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Clin Exp Immunol. Dec 2000; 122(3): 477–483.
PMCID: PMC1905793

Parasite-mediated down-regulation of collagen-induced arthritis (CIA) in DA rats

Abstract

Microbial infection can impact on the course of autoimmune disease, both in disease-inducing and disease-protecting capacities. Here we investigated if infection with Trypanosoma brucei brucei (Tbb), the protozoan causative agent of African Sleeping Sickness, could ameliorate the course of CIA in the Dark Agouti rat, an experimental model which shares many features with human rheumatoid arthritis. Infection of animals with living, but not inoculation with dead Tbb resulted in complete or significant reduction of clinical arthritic symptoms. Infection prior to collagen immunization was more effective than a later treatment, and this effect was related to the level of parasitaemia. Using reverse transcriptase-polymerase chain reaction we detected an increase in interferon-gamma mRNA in the draining lymph nodes of Tbb-treated animals relative to controls at day 28 after disease induction. Transforming growth factor-beta could be detected in the lymph nodes in four out of six animals that had received Tbb. In the joints, immunohistochemistry revealed reduced production of tumour necrosis factor-alpha in Tbb-treated animals relative to controls. The most striking difference between Tbb-infected and control groups, as measured by ELISA, was the down-regulation of anti-collagen II IgG antibody responses in parasite-infected animals. We conclude that live parasites can exert an immunomodulatory and protective effect in CIA in which several mechanisms may work in parallel, although the almost complete down-regulation of the anti-collagen antibody response may alone explain the protective effect in CIA. The described model may be useful in further attempts to use the mechanisms involved in parasite immune defence to prevent and treat certain autoimmune conditions.

Keywords: autoimmunity, protozoan parasites, immunomodulators, cytokines, antibodies

INTRODUCTION

Microbial infection has for the most part been reported as a means of inducing autoimmune disease through mechanisms of molecular mimicry [1], superantigenic induction [2] or adjuvant-induced stimulation of the immune system [3]. However, others have proposed that infection might have beneficial effects on subsequent development of autoimmune disease [4], and epidemiological studies lend support to this concept. Thus insulin-dependent diabetes mellitus (IDDM) is less common in genetically susceptible people who have experienced many severe infections at a young age [5], and rheumatoid arthritis (RA) is less common in certain areas of tropical countries [68] in which there is a high incidence of infectious diseases and in particular of parasitic infections. Thus it is of interest to study the impact of an infection on an experimental model of autoimmunity.

CIA in the DA rat is an experimental autoimmune disease sharing many features with human RA [9,10]. In this model there is significant production of proinflammatory cytokines such as interferon-gamma (IFN-γ), IL-1 and tumour necrosis factor-alpha (TNF-α) in the draining lymph nodes even before the appearance of clinical symptoms [11]. At the peak of disease there is also a strong local production of TNF-α in the inflamed joints [12]. That B cells are required to develop disease is demonstrated by the fact that mice with a B cell defect do not develop CIA [13]. In addition, passive transfer of anti-collagen antibodies can induce arthritis [14].

Trypanosoma brucei spp. are tsetse fly-transmitted parasitic protozoa that cause African sleeping sickness in both man and other mammals. Infection causes a polyclonal activation of B cells as well as a specific antibody response to variable surface glycoprotein (VSG). The dominant part of the specific immune response is a T cell-independent component but there is also a T cell-dependent IgG response [15]. Parasitaemia is cyclical due to repetitive proliferation and elimination of successive parasite populations due to antigenic variation of VSG. Infection with Trypanosoma brucei brucei (Tbb) eventually causes a state of immunosuppression [15] which is mediated by macrophages producing prostaglandin E2 (PGE2) and nitric oxide (NO) [16,17]. The activation of macrophages is potentially mediated by IFN-γ, the synthesis of which is significantly up-regulated following infection. The potential sources of IFN-γ are VSG-specific CD4 T cells [18], CD8 T cells stimulated by trypanosome-derived lymphocyte triggering factor (TLTF) in an antigen non-specific manner [19], and natural killer (NK) cells [15].

That a parasite-induced activation of the immune system can indeed immunomodulate other conditions has been reported in experimental studies using live parasite infections [20,21]. Despite the known immunosuppressive capacity of a Tbb infection no one has investigated the potential of this parasite to modulate an autoimmune disease. In the present study, we observed that arthritis development was suppressed by concurrent parasite infection with Tbb. This finding led us to explore possible mechanisms mediating this effect.

MATERIALS AND METHODS

Animals

In all experiments male Dark agouti rats 8–12 weeks old were used.

Collagen II preparation

Bovine CII (bCII) was used in all experiments and was prepared from calf nose cartilage as previously described [22,23].

Induction and evaluation of arthritis

Rats were immunized intradermally in the base of the tail with a collagen/Freund's incomplete adjuvant (FIA) emulsion (300 μl emulsion containing 150 μg bCII per rat). Rats were individually scored blindly by two independent persons according to a previously described procedure [24]. In brief, 1 point signifies swelling of one group of joints (for example metatarsophalangeal (MTP), metacarpophalangeal (MCP) joints or peripheral interphalangeal (PIP) joints), 2 points signifies two groups of swollen joints, 3 points signifies three groups of swollen joints (for example PIP, MCP and wrist or ankle joints), and 4 points signifies swelling of the entire paw. The maximum score for each rat is 16.

Parasite treatment and counting

Stock stabilates of Tbb AnTat1.1E were diluted in sterile PBS to 105 parasites/ml and 0·5 ml of this solution was injected intraperitoneally into each rat giving a dosage of 5 × 104 parasites per rat. Samples (5 μl) of tail-bled blood were collected from parasite-infected animals every second day, and microscopic evaluation of parasitaemia was conducted. Parasites were killed through fixation in 3% formaldehyde for 10 min and washed in PBS before immunization.

Cytokine quantification in lymph node and spleen cells

The inguinal lymph nodes were dissected from the rats at day 28 post-immunization (p.i.) and the cells were washed, counted and kept at −70°C until RNA preparation. Extraction of RNA, synthesis and amplification of cDNA was performed as previously described [25].

Quantification of the amplified cDNA was performed with a specific polymerase chain reaction (PCR)-ELISA described previously [25]. By including serial dilutions of standard samples in each experiment the linear phase of the amplification reaction could be defined. Unknown samples were carefully titrated to ensure that the PCR reaction was not run to completion. A semiquantitative evaluation was performed by calculating the fluorescence ratio of cytokine/housekeeping enzyme products, where the average value of β-actin and GADPH was used as a measure of the housekeeping enzyme activity.

The relative lymph node expression was also measured at day 7 after CIA induction and Tbb treatment. Lymph nodes were frozen after dissection, RNA was extracted using Qiagen kit and cDNA was reversed transcribed as above. Quantitative PCR analysis of cDNA was performed using the Taqman methodology (Perkin Elmer, Norwalk, CT) according to the manufacturer's instructions. In order to obtain a measurement of the type 1/type 2 T cell responses the ratio IFN-γ and IL-4 was also calculated using the average values of two PCR-ELISA runs for each cytokine.

Immunohistochemical detection of TNF-α and transforming growth factor-beta

At day 21 after inoculation with either bCII/FIA, bCII/FIA + Tbb or Tbb alone, inguinal lymph nodes and synovial membranes (SM) were analysed for TNF-α as previously described [26]. Transforming growth factor-beta (TGF-β) stainings were performed as previously described [26,27], with the exception that 4% normal horse serum was used in the second blocking step.

Quantification of anti-bCII and anti-ovalbumin antibodies of total IgG and of IgG isotypes

Individual sera were collected on days 21 (from tail) and 28 (from heart) p.i. from bCII/FIA-immunized rats receiving parasite treatment on days 0 or 7, respectively, or from control rats, and were stored at −20°C until analysed according to a previously described procedure [28]. Sera from the control group of rats were pooled and such pools were used as standards. The 1:50 dilution of this standard serum was arbitrarily set to 1000 U.

The determination of anti-bCII IgG isotypes IgG1, IgG2a and IgG2b was performed as previously described [25].

Statistical analysis

The arthritic score was evaluated not daily but by accumulating the score for each animal over the whole experimental period, thus giving one value of disease severity for each rat. This value was analysed using non-parametric analysis, i.e. Mann–Whitney for two-group analysis and Kruskall–Wallis followed by Dunn's test for multigroup analysis.

Cytokines were analysed using non-parametric analysis as above, i.e. Mann–Whitney for two-group analysis and Kruskall–Wallis followed by Dunn's test for multigroup analysis.

The antibody titres were analysed using anova with Bonferroni/Dunn post hoc test.

RESULTS

Clinical arthritis course is modified by active infection

We investigated if we could modulate arthritis development by inoculation with live Tbb. Infection with live Tbb on day 0 gave protection but a later infection (day 7) did not significantly reduce clinical scores overall, although there was a significant difference in score on the days when the parasitaemia had its maximal levels (days 21 and 28) (Fig. 1a). A treatment group was included with formaldehyde-fixed (dead) Tbb day 0. Arthritis development in this group and in the control group was not significantly different. In a separate experiment it was demonstrated that Tbb infection 7 days prior to CIA induction fully protected animals from development of arthritis (Fig. 1b).

Fig. 1
(a) Infection of Trypanosoma brucei brucei (Tbb) before or on the day of CIA induction ameliorates CIA disease course. (a) Infection with Tbb was initiated on day 0 (n = 7), day 7 (n = 7) and compared with dead Tbb given day 0 (n = 6) and untreated CIA ...

The degree of protection was correlated with the degree of patent parasitaemia in the Tbb-infected groups at the peak of CIA disease, those being infected on day 0 having higher accumulated parasitaemias than the day 7-infected animals (P < 0·01) during the course of CIA (Table 1).

Table 1
The relationship between incidence and severity of arthritis, anti-collagen titre and parasitaemia 21 days after CIA induction*

Cytokines and cytokine mRNAs in spleen, lymph nodes and joints

The production of cytokine mRNAs was measured in the lymph nodes on days 7 and 28 after CIA induction (Table 2a). On day 7 there was no difference in IFN-γ or IL-4 mRNA induction between Tbb-treated CIA animals and controls having only CIA (Table 2a). On day 28 the production of IFN-γ mRNA was most significantly increased, but the levels of IL-2 mRNA were also increased in the live Tbb-treated animals (Table 2b). There was a tendency for IL-4 also to be up-regulated so that the ratio IFN-γ/IL-4 was unchanged between the groups, indicating that at this late stage of disease there was also no bias towards a type-2 immune response. In contrast, the spleen demonstrated a clear type-1 bias with increased IFN-γ and decreased IL-4 mRNA production at day 28 in the Tbb-treated groups (data not included).

Table 2
Semiquantitative determination of cytokine mRNA on day 28 p.i. in lymph nodes at (a) day 7 and (b) at day 28

The production of TGF-β and TNF-α was also analysed by immunohistochemical staining of lymph nodes taken 21 days p.i. While there was no difference in TNF-α between the specimens, TGF-β was only detected in animals that received Tbb alone or in combination with bCII (Table 3), although not in all animals. The production of TGF-β and TNF-α on day 21 p.i. was similarly assessed in the synovial membrane. Intense TNF-α staining close to cartilage could be detected only in animals with high arthritic scores in the control bCIA group, whereas only limited expression of TNF-α was observed in the other two groups (Table 3). The staining was especially strong in the lining layer of the arthritic rats (Fig. 2A).

Fig. 2
Tumour necrosis factor-alpha (TNF-α) production in the synovial membrane. Rats were immunized with bovine CII (bCII)/Freund's incomplete adjuvant (FIA) and were treated with live Trypanosoma brucei brucei (Tbb) intraperitoneally (n = 3) the same ...
Table 3
Analysis of the cytokines tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) by immunohistochemical analysis of the synovial membrane and the lymph nodes, at day 21 after CIA induction and parasite treatment ...

Anti-collagen antibody production but not DTH is suppressed by active infection

Results of the total anti-bCII IgG for all treatment groups are presented (Fig. 3). Compared with the control animal CIA in which there was significant production of serum anti-bCII antibodies detected on both days 21 and 28, sera from animals infected on day 0 with live Tbb contained markedly reduced levels of collagen-specific antibodies, while sera from animals injected with dead Tbb were not significantly different from controls. Levels of anti-bCII antibodies were also reduced in sera at day 21 from the group infected with live Tbb on day 7, but levels were much higher than in the live Tbb day 0 group, although at day 28 the levels were comparable in these two groups. The anti-CII-specific antibody response of the isotypes IgG1, IgG2a and IgG2b was analysed but did not demonstrate any shift favouring one isotype or another and all individual isotypes mirrored results of the total IgG (data not shown).

Fig. 3
Anti-collagen II IgG antibody titres are reduced in the serum of Trypanosoma brucei brucei (Tbb)-infected rats. Serum collected at days 21 (□) and 28 ([filled square]) p.i. for the experiment described in Fig. 2 were analysed by ELISA. CIA was induced ...

The DTH response from a recall stimulation with bCII 21 days after immunization did not demonstrate any significant difference between Tbb-treated and control animals (data not included).

DISCUSSION

An interesting question in understanding the epidemiology of autoimmune diseases is to consider the impact of infections on disease development. In this study we studied the modulating effect of the protozoan parasite Trypanosoma brucei brucei (Tbb) on CIA in DA rats. Trypanosomes are known to have a variety effects on host immune function, polyclonal expansions of B and T cell compartments and associated production of proinflammatory cytokines being the hallmarks of disease. This model system thus allowed the impact of infection on each of these immunological aspects in autoimmune pathogenesis to be addressed.

Animals infected with patent Tbb (on days −7 or 0 post-bCII inoculation, respectively) exhibited significantly milder disease courses with respect to both incidence and arthritic scores. Since neither bovine serum albumin (BSA) (data not shown) nor dead Tbb was effective in modulating the disease, the observed phenomenon was specific to concurrent infection with live Tbb.

We observed the most significant effect on B cells, since we could demonstrate that there was a strong reduction in anti-bCII antibodies in the groups infected with Tbb. This effect correlated with the clinical scores, since dead Tbb could neither suppress the anti-collagen titre nor modulate arthritis. When comparing treatment on day 0 with day 7 was there also a correlation between parasitaemia, anti-bCII antibody titre at day 21 and clinical score. Taking into account the many reports of the importance of an intact humoral response to CII in the pathogenesis of CIA [13,14] (reviewed in [29]), this result serves as one explanation for the modulation of arthritis we observed. The reason for suppressed anti-bCII antibody titres could be one of immunodominance, i.e. the immune system focuses on the much more immunogenic parasitic antigens, exhausting its resources with each new wave of parasitaemia, resulting in a relatively deprived humoral response to bCII.

We next investigated the function of the T cell compartment, through study of the effect of Tbb infection on DTH responses. There was no significant change in collagen DTH reaction at the peak of disease recorded in Tbb-infected animals, arguing less for the cellular response being important in arthritis pathogenesis. This effect is not specific to bCII, as the DTH response to ovalbumin (OVA) was also unaffected in a similar experimental set-up, although the anti-OVA antibody response was similarly drastically reduced by concurrent Tbb infection (Mattsson, Larsson & Harris, unpublished observations).

When comparing resistant and susceptible rat strains, CIA pathogenesis is associated with induction of proinflammatory cytokines such as IFN-γ and TNF-α, and many CIA modulating protocols act by skewing the cytokine profile towards production of type-2 cytokines [12,25,30]. The enhanced systemic IFN-γ production characteristic of Tbb infections would thus be expected to accelerate CIA development upon co-immunization. We therefore investigated whether the cytokine balance was altered in our animals with concurrent Tbb infection. Analysis of the lymph nodes before the onset of disease (day 7) demonstrated no significant changes in IFN-γ or IL-4 production, indicating that in this treatment regime there is no skewing towards type-2 cytokines. Late in the disease process there were increased levels of both IFN-γ and IL-4, although consequently no change in the IFN-γ/IL-4 ratio. By contrast, cytokine analysis in the spleens of Tbb-treated animals demonstrated increased levels of IFN-γ and decreased levels of IL-4. In conclusion, in addition to the absence of a change in the isotype profile of the anti-bCII antibodies, these results indicate that that the mechanism of Tbb amelioration of CIA is not due to a shift to type-2 cytokine production.

While general cytokine profiles revealed no major differences between groups, we were particularly interested in studying two cytokines with known importance in CIA pathogenesis, namely TGF-β and TNF-α. TGF-β-producing regulatory T cells induced by oral antigen have a known general down-regulatory effect on experimental autoimmune disease [31] and induction of TGF-β has been previously reported in experimental trypanosomiasis [32]. We could detect this cytokine in the lymph nodes of 4/6 animals infected with Tbb, and TGF-β may thus be a contributing factor by which Tbb exerts its effect in our system. However, as TGF-β was not detected in all our parasite-treated animals, although a CIA-suppressive effect was observed in all animals, we do not believe that this cytokine is solely responsible for the amelioration of clinical arthritis. We have previously reported production of TGF-β locally in SM in rat CIA [33]. However, in the current study we did not detect this cytokine in control group (CIA) tissues and only detected production in the lymph nodes of some of the parasite-treated groups, arguing against any local immunosuppressive effect of this cytokine. This apparent difference in detection of TGF-β in different studies might be explained by the use of different anti-TGF-β immunoreagents, the polyclonal antiserum utilized in our previous study probably recognizing a wider range of epitopes than the MoAb used in the current study.

The importance of TNF-α in the pathogenesis of both experimental arthritis and in human rheumatoid disease has been underlined by successful therapeutic intervention aimed at neutralizing this cytokine [34,35]. In our system the local production of TNF-α was only up-regulated in animals with severe arthritis, indicating that the parasite exerts its immunomodulatory effects prior to this stage. Local production of TNF-α could also be detected in the joints after Tbb infection alone. Taken together, the analysis of TNF-α and TGF-β does not suggest that the modulatory effects of Tbb are exerted locally in the joint.

Although there are several possible mechanisms by which Tbb could ameliorate CIA, since the most significant effect in our system was the decreased anti-bCII production, we suggest that this may be the major mechanism for arthritis suppression. One possible explanation of these data is that a strong antigenic challenge such as a sustained Tbb infection constitutes such a powerful and continuous stimulus for antibody production [36] that the animal's capacity for antibody production is overloaded. The result would be a relative reduction of antibodies to less immunogenic antigens such as collagen when co-immunized. Such ‘immunoexhaustion’ has previously been referred to in studies of co-infection with parasites [37], and is different from the antigen inhibition of CIA described previously [38] in which inhibitory proteins were effective when included in the collagen inoculum or when injected intraperitoneally in extremely high (150 mg) amounts. In that study, the anti-collagen II antibody titres were unchanged upon treatment, which further strengthens the notion that protection from CIA with live Tbb is a different phenomenon with a different mechanism. Since an infection with Tbb exerts a vast number of effects on the immune system it is highly likely that several mechanisms might act in parallel. The effect of Tbb-induced suppressor macrophages in down-regulating the arthritogenic process cannot be discounted, although it is still difficult to reconcile the activated state of such macrophages (increased TNF-α production in particular) with alleviation of arthritis.

In conclusion, we demonstrate that in a defined experimental system, microbial infection can beneficially impact on the course of autoimmune arthritis. To our knowledge this study is the first in trying to characterize the impact of a parasitic infection on the collagen-specific arthritic process, and may indicate a contribution of parasitic infection in autoimmune epidemiology. This model system is also useful for further study of the mechanisms by which Tbb infection can ameliorate CIA, which may yield new approaches for how to treat this condition. We submit the idea that activating the immune system with foreign microbes provides a new mechanism for ameliorating an autoimmune process, and could be a concept for developing new treatment regimes.

Acknowledgments

We thank Leif Ehlin, Erik Mussener and Anna Rennermalm for technical assistance. Trypanosome material was delivered by the WHO Central Serum Bank for Sleeping Sickness. This research was supported by funds from KI fonder, Stiftelsen Professor Nanna Svartz, Konung Gustav V:s 80-arsfond and Ake Wiberg Stiftelse

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