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Biomedical subjects

M Hummel

Publications and source records attributed to M Hummel.

At least 73 records · Page 4Linked to original sources
PubMed2001

The diversity of rearranged immunoglobulin heavy chain variable region genes in peripheral blood B cells of preterm infants is restricted by short third complementarity-determining regions but not by limited gene segment usage.

The immunoglobulin diversity is restricted in fetal liver B cells. This study examined whether peripheral blood B cells of extremely preterm infants show similar restrictions (overrepresentation of some gene segments, short third complementarity-determining regions [CDR3]). DNA of rearranged immunoglobulin heavy chain genes was amplified by polymerase chain reaction, cloned, and sequenced. A total of 417 sequences were analyzed from 6 preterm infants (25-28 weeks of gestation), 6 term infants, and 6 adults. Gene segments from the entire V(H) and D(H) gene locus were rearranged in preterm infants, even though the D(H)7-27 segment was overrepresented (17% of rearrangements) compared to term infants (7%) and adults (2%). CDR3 was shorter in preterm infants (40 +/- 10 nucleotides) than in term infants (44 +/- 12) and adults (48 +/- 14) (P <.001) due to shorter N regions. Somatic mutations were exclusively found in term neonates and adults (mutational frequency 0.8% and 1.8%). We conclude that preterm infants have no limitations in gene segment usage, whereas the diversity of CDR3 is restricted throughout gestation.

Adult↗
PubMed2001

Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription.

In contrast to the tumor cells (L&H cells) of lymphocyte predominant Hodgkin disease (LPHD), Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD) are unable to transcribe immunoglobulin, despite the presence of rearranged immunoglobulin genes. Although initial studies have suggested crippling immunoglobulin gene mutations to be the cause of absent immunoglobulin expression in cHD, recent work of our group has demonstrated an impaired activation of the immunoglobulin promoter as a superior mechanism. As immunoglobulin transcription is mainly regulated by the B-cell transcription factors Oct2 and BOB.1/OBF.1, we analyzed 35 cases of LPHD, 32 cases of cHD, and 2 Hodgkin disease cell lines for the expression of these transcription factors and also in parallel for immunoglobulin expression. Our results demonstrate an absence of Oct2 and/or BOB.1/OBF.1 in cHD and a striking overexpression of Oct2 in LPHD. Immunoglobulin expression was lacking in cHD but present in LPHD. Furthermore, the reintroduction of BOB.1/OBF.1 and Oct2 into cultured HRS cells restored the activity of cotransduced immunoglobulin promoter constructs. Our findings dismiss the concept that the different immunoglobulin expression in cHD and LPHD is due to disrupting mutations of immunoglobulin V genes in cHD but is most likely due to a down-regulation of Oct2 and/or BOB.1/OBF.1. This study further revealed Oct2 as a new and valuable marker for the identification of L&H cells and their distinction from HRS cells. The impairment of immunoglobulin transcription with a down-regulated synthesis of Oct2 and BOB.1/OBF.1 is the first established general recurrent defect found in HRS cells.

Cell Line↗
PubMed2001

Analysis of single EBER-positive and negative tumour cells in EBV-harbouring B-cell non-Hodgkin lymphomas.

In situ hybridization for Epstein-Barr virus (EBV) encoded small nuclear RNAs (EBERs) is the method of choice for the detection of EBV infection at the single cell level. With the application of this technique it was shown that non-Hodgkin's lymphomas of B-cell type may be associated with an EBV infection of tumour cells. Interestingly, in many EBV-positive cases, only a proportion of the tumour cell population has been found to be EBER-positive. To clarify whether EBV is absent or whether EBER gene expression is downregulated in EBER-negative tumour cells, single EBER-positive and negative tumour cells were isolated from paraffin sections from four B-cell non-Hodgkin's lymphoma cases with partial EBER expression in the neoplastic cells. These single cells were then screened for the presence of EBV DNA by a nested single cell PCR. EBV DNA was undetectable in all but one of the 86 EBER-negative cells, whereas in the EBER-positive cells EBV-specific DNA amplificates could be generated following single cell PCR. This finding prompts the conclusion that the inability to detect EBERs in a proportion of tumour cells is not due to a down-regulation of gene expression but to a real absence of EBV from these cells. This partial absence of EBV is thought to be caused by a loss of the EBV episomes during cell division, rather than by infection of only a proportion of the tumour cells.

Cell Separation↗
PubMed2001

Secondary ocular involvement in systemic "memory" B-cell lymphocytic leukemia.

OBJECTIVE: Recently, B-cell chronic lymphocytic leukemia (B-CLL) has been subdivided into "naive" B-CLL and "memory" B-CLL on the basis of the presence of somatic mutations in the variable region of the immunoglobulin heavy chain gene (IgH). The aim of the current paper was to report the clinical, histopathologic, and molecular biologic findings of intraocular and ocular adnexal involvement in a patient with systemic B-CLL. DESIGN: Case report. INTERVENTION: Treatment consisted of systemic chemotherapy, conjunctival biopsies, and, ultimately, enucleation of the left eye. METHODS: Histopathologic findings of a bone marrow biopsy, the conjunctival biopsies, and the enucleated eye were compared. Further, extensive immunohistochemistry, polymerase chain reaction (PCR) for the detection of heavy chain (IgH) gene rearrangement, gene scan analysis, and DNA sequencing were performed on all tissues. RESULTS: The tumor manifestations in all specimens demonstrated similar morphologic and immunophenotypic characteristics, consistent with the diagnosis of B-CLL. Immunoglobulin-H PCR and gene scan analysis showed that the B-CLL infiltrates consisted of B cells derived from the same clone. DNA sequencing demonstrated the presence of eight somatic mutations in the variable region of IgH, consistent with "memory" B-CLL. CONCLUSIONS: Secondary ocular manifestations of B-CLL occur relatively commonly during disease progression. In the current case of memory B-CLL, ocular manifestation of the disease occurred 16 years after initial diagnosis, agreeing with clinical studies suggesting that a less aggressive course is seen in "memory" B-CLL than its counterpart, "naive" B-CLL. Somatic mutation analysis in the variable region of IgH in B-CLL should be part of routine staging investigations to aid the prediction of the individual clinical course in B-CLL patients and to determine new therapeutic strategies.

Antibodies, Monoclonal↗
PubMed2001

Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy.

OBJECTIVES: We studied the clinical and genetic features of hypertrophic cardiomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of European descent. BACKGROUND: Mutations in the MYBPC3 gene represent the cause of HCM in approximately 15% of familial cases. MYBPC3 mutations were reported to include mainly nonsense versus missense mutations and to be characterized by a delayed onset and benign clinical course of the disease in Japanese and French families. We investigated the features that characterize MYBPC3 variants in a large, unrelated cohort of consecutive patients. METHODS: The MYBPC3 gene was screened by single-strand conformational polymorphism analysis and sequencing. The clinical phenotypes were analyzed using rest and 24-h electrocardiography, electrophysiology, two-dimensional and Doppler echocardiography and angiography. RESULTS: We identified 13 mutations in the MYBPC3 gene: one nonsense, four missense and three splicing mutations and five small deletions and insertions. Of these, 11 were novel, and two were probably founder mutations. Patients with MYBPC3 mutations presented a broad range of phenotypes. In general, the 16 carriers of protein truncations had a tendency toward earlier disease manifestations (33 +/- 13 vs. 48 +/- 9 years; p = 0.06) and more frequently needed invasive procedures (septal ablation or cardioverter-defibrillator implantation) compared with the 9 carriers of missense mutations or in-frame deletions (12/16 vs. 1/9 patients; p < 0.01). CONCLUSIONS: Multiple mutations, which include missense, nonsense and splicing mutations, as well as small deletions and insertions, occur in the MYBPC3 gene. Protein truncation mutations seem to cause a more severe disease phenotype than missense mutations or in-frame deletions.

Adolescent↗
PubMed2001

Plasmapheresis and cyclophosphamide in the treatment of humoral rejection after heart transplantation.

BACKGROUND: Clinical reports on humoral rejection after heart transplantation showed that these episodes were often more severe than those mediated through T lymphocytes and that the patient's prognosis was significantly worsened. METHODS: To evaluate the impact of plasmapheresis on the course of humoral rejection with hemodynamic compromise (HRHC) episodes, we retrospectively investigated the records of 1,108 heart transplant patients. All patients received triple-drug immunosuppression (cyclosporine a, azathioprine, prednisone) and cytolytic antibodies for induction. Between April 1986 and December 1990, HRHC episodes were treated with cortisone boli and cytolytic antibodies for at least 3 days (Group A). Between January 1991 and April 1999, HRHC episodes were treated with cortisone boli, cytolytic antibodies, and plasmapheresis for at least 3 days (Group B). All patients who survived their first HRHC episode received cyclophosphamide instead of azathioprine as maintenance immunosuppression. RESULTS: Altogether we observed 29 HRHC episodes. In 11 cases, no therapy could be administered or the therapy regimen did not correspond to either Protocol A or B. In the remaining 18 HRHC episodes, 7 episodes in 7 patients were treated without plasmapheresis (Group A), but only 2 patients survived, whereas in 11 HRHC episodes in 6 patients, therapy included plasmapheresis (Group B) and all patients survived (p = 0.002). Four of 6 patients who received cyclophosphamide after their first HRHC episode experienced at least 1 further HRHC episode. CONCLUSIONS: Plasmapheresis seems to improve outcomes in HRHC. However, cyclophosphamide as a maintenance immunosuppressive drug failed to prevent further humoral rejection episodes.

Adolescent↗
PubMed2001

Extranodal mantle cell lymphoma mimicking marginal zone cell lymphoma.

AIM: We report a case of mantle cell lymphoma masquerading as a marginal zone cell lymphoma. METHODS AND RESULTS: In the initial manifestation in the palatine tonsils, the neoplastic cells were found to grow exclusively within the marginal zones of secondary follicles which showed a preserved mantle zone. The few immunostains performed showed a B-cell phenotype including an immunoglobulin light chain restriction. The extranodal manifestation, the growth pattern, and the immunophenotype led to the diagnosis of an extranodal marginal zone B-cell non-Hodgkin's lymphoma (NHL). The specimen from the relapse occurring 8 months later exhibited diffuse monomorphous cells co-expressing B-cell antigens and CD5, CD43 and cyclin D1, leading to the diagnosis of mantle cell lymphoma. Re-investigation of the initial biopsy revealed that the neoplastic cells within the marginal zones had a mantle cell lymphoma immunophenotype expressing cyclin D1, the immunoglobulin heavy chains IgD and IgM and partly CD5. Both lesions harboured identical clonal immunoglobulin gene rearrangements proving that they represented different manifestations of the same lymphoma. CONCLUSION: This case emphasizes the importance of broad immunohistological investigation of B-cell NHLs involving the marginal zone.

Antigens, CD↗
PubMed2001

Heart transplantation indicated only in the most severely ill patient: perspectives from the German heart transplant experience.

The COCPIT study, performed in a complete national cohort of adult patients consecutively listed for cardiac transplantation in Germany in 1997, found a beneficial effect only in the group that was at high risk of dying from heart failure without transplantation. If these results can be reproduced in other countries, the discussion on the respective roles of pharmacological and organ-saving surgical therapies for advanced heart failure, medical urgency and waiting time as heart transplantation allocation criteria, and the feasibility of a randomized clinical trial testing the survival benefit of transplantation must be reopened.

Adult↗
PubMed2001

Allogeneic transplantation induces expression of cytomegalovirus immediate-early genes in vivo: a model for reactivation from latency.

Reactivation of cytomegalovirus (CMV) from latency is a frequent complication of organ transplantation, and the molecular mechanism by which this occurs is unknown. Previous studies have shown that allogeneic stimulation induces reactivation of human CMV (HCMV) in vitro (64). We find that transplantation of vascularized allogeneic kidneys induces murine CMV (MCMV) and HCMV immediate-early (ie) gene expression. This induction is accompanied by increased expression of transcripts encoding inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-2, and gamma interferon, and by activation of NF-kappaB. TNF alone can substitute for allogeneic transplantation in inducing HCMV and MCMV ie gene expression in some tissues. Our studies suggest that reactivation is a multistep process which is initiated by factors that induce ie gene expression, including TNF and NF-kappaB. Allogeneic transplantation combined with immunosuppression may be required to achieve complete reactivation in vivo.

Animals↗