Biomedical subjects

Jeanette Seyfarth

Publications and source records attributed to Jeanette Seyfarth.

4 recordsLinked to original sources

PubMed2005

The 'involution' of mannose-binding lectin.

Mannose-binding lectin (MBL) acts as a serum opsonin in innate immune defense and induces complement activation by the lectin pathway. In humans, low levels of functional serum MBL are caused by the dominant action of three single nucleotide substitutions in exon 1 that disrupt the glycine-rich backbone structure of the protein. The presence of common MBL variant alleles is associated with both infectious and autoimmune diseases. Conversely, it has also been suggested that MBL variants are maintained because of selective advantages for the host. In man, the MBL genetic system comprises one functional gene (MBL2) and one expressed pseudogene (MBL1P1), whereas the lower primate, the rhesus monkey resembles rodents with two functional MBL genes. We have investigated the molecular mechanisms behind the evolutionary loss of MBL expression from lower primates to man, including silencing of the MBL1P1 gene and the generation of MBL2 variant structural alleles and promoter polymorphisms leading to the present human MBL2 haplotypes. We present data showing that the MBL1P1 gene has been repeatedly hit throughout evolution and silenced eventually by mutations in the glycine residues of the collagen-like region. Our results indicate that the MBL1P1 gene has been selectively turned off during evolution through the same molecular mechanisms causing the MBL2 variant alleles in man, suggesting an evolutionary selection for low-producing MBL genes.

Alleles↗

PubMed2005

Extra-hepatic transcription of the human mannose-binding lectin gene (mbl2) and the MBL-associated serine protease 1-3 genes.

Mannose-binding lectin (MBL) is a part of the innate immune defense and activates complement via MBL associated serine proteases (MASPs). Human MBL is expressed by hepatocytes, but recent evidence in mice indicates a substantial extra-hepatic transcription. Therefore, we investigated whether mRNA transcribed from the human mbl2 gene as well as the masp genes was present in different tissues. The transcription of human mbl2 is regulated by two alternative promoters (named 0 and 1) where promoter 0 derived transcripts include an additional 5' untranslated part encoded by an extra exon (exon 0). Low extra-hepatic levels of mbl2 mRNA were predominantly found in small intestine and testis tissue, and were quantitatively dominated by promoter 1 transcripts. Moreover, these transcripts varied due to the use of alternative acceptor splice sites positioned inside exon 1. The mRNA distribution of masp1 and masp2 were found very similar to that of mbl2, while masp3 mRNA seemed ubiquitous present at quite high levels when compared to liver. These results indicate that the regulation of mbl2 gene expression in man is more complex than previously anticipated and that local expression of MBL may be relevant in local immune defense, particularly in restricted areas of the gastrointestinal and reproductive tracts.

Alternative Splicing↗

PubMed2003

Post-induction residual disease in translocation t(12;21)-positive childhood ALL.

BACKGROUND: t(12;21)(p1 3;q22), the most frequent chromosomal translocation found in childhood acute lymphoblastic leukemia (ALL), occurs in approximately 25% of B-lineage ALL cases and has been claimed to carry a good prognosis. PROCEDURE: As part of the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-MRD 95 study, which includes children from Iceland, Norway, and Denmark diagnose d with ALL, patients were screened for the presence of t(12; 21) by reverse transcriptase-polymerase chain reaction (RT-PCR) at diagnosis, and their residual disease was quantified after 4 weeks of induction therapy (prednisolone, vincristine, doxorubicin, i.t. methotrexate) by a competitive, clone-specific, semi-nested PCR analysis. RESULTS: Among 96 children diagnosed with ALL, and quantified for post induction residual disease, 32 were t(12;21)-positive. The median residual disease was similar for B-precursor ALL patients with and without t(12;21) (0.009 vs. 0.03%, P = 0.12). CONCLUSIONS: Al though patients with t(12;21)-positive ALL have been claimed to have a good outcome, these data indicate that this does not reflect a high sensitivity to prednisolone, vincristine, and doxorubicin given during induction therapy.

Adolescent↗

PubMed2002

Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome.

The postinduction level of minimal residual disease (MRD) was quantified with a competitive polymerase chain reaction (PCR) technique in 104 children with acute lymphoblastic leukemia (ALL) diagnosed between June 1993 and January 1998 and followed for a median of 4.2 years. A significant correlation was found between the MRD level on day 15 (D15) and day 29 (D29) after the start of induction therapy (r(s) = 0.70, P <.0001). The 15 patients with T-cell disease had higher D29 MRD than those with B-lineage ALL (P =.01). Age was positively related to D29 MRD (r(s) = 0.32, P =.001). The 16 patients who had a relapse had higher D15 and D29 MRD levels than the patients who stayed in remission (median levels D15, 1% versus 0.1%, P =.03; D29, 0.4% versus 0.01%, P =.0001). No patients with a MRD level less than 0.01% on D29 have so far had a relapse, whereas the 7-year probability of event-free survival for patients with higher MRD levels was 0.52 (P =.0007). The group of patients with a D29 MRD less than 0.01% included patients with T-cell disease, white blood cell count more than 50 x 10(9)/L at diagnosis, or age 10 years or older, and could not be identified by up-front criteria. The best-fit Cox model to predict the risk of relapse included D29 MRD (P =.004) and age (P =.009). These findings indicate that with the present treatment protocol MRD quantification at an early stage of therapy identifies patients with a very low risk of relapse. Further trials are needed to reveal whether such patients with D29 MRD less than 0.01% can be cured with less intensive chemotherapy, which would reduce the risk of serious late effects as well as the costs of therapy.

Adolescent↗