 fragments of IVIg. The binding to 2,4,6-trinitrophenyl (TNP) of a polyreactive IgM with anti-TNP specificity, was inhibited by F(ab')2 fragments from IVIg, indicating the presence in IVIg of anti-idiotypes that may interfere with the antibody-combining site of polyreactive IgM antibodies. The ability of IgM antibodies to interact with idiotypes on IVIg was not related to the degree of polyreactivity of natural antibodies. Our observations further document that IVIg contain antibody specificities against Ig from normal individuals and suggest that IgG originating from the physiologically expressed repertoire may modulate the expression of the potential B cell repertoire. The results may be relevant to the suppressive effect of IVIg in autoimmune diseases.

Antibody Specificity

Immunochemical studies of a murine polyreactive IgG2b autoantibody with rheumatoid factor activity.

The hybridoma, 62H3, which secretes a monoclonal IgG2b with anti-HLA-DR specificity, was expanded in pristane-primed BALB/c mice and the antibody was isolated from the ascitic fluid by affinity chromatography on Protein A-Sepharose. The purified IgG2b antibody was tested by an enzyme immunoassay for antibody activity against a panel of 40 self and non-self antigens. It was found to react strongly with beta-galactosidase, actin, glutamate dehydrogenase, rabbit and human IgG and di- and trinitrophenyl groups; and moderately with tubulin, insulin and phosphorylcholine; but it did not react with various other self and non-self antigens, such as DNA, albumin, keyhole limpet hemocyanin, hen lysozyme and horseradish peroxidase. Fab and Fc fragments were prepared from this IgG2b by papain proteolysis. The Fab fragment possessed the same spectrum of polyreactivities as the native IgG2b, whereas no activity was detected with the Fc fraction. In order to investigate the properties of the antigen binding site, the actin, TNP and rabbit IgG antibody activities were studied in more detail by enzyme immunoassay, Western blot and immunocytochemistry. The monomolecular nature of this multireactivity was confirmed by immunoabsorption analysis. Furthermore, 62H3 monoclonality was also verified by comparative isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis with other monospecific antibodies. The dissociation constants (Kd) of antigen-antibody equilibria in solution were measured. The Kd for actin was 1.11 +/- 0.24 x 10(-5) M and the Kd for TNP-BSA was 8.7 +/- 0.51 x 10(-7) M. No interaction with rabbit IgG could be detected in solution. These findings raise the question of the possible implication in autoimmune pathology or in normal physiology of IgG class polyspecific antibodies with solid-phase restricted cross-reactive rheumatoid factor activity.

Animals

Anti-tubulin antibodies in rabbits before and after immunization with pig tubulin.

Sera from rabbits before and after repeated injections of pig tubulin in complete Freund's adjuvant were examined for antibody activity against pig and rabbit tubulins and against a panel of antigens: actin, myosin, DNA, TNP/BSA. Antibody activity against all the antigens of the panel (PAg) increased moderately after the first but not after subsequent injections. Antibody activity against pig and rabbit tubulins strongly increased after the second immunization when the maximum was reached. Isolation of anti-tubulin antibodies from normal or immune sera on tubulin-immunoadsorbent demonstrated the presence of three different antibody populations: (1) polyspecific IgM reacting with the PAg and the tubulins, present in substantial amounts in normal sera and moderately increased in immune sera; (2) small amounts of polyspecific IgG detected only in immune sera; (3) high amounts of specific IgG reacting with pig and rabbit tubulins, present in immune but not normal sera. Western blot analysis of the specific IgG population showed that it contained antibodies reacting with both native pig and rabbit tubulins, as well as antibodies recognizing only the 30,000 proteolytic fragment of pig, but not that of rabbit tubulin. The results indicate that the immunization of rabbits with heterologous tubulin induced specific IgG anti-tubulin antibodies which recognize the self and non-self antigens differently.

Animals