PubMed Health⌕ Search

Biomedical subjects

T Logtenberg

Publications and source records attributed to T Logtenberg.

At least 55 records · Page 3Linked to original sources
PubMed1995

Increased frequencies of HPRT mutant T lymphocytes in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy: further evidence for a role of T cells in the etiopathogenesis of peripheral demyelinating diseases.

We have used the HPRT mutant clonal assay to determine the frequency of mutant T lymphocytes (FMC), as a measure of recent T cell stimulation, in the blood of patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We found that, compared to healthy controls, the FMC in patients with GBS (16) and CIDP (10) was significantly increased in the progressive phase of the neuropathy. FMC returned to normal values during recovery, suggesting a relationship between FMC and disease activity. No correlation was found between FMC values and motor deficit or severity of the neuropathy. The FMC of the GBS patients with a history of infection before onset of neurological symptoms or with insufficient respiration was not significantly different from the other GBS patients. Immunophenotypic analysis showed that the fraction of CD8+ HPRT mutant T cell clones was significantly increased in GBS patients (48%) compared to healthy controls (3%) or CIDP patients (4.5%). Our results are compatible with the notion that T cells are involved in the pathogenesis of demyelinating inflammatory neuropathies.

Adolescent↗
PubMed1995

Intestinal T lymphocytes.

The intestine is largely colonized by bacteria and further exposed to an immense array of ingested and shed immunogenic material. Therefore, the gut associated lymphoid tissue plays a major role in the human immune system. It may even constitute a unique immune system of its own, since it has been demonstrated to differ anatomically, phenotypically, functionally and on a molecular basis from its systemic counterpart and other peripheral lymphoid tissue. This is ultimately reflected by the observation in (transgenic) mice that intraepithelial T cells can develop independently of the thymus. Along the same lines, a rapidly growing body of evidences suggests that human bone marrow precursors can home to the gut epithelium, rearrange their T cell receptor genes and further differentiate in the mucosal micro environment. This, and other features that characterize the 'diffuse' mucosal T cell infiltrate will be discussed.

Animals↗
PubMed1994

In vivo and in vitro IgE isotype switching in human B lymphocytes: evidence for a predominantly direct IgM to IgE class switch program.

Molecular analysis of circular excision products and composite genomic switch regions has demonstrated that in mice, immunoglobulin (Ig) isotype switching from IgM to IgE often proceeds sequentially via IgG1. Based on analysis of Ig production in cell cultures, it has been suggested that human B cells may switch to IgE via IgG4, whereas limited molecular data from in vitro switched B cells suggest a direct IgM to IgE switch program. To obtain a quantitative assessment of direct versus sequential IgE switching in humans, we have analyzed the nucleotide sequences of 29 composite S mu/S epsilon switch regions from freshly isolated human B lymphocytes from patients with atopic dermatitis and from B lymphocytes induced to switch to IgE synthesis in vitro. The data show that in these B cells IgE isotype switching progressed directly from IgM to IgE. We conclude that, in contrast to the murine IgM/IgE switch program, the IgM to IgE switch in B lymphocytes from patients with atopic dermatitis as well as in vitro stimulated B cells from healthy donors preferentially proceeds via direct S mu to S epsilon switch recombination.

B-Lymphocytes↗
PubMed1994

How unique are pathogenic anti-DNA autoantibody V regions?

Unique characteristics of the molecular structure of V regions encoding pathogenic anti-DNA autoantibodies have become apparent upon comparison of a large number of nucleotide sequences encoding this autospecificity. Moreover, the generation of transgenic animals expressing V regions encoding anti-DNA autoantibodies has shed light on the tolerizing mechanisms that regulate B cells producing antibodies against DNA.

Animals↗
PubMed1993

Peripheral human CD5+ and CD5- B cells may express somatically mutated VH5- and VH6-encoded IgM receptors.

Previous studies have indicated that a sizable fraction of adult human peripheral blood B cells may express IgM receptors encoded by somatically mutated V regions. From these studies it was uniquely associated with the peripheral blood B cell compartment, was uniquely associated with the peripheral blood B cell compartment, associated with particular VH gene segments and/or B cell subpopulations. We have addressed these issues by analyzing > 80 VH5 and VH6-encoded mu transcripts from unseparated peripheral blood, tonsil, and spleen B cells, as well as from B cells separated on the basis of CD5 Ag expression. The results demonstrate that somatically mutated VH5 and VH6 regions are ubiquitously expressed in IgM-bearing B cells in all peripheral adult human lymphoid organs, and that the occurrence of somatic mutations does not segregate with either CD5+ or CD5- B cell populations. The distribution and nature of mutations, as well as the occurrence of clonally related but divergent transcripts suggests that at least some of the mutations were selected by Ag.

Adult↗
PubMed1993

VH4.21-encoded natural autoantibodies with anti-i specificity mirror those associated with cold hemagglutinin disease.

The Ig VH regions of virtually all human pathogenic cold agglutinin (CA) anti-i/l autoantibodies are encoded by a single Ig VH gene segment, VH4.21, in conjunction with a highly variable CDR3 structure. The anti-I specificity is often associated with V kappa III-encoded L chains, whereas anti-i autoantibodies appear to use a broader array of kappa and lambda VL gene segments. B cells expressing VH4.21 are abundantly present in adult lymphoid tissues from healthy individuals but their relationship with B cells secreting pathogenic CA is unknown. Herein we have analyzed the distribution of VH4.21-expressing B cells in fetal, neonatal, and adult B cell populations using the monoclonal anti-VH4.21 antibody 9G4. In addition, we have analyzed the anti-i and anti-I binding capacity and V regions of 19 VH4.21-encoded mAb secreted by cord and adult blood-derived cell lines from healthy individuals. The results show that VH4.21 expressing B cells are overrepresented in all repertoires studied and are evenly distributed over cord blood CD5+ and CD5- B cell populations. VH4.21-encoded H chains strongly predispose for anti-i binding capacity, regardless of the VL regions or H chain CDR3 structure. The avidity of some of these antibodies was similar to those of pathogenic CA. In addition, we found evidence for monospecific anti-I binding in antibodies encoded by other members of the VH4 gene family. We conclude that VH4.21-encoded antibodies with anti-i specificity from the normal B cell repertoire mirror their pathogenic counterparts and that naturally occurring anti-I antibodies may be encoded by a more diverse array of VH4 genes.

Agglutinins↗
PubMed1993

Molecular analysis of VH and VL regions expressed in IgG-bearing chronic lymphocytic leukemia (CLL): further evidence that CLL is a heterogeneous group of tumors.

We report the heavy (H) and light (L) chain variable (V) region sequences of cDNAs encoding the Ig receptor of two cases of CD5+ IgG-bearing CLL P87 and P103. In both CLL cases the H chain was encoded by members of the VH3 gene family. The L chain expressed by P87 belonged to the V lambda IV subgroup, whereas P103 used a member of the V kappa III subgroup. The VH3.P87 gene differed by only three nucleotides from 38P1, a VH3 gene previously cloned from a fetal liver cDNA library. Nucleotide sequence analysis demonstrated that the V kappa III.P103 gene differed by seven nucleotides from its most homologous germline counterpart, the Humkv325 gene, a highly conserved gene frequently expressed in IgM-bearing CLL. The nucleotide sequences of VH3.P103 and V lambda IV.P87 could not be reliably matched with reported germline V genes. The analysis of multiple independently obtained VH and VL cDNA clones from each tumor showed a lack of intraclonal diversification. The data show that V regions expressed in isotype-switched CD5+ CLL may be either in/near germline configuration or somatically mutated. Furthermore, these tumors, like their IgM-bearing counterparts, do not seem to undergo intraclonal diversification.

Amino Acid Sequence↗
PubMed1993

Molecular evolution of the human immunoglobulin E response: high incidence of shared mutations and clonal relatedness among epsilon VH5 transcripts from three unrelated patients with atopic dermatitis.

We have analyzed the nucleotide sequences of 19 epsilon VH5 transcripts derived from in vivo isotype switched peripheral blood B cells of three patients with atopic dermatitis. Comparison with the patients' own germline VH5 gene segments revealed that the epsilon transcripts were derived from both functional members of the human VH5 gene family and harbored numerous somatic mutations (range 5-36 per VH5 gene). In two patients, we detected clonally related but diverged transcripts, permitting the construction of a genealogical tree in one patient. We observed a high proportion of shared silent (S) and replacement (R) mutations among epsilon VH5 sequences derived from all three individuals, even among transcripts descending from the two different germline VH5 gene segments. A remarkably high number of these mutations is shared with previously reported VH5 genes encoding antibodies with defined specificities. The shared S mutations, and likely a fraction of the R mutations, appear to mark preferential sites ("hot spots") of somatic hypermutations in human VH5 genes. The distribution of R and S mutations over complementarity determining region and framework regions in the majority of VH regions deviated from that characteristic of antigen-driven immune response. We hypothesize that the V regions of immunoglobulin E-bearing B cells have accumulated "selectively neutral" mutations over extended periods of clonal expansion, resulting in unusual R/S ratios. We propose that the molecular characteristics of the epsilon VH regions in atopic dermatitis may be representative of antigens that recurrently or chronically stimulate the immune system.

Adult↗
PubMed1993

Expression pattern of the most JH-proximal human VH gene segment (VH6) in the B cell and antibody repertoire suggests a role of VH6-encoded IgM antibodies in early ontogeny.

We have developed a mAb (JE-6) that recognizes an Id encoded by the most JH-proximal human VH gene segment (VH6) in or near germ-line configuration. This mAb was used to determine the frequency of Id JE6+ B cells in large collections of monoclonal EBV-transformed and short term B cell lines derived from fetal, neonatal, and adult lymphoid tissues. Moreover, we investigated the presence of Id JE-6+ Ig in sera from neonates and adults and determined the (auto)antigen binding properties of VH6-encoded IgM mAb. We detected a fivefold overrepresentation of VH6-expressing IgM producing B cells in fetal tissues, cord blood, and adult bone marrow relative to adult blood. In cord blood, but not in adult blood sera, germ-line VH6-encoded IgM molecules were readily detectable. IgM secreted by VH6-expressing B cell clones displayed highly conserved and virtually identical autoantigen binding properties, independent of the length and composition of the IgH chain CDR3 region and L chain isotype. Collectively, these results suggest that the VH6 gene and the antibodies it encodes play an important role in early human ontogeny.

Adult↗
PubMed1993

The majority of human tonsillar CD5+ B cells express somatically mutated V kappa 4 genes.

We have fractionated human tonsillar B cells on the basis of CD5 expression and determined the nucleotide sequences of immunoglobin light chain variable (V) regions encoded by the single member of the V chi 4 gene family in both CD5+ and CD5- populations. The majority of cDNA from both CD5+ and CD5- B cells populations harbored somatic mutations. Thus, human tonsillar CD5+ B cells, unlike their murine counterparts, are capable of activating their somatic hypermutation mechanism, resulting in the accumulation of somatic mutation in the VL regions.

Amino Acid Sequence↗
PubMed1993

Phenotypic and molecular characterization of human monoclonal TCR gamma/delta T-cell lines from jejunum and colon of healthy individuals.

We have performed a phenotypic and molecular analysis of monoclonal TCR gamma/delta T-cell lines derived from jejunal and colonic biopsies of healthy individuals. Flow cytometric analysis employing a panel of 24 monoclonal antibodies (MoAbs) demonstrated that intestinal TCR gamma/delta intraepithelial lymphocytes (IEL) constitute a phenotypically heterogeneous population. Nucleotide sequence analysis of expressed TCR delta variable (V) regions revealed the dominant utilization of the V delta 2 and D delta 3 gene segments and frequent rearrangement of J delta 3. IEL V delta regions displayed extensive junctional diversity as a result of N and P insertion and the utilization of D delta 3 in all three reading frames. The results demonstrate that intestinal TCR gamma/delta T cells from healthy individuals constitute a phenotypically heterogeneous population expressing V delta regions that differ from their systemic counterparts.

Amino Acid Sequence↗
PubMed1992

Deletion mapping of Ig VH gene segments expressed in human CD5 B cell lines. JH proximity is not the sole determinant of the restricted fetal VH gene repertoire.

VH gene segments expressed in a panel of monoclonal human CD5 B cell lines have been positioned on the IgH locus by deletion mapping. The analysis yielded a relative order of VH fragments of the VH2, VH4, VH5, and VH6 gene families that was consistent with, and provided a further refinement of existing maps of the human IgH locus. We demonstrate that four of six VH gene segments expressed in the CD5 B cell lines map > 500 kb from the cluster of JH segments. Two of the gene segments, positioned at approximately 850 kb (58p2) and approximately 500 kb (1-9III) from the JH segments, respectively, belong to the previously identified small cohort of second trimester fetal VH gene segments. The data show that JH proximity is not the sole determinant of restricted VH gene utilization in early human ontogeny.

Antigens, CD↗
PubMed1992

A human systemic lupus erythematosus-related anti-cardiolipin/single-stranded DNA autoantibody is encoded by a somatically mutated variant of the developmentally restricted 51P1 VH gene.

We report the Ig H and L chain V region sequences from the cDNAs encoding a monoclonal human IgG anti-cardiolipin/ssDNA autoantibody (R149) derived from a patient with active SLE. Comparison with the germ-line V-gene repertoire of this patient revealed that R149 likely arose as a consequence of an Ag-driven selection process. The Ag-binding portions of the V regions were characterized by a high number of arginine residues, a property that has been associated with anti-dsDNA autoantibodies from lupus-prone mice and patients with SLE. The VH gene encoding autoantibody R149 was a somatically mutated variant of the 51P1 gene segment, which is frequently associated with the restricted fetal B cell repertoire, malignant CD5 B cells, and natural autoantibodies. These data suggest that in SLE patients a common antigenic stimulus may evoke anti-DNA and anti-cardiolipin autoantibodies and provide further evidence that a small set of developmentally restricted VH genes can give rise to disease-associated autoantibodies through Ag-selected somatic mutations.

Amino Acid Sequence↗
PubMed1992

Sequence analysis of members of the human Ig VH4 gene family derived from a single VH locus. Identification of novel germ-line members.

We have generated a mouse x human heterohybridoma that contains a single copy of chromosome 14 and, thus, a haploid set of Ig VH genes. This cell line was used to investigate the germ-line content and nucleotide sequences of members of the VH4 gene family in a polymerase chain reaction-based approach. The analysis of 58 full-length sequences revealed the presence of 12 different germ-line VH4 genes, each of which is potentially functional. These germ-line VH4 genes were compared with the nucleotide sequences of published VH4 genes. Three VH4 genes were 100% identical to previously published sequences and belong to a group of VH4 genes that are strongly conserved and highly prevalent in the human population. Three VH4 genes in our collection displayed greater than 99.3% sequence identity with reported germ-line VH4 sequences and likely represent allelic counterparts of these genes. Six genes displayed less than 97.2% sequence identity with published VH4 genes and were identified as novel members of the human VH4 gene family or more distantly related alleles of known VH4 genes. Collectively, these data suggest that, overall, the human VH4 gene family may be more diverse than hitherto assumed, whereas a number of individual members are nonpolymorphic and extremely well conserved.

Amino Acid Sequence↗
PubMed1992

High frequency of somatically mutated IgM molecules in the human adult blood B cell repertoire.

Nucleotide sequence analysis of cDNA encoded by the single member of the human immunoglobulin VH6 gene family show that blood B cells in adults, but not in neonates, frequently express somatically mutated IgM molecules. The number of mutations in VH6-encoded cDNA from adult blood ranged from 2 to 19 mutations/VH gene (average 10.1/VH gene). The distribution of silent and replacement mutations suggests that at least some of the VH6 genes were derived from B cells that were activated and selected by antigen. We conclude that the blood B cell repertoire in adult humans, in contrast to its much-studied murine splenic counterpart, is a rich source of highly mutated IgM molecules.

Adult↗
PubMed1992

Expression of members of the immunoglobulin VH3 gene families is not restricted at the level of individual genes in human chronic lymphocytic leukemia.

Previous studies on the repertoire of Ig VH genes utilized in the malignant cells of chronic lymphocytic leukemia (CLL) have suggested a non-random expression pattern. In particular, individual genes from the VH1, VH5, and VH6 gene families have been frequently found in CLL. With regard to other VH gene families, including the large VH3 family which is expressed in greater than 50% of CLL cases, it is unknown whether CLL cells utilize either a broad or a restricted repertoire of VH genes. In the present paper, we analyzed the VH genes expressed in a collection of 11 CLL cases. The results of these experiments demonstrate that there is no apparent restriction in the usage of individual members of the VH3 gene families in CLL.

Base Sequence↗
PubMed1992

Molecular approaches to the study of human B-cell and (auto)antibody repertoire generation and selection.

We have shown that the restricted repertoire of VH genes expressed in second trimester human fetal liver is not solely determined by JH proximity. Furthermore, by following the fate of two VH gene segments in different B-cell repertoires, we have provided evidence that multiple factors contribute to the frequency with which individual VH genes are utilized. We found that the repertoire of adult blood IgM-bearing B cells contains a high proportion of B lymphocytes that express extensively mutated VH genes. Finally, we show that somatically-mutated variants of particular VH and VL genes that, in germline configuration, are frequently found in the early B-cell repertoire and in natural autoantibodies, encode pathogenic IgG autoantibodies characteristic of human SLE. These VH and VL genes harbor all the characteristics of an antigen-driven B-cell activation and selection process.

Amino Acid Sequence↗