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International Immunology Advance Access published online on November 13, 2007
International Immunology, doi:10.1093/intimm/dxm118
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Testis-expressed protein TSGA10 – an auto-antigen in autoimmune polyendocrine syndrome type I

Koit Reimand1, Jaakko Perheentupa2, Maire Link1, Kai Krohn3, Pärt Peterson1 and Raivo Uibo1

1 Immunology and Molecular Pathology Groups, Centre of Molecular and Clinical Medicine, University of Tartu, 19 Ravila Street, Tartu 50411, Estonia
2 Hospital for Children and Adolescents, University of Helsinki, Helsinki FIN-00290, Finland
3 Institute of Medical Technology, University of Tampere, Tampere FIN-33014, Finland

Correspondence to: Correspondence to: R. Uibo; E-mail: raivo.uibo{at}ut.ee


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autosomal recessive disorder. Autoimmune gonadal failure is often one of its features. The aim of this study was to identify targets of immune reactions associated with male autoimmune hypogonadism in APS1. Human testis cDNA expression library immunoscreening with APS1 patients' sera identified the protein testis-specific protein 10 (TSGA10), which is a testis-expressed protein with a key role in spermatogenesis. The corresponding serum autoantibodies were detected by Radioimmunoprecipitation assay in 3 of 40 male (7.5%) and 2 of 26 female (7.7%) APS1 patients but in none of either 32 patients with Addison's disease or 116 healthy controls (p=0.0055). However, the TSGA10 antibodies in APS1 patients showed no correlation with testicular or ovarian failure or with autoimmune hypogonadism markers. Nevertheless, their presence in a proportion of patients with APS1 highlights the role of TSGA10 as a target of immune reactions in APS1.

Keywords: APECED, APS1, cDNA library


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
Autoimmune polyendocrine syndrome type 1 (APS1; OMIM #240300), also known as autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy, is a rare monogenic autosomal recessive disorder caused by mutations of autoimmune regulator (AIRE gene) (OMIM *607358) gene (1, 2). Clinical diagnosis of APS1 requires identification of at least two of the three main features of the syndrome: mucocutaneous candidiasis, adrenocortical insufficiency and hypoparathyroidism. Other common features of proved or probable autoimmune origin in APS1 are as follows: a failure of gonadal function, chronic active hepatitis, alopecia, vitiligo, type 1 diabetes and gastrointestinal dysfunction (3). This broad spectrum of organ-specific autoimmunity is accompanied by a variety of autoantibodies against intracellular or cell-surface auto-antigens, which are expressed in the affected organs.

The prevalence of hypogonadism in APS1 females is 35–69% and, depending on the age of the studied patients, is three times lower (8–28%) in males (4). Several reports have connected hypogonadism in APS1 to the presence of steroid cell antibodies or to autoantibodies against steroidogenic enzymes, cytochrome p450 21-hydroxylase (CYP21A2), cytochrome p450 17{alpha}-hydroxylase (CYP17) and cytochrome p450 side-chain cleavage enzyme (CYP11A1) (4–6). All three enzymes are expressed in the adrenal cortex and the latter two are also expressed in the gonads. Although these autoantibodies are quite well associated with ovarian failure in female APS1 patients, there is no such clear-cut association with gonadal dysfunction with the presence of steroid cell autoantibodies in male patients (6, 7). Indeed, only half of APS1 male patients with hypogonadism have autoantibodies to CYP11A1 or CYP17 (6, 7). Thus, one could not exclude the possibility that these autoantibodies are primarily connected to adrenal autoimmunity and have no direct relationship to autoimmune processes in the testes (8) where testis-specific auto-antigens could be primarily involved. One reason to assume the existence of testis-specific auto-antigens in APS1 is the fact that male mice with defective AIRE gene, as a murine model of APS1, develop an immune response against the testes (9). Unfortunately, auto-antigenic targets, specifically responsible for the autoimmune destruction of the testes, have not been identified in these animal models.

In the present study, we aimed to search for the testicular proteins that could be targets for autoimmune reaction in male hypogonadism in APS1. The selected method of testicular cDNA expression library immunoscreening has repeatedly given successful results in the characterization of novel auto-antigens including many target proteins, which have been proved to be usable for development of clinically significant autoantibody assays (10–12). We here report that the testis-specific protein 10 (TSGA10; OMIM* 607166 [OMIM] ) is a novel auto-antigen in APS1 patients.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 References
 
Patients and controls
Sera from 66 APS1 patients (40 men and 26 women) of Finnish origin were used in the study. Sera were obtained from the patients after informed consent and the study was approved by the ethics committees of both Helsinki and Tampere University Hospitals. Testicular hypofunction (azoospermia or testicular atrophy) was diagnosed in 5 of the 40 male patients and ovarian dysfunction (primary or secondary amenorrhoea) was diagnosed in 12 of the 26 female patients. Autoantibodies against CYP17 and/or CYP11A1, as tested by radioimmunoprecipitation assay (RIPA) with recombinant auto-antigens, were found in 1 of the 5 male patients and in all 12 female patients with hypogonadism (5). Two control groups were used for the study: (i) sera from a ‘healthy’ group of 20 males of Finnish origin and 96 blood donors of Estonian origin (50 males and 46 females) and (ii) sera from an autoimmune Addison's disease group of 32 patients (13 males and 19 females) of Estonian origin.

Six APS1 male patient sera were selected from these serum samples for cDNA library immunoscreening. Five were selected on the basis of clinical signs of hypogonadism and one for giving a weak positive immunofluorescence reaction with testis tissue substrate. Two of the selected sera have been previously tested by RIPA to be positive for autoantibodies to CYP11A1, and one of them was also positive for CYP17 (5).

Screening of cDNA library
Human testis cDNA library in {lambda}TriplEx vector (Clontech, Palo Alto, CA, USA) was screened by plating out 2 x 106 plaque-forming units. For library immunoscreening, the selected six sera were pooled to get the final dilution of 1:50 for every serum in 5% skimmed milk and 0.05% Tween 20 in 20 mM Tris–HCl pH 7.5 and 150 mM NaCl buffer (TBS-MT) containing 0.25% NaN3. In order to reduce the non-specific background due to presence of Escherichia coli antibodies, sera were pre-absorbed with sonicated lysate of the bacteriophage plating bacteria (E. coli XL-1 Blue). The TBS-MT buffer was used for the nitrocellulose filter (NitroBind 0.45 µm, Osmonics, Minnetonka, MN, USA) blocking, for primary and secondary antibody dilutions as for washing steps.

After overnight incubation with the pool of sera and subsequent extensive washings, the filters were incubated with biotinylated anti-human IgG, supplemented with HRP–Avidin D (both from Vector Laboratories, Burlingame, CA, USA). Prior to colour development with 4-chloro-1-naphthol, the filters were extensively washed with TBS-MT and once with TBS. The positive clones were collected and repeatedly re-screened until pure clone isolates were obtained. The false-positive bacteriophage isolates were excluded by testing all clones with the secondary antibody alone and comparing the results with replicas obtained by immunoscreening. The positive bacteriophage {lambda}TriplEx clones were converted to plasmid pTriplEx clones as specified in the library manual. The DNA inserts of bacteriophage clones were sequenced by ABI PRISM 310 with a BigDye sequencing kit (PE Applied Biosystems, Foster City, CA, USA) and the sequences were identified by similarity search with BLAST program (http://www.ncbi.nlm.nih.gov/BLAST/).

Recombinant TSGA10
Normal human testis RNA was reverse transcribed by a FirstStrand cDNA Synthesis Kit (Fermentas, Vilnius, Lithuania). The full-length TSGA10 cDNA was amplified from the testis cDNA with the TSGA10-specific primers and Pfu DNA polymerase (Fermentas) and further cloned into two expression vectors, pGEX1ZT-SH3 (a gift from Kalle Saksela, University of Tampere) and pcDNA3.1/myc-His(–)B (Invitrogen, Carlsbad, CA, USA). The constructs were verified by restriction enzyme analysis and DNA sequencing from both directions of the inserted fragments. The [S-35]-radiolabelled in vitro transcribed/translated TSGA10 protein was produced with pcDNA3.1-TSGA10 plasmid and TNT T7-coupled reticulocyte lysate system (Promega, Madison, WI, USA), followed by purification with Sephadex G-25 column (NAP-5 columns, Amersham Biosciences, Uppsala, Sweden). For bacterial expression as a glutathione-S-transferase (GST)-fusion protein, the E. coli strain DH5 transformed with pGEX-TSGA10 plasmid was induced by 1 mM isopropyl-beta-D-thiogalactopyranoside. The bacterial pellet was lysed by ultrasonication and the recombinant GST-fusion protein was purified by Glutathione Sepharose (Amersham Biosciences).

Immunoblotting
Immunoblotting with purified GST-fused TSGA10 protein was performed using Mini-Protean II and Mini Trans-Blot apparatuses (Bio-Rad, Hercules, CA, USA). PAGE with 0.1% SDS was followed by the transfer of polypeptides to nitrocellulose membrane (Hybond-ECL 0.45 µm pore, Amersham Biosciences, Little Chalfont, Buckinghamshire, UK) and membrane blocking with 4% skimmed milk in TBS. The membrane strips were incubated with 1:100 sera dilutions overnight at +4°C. Rabbit polyclonal anti-GST antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) at dilution 1:1000 was used as a positive control for the recombinant protein. After the washing steps, the strips were treated with alkaline phosphatase-conjugated secondary antibodies against human IgG (rabbit) or against rabbit Igs (swine; both from DAKO, Glostrup, Denmark) and the immune complexes were visualized by BCIP/NBT colour development.

Radioimmunoprecipitation
The radiolabelled TSGA10 protein [40 000 counts per minute (c.p.m.) per sample] in 50 µl RIPA buffer (150 mM NaCl, 10 mM Tris–HCl pH 7.4, 5 mM EDTA, 0.05% Tween 20 and 1% gelatin hydrolysate) and human serum samples (50 µl, 1:10 diluted) were mixed in 1.5-ml microcentrifuge tubes and then incubated at room temperature (RT) for 15 min. Then, 50 µl Protein G Sepharose (Amersham Biosciences, Uppsala, Sweden), 15% slurry in RIPA buffer (v/v), was added to each sample and incubated at RT in gentle overhead mixing for 45 min. Samples were washed six times with 1 ml RIPA buffer by centrifugation, which was followed by vacuum aspiration of supernatant fluid. Finally, the test tube bottoms containing Protein G Sepharose were sliced into scintillation vials, scintillation fluid was added and mixed and the scintillation was counted by Wallac Guardian 1414 liquid scintillation counter (Wallac OY, Turku, Finland). Every run of assay included a positive and a negative control sample. For the positive control, we used the serum from an APS1 patient that was included in the pool of sera used for library immunoscreening and showed the highest reactivity, whereas the negative control was a TSGA10 autoantibody-negative APS1 serum. Samples were analysed in duplicates and the results were expressed as TSGA10 radioimmunoprecipitation index units {RIU [(c.p.m. sample – c.p.m.negative control)/(c.p.m.positive control – c.p.m.negative control)] x 100}. An index of six units was chosen as the upper limit of normal results based on the results of the healthy controls.

Statistics
Fisher's exact test and Wilcoxon Mann–Whitney U-test were used for statistical analysis with R language and environment for statistical computing (13).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
Identification of TSGA10 as a novel auto-antigen in APS1
Altogether 10 independent recombinant {lambda}-phage clones were isolated after the immunoscreening of the human testis cDNA library. Inserts of the clones were sequenced and identified by database searches. Eight of the 10 positive clones contained cDNA fragments identical to human testis-specific gene TSGA10 mRNA (NM_025244) as revealed by DNA sequence similarity analysis with BLAST program. Entire inserts of these eight clones corresponded to the mRNA-coding regions and all fragments ended at the XbaI restriction enzyme site that was located within the cDNA. As during the cDNA library construction the XbaI digestion was used for the cloning of the 3' ends of inserts, all purified clones lacked the sequence encoding the last 132 C-terminal amino acids (aa). At their 5' ends, the clones were different by insert size with the shortest fragment encoding for 175 aa and the longest for 494 aa from the total 698 aa of full-length TSGA10 protein. In addition, an alternative splicing was detected in two of the cDNA clones as one fragment lacked the exon 15 and another lacked the exon 11.

Cloning of full-length TSGA10 cDNA and autoantibody analyses
TSGA10 full-length cDNA was amplified with the gene-specific primers from the human testis mRNA sample and cloned further to pGEX1ZT expression vector as to pcDNA3.1 expression vector. The latter was transcribed with T7 RNA polymerase and the in vitro translated and [S-35]-labelled product appeared as expected as 82-kDa band after SDS–PAGE and subsequent autoradiography (Fig. 1).


Figure 1
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  		Fig. 1. RIPA test results with TSGA10 as revealed by SDS–PAGE and autoradiography. Lane (a), molecular weight markers; lane (b), control of TSGA10 antigen (20% amount); lane (c), APS1 serum with TSGA10 antibodies (high RIPA index = 92 RIU); lane (d), healthy control serum; lane (e), APS1 serum without TSGA10 antibodies but positive for CYP17 and CYP11A1 antibodies and lane (f), APS1 serum with TSGA10 antibodies (low RIPA index = 10 RIU).

 
Bacterially expressed and glutathione affinity-purified GST–TSGA10 fusion protein was used as an antigen in immunoblotting with five APS1 male sera and 34 sera from controls. In addition to one recombinant 108-kDa (TSGA10 82 kDa + GST 26 kDa) protein band, several smaller bands appeared in Coomassie-stained SDS–PAGE. There were no differences, according to immunoblot analysis, between the APS1 and healthy controls in immunoreactivity. The majority of the control sera demonstrated the same pattern of immunoreactivity as APS1 sera, including reactivity against 108-kDa full-length uncleaved fusion protein (data not shown).

Radioimmunoprecipitation analysis of serum samples from three (7.5%) male and two (7.7%) female APS1 patients showed antibody reactivity against full-length TSGA10 protein above the cut-off value of six units of index (Table 1, Figs 1 and 2). Higher index values were revealed in TSGA10 antibody-positive males (92, 60 and 20 RIU) than females (11 and 10 RIU). All healthy control group sera, of either Finnish or Estonian origin, gave negative values and the frequency of antibodies was significantly different from that in APS1 group (P = 0.0055). No antibody-positive cases were found among the 32 Addison's disease patients. There was a statistically significant difference in the RIPA index values between APS1 and all the healthy control groups (P = 0.039).


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  		Table 1. Results of TSGA10 autoantibody analysis by RIPA in the APS1, healthy controls and Addison's disease control groups

 

Figure 2
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  		Fig. 2. RIPA test results as expressed in RIPA index values (RIU) in APS1, healthy controls (C) and Addison's disease group (AD).

 
Clinical associations
None of the three TSGA10 antibody-positive APS1 male patients had any clinical signs suggesting testicular failure. On the other hand, none of the five APS1 males with clinical signs of hypogonadism had antibody reactivity against TSGA10. One of the TSGA10 antibody-positive males had these autoantibodies in all four sera available from a 26-year follow-up medical record. Indirect immunofluorescence of his sera and of a serum from another patient with antibodies against TSGA10 revealed a speckled staining pattern in the cytoplasm of spermatocytes/spermatids on testicular tissue (Fig. 3). Although this was distinguishable from patterns seen with a number of TSGA10 antibody-negative sera, other sera with TSGA10 antibodies did not reveal such definite immunofluorescence characteristics. Another TSGA10 antibody-positive patient had sera from 18-year period and all three samples contained these antibodies. A third TSGA10 antibody-positive male patient had, according to a 25-year follow-up medical record, developed antibodies at the age of 33 years. From the two TSGA10-positive APS1 female patients, one had secondary amenorrhoea at the age of 18.5 years and gonadal insufficiency. None of the other 11 female APS1 patients with hypogonadism had TSGA10 antibodies. Also, there was no statistically significant correlation between the TSGA10 antibody positivity and gonadal failure or antibodies to CYP11A1 and CYP17 in the studied sera (data not shown). Hence, the presence of TSGA10 antibodies has no correlation with testicular or ovarian failure or autoimmune hypogonadism markers in APS1 patients. There were no malignancies in any of the studied patients.


Figure 3
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  		Fig. 3. Indirect immunofluorescence tests results with APS1 sera. The antigenic substrate is rat testicular tissue, x40 magnification. (a) Testis-reactive TSGA10-positive serum with speckled staining pattern in spermatocytes/spermatids cytoplasm. (b) Testis-reactive TSGA10-negative serum with Leydig cell-staining pattern. (c) Testis non-reactive serum.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
The present study complements the list of auto-antigens involved in autoimmune processes in APS1—a multifaceted syndrome developed as a result of the AIRE, gene mutations. Using testis cDNA expression library immunoscreening by sera from male hypogonadic patients and a patient with positive immunofluorescence serum reaction on testicular tissue, we cloned a TSGA10 gene cDNA which has been shown to be specific for testicular tissue in the seminal study of Modarressi et al. in 2001 (14). The in vitro transcription/translation of the full-length cDNA of TSGA10 and the protein immunoreactivity analysis in RIPA enabled us to demonstrate the occurrence of autoantibodies to TSGA10 in 7.5% of patients with APS1, whereas healthy control sera were negative. At the same time, no positive reactions were revealed with the patients' sera on immunoblotting using TSGA10 protein expressed and purified from E. coli. The discrepancy between the results of the two assays may be due to a number of factors of which the most likely explanation is the recognition of the conformational TSGA10 epitopes in the immunoprecipitation assay with in vitro transcribed/translated antigen but not in the immunoblotting using TSGA10 expressed in E. coli. Similar differences between RIPA and immunoblot analysis with recombinant auto-antigens have been reported in many studies (15, 16). As most of the epitopes, recognized by autoantibodies, are conformational (17), the RIPA can be considered as more suitable assay for autoantibody detection compared with the immunoblot. Most interestingly, both male and female sera reacted with TSGA10. Originally, TSGA10 was identified as testis-specific protein with a key role in spermatogenesis (14). Subsequent studies, however, indicated its over-expression in various types of malignant tumours (18–20) and actively dividing foetal tissues (21). More recently, evidence was presented for a broader distribution of TSGA10 in embryogenesis but also in some normal tissues, especially in neural crest derivates, actively dividing or post-mitotic cells (22). Therefore, the development of autoantibodies against TSGA10 could not be limited to testicular autoimmunity, as seen by the absence of correlation between hypogonadism and TSGA10 autoantibody positivity in males. However, as Perheentupa (4) explains, testicular failure in APS1 is heterogeneous and rather difficult to diagnose. Nevertheless, the presence of a high amount of TSGA10 autoantibodies in an APS1 patient without gonadal failure, with a 26-year follow-up medical record, strongly supports the idea that tolerance to TSGA10 in APS1 patients could be lost without involvement of progressing autoimmune destruction of testicular tissue. Malignancies are ruled out because the patients have undergone extensive clinical investigations during the whole study period.

Although new data about TSGA10 are steadily accumulated, still not enough is known about the functions of the protein itself. Experiments with mouse homologue, Mouse TSGA10 (NM_207228, 89% DNA and 94% aa level identity with human TSGA10), demonstrate predominant translation of 65-kDa Mouse TSGA10 protein in the post-meiotic phase in spermatogenesis (21). Full-length 65-kDa Mouse TSGA10 protein appears to be processed to a 27-kDa structural protein of fibrous sheath in the principal piece of the sperm tail. TSGA10, being predominantly expressed in testis and over-expressed in several malignant tumours, is considered to belong to the cancer/testis (CT) antigen group (18). Therefore, CT antigens can be considered functionally tumour specific and attractive targets for tumour immunotherapy (23). The recently described role of TSGA10 in active cell division, differentiation and migration of cells (22) and interaction with hypoxia-inducible factor-1{alpha} (24) provides several new study avenues for this protein.

The cause of TSGA10 antibodies development in APS1 patients remains unresolved. Antibodies were detected in a limited number of patients without any other features to distinguish them from the other patients. Characteristically, sera of APS1 patients contain a variety of specific autoantibodies, frequently in high titre. Some of these autoantibodies, like against enzymes CYP21A2 or GAD65, are commonly detected in APS1 patients such as those with isolated organ-specific autoimmune diseases (25, 26). On the other hand, some autoantibodies such as AADC and CYP1A2 are found almost exclusively in APS1 (27, 28). The present study does not clarify whether TSGA10 autoantibodies are exclusive for APS1 or not. The prevalence of TSGA10 antibodies is ~7% in the APS1, which is relatively low but in the same magnitude of prevalence as IA-2 and CYP1A2 autoantibodies in APS1. Similarly to TSGA10, these autoantibodies do not correlate with any other specific clinical or immunologic features.

In our RIPA test system, however, the low number of positive reactions might be connected to limitations of our methodological approaches. Namely, the structure and biological function of auto-antigens produced by in vitro cDNA transcription and translation procedure could be somewhat abnormal due to the absence of their glycosylation and therefore not ‘reactive’ enough for the detection of pathogenic antibodies. Also, the difference between in vitro produced and native auto-antigenic molecules could easily explain the discrepancy between the results of RIPA and immunofluorescence assays. To overcome these problems, one could suggest the use of alternative strategies for auto-antigens characterization in autoimmune diseases. Here, glycopeptides libraries could be reliable tools for further studies (29).

In a virus-induced autoantibody responses experiment in mice (30), the recognized autoantigens were mostly intracellular and non-organ-specific, one of them being Mtsga10, which was identified in a murine ovary cDNA expression library. Interestingly, the majority of other targets identified in this study were orthologs or homologs of known autoantigens in different human diseases (30).

Taken together, we have revealed an association between autoantibodies to testis-expressed and active cell division protein TSGA10 and a portion of patients with APS1. Although the mechanism of development and exact role of these antibodies remains to be evaluated in further studies, particularly in males among couples having so-called male infertility factor, we stress the role of TSGA10 as a target of immune reactions in APS1.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
Estonian Foundation (6514); European Union (LSHM-CT2005 005223).


   Acknowledgements
 
We thank Tambet Teesalu, University of Tartu, who provided human testis RNA for cloning of human TSGA10.


   Abbreviations
 
aa, amino acid
AIRE, autoimmune regulator
APS1, autoimmune polyendocrine syndrome type I
c.p.m., counts per minute
CT, cancer/testis
CYP11A1, cytochrome p450 side-chain cleavage enzyme
CYP17, cytochrome P450 17{alpha}-hydroxylase
CYP21A2, cytochrome P450 21-hydroxylase
GST, glutathione-S-transferase
Mtsga10, mouse TSGA10NM_207228
RIPA, radioimmunoprecipitation assay
RIU, radioimmunoprecipitation index units
RT, room temperature
TBS-MT, tris buffered saline with 5% skimmed milk and 0.05% Tween 20
TSGA10, testis-specific protein 10

   Notes
 
Transmitting editor: A. Cooke

Received 16 March 2007, accepted 15 October 2007.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 

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