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Rheumatology Advance Access originally published online on March 27, 2008
Rheumatology 2008 47(5):622-626; doi:10.1093/rheumatology/ken042
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Autoimmune reactivity against the 20S-proteasome includes immunosubunits LMP2 (β1i), MECL1 (β2i) and LMP7 (β5i)

S. Scheffler1, U. Kuckelkorn2, K. Egerer1, T. Dörner1, K. Reiter1, A. Soza2,3, G.-R. Burmester1 and E. Feist1

1Department of Medicine/Rheumatology and Clinical Immunology, 2Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, Germany and 3Depo de Immunologia Clinica I Reum, P. Universidad Catolica de Chile, Santiago, Chile.

Correspondence to: E. Feist, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. E-mail: eugen.feist{at}charite.de


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. Autoantibodies against the 20S-proteasome display a broad diversity with a remarkably low frequency of individual cross-reactivity against the different subunits of the proteasome. Although their pathogenic and diagnostic significance remains obscure, an involvement in the clearance of circulating proteasomes as well as an interaction with the activity of the proteolytic complex was assumed in previous studies.

Methods. To investigate the anti-proteasome response in more detail and to disclose reactivities against former neglected subunits, two-dimensional electrophoresis followed by immunoblotting was used. As a novel antigen source, the immunosubunits LMP2 (β1i) and LMP7 (β5i) were expressed as recombinant proteins and employed in ELISA.

Results. The subunits Iota ({alpha}1) and Zeta ({alpha}5) of the outer rings as well as the catalytic subunit Delta (β1) and all three immunosubunits [MECL-1 (β2i), LMP2 (β1i) and LMP7 (β5i)] of the inner rings of the proteasome were identified as autoantigens for the first time. Using a panel of anti-proteasome antibody-positive sera of patients with SLE, autoimmune myositis (PM/DM) and primary Sjögren's syndrome (pSS), an autoimmune response was documented against LMP2 (β1i) and LMP7 (β5i) in all three patient groups in ELISA.

Conclusions. The frequent autoimmune response against LMP2 (β1i) and LMP7 (β5i) might indicate a role of inflammatory processes in the primary induction of the anti-proteasomal immune reaction, while the diversity of the humoral response against the proteasome system supports the assumption of a specific antigen-driven process leading to these extended autoimmune reactivities.

KEY WORDS: Proteasome, Immunosubunits, Autoantibodies, Autoimmunity


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Autoantibodies in systemic autoimmune diseases are often directed against enzymatically active proteins or protein–RNA complexes playing important roles in replication, transcription or translation [1–3]. In recent years, the 20S-proteasome, the central protein degrading enzymatic complex in eukaryotic cells, was shown to be an another major target for B-cell response in a number of CTDs as well as in some other organ-specific autoimmune diseases [4–6]. Proteasomes are involved in numerous crucial processes like cell cycle regulation and, moreover, are the major source of antigenic peptides presented by the MHC class I molecules [7–9]. This makes a potential pathogenic role of anti-proteasomal antibodies an intriguing possibility.

The 20S-proteasome consists of a symmetrically arranged cylindrical structure of four stacked rings, each one composed of seven different subunits [10]. Both inner rings are composed of β-subunits, which carry the three catalytic subunits [11]. Three of the proteasome β-subunits can be exchanged for alternative β-subunits (so-called immunosubunits) resulting in different proteolytic properties. This process is induced by inflammatory cytokines (i.e. IFN-{gamma} and TNF-{alpha}) and is considered to influence immune responses [12–16]. In this context, the subunits LMP2 (β1i), MECL-1 (β2i) and LMP7 (β5i) are overexpressed and integrated into the proteasomal complex instead of the house keeping catalytic subunits Delta (β1), Z (β2) and MB-1 (β5), respectively. The outer rings are formed by seven different {alpha}-type subunits. They are responsible for the assembly of the proteasome and bearing nuclear localization signals [17, 18]. Moreover, the outer rings interact with regulatory complexes, for example, with the proteasome activator PA28, which is supposed to enhance the efficiency of processing for some antigenic peptides. The complexity of proteasome composition is reflected by the diversity of anti-proteasomal autoantibodies.

In former studies, an obvious wide variability of autoimmune reactions against different proteasomal subunits was observed using one-dimensional (1D) electrophoresis combined with immunoblotting (IB). However, a specific determination of the targeted subunits is only possible using 2D separation of the proteasome or recombinant expressed antigens. In this context, a predominant antibody reactivity was initially described against the subunit C9 ({alpha}3) in autoimmune myositis and SLE [5]. In contrast, a more polyspecific reactivity pattern against proteasomal subunits was found in patients with primary Sjögren's syndrome [19]. Storstein et al. [20] identified subunits with a relatively low molecular weight (23 and 25 kDa) as the predominant antigenic subunits in paraneoplastic cerebellar degeneration. Mayo et al. [6] found autoantibodies against proteasomal subunits C2 ({alpha}6), C5 (β6), C8 ({alpha}7) and C9 ({alpha}3) in patients with multiple sclerosis using recombinant human antigens. Nevertheless, in the aforementioned studies, only a minor fraction of antigenic subunits was characterized and identified as a definite proteasomal subunit. To disclose the diversity of the anti-proteasome response in more detail and also to focus on novel and important immunosubunits, sera from patients with positive anti-proteasome antibody reactivity were further investigated.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Selection of patients
Anti-proteasome antibodies were prospectively determined in patients with suspected autoimmune disorders using an ELISA. In the sequence of appearance of a positive result, sera of patients with SLE, primary Sjögren's syndrome (pSS), PM and DM were selected for testing in another ELISA using the recombinant immunosubunits LMP2 (β1i) and LMP7 (β5i). By this procedure, 27 patients with SLE fulfilling the 1982 revised ACR criteria [21], 26 patients with PM/DM classified according to Bohan and Peter [22, 23] and 22 patients with primary Sjögren's syndrome (pSS) diagnosed according to Vitali et al. [24] were analysed.

Furthermore, all anti-proteasome antibody-positive sera from ELISA were subsequently tested in anti-proteasome (1D) IB. Those sera, which showed a positive reactivity against subunits of different molecular weights, were further characterized using 2D separation of proteasomal subunits followed by IB (2D-IB). In the sequence of appearance, sera of patients with the following autoimmune diseases were tested in 2D-IB: SLE (n = 2), UCTD (n = 3), scleroderma (n = 1), WG (n = 1) and pSS (n = 2). All patients were treated at the Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin. The study was performed after approval from the local ethical committee. Informed patient consent was also obtained prior to carrying out this study.

Detection of anti-20S-proteasome autoantibodies in immunoblotting
The 20S-proteasome was isolated from human erythrocytes following standard procedures [25]. For 1D-IB, 5 µg/lane of purified 20S-proteasome was separated by 15% SDS–PAGE. 2D electrophoresis was used for separation of individual proteasomal subunits as described [26]. The same amount of purified 20S-proteasome of 50 µg was applied for each separation—first dimension non-equilibrium pH gradient electrophoresis (NEPHGE), second dimension SDS–PAGE. After transfer onto nitrocellulose membranes, the remaining binding sites were blocked with phosphate buffered saline (PBS), pH 7.4 containing 5% skim milk for 2 h. Subsequently, patient sera (diluted 1:100) were added. Bound antibodies were detected by goat-anti-human IgG coupled with horseradish peroxidase diluted 1:1000 in PBS/0.1% Tween-20/5% skim milk. Antibodies bound were visualized using X-ray films exposed to ECL-treated blots (Boehringer, Mannheim, Germany).

Detection of anti-proteasome antibodies in ELISA
Detection of anti-20S-proteasome autoantibodies in ELISA was carried out as described [19]. For detection of anti-LMP2 and anti-LMP7 antibodies in ELISA, 96-well plates were incubated with 4 µg/ml of purified proteasome solution or 5 µg/ml rLMP2 or rLMP7 proteins in carbonate buffer pH 9.5 for 24 h at 4°C. Patient sera were diluted 1:100 in PBS/0.1% Tween-20 pH 7.2. As a secondary antibody, a goat-anti-human-POD-labelled antibody was used in PBS/0.1% Tween-20, pH 7.2. Bound antibodies were visualized with tetramethyl benzidine (TMB) solution. Standard curves were established by using standard patient sera of the Charité University Hospital. The cut-off levels (mean value plus 3-fold S.D.) for anti-rLMP2 (>4.2 U) and anti-rLMP7 (>1.7 U) antibodies were calculated from 53 healthy persons. Detection of anti-proteasome antibodies in IB was performed as described previously [4]. Recombinant LMP2 and LMP7 cDNAs were cloned into pQE31 (Qiagen, Hildesheim, Germany). The His-tagged recombinant proteins were expressed in Escherichia coli DH5{alpha} and were purified according the Qiagen protocol.

Statistical analysis
Statistics were performed using the non-parametric Mann–Whitney U-test and Spearman correlation to compare the reactivities against the immunoproteasome subunits between the patient groups investigated. P-values of < 0.05 were considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Diversity of anti-proteasomal autoantibodies
Immunoblot analyses of sera from patients with CTD showed a variety of recognition patterns against 20S-proteasomal proteins in routine diagnostic analysis. To identify the different antigenic subunits targeted, we investigated nine anti-proteasome antibody-positive sera with different recognition patterns using 2D electrophoresis for proteasome separation (Table 1). As a result, a pronounced diversity was observed regarding reactivities against {alpha}- and β-type subunits of the 20S-proteasome. Representative results from IB are shown in Fig. 1. Interestingly, one patient with SLE reacted against MECL1 (β2i). This finding was unexpected since proteasome preparations from human erythrocytes are not supposed to contain immunosubunits of the proteasome. However, in our experience, MECL1 (β2i) can be identified in certain preparations of human erythrocytes and in this case its identity was also confirmed by subsequent IB using an affinity-purified rabbit anti-mouse MECL1 antibody (Fig. 2). Thus, active subunits of the constitutive proteasome complex Z (β2) and Delta (β1) as well as the immunosubunit MECL-1 (β2i) were targeted by autoimmune sera.


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  		TABLE 1. Characterization of anti-proteasomal response in patients with systemic autoimmune diseases by 2D-IB

 

Figure 1
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  		FIG. 1. Individual proteasome subunits separated by 2D electrophoresis were recognized by patient's antibodies. Analyses were performed with 20S-proteasome of human red blood cells (first dimension NEPHGE, second dimension SDS–PAGE). Upper panels show the Coomassie brilliant blue staining of the proteasome subunits in 2D gels, lower panels show the detection of the antigenic proteasomal subunits by immunoblot. (A) Patient P4 reacted against subunits C3 ({alpha}2) and Zeta ({alpha}5). (B) Patient P7 reacted against Iota ({alpha}1). (C) Patient P2 reacted against C2 ({alpha}6). (D) Patient P3 reacted against C8 ({alpha}7).

 

Figure 2
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  		FIG. 2. Detection of an autoimmune reaction against the proteasomal immunosubunit MECL1 (β2i). (A) 2D gel of 20S-proteasome prepared from human erythrocytes, stained with Coomassie brilliant blue. (B) Immunoblot of Patient P8. (C) The identity of the detected immunosubunit was confirmed by an immunoblot with affinity-purified rabbit anti-mouse MECL1 antibody.

 
Reactivity against the immunosubunits LMP2 (β1i) and LMP7 (β5i)
To extend the analysis of an anti-proteasomal response against the catalytic site bearing immunosubunits, recombinant LMP2 (β1i) and LMP7 (β5i) proteins were used as antigens in ELISA. Only one healthy control was tested positive for anti-rLMP7 (β5i) antibodies (reactivity of 1.79 U). No reactivity against LMP2 (β1i) was detected in the control group. Subsequently, sera of patients with SLE, pSS and PM/DM with a formerly documented positive reactivity against constitutive 20S-proteasome in ELISA were investigated. In these three different systemic autoimmune disorders, reactivity against rLMP2 was found in 33% (9/27) of patients with SLE, in 54% (12/22) of patients with pSS and in 53% (14/26) of patients with PM/DM (Fig. 3). In most of the patients, the antibody reactivity was rather weak, whereas high-titre anti-rLMP2 antibodies (defined by a 2-fold cut-off level of >8.2 U) were observed only in two patients with SLE, two patients with pSS and four patients with PM/DM. Antibodies against rLMP7 were positive in 62% (17/27) of patients with SLE, in 72% (16/22) of patients with pSS and in 65% (17/26) of patients with PM/DM. Strong reactivity against rLMP7 (defined by a 2-fold cut-off level of >3.4 U) was detectable in seven patients with SLE, seven patients with pSS and nine patients with PM/DM. In fact, antibody titres against rLMP2 and rLMP7 were significantly elevated in patients with SLE, pSS and PM/DM compared with healthy controls (P < 0.001). Moreover, patients with pSS and PM/DM showed significantly higher antibody reactivities against rLMP2 compared with patients with SLE (P < 0.03).


Figure 3
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  		FIG. 3. Reactivity of proteasome-positive patients’ sera against catalytic immunosubunits rLMP2 (A) and rLMP7 (B) in ELISA. The respective cut-off value is indicated (–).

 
All SLE patients and virtually all patients with pSS and PM/DM exhibited anti-rLMP2 antibodies and were also positive for anti-rLMP7 antibodies. Antibody responses against both immunosubunits were significantly correlated in patients with SLE (Spearman r = 0.8, 95% CI 0.63, 0.92, P < 0.0001), in patients with pSS (Spearman r = 0.56, 95% CI 0.17, 0.8, P < 0.0064) and in patients with PM/DM (Spearman r = 0.84, 95% CI 0.66, 0.93, P < 0.0001).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
In this study, our results place emphasis on the autoimmune reaction against proteasomal immunosubunits in patients with different systemic autoimmune diseases. As a result, autoantibodies against LMP2 (β1i) and LMP7 (β5i) were found in a significant number of anti-proteasome antibody-positive sera from patients with SLE, pSS and autoimmune myositis. In previous studies, preparations from erythrocytes had generally been used for the detection of anti-proteasome antibodies. However, immunosubunits are not expressed in this antigen source with the rare exception of MECL1. Thus, for further detailed characterization of the anti-proteasome response including immunosubunits, it is necessary to use recombinant antigens or immunoproteasome preparations from cell cultures after exposure to IFN-{gamma}.

The autoantibodies so far identified against 20S-proteasomes are directed against all subunits of the outer rings ({alpha}1–{alpha}7) as well as against all active β-subunits (constitutive β1, β2, β5 and inducible β1i, β2i and β5i). In addition, anti-proteasome antibodies also targeted the subunits C5 (β6) and N3 (β7) of the inner rings [4–6, 19, 20, 27]. Therefore, the extended diversity of anti-proteasome antibody reactivity is directed against almost all subunits of the 20S-complex as shown in Fig. 4.


Figure 4
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  		FIG. 4. 20S-proteasome subunits recognized by patient autoantibodies. The seven {alpha}-type (upper panel) and β-type (lower panel) subunits, which form the {alpha}- and β-rings of the 20S-proteasome complex targeted by autoantibodies are indicated with a ‘Y’. The constitutional β-type subunits MB1 (β5), Delta (β1) and Z (β2) are replaced by inducible subunits LMP7 (β5i), LMP2 (β1i) and MECL-1 (β2i) to form the immunoproteasome.

 
The remarkable frequency of anti-LMP2 (β1i) and anti-LMP7 (β5i) autoantibodies in anti-proteasome antibody-positive sera from patients with three different systemic autoimmune diseases suggests a possible triggering role of these immunosubunits in the induction of the anti-proteasome autoreactivity. So far, little is known about mechanisms of induction or antigen spreading of the rather heterogeneous anti-proteasomal immune response. This process might be triggered by the existence of high levels of circulating intact immuno- and constitutive proteasomes, which have been observed in systemic autoimmune diseases [28, 29]. Further investigations are required to confirm a possible intra- or inter-molecular spreading of the autoimmune response against proteasomal subunits, as it was shown for the Ro/La-antigenic complex [30]. Since sequences of all {alpha}-type subunits of the proteasome show a similarity of at least 20% with each other, and conservation between species is generally very high, cross-reactivity between antibodies against {alpha}-type subunits might occur [31]. In contrast, proteasomal β-type sequences are less well-conserved, and their homology scores are always <20%. In our study, we used recombinant mice LMP2 (β1i) and LMP7 (β5i) proteins as the only recombinant source available so far for detection of anti-proteasome antibodies in ELISA. The genes for LMP2 (β1i) and LMP7 (β5i) have been mapped to the MHC-locus on chromosome 6 in humans and 17 in mice, whereas MECL-1 (β2i) maps to chromosome 16 in humans [32]. However, the sequence similarity for LMP2 (β1i) is 96.8% and for LMP7 (β5i) 95.6% between human and mouse (identity of amino acid sequences of 88.6 and 88.7%, respectively).

It remains unclear, whether anti-proteasome antibodies should be considered as an epiphenomenon or whether they are involved in pathophysiological processes of systemic autoimmune disorders. Recently, it was shown that anti-proteasome antibodies contribute significantly to the overall repertoire of autoantibodies and interfere with known patterns in ANA staining [33]. However, as far as it is recognized today, anti-proteasome antibodies are not disease specific and therefore, their diagnostic significance has to be considered as relatively low. Interestingly, anti-proteasome antibodies are able to block the interaction between the 20S-proteasome complex and the proteasome activator PA28 in vitro [27]. This effect is clearly attributable to antibodies against {alpha}-type subunits. However, a pathophysiological significance of such 20S-proteasome inhibition is unlikely, since there is no evidence that the intracellular ubiquitin–proteasome system is accessible to these autoantibodies. The active sites of the 20S-proteasome itself are located in-site of the cylindrically shaped complex and are not accessible to antibodies. Thus, for antibodies against β-type subunits an influence on proteasome function cannot be anticipated and their significance remains obscure. Nevertheless, the mechanism as to how these particular subunits became autoantigenic is of special interest. In this context, a possible function of anti-proteasome antibodies clearing circulating proteasomes is the focus of ongoing studies. Given the central role of the ubiquitin–proteasome system for cellular homeostasis and the regulation of apoptosis as well as inflammatory responses, further characterization of autoimmune reactivity against the catalytic core complex is of particular importance, since these antibodies can also be used as tools to probe the function of the proteasome system.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Peter-M. Kloetzel (Institute of Biochemistry, Charité, Berlin) for his support and Christine Knuehl for providing us with the affinity-purified anti-MECL1 antibody.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 18 September 2007; revised version accepted 16 January 2008.
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