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H P Rihs

Publications and source records attributed to H P Rihs.

At least 19 recordsLinked to original sources
PubMed2002

IgE reactivity to profilin in pollen-sensitized subjects with adverse reactions to banana and pineapple.

BACKGROUND: The so-called 'latex-fruit syndrome' is a well-documented phenomenon in cross-reactive allergies. By contrast, there is a lack of information about allergy to exotic fruits in patients with a predominant pollen sensitization. Since the ubiquitous protein profilin has been identified as an allergen in natural rubber latex as well as in pollen-related foods, the aim of this study was to investigate the role of profilin in allergy to certain exotic fruits. METHODS: Recombinant profilins from banana and pineapple were cloned by a PCR technique after isolation of total RNA using degenerated profilin-specific primers. The unknown 5' ends of copy DNA (cDNA) were identified by rapid amplification of 5'cDNA ends (5'-RACE) and expression in Escherichia coli BL21(DE3) cells. The recombinant profilins were purified by affinity chromatography using poly-(L)-proline as the solid phase. IgE-binding capabilities were characterized by means of immunoblot and Enzyme Allergosorbent Test (EAST). The cross-reactivity to birch pollen profilin and latex profilin was studied by EAST as well as by immunoblot inhibition experiments. RESULTS: Both banana and pineapple profilin were found to consist of 131 amino acid residues with high amino acid sequence identity to known allergenic pollen and food profilins (71-84%). IgE binding to the recombinant profilins was observed in 7/16 sera from subjects with suspected banana allergy (44%) and in 8/19 sera from subjects with suspected pineapple allergy (42%). Inhibition experiments indicated similar IgE reactivity of natural and recombinant allergens. In addition, high cross-reactivity to birch pollen profilin Bet v 2 and latex profilin Hev b 8 was demonstrated by immunoblot inhibition as well as EAST inhibition experiments. CONCLUSIONS: Since a high IgE-binding prevalence of about 40% was obtained in both banana and pineapple allergy, we conclude that profilin is an important mediator of IgE cross-reactivity between pollen and exotic fruits.

Adult↗
PubMed2002

Interest of two-dimensional electrophoretic analysis for the characterization of the individual sensitization to latex allergens.

BACKGROUND/OBJECTIVE: Latex allergy is a type 1 hypersensitivity reaction that mainly affects high-risk populations such as health care workers, spina bifida-affected or multiply-operated children. Ten molecules have so far been identified and registered as latex allergens (Hev b 1 to Hev b 10). The aim of the present investigation was to identify the major latex allergens by an individual analysis of the IgE response of latex-allergic patients to latex proteins separated by two-dimensional (2-D) gel electrophoresis. MATERIALS AND METHODS: Latex proteins from a sap or a glove extract were separated by 2-D electrophoresis and transferred to a nitrocellulose membrane. Each membrane was incubated with the serum of one latex-allergic patient. The most frequently recognized latex allergens were characterized in sap and glove extracts using monoclonal antibodies or amino acid microsequencing. RESULTS: The one-dimensional screening of 54 patient sera revealed 4 major bands recognized by IgE. The 2-D analysis of the sensitization to latex allergens allows the identification of allergen isoforms and the characterization of an individual response diversity. Hev b 6.01 was recognized by 88.9% of the patients. Protein spots around 14 kD were recognized by 48.1% of the patients and corresponded to Hev b 6.03 as well as other proteins. A not yet characterized doublet of acidic proteins with molecular masses of 43 and 94 kD was recognized by 20.4% of the sera. Only 5.5% of the sera did not recognize any of these 4 major allergens. Hev b 1 is the main protein from the glove extract but was not constantly found in sap extracts. CONCLUSIONS: One-dimensional electrophoretic analysis of the allergen is usually not sufficient to characterize the individual specificity of the IgE response to latex allergens. Latex-glove proteins which are allergens can be absent from the sap extracts and the sensitization to these allergens could be underestimated. Individual 2-D analysis of the sensitization to latex allergens is useful to define the best allergen mixture required for diagnosis and needed for individual therapy monitoring.

Allergens↗
PubMed2000

PCR-based cloning, isolation, and IgE-binding properties of recombinant latex profilin (rHev b 8).

BACKGROUND: Profilin (Hev b 8) in natural rubber latex (NRL) has been assumed to be an important allergen. Since latex profilin has a molecular mass similar to two other latex allergens (Hev b 1 and Hev b 6.03) in the 14-kDa range, it is difficult to obtain sufficient amounts of purified native profilin for investigations and diagnostics. The present study aimed to produce recombinant latex profilin (rHev b 8) and study its IgE-binding reactivity. METHODS: A profilin-specific cDNA encoding the latex profilin from Hevea brasiliensis leaves was synthesized and subcloned, and the rHev b 8 was overexpressed in fusion with the maltose-binding protein (MBP) in E. coli. The IgE-binding reactivity of rHev b 8 was studied by immunoblotting, immunoblot inhibition experiments, and the Pharmacia CAP method, with 25 sera from health-care workers with latex allergy and 17 sera from latex-sensitive spina bifida patients. RESULTS: rHev b 8 was found to have 131 amino acids and a sequence identity of 75% with birch profilin (Bet v 2). Analysis by the CAP system revealed the presence of rHev b 8-specific IgE antibodies in two out of 17 sera from spina bifida patients and in five out of 25 sera (20%) from health-care workers. Two subjects of the latter group with rHev b 8-specific IgE showed negative results in the skin prick tests with tree-pollen extracts and had no IgE to rBet v 2, indicating the presence of IgE-binding epitopes on the Hev b 8-molecule which do not cross-react with birch profilin. Immunoblot inhibition assays using MBP-rHev b 8 as inhibitor confirmed the presence of latex profilin in the NRL extract. IgE binding to the native latex profilin could be completely inhibited by the MBP-rHev b 8. CONCLUSIONS: Latex profilin represents a minor allergen in NRL and may have IgE-binding epitopes different from Bet v 2.

Adult↗
PubMed2000

Recombinant Hev b 1: large-scale production and immunological characterization.

BACKGROUND: Hev b 1 represents one of the most important allergens in Hevea brasiliensis latex. It is difficult to get an appropriate amount of native Hev b 1 (nHev b 1) for research purposes. OBJECTIVE: The aim of this study was to produce sufficient amounts of Hev b 1 by recombinant methods to prove its suitability for latex allergy diagnostics. METHODS: We isolated total RNA of Hevea brasiliensis leaves and synthesized cDNA by RT PCR. Recombinant Hev b 1 (rHev b 1) as well as three fragments (amino acid residues 29-137, 48-137, 78-137) were subcloned and expressed as fusion proteins with Maltose-binding protein (MBP) in Escherichia coli. The MBP-rHev b 1 fusion protein was examined by RAST with the CAP method, histamine release test and immunoblots with human sera from spina bifida patients as well as from health care workers with latex allergy and monoclonal antibodies. RESULTS: Histamine release test and immunoblots revealed the high allergenicity of the MBP-rHev b 1 construct. By the CAP method, 54 out of 58 serum samples (93%) from latex-sensitized spina bifida patients previously showing immunoglobulin (Ig) E to nHev b 1 exhibited IgE-binding to rHev b 1. Among 71 latex-allergic health care workers tested, 16 (22.5%) had IgE antibodies to rHev b 1. The analysis of the fusion proteins carrying rHev b 1 fragments revealed that the loss of the N-terminal 28 amino acid residues did not affect IgE-binding. In contrast, the lack of the first 47 amino acid residues led to decreased IgE-binding reactivity in two out of four sera tested, whereas the absence of the N-terminal 77 residues abolished IgE-binding in these two sera. CONCLUSION: The MBP-rHev b 1 fusion protein exhibits a corresponding IgE-binding reactivity to nHev b 1 and may therefore substitute natural Hev b 1 for both in vitro diagnostics and research purposes.

ATP-Binding Cassette Transporters↗
PubMed2000

T-cell receptor repertoire expression in workers with occupational asthma due to platinum salt.

There is a high incidence of asthma, rhinitis, conjunctivitis and contact urticaria in workers of precious metal refineries. Symptoms are closely associated with sensitization to halogenated platinum compounds, as assessed by skin-prick test. The aim of the present study was to examine the molecular mechanisms involved by describing the T-cell receptor (TCR) repertoire distribution of peripheral blood mononuclear cells (PBMCs) without and after in vitro stimulation with sodium hexachloroplatinate. PBMCs of 17 sensitized subjects with work-related asthma and a positive skin-prick test result to sodium hexachloroplatinate and of 15 nonexposed subjects were isolated and TCR expression determined by flow cytometry. Furthermore, the sodium hexachloroplatinate-mediated in vitro effects on the frequency of Vbeta-expressing T-cells, the proliferation response and the expression of cell surface molecules like CD71, CD25, CD95 and HLA-DR were studied. CD3-positive lymphocytes of platinum salt-sensitized workers had a significantly higher frequency of Valpha2a+, Vbeta11+ and Vbeta21.3+ T-cells than controls (p<0.01, p<0.01 and p<0.001 respectively). In vitro stimulation of PBMCs from platinum salt-sensitized as well as control subjects with sodium hexachloroplatinate increased the percentage of CD3-positive cells bearing specific TCRs, especially Vbeta5.3, Vbeta6.7, Vbeta8a, Vbeta20 and Vbeta21.3. This effect was time- and dose-dependent. The present results indicate that the frequencies of Valpha2a-, V11 and Vbeta21.3-bearing blood T-cells and platinum salt-induced lymphocyte proliferation are strongly enhanced in subjects who suffer from asthma due to platinum salt. In addition, in vitro stimulation with sodium hexachloroplatinate modulates the frequencies of certain T-cell receptor-bearing T-cells.

Adult↗
PubMed1999

Plant importin alpha binds nuclear localization sequences with high affinity and can mediate nuclear import independent of importin beta.

Nuclear import of conventional nuclear localization sequence (NLS)-containing proteins initially involves recognition by the importin (IMP) alpha/beta heterodimer, where IMPalpha binds the NLS and IMPbeta targets the IMPalpha/NLS-containing protein complex to the nuclear pore. Here we examine IMPalpha from the plant Arabidopsis thaliana (At-IMPalpha), which exhibits nuclear envelope localization typical of IMPbeta rather than IMPalpha in other eukaryotic cell systems. We show that At-IMPalpha recognizes conventional NLSs of two different types with high affinity (K(d) of 5-10 nM), in contrast to mouse IMPalpha (m-IMPalpha), which exhibits much lower affinity (K(d) of 50-70 nM) and only achieves high affinity in the presence of m-IMPbeta. Unlike m-IMPalpha, At-IMPalpha is thus a high affinity NLS receptor in the absence of IMPbeta. Interestingly, At-IMPalpha was also able to bind with high affinity to NLSs recognized specifically by m-IMPbeta and not m-IMPalpha, including that of the maize transcription factor Opaque-2. Reconstitution of nuclear import in vitro indicated that in the absence of exogenous IMPbeta subunit but dependent on RanGDP and NTF2, At-IMPalpha was able to mediate nuclear accumulation to levels comparable with those mediated by m-IMPalpha/beta. Neither m-IMPalpha nor -beta was able to mediate nuclear import in the absence of the other subunit. At-IMPalpha's novel NLS recognition and nuclear transport properties imply that plants may possess an IMPalpha-mediated nuclear import pathway independent of IMPbeta in addition to that mediated by IMPalpha/beta.

Amino Acid Sequence↗
PubMed1999

IgE binding of the recombinant allergen soybean profilin (rGly m 3) is mediated by conformational epitopes.

BACKGROUND: Soybean proteins are constituents of a number of food products and represent a panel of potential allergens. Thus far, little is known about the molecular characteristics of soybean allergens. OBJECTIVE: The aim of this study was to identify the soybean profilin by PCR-based complementary (c)DNA cloning and to elucidate its allergenic characteristics. METHODS: Highly degenerate profilin-specific primers were used to identify, by means of PCR, 2 soybean profilin isoforms (GmPRO1 and GmPRO2) by using soybean cDNA as a target. One isoform (GmPRO1) with a length of 394 bp corresponding to 131 amino acid residues was subcloned and expressed in fusion with the maltose-binding protein. Moreover, 3 overlapping recombinant soybean profilin fragments comprising amino acid residues 1-65, 38-88, and 50-131 were also prepared as maltose-binding protein fusion proteins. IgE-binding reactivity of the recombinant proteins and the cross-reactivity of soybean profilin with birch profilin was studied by immunoblotting, enzyme-linked allergosorbent assays (EASTs), and competitive inhibition experiments by using serum samples from 13 soybean-sensitized subjects. RESULTS: Results of immunoblot analysis, EAST, and EAST-inhibition experiments indicate the presence of profilin in soybean extract. The recombinant soybean profilin (rGly m 3) was recognized by IgE in 9 (69%) of the 13 sera tested. Only the full-length rGly m 3 was able to bind with IgE antibodies, whereas the 3 soybean profilin fragments did not show significant binding reactivity, indicating that the IgE binding to rGly m 3 depends on the integrity of a conformational structure, which was not present in the overlapping profilin fragments. The rGly m 3 cross-reacted with birch pollen profilin (Bet v 2), and the IgE binding to Bet v 2 could be inhibited by rGly m 3. CONCLUSIONS: rGly m 3 represents a new soybean allergen with well-characterized primary sequence, and its IgE-binding reactivity is mediated by conformational epitopes.

Adolescent↗
PubMed1998

Different distribution of HLA class II and tumor necrosis factor alleles (TNF-308.2, TNFa2 microsatellite) in anti-topoisomerase I responders among scleroderma patients with and without exposure to quartz/metal dust.

OBJECTIVE: To investigate the influence of quartz/ metal dust exposure on the pathogenesis of systemic sclerosis (SSc; scleroderma), by an immunogenetic comparison of HLA class II and tumor necrosis factor (TNF) alleles in patients with and without exposure. METHODS: A retrospective study of 30 SSc patients exposed to quartz/metal dust (qSSc) and 50 patients with idiopathic SSc (iSSc) was conducted by DNA-based typing of HLA, TNF-308, and TNFa/b microsatellite alleles. RESULTS: A neutral or protective haplotype in iSSc anti-topoisomerase I (anti-topo I) responders was found to be a susceptibility haplotype in qSSc patients. HLA-DRB1*0301 (DR3), a component of the extended haplotype HLA-DQA1*0501;B1*0201;DRB1*0301; TNF-308.2;TNFa2/b3, had a decreased frequency in iSSc anti-topo I responders compared with non-responders (P = 0.03, odds ratio [OR] 0.11, 95% confidence interval [95% CI] 0.00-0.95), but a significantly increased frequency in qSSc anti-topo I responders compared with controls and with iSSc anti-topo I responders (P = 0.00004, Pcorr = 0.006, OR 11.38, 95% CI 3.17-44.35 and P = 0.0002, Pcorr = 0.02, OR 30.0, 95% CI 2.05-986, respectively). In contrast, DRB1*1104 (DR5) and DRB1*11/15 (DR5/DR2) with no TNF-308.2 and TNFa2 alleles were prevalent in only the iSSc anti-topo I responders compared with controls (P = 0.0005, Pcorr = 0.04, OR 11.0; 95% CI 2.68-45.93 and P = 0.0002, Pcorr = 0.02, OR 12.43, 95% CI 3.65-40.04, respectively). CONCLUSION: The mechanisms that lead to the development of anti-topo I in qSSc and iSSc patients are suggested to be distinct, although it is not clear that the two diseases themselves are different.

Autoantibodies↗
PubMed1998

Molecular analysis of DRB and DQB1 alleles in German spina bifida patients with and without IgE responsiveness to the latex major allergen Hev b 1.

BACKGROUND AND OBJECTIVE: Spina bifida patients are at a high risk of developing latex allergy. Recently, we found a relationship between the IgE responsiveness to latex allergen hevein and human leucocyte antigen (HLA) alleles DRB1*04(DR4) as well as DQB1*0302(DQ8). This study was carried out to investigate the association between HLA class II alleles and the specific IgE response to latex allergen Hev b 1 in spina bifida patients. METHODS: Blood samples from 103 unrelated German spina bifida patients exposed to latex products and from 90 unsensitized controls were examined. Genomic DNA isolation followed by HLA-D-specifc polymerase chain reaction (PCR) amplification was used to perform HLA typing of allelic polymorphisms in exon 2 of DQB1 and of DRB1,3,4,5 with sequence-specific oligonucleotide probes (SSOPs). RESULTS: Fifty-one out of 103 spina bifida patients were found to have anti-latex IgE antibodies; 40 had also anti-Hev b 1 antibodies. Further, we observed that 80% of the Hev b 1 responders underwent five or more surgeries whereas 55% of the Hev b 1 non-responders and 75% of the latex-non-responders underwent less than five surgical interventions. From the latex-sensitized group 33% showed an elevated phenotype frequency of DRB1*0701(DR7) when compared with unsensitized patients (12%, P = 0.0095, Pc = NS) and with controls (17%; P = 0.035, Pc = ns). Fifteen out of 40 Hev b 1 responders also exhibited an elevated DR7 frequency when compared with latex-sensitive but Hev b 1-negative patients (38% vs 18%, P = NS) or with unsensitized controls (38% vs 17%, P = 0.013, Pc = NS). CONCLUSIONS: Although we found that the DRB1*0701 (DR7) phenotype frequency was elevated in SB patients with latex- as well as with Hev b 1-IgE responsiveness, the analyses of the other class II alleles clearly demonstrate that the HLA-D region does not play a major role in the pathogenetic way of sensitization to Hev b 1.

Adolescent↗
PubMed1998

Analysis of T-cell reactive regions and HLA-DR4 binding motifs on the latex allergen Hev b 1 (rubber elongation factor).

BACKGROUND: The rubber elongation factor in Hevea rubber (Hev b 1) is one of the important latex-allergenic proteins inducing the production of specific IgE antibodies in latex-exposed subjects. In addition, Hev b 1 induces lymphocyte proliferation responses. A study about detailed T-cell epitope analysis of major latex allergens has not been published yet. OBJECTIVE: The aim of this study was to define the T-cell reactive regions on the latex allergen Hev b 1. METHODS: Nine overlapping peptides with 19 or 17 amino acid lengths representing the complete sequence of Hev b 1 were used for T-cell epitope mapping. Peripheral blood mononuclear cells (PBMCs) of latex-sensitized patients and healthy subjects were isolated and stimulated with the synthetic peptides to determine the specific proliferation response. The examined patients were sensitized to latex by occupational exposure (n=14) and suffered from rhinitis, conjunctivitis, contact urticaria and/or asthma. Two control groups of non-sensitized subjects were studied, one occupationally exposed to latex (n=4), the other one not exposed to latex (n=4). RESULTS: Positive proliferation response induced by one or more peptides was detected in 10 of the latex-sensitized patients and in two of the latex-exposed non-sensitized subjects. Each patient exhibited an individual epitope reactivity pattern. The whole protein was found to be immunogenic, but the intensity of lymphocyte responses induced by the peptides was different. The majority of the patients' PBMCs (more than 66%) responded to the peptides 31-49 and 91-109. Using the peptide selection of Stille's algorithms, three epitopes were predicted covering region 38-74 and two others covering region 82-104; the two peptides 31-49 and 91-109 are part of these regions. A strong HLA-DR4Dw4 (DRB1*0401)-binding motif according to published DR4w4 binding motifs was predicted in the region of 102-110 including peptide 91-109 to which the majority of tested HLA-DR4-positive patients responded. CONCLUSIONS: Our data indicate that the whole 14 kDa protein Hev b 1 is immunogenic having regions that demonstrate individual and varying PBMC stimulation. Experimental data of T-cell reactive regions based on PBMC-stimulation complement the information on T-cell epitope prediction. In addition, the Hev b 1 molecule contains a HLA-DR4Dw4 (DRB1*0401)-binding motif.

Adult↗
PubMed1997

No evidence for the influence of HLA class II in alleles in isocyanate-induced asthma.

Isocyanates are one of the main causes of occupational asthma. The aim of this investigation was to study the possible genetic background of isocyanate-induced asthma under consideration of the atopy status and different lung function parameters. We investigated the human leukocyte antigen (HLA) genes DRB1,3,4,5, DQB1, and DQA1 in 55 isocyanate-exposed patients with workplace-related dyspnea (32 asthmatics, 23 nonasthmatics) and 90 nonexposed controls. In contrast to other studies, we found no significant differences for any HLA class II allele tested in our study group. Furthermore, no significant differences concerning the aspartic amino acid residue 57 of DQB1 was observed. Therefore, we are unable to confirm an involvement of a specific HLA class II allele or DQB1-Asp57 in conferring susceptibility to isocyanate asthma in our study group.

Adult↗
PubMed1997

On the allergenicity of Hev b 1 among health care workers and patients with spina bifida allergic to natural rubber latex.

BACKGROUND: Recent studies have caused much controversy about the prevalence of IgE antibodies to Hev b 1 among health care workers (HCWs) and patients with spina bifida (SB) who are allergic to latex. This investigation was carried out to verify the results reported. METHOD: Serum samples from 140 patients with SB as well as from 105 HCWs allergic to latex were tested by enzyme allergosorbest test (EAST) and EAST-inhibition assay to evaluate the rate and degree of sensitization to highly purified Hev b 1. RESULTS: Eighty-one percent of patients with SB who were allergic to latex had IgE antibodies against Hev b 1. The prevalence of anti-Hev b 1 antibodies among HCWs allergic to latex was 52.3%. In 15 of 33 serum samples from patients with SB that were randomly tested, the IgE binding to commercial latex allergens could be completely inhibited by Hev b 1; in only six cases was the maximum inhibition of IgE binding to latex by Hev b 1 less than 50%. Testing two monoclonal anti-Hev b 1 antibodies with extracts of five brands of latex gloves revealed a predominant presence of Hev b 1 protein as a monomer or its aggregates. Molecular analysis of human leukocyte antigen-D region genes DRB and DQB1 suggested no statistically significant correlation between the human leukocyte antigen alleles tested and IgE responsiveness to Hev b 1. CONCLUSIONS: Our results indicate that Hev b 1 not only makes significant contributions to the IgE binding to latex, but it is also the unique sensitizer in about 45% of patients with SB who are allergic to latex.

Allergens↗
PubMed1997

HLA class II antigens DR4 and DQ8 are associated with allergy to hevein, a major allergen of Hevea latex.

In this study we investigated the relationship between HLA class II alleles and the IgE-specific immune response to the 4.7 kDa polypeptide hevein of Hevea brasiliensis, a major latex allergen, 51 individuals with immediate-type latex allergy and 90 controls were examined for the polymorphisms in exon 2 of HLA-DRB1, 3, 4, 5 and DQB1 by sequence-specific oligonucleotide probe typing. 35 (69%) out of 51 latex-sensitized subjects showed positive hevein-specific IgE values. Analysis of the HLA data among these 35 subjects revealed increased phenotype frequencies for DR4 (22/35, 63%) and DQ8 (18/35, 51%) when compared with those in the 16 hevein-negative but latex-positive subjects (DR4: 2/16, 13%, p = 0.0009, Pc = 0.047; DQ8: 0/16, p = 0.0003, pc = 0.018) and with healthy controls (DR4: 22/90, 24%, p = 0.00012, pc = 0.013; DQ8: 16/89, 18%, p = 0.0003, pc = 0.036). Finally the DR4-DQ8 haplotype frequency was significantly elevated in hevein-positives when compared with hevein-negatives (51% vs. 0, p = 0.0003, pc = 0.034) or controls (51% vs. 18%, p = 0.0002, pc = 0.045) The present data suggest DR4 and DQ8 to be operating jointly as susceptibility factor for the allergy to hevein.

Adolescent↗
PubMed1996

Combined detection of CD44 isoforms by exon-specific RT-PCR and immunohistochemistry in primary human brain tumors and brain metastases.

Expression of CD44 has been implicated in tumor growth and metastasis. Here we demonstrate CD44 expression in primary human brain tumors (n = 44) and brain metastases (n = 7) by RT-PCR and immunohistochemistry. Standard CD44 was found to be expressed by the majority of primary brain tumors and brain metastases. For the first time to our knowledge, CD44 expression is demonstrated for acoustic neurinomas and pituitary adenomas. Exon-specific analysis by RT-PCR and indirect immunofluorescence revealed expression of alternatively spliced CD44 isoforms in the group of brain metastases only. However, in one glioblastoma multiforme, expression of CD44v5 and CD44v6 was found immunohistochemically. This tumor took an unusual clinical course giving rise to multiple intrahepatic and lymph node metastases. Quantitatively different expression of standard CD44 in gliomas versus meningiomas is reported (p < 0.01).

Alternative Splicing↗
PubMed1996

Systemic sclerosis in German uranium miners under special consideration of autoantibody subsets and HLA class II alleles.

Systemic sclerosis (scleroderma) is a connective tissue disease with a wide range of clinical manifestations, with high or low degrees of skin and internal organ involvement together with different antinuclear antibody (ANA) specificities. Several studies provide evidence that males, who are rarely affected by systemic sclerosis, have an increased risk when working in mines. Therefore we reinvestigated 21 male subjects and 6 cases of deceased male patients who had been engaged in East German uranium mines and had shown evidence of this disease in medical examinations. Dermatological investigations, evaluation of chest X-rays and autoantibody estimation were performed. PCR-sequence-specific oligonucleotide typing was used to study the genetic association of HLA-D alleles with autoantibodies typical for scleroderma in these uranium miners suffering from systemic sclerosis and in patients with idiopathic systemic sclerosis. The determined HLA phenotype frequencies and the following statistical analysis (Fisher's exact test (2-sided)) revealed that in comparison with randomly selected controls, alleles DRB1*0300 (DR3) and DQB1*0201 (DQ2) were distinctly increased in the group of affected uranium miners, especially in those with anti-Scl-70 positivity. In contrast, we did not observe significant differences between affected and unaffected miners. Comparing anti-Scl-70-positive affected uranium miners with anti-Scl-70-positive idiopathic systemic sclerosis cases. DRB1*0300 as well as DQB1*0201 were also significantly enhanced in the former group. ACA-positive systemic sclerosis miners had significantly elevated frequencies in DRB1*0100 (DR1) and DRB1*0800 (DR8) only in comparison with unaffected miners and unexposed controls. Our genetic and immunological data lead to the assumption that a different set of HLA-D alleles in combination with exogenous factors is involved in the induction of anti-Scl-70 antibodies in uranium miners that might influence their susceptibility to the disease, whereas the same occupational exposure seems to have no influence on the induction of ACA antibodies.

Adult↗
PubMed1996

Molecular analysis of HLA-DPB1 alleles in idiopathic systemic sclerosis patients and uranium miners with systemic sclerosis.

According to clinical mainifestation and autoantibody pattern [anti-Scl-70, anti-centromere antibodies (ACAs)], systemic sclerosis is a connective tissue disease with heterogenous subgroups. PCR-sequence-specific-oligonucleotide typing was used to study the genetic association of HLA-DPB1 alleles in 54 patients with idiopathic systemic sclerosis, 26 uranium miners with systemic sclerosis and 70 unrelated healthy control subjects. Systemic sclerosis patients with and without former employment in mines were divided into two subgroups according to their scleroderma-typical autoantibody specificities--anti-Scl-70 positive and ACA positive--and third subgroup comprising the rest. Statistical analysis revealed a significantly increased frequency of DPB1*1301(p=0.0001, corrected p=0.011) in idiopathic anti-Scl-70-positive systemic sclerosis cases when compared with unexposed controls. In the same group, we observed an enhanced frequency of DPB1*0601 and *1701 alleles. Since these three alleles carry the information for a glutamic acid residue in position 69 of DPB1, we tested the association of this residue with anti-Scl-70 expression. A strong association between anti-Scl-70 positivity in idiopathic systemic sclerosis patients and amino acid residue 69 of DPB1 was observed when compared with anti-Scl-70-negative idiopathic systemic sclerosis patients (p=0.0009) or unrelated controls (p=0.0007). ACA expression was not associated with the presence of any DPB1 allele tested. The data show that anti-Scl-70 expression in idiopathic systemic sclerosis patients is linked with DPB1*1301 whereas anti-Scl-70-positive miners do not show such a DPB1 association. Futhermore, the data indicate that glutamate 69 of DPB1 might be involved in the susceptibility to idiopathic anti-Scl-70 expression.

Alleles↗