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Biomedical subjects

E Albert

Publications and source records attributed to E Albert.

At least 37 records · Page 2Linked to original sources
PubMed1998

Virtual DNA analysis--a new tool for combination and standardised evaluation of SSO, SSP and sequencing-based typing results.

In order to obtain reliable information on HLA types, DNA typing with sequence-specific oligonucleotide/primer (SSO/SSP) typing sets or sequencing-based typing (SBT) is increasingly performed. The quality of the evaluation depends on the presence of a complete listing of all typed alleles as well as on the ability of detecting all corresponding alleles/allele pairs. We have developed the concept of virtual DNA analysis (VDA), which is able to combine all types of SSO/SSP/SBT results and evaluate this typing in combination according to the latest published allele sequence lists. The concept is based on the target DNA recognised by the respective typing techniques. All SSO/SSP or SBT results are transformed to a virtual sample DNA, which subsequently is analysed. Evaluation of generic or allele-specific DNA typing or the combination of both is supported. Due to this flexible approach, all kinds of SSO/SSP sets, as far as the respective SSO/SSP sequences are available, can be entered and evaluated immediately. The combination of collected data of different typing sets and procedures leads to the highest possible typing resolution. If more than one possible allele combination persists, the program reduces the result to the most specific common denominator in a stepwise manner. VDA offers the possibility of re-evaluation of former SSO/SSP/SBT results, alone or in combination. No solutions are omitted. This might be a first step towards standardisation of evaluating DNA-based HLA typing results or transfer of the respective typing data for later evaluation.

Databases, Factual↗
PubMed1997

German consensus on immunogenetic donor search for transplantation of allogeneic bone marrow and peripheral blood stem cells.

In Germany allotransplantation of bone marrow or peripheral blood stem cells is presently performed by 34 different teams operating more or less independently. Thus, strategies of immunogenetic donor search, use of the various tissue typing techniques and policy on acceptable HLA mismatches in related and unrelated settings may vary considerably from one transplant centre to another. This paper summarises the results of the first German consensus meeting on immunogenetic donor search for bone marrow/peripheral blood stem cell grafting. The main goal of the participating transplant physicians and immunogeneticists was to define national standards for the above issues.

Bone Marrow Transplantation↗
PubMed1997

Lack of association between an interleukin-1 receptor antagonist gene polymorphism and ulcerative colitis.

BACKGROUND: Recently, the association of a polymorphism in the gene coding for the anti-inflammatory cytokine interleukin-1 receptor antagonist with ulcerative colitis has been reported. This was interpreted as a possible genetic predisposition for severity of the inflammatory response. AIMS: To examine this polymorphism in a southern German population. SUBJECTS: The study included 234 healthy controls, 57 patients with ulcerative colitis, including 31 patients with pancolitis, 44 first degree healthy relatives of patients with ulcerative colitis, and 65 patients with Crohn's disease. METHODS: Genotypes were determined by a polymerase chain reaction amplification of the intron 2 fragment harbouring a variable number of tandem repeat nucleotide sequences. Amplification products were separated on a 2% agarose gel. RESULTS: The allele frequency for allele 2 was 27% in healthy controls, 28% in Crohn's disease, and 21% in patients with ulcerative colitis. The same allele frequency (21%) was found in a subgroup of patients with ulcerative colitis affecting the whole colon. Thus for allele 2 as well as for all other alleles, genotypes, or carriage rates no significant differences were found compared with controls. All allele frequencies in the control population were similar to those in earlier studies. CONCLUSIONS: No association of a polymorphism in the interleukin-1 receptor antagonist gene with ulcerative colitis could be identified in this southern German population. The findings of an earlier study reporting an increased frequency of allele 2, particularly in patients with pancolitis, could not be confirmed.

Adult↗
PubMed1997

Routine molecular genotyping of HLA-B27 in spondyloarthropathies overcomes the obstacles of serological typing and reveals an increased B *2702 frequency in ankylosing spondylitis.

OBJECTIVE: To evaluate the reproducibility and reliability of polymerase chain reaction (PCR) in HLA-B27 typing compared to the conventionally used microlymphocytotoxicity test (MLCT). To determine the HLA-B27 subtype frequencies (B*2701-B*2709) in patients with HLA-B27 associated disease and healthy persons using sequence specific oligonucleotides (SSO). METHODS: 398 consecutive patients were HLA-B27 typed by MLCT and PCR. Subtyping by SSO was performed in 142 patients with HLA-B27 associated disease [ankylosing spondylitis (AS) n = 38, reactive arthritis 44, undifferentiated spondyloarthropathy (uSpA) 45, psoriatic arthritis 15] and 125 healthy HLA-B27 controls. RESULTS: MLCT identified 61 HLA-B27 positive patients (15.3%); PCR identified 78 positive patients (19.6%). MLCT gave false negative results for 8 patients (2.0%) and false positives for a further 7 (1.8%). Only subtypes B*2702 and B*2705 were present in patients and controls. Overall frequencies of B*2702 in patients and controls were 14.1 and 9.6%, respectively. The B*2702 frequency was significantly (pcorr. < 0.04) higher in AS (23.7%) and lower in uSpA (6.7%) patients. CONCLUSION: HLA-B27 typing by PCR is reliable and reproducible and therefore recommended for routine typing. It overcomes the obstacles of serological typing, i.e., equivocal results and cross-reactivity. In addition, subtype frequencies (B*2702 and B*2705) are equally distributed among patients and controls, although subtype B*2702 seems to be more frequent in AS and less so in uSpA.

Amino Acid Sequence↗
PubMed1996

Early renal graft dysfunction. The role of preformed antibodies to DR-typed lymphoblastoid cell lines.

Diverse pathogenetic factors may lead to the complex syndrome of early graft dysfunction, an important determinant of later renal graft outcome. That humoral factors could play a prominent role in the development of the syndrome was suggested by the capillary deposition of complement fragment C4d in about 50% of graft biopsies. This study investigates whether the presumed classical activation of complement is derived from preformed antibodies that would possibly react against endothelial HLA-class II molecules. Such antibodies were detectable by flow cytometry using a representative collection of 11 DR-typed lymphoblastoid cell lines (LCL) as targets. Simultaneous discrimination between complement-activating and -nonactivating antibodies was achieved by two-color FACS analysis. Using this method, 44 out of 86 pretransplant serum samples from recipients with early dysfunction showed reactivity against LCL (18 complement-activating, 14 nonactivating, 12 complement-activating non-IgG). Conventional panel-reactivity was observed in 20 sera only (14 also LCL-reactive). Evaluation of corresponding graft biopsies revealed that capillary C4d was associated with LCL (P = 0.018) and panel reactivity (P = 0.015) alone and in combination (P = 0.001; Pearson's chi-square test). Thirteen subsequent graft losses within one year were observed in the LCL-reactive group as compared with seven losses in the nonreactive group (panel-reactive: 7; nonreactive: 13). Thus, measurement of LCL-reactive antibodies in prospective transplant recipients improves the assessment of an individual immunological risk. The results further demonstrate that performed antibodies do not simply reflect the enhanced overall immune reactivity of certain recipients but rather act locally in vivo, thus emphasizing the role of humoral factors in the development of early graft dysfunction.

Antibodies↗
PubMed1996

[Psychogenic hand dystonia and hereditary polyneuropathy with liability to pressure palsies. A contribution to etiology of dystonias].

We report on a case of a female who had developed a fixed flexion contracture of the 4th and 5th fingers of the right hand which was painless and at-rest right in the beginning at the age of 19. By means of neurographical examinations a hereditary neuropathy with liability to pressure palsies was established in her and her mother, which had clinically manifested with symptoms of the ulnar nerve at the affected hand. The dystonic symptoms did not show any progression within ten years follow-up. A remarkable feature of the course was the twice repeated occurrence of short, sudden and complete remissions immediately following invasive diagnostic procedures. The thorough discussion of differential diagnostic aspects and the analysis of the familiar situation and psychodynamics of the patient resulted in the diagnosis of a psychogenic hand dystonia.

Adult↗
PubMed1995

Evidence for an antigen-specific cellular immune response in skin lesions of patients with psoriasis vulgaris.

Psoriasis vulgaris is an inflammatory skin disease characterized by excessively increased keratinocyte proliferation. Several lines of evidence support the idea that T cells infiltrating psoriatic skin lesions play a vital role in the pathogenesis of the disease. To establish whether lesional accumulation and activation of T lymphocytes reflect a specific local immune response, the TCR beta-chain variable (V beta) region gene usage was studied in chronic psoriatic plaques, normal skin, and paired blood lymphocytes. By semiquantitative PCR, we found that overexpression of either or both V beta 2 and V beta 6 gene families characterized the TCR repertoires of normal skin and psoriatic skin lesions. However, sequence analysis of the complementarity-determining region 3 (CDR3) of these V beta gene families demonstrated a marked TCR oligoclonality only in psoriatic lesions, not in normal skin or in blood lymphocytes. The amino acid sequences of the lesional TCR clones revealed that certain conserved junctional motifs were shared by different patients. A second biopsy taken from one of the psoriasis patients 18 mo later from a different anatomical site disclosed that the same TCR clones were again dominating. These data suggest that lesional psoriatic T lymphocytes expressing the prevailing TCR V beta genes represent an oligoclonal T cell subset that expanded from a few progenitor T cells in response to Ag in the skin of psoriasis patients. They are derived from a polyclonal T cell population that, by the expression of V beta 2 or V beta 6 TCR, appears to be predisposed for homing to the skin.

Adolescent↗
PubMed1995

Genetic control of multiple sclerosis: increased production of lymphotoxin and tumor necrosis factor-alpha by HLA-DR2+ T cells.

Lymphotoxin (LT) and tumor necrosis factor-alpha (TNF-alpha) play an important role in the pathogenesis of multiple sclerosis (MS). MS is associated with the HLA-DR2, Dw2, DQ6 HLA class II haplotype. Because both LT and TNF-alpha are encoded in the HLA region, the HLA association of MS may be related to the production of these cytokines. To test this hypothesis, we investigated the production of LT, TNF-alpha, and interferon-gamma (IFN-gamma) by CD4+ T-cell lines (TCLs) specific for myelin basic protein (MBP) or tetanus toxoid (TT) isolated from MS patients and normal controls. After stimulation with specific antigen but not mitogen, TCLs from HLA-DR2+ donors produced significantly more LT and TNF-alpha than TCLs from DR2- donors. In contrast, HLA-DR2+ and DR2- TCLs did not differ in the production of IFN-gamma, a cytokine also produced by T cells but not encoded in the HLA region. Increased secretion of LT and TNF-alpha was unrelated to the specificity (MBP vs TT), MHC restriction (HLA-DR2 vs other DR molecules), or source (MS vs normal) of the TCLs. There was no significant association of the cytokine production with individual LT or TNF-alpha alleles, indicating that the increased production of these cytokines may be linked to other polymorphic genes in this region. The results suggest that the association of MS with HLA-DR2 implies a genetically determined propensity of T cells to produce increased amounts of LT and TNF-alpha.

Animals↗
PubMed1995

Pvu II polymorphism in the primate homologue of the mouse B144 (LST-1). A novel marker gene within the tumor necrosis factor region.

A Pvu II RFLP was mapped within the LST-1 gene, the human homologue of the mouse B144 sequence, establishing LST-1 as a new marker gene within the TNF region. We investigated the distribution of this Pvu II RFLP in 274 unrelated individuals, 132 additional HLA-DR7-positive individuals, 86 homozygous lymphoblastoid cell lines, and in four families. Seventeen of 274 individuals (6.2%) were heterozygous for the Pvu II restriction site (ADB1 = lack and ADB2 = presence of the Pvu II restriction site). In our study population the polymorphism has a much wider distribution than that previously reported in an analysis of selected haplotypes. Besides a strong association of ADB1 with HLA-B14, -DR7, we found a further association with HLA-B35. These results were also validated by family segregation studies and analyses of homozygous cell lines. In addition, five of 17 individuals carrying the ADB1 allele had HLA types other than B14 or B35, emphasizing that the presence of ADB1 is not limited to the HLA-B14, DR7 haplotype. LST-1 and its polymorphism may be used as an additional marker of the TNF region, where genes responsible for autoimmune diseases are suspected to be localized.

Alleles↗
PubMed1995

Immunoprinting excludes many potential susceptibility genes as predisposing to early onset pauciarticular juvenile chronic arthritis except HLA class II and TNF.

DNA profiles (immunoprints) were generated for 120 patients suffering from early onset pauciarticular chronic arthritis (EOPA-JCA) and > 500 healthy controls utilizing highly polymorphic microsatellites in the vicinity of immunorelevant genes. Six T cell receptor (TCR) markers for the CD3D, TCRDVAJ, TEA, TCRBV6S1, BV6S3, BV6S7 and BV13S2 genes were analysed. Furthermore markers for the cell surface molecule CD40L, for cytokine genes (IL-1A, IL-2, IFN-alpha, FGF-alpha, TNF-alpha), the chromosomal region of the IRF2 and the cytokine receptor gene IL5RA were studied as well as two polymorphisms within the promotor region of the TNF-alpha gene. Coding region polymorphisms were evidenced indirectly by repeat length variation or they were predicted from the microsatellite distribution profiles and then confirmed by direct sequence analysis. Statistical evaluations were performed with respect to known predispositions, predominance of females (> 80%) and HLA-DR and -DQ haplotypes. Cell surface molecules (TCR, CD40L, IL5RA) as well as almost all cytokines (IL-1A, IFN alpha, FGFA, IRF2 region) were excluded as predisposing in our JCA panel. The TNF-alpha microsatellite alleles (GT)10-12 contribute considerably to manifestation of the disease, in HLA-DRB1*11(12) individuals (RR = 12.8). The TNF-alpha allele is not found in linkage disequilibrium with HLA-DRB1*11(12) and may be present on either chromosome 6. Thus, a novel susceptibility factor probably within the TNFA/TNFB gene region has been identified via linkage with the TNF-alpha microsatellite allele. Apparently complex compositions of the genetic background rather than single genes provide the precondition for manifestation of the autoimmune disease EOPA-JCA. Immunoprinting unravels the variability of the immunological genome via the semi-directed microsatellite approach efficiently.

Age of Onset↗
PubMed1994

Clinical and pharmacokinetic overview of parenteral etoposide phosphate.

Etoposide phosphate (Etopophos, BMY-40481) is a water-soluble derivative of the widely used podophyllotoxin etoposide (VP-16). The phosphate ester renders the compound water-soluble, eliminating the need for formulation in polysorbate (Tween) 80, ethanol, and polyethylene glycol. As a result the compound can be given at high concentrations and as a bolus. In animals and in vitro, etoposide phosphate (EP) is rapidly and completely converted to VP-16. Clinical development of the i.v. formulation has focused on the identification of the maximum tolerated dose (MTD) and pharmacokinetic characteristics of the drug using a 5 daily dose schedule and a days 1, 3, and 5 schedule, with the drug being given over 30 or 5 (bolus) min. Myelosuppression was dose-limiting. Data from these trials show the rapid and complete conversion of EP to VP-16, a pharmacokinetic/pharmacodynamic relationship for myelosuppression and exposure to VP-16, and an MTD of 100 and 150 mg/m2 (molar equivalent to VP-16) when EP is given daily for 5 days and on days 1, 3, and 5, respectively. A formal randomized trial has been conducted to show the pharmacokinetic comparability of EP and VP-16. In this trial, exposure to VP-16 was the same after the parenteral administration of equimolar doses of EP or VP-16. The feasibility of bolus dosing and treatment at high concentrations has been demonstrated, with no effects on the cardiovascular system being noted. Parenteral EP is pharmacokinetically and biologically equivalent to VP-16 and has the advantages of the elimination of potentially toxic excipients; more convenient administration; and ability to be given as a bolus, at high concentrations, and as a continuous infusion.

Animals↗
PubMed1994

Human astrocytes are only partially competent antigen presenting cells. Possible implications for lesion development in multiple sclerosis.

Highly purified astrocyte cultures from human embryonic brain were examined for their capacity to present antigen to human leukocyte antigen (HLA) class II compatible, cytolytic CD4+ T lymphocytes. Most astrocytes constitutively expressed HLA class I products and LFA-3 (CD58). Constitutive expression of HLA class II, LFA-1 alpha (CD11a) and ICAM-1 (CD54) was lower and varied among different cultures, while LFA-2 (CD2) was absent. IFN-gamma alone or in combination with TNF-alpha strongly enhanced expression of HLA class I, HLA-DR, -DP, -DQ, LFA-1 alpha and ICAM-1, but did not affect expression of LFA-2 (CD2) and LFA-3 (CD58). TNF-alpha alone induced only HLA class I and ICAM-1, but not HLA class II or LFA-1 alpha. Cytokine treated, but not untreated astrocytes were able to present protein (auto-)antigens to specific T lymphocyte lines. Astrocytes expressing appropriate major histocompatibility complex class II products were lysed by CD4+ T cells specific for myelin basic protein or tetanus toxoid. The lytic response was antigen dose dependent and HLA-DR restricted. It could be blocked by antibodies against HLA-DR determinants and against the adhesion molecules LFA-1 alpha and ICAM-1. In remarkable contrast to their susceptibility to T cell lysis, antigen presenting astrocytes were not only completely unable to induce T cell proliferation but even inhibited proliferation. The results indicate that, although human astrocytes have the potential to present protein antigens to CD4+ T cells, they do not induce the co-stimulatory factors required to trigger the complete T cell activation programme.

Antigen-Presenting Cells↗
PubMed1993

No direct correlation between HLA-DPB1 and antibodies against recombinant Ro (SS-A)/La (SS-B) proteins in systemic lupus erythematosus. SLE Study Group.

We investigated the association of HLA-DPB1 alleles with the occurrence of autoantibodies against Ro (SS-A) or La (SS-B) using recombinant 52 kD-Ro, 60 kD-Ro and La proteins in 177 German patients with systemic lupus erythematosus (SLE). A significant increase in the frequency of DPB1*0101 is observed in SLE patients compared to healthy controls (Pcorr.. < 0.004). Antibodies against 52 kD-Ro, 60 kD-Ro and La are tested by ELISA and are found with a frequency of 25.4%, 33.9% and 17.5% in the patients, respectively. An association with HLA-DPB1*0101 is observed for antibodies against La (P < 0.01) and 52 kD-Ro (P < 0.01), but not for 60 kD-Ro in the absence of La/52 kD-Ro. Since there is a strong linkage disequilibrium between DPB1*0101 and DR3 in the normal population and in SLE patients, and since there is an association between DR3 and SLE, as well as between DR3 and the occurrence of recombinant Ro/La antibodies in SLE patients, we investigated whether DPB1*0101 is associated per se or via linkage disequilibrium with DR3. DPB1*0101 in the absence of DR3 is not more common in patients than in controls and not in patients with autoantibodies to Ro and La than without autoantibodies. We conclude that there is no evidence for a direct involvement of DPB1*0101 in the production of Ro/La autoantibodies in SLE patients.

Alleles↗
PubMed1993

Capillary deposition of C4d complement fragment and early renal graft loss.

Clinical outcome of kidney grafts that are affected by the complex syndrome of 'early graft dysfunction' is uncertain and rather unpredictable. In this study, an individual prognosis for dysfunctioning allografts (N = 93) is attempted by the immunohistological assessment of vascular classical complement activation in graft biopsies. Thus, capillary deposition of complement fragment C4d was observed in the majority (N = 51) of early dysfunctioning grafts. In 43 biopsies, abundant deposition of fragment C4d was present in all capillaries, whereas in eight specimens a segmental distribution of capillary C4d was observed. In 42 grafts with early dysfunction no capillary C4d was detectable. Eighteen subsequent graft losses within one year (16 early losses) were recorded in the subgroup with C4d in all capillaries, and three early losses in the group with segmentally distributed C4d. Only four graft losses (3 early losses) were recorded in the C4d-negative group (P = 0.0027; Pearson's chi square test). The resulting one-year graft survival rates (72% for the study group) differed markedly between the subgroups. Grafts with generalized or segmental capillary deposition of C4d had 57% and 63% survival, respectively, contrasted by 90% survival in the C4d-negative group. It is of note, however, that also three of the four grafts that were finally lost within the C4d-negative group, showed distinct capillary deposition of C4d in second biopsies. Vascular deposition of complement fragment C4d therefore represents a clinically relevant factor that contributes to early graft dysfunction. Its assessment is helpful for an individual graft prognosis.

Animals↗