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Results for “Gene Rearrangement, T-Lymphocyte”

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PubMedDate not supplied

A V(D)J site-specific recombination model involving no compulsory double-stranded break formation at the coding segments.

Complete immunoglobulin and T-cell-receptor genes are assembled by site-specific recombination of separately encoded gene segments. We present a novel recombination model which accounts for all the characteristics of V(D)J recombination that have been described. The sequence of events proposed implies no formation of double-stranded breaks at the coding ends, ensuring continuity between the recombination partners during the reaction, and solves the problem of the ligation of extremities which have no complementarity. According to this recombination model, the formation of covalently sealed coding ends does not constitute a compulsory step in the recombination process.

Animals↗

PubMed1992

[Demonstration of Epstein-Barr virus DNA and determination of immunoglobulin and T-cell receptor gene rearrangerments in diagnostic lymph node biopsies from patients with Hodgkin's disease].

Lymph node biopsies of 52 patients with Hodgkin's disease were analyzed by Southern blot hybridization for the presence of monoclonal rearrangements of immunoglobulin and T cell receptor genes. The same tissues were tested for Epstein-Barr virus DNA by the polymerase chain reaction using four different sets of primers. Monoclonal rearrangements were identified in only four tumors, whereas Epstein-Barr virus was present in 79% of biopsies. A correlation between the degree of infiltration by Reed-Sterberg cells, clonality and the presence of Epstein-Barr virus could not be found. These results are in agreement with similar studies reported in the literature. The nature of the malignant cell in Hodgkin's disease and the role of Epstein-Barr virus in the etiology of this tumor remains to be established.

Base Sequence↗

PubMed1992

Lymphadenopathy, oligoclonal T cell receptor rearrangement and systemic lupus erythematosus.

To investigate the cause of generalized lymphadenopathy in case of systemic lupus erythematosus (SLE), we performed a molecular genetic analysis of lymph node, peripheral blood mononuclear cell and bone marrow specimens with T cell receptor and immunoglobulin gene probes. Oligoclonal T cell receptor rearrangements were detected in the lymph node cells. The oligoclonal T cell expansion observed is the first such example reported in SLE, and may be indicative of an immune response to specific antigenic challenge. Alternatively, these changes may represent the earliest phases of a malignant process. Molecular genetic investigations in autoimmune disease such as SLE can provide opportunities to enhance our understanding of the underlying condition, or reveal unexpected abnormalities requiring further assessment.

Blotting, Southern↗

PubMed1992

The T cell receptor gene and its association with human diseases.

The genetic organization and protein structure of the T cell receptor (TCR)/CD3 complex are currently under investigation, and recent work has provided information about its assembly, expression and function. This article reviews what is currently known about the structure and assembly of the TCR/CD3 complex. The TCR chains are members of the immunoglobulin gene superfamily and are generated by combinatorial associations of V, J, D, and C genes. The presence of certain gene rearrangements within these chains has been associated with lymphoproliferative disorders, autoimmune disease and immunodeficiencies. TCR rearrangements can be useful in the diagnosis of lymphoproliferative disorders and in the identification of patients who will subsequently relapse, once in remission. With respect to autoimmune disease, the possibility now exists of immunotherapy with TCR designer polypeptides to prevent disease. In patients with primary immunodeficiencies secondary to defects in expression of the TCR, the possibility of somatic gene therapy now exists. As more information unfolds about the role that TCR gene rearrangements have in various diseases, new insights are gained into better diagnosis and treatment.

Autoimmune Diseases↗

PubMed1992

Polyclonal origin of rheumatoid synovial T-lymphocytes.

Nineteen T-cell clones from seven patients with RA were obtained by cloning infiltrating lymphocytes from needle synovial biopsies. Southern blot analysis of the T-cell receptor (TCR) beta-chain genes in these clones revealed that there were no T-cell clones with an identical rearrangement of the TCR beta gene. These results do not support the idea that the infiltrating T-lymphocytes in RA are of monoclonal or oligoclonal origin.

Arthritis, Rheumatoid↗

PubMed1992

Study of the major phenotype of large granular T-cell lymphoproliferative disorder.

Six cases of large granular T-cell lymphoproliferative disorder with a selected immunophenotype (CD3+, CD4-, CD8+, CD16+) were studied to characterize a homogeneous group of patients. It was found that most of these patients did not exhibit the clinical features frequently described in large granular T-cell lymphoproliferative disorder--recurrent infection, rheumatoid arthritis, and splenomegaly. The laboratory tests usually positive in large granular T-cell lymphoproliferative disorder, including rheumatoid factor and anti-nuclear antibodies, also were frequently negative. The pathognomonic features were found to be neutropenia and large granular lymphocytosis with positive killer cell markers. All six cases showed T-cell receptor gene rearrangement that indicated a monoclonal proliferation of lymphoid cells, which were natural killer-like T cells by immunophenotyping. B cells were essentially absent in all cases. It should be emphasized that bone marrow aspirates are as informative as peripheral blood samples for the diagnosis of large granular T-cell lymphoproliferative disorder; indeed, phenotypes of blood and marrow in one case were identical in terms of percentages of markers. In this selected group of patients, the clinical courses were indolent with uncomplicated outcomes. In three patients, chemotherapy did not induce an obvious clinical response, but all patients' conditions remained stable with only supportive care.

Adult↗

PubMed1992

The immunogenetics of immune senescence.

Immune senescence is characterized by a dysregulation of the immune system. With respect to humoral immunity, aging is associated with an increased level of many autoantibodies and a decreased antibody response to most foreign antigens. This observation reflects a decreased capacity to activate antibody production by CD5-negative B cells despite a normal or increased capacity to generate antibodies produced by the CD5-positive B cells. A similar dysregulation of cell-mediated immunity is manifested by an altered balance in cytokine production by T cells from old as compared to young subjects. Thus, the production of interleukin-2 (IL-2), IL-3 and granulocyte-macrophage colony-stimulating factor by T cells from old subjects is decreased although the production of IL-4, IL-5 and IL-6 is undiminished or actually increased.

Aged↗

PubMed1992

Novel excision products of T cell receptor gamma gene rearrangements and developmental stage specificity implied by the frequency of nucleotide insertions at signal joints.

We have cloned circular DNA excised by T cell receptor (TcR) gamma 1, gamma 2 and gamma 3 gene rearrangements in fetal and adult mouse thymocytes. Circular DNA contained a signal joint reciprocal to the genomic V-J coding joint. Although signal joints without nucleotide insertions are common in immunoglobulin (Ig) and TcR gene rearrangements, the signal joint of gamma found in adult thymocytes contained non-germ-line element (N) insertions at high frequency, while no insertions were found in fetal thymocytes. Thus developmental stage specificity of TcR gamma gene rearrangements is faithfully reflected on the signal joint of excision products. In addition, examination of gamma gene excision products revealed circular DNA products of TcR gamma-alpha transrearrangements, but no evidence of V gamma gene replacement in a rearranged segment.

Age Factors↗

PubMed1992

Variable gene usage of T cell receptor gamma- and delta-chain transcripts expressed in synovia and peripheral blood of patients with rheumatoid arthritis.

The synovial tissue and fluid of patients with rheumatoid arthritis (RA) contain activated T cells that probably have a central role in the disease process which leads to joint destruction. A subset of T cells, gamma delta T cells detected at the site of inflammation, may be important in the pathogenesis of the disease. This study investigated variable (V) gene usage of gamma delta T cell receptors (TcRs) expressed in synovia and peripheral blood of patients with RA by using the polymerase chain reaction (PCR) to amplify TcR gamma- and delta-chain transcripts. Most patients showed no restriction in V gamma gene usage since synovial mononuclear cells (SMC) expressed TcR gamma-chain transcripts which used the same set of V gamma genes as peripheral blood mononuclear cells (PBMC). In contrast, the majority of patients expressed a restricted SMC V delta-chain repertoire biased towards V delta 1, but V delta 2 mRNA transcripts were also detected, albeit at low levels in some patients. The TcR delta-chain repertoires of PBMC from healthy control subjects were also characterized. There was variation in the TcR delta-chain repertoires of PBMC from patients when compared with controls, particularly with respect to expression of V delta 4. V delta 4 mRNA transcripts were expressed in PBMC of only two of seven RA patients in contrast with eight of the nine controls (P = 0.03). These findings are compatible with reports that gamma delta T cells in the rheumatoid synovium are reactive to Mycobacterium tuberculosis and that response to M. tuberculosis is restricted to V gamma 9/V delta 2-bearing T cells, if a superantigen is involved in the pathogenesis of RA.

Arthritis, Rheumatoid↗

PubMed1979

Non-random duplication of chromosome 15 in murine T-cell leukemias induced in mice heterozygous for translocation T(14:15)6.

Trisomy of chromosome 15 is a highly regular feature of murine T-cell leukemogenesis. We have studied the chromosomal constitution of 7,12-dimethylbenza(a)anthracene (DMBA)-induced T-cell leukemias in C57BL X CBAT6T6 F1 mice. The CBAT6T6-derived chromosome T(14:15)6 was regularly duplicated whereas the C57BL-derived normal chromosome 15 was only present in one copy. It was concluded that the gene(s) that tend to duplicate in parallel with the neoplastic transformation of the prothymocyte to an overt leukemic cell have a greater chance of duplicating and/or may have a stronger promoting effect on leukemogenesis if stronger promoting effect on leukemogenesis if located on the CBA-derived, structurally rearranged T(14:15)6 than the corresponding genes located on the C57BL-derived normal chromosome 15.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1992

Mechanisms that generate junctional diversity in alpha and delta chains that use the Tcrd-V3 gene product.

The signals that dictate whether a thymocyte will express the alpha beta or gamma delta T-cell receptors are unknown. Although it is also not known if these two different cell types use identical recombinational machinery during rearrangement, the same variable (V) region genes can be used by both alpha and delta chains. By examining the products of rearrangements in alpha beta or gamma delta thymocytes that express identical V genes, we hoped to determine whether these cell types might differ in particular aspects of their recombinational activity. The polymerase chain reaction was used to show that the Tcrd-V2, Tcrd-V3, and Tcra-V3 genes are expressed as both Tcra and Tcrd transcripts in fetal and adult BALB/c mice. Sequencing of V delta 3 isolates was performed in order to compare the contribution of various mechanisms to the generation of junctional diversity. Extensive junctional diversity was present at all stages of development examined (fetal, newborn, and adult). During early development both alpha and delta chain junctional diversity is generated primarily by variability in the position of joining two gene segments (i.e., Tcrd-V3 to Tcra-J in alpha chains; Tcrd-V3 to Tcrd-D2 and Tcrd-D2 to Tcrd-J1 in delta chains). The pattern of base pair deletion from the end of the Tcrd-V3 gene was identical in alpha and delta chains and deletions occurred in fetal as well as adult T cells. In later development T cells use not only this mechanism for alpha and delta chains but also the addition of bases at gene segment junctions, presumably through the action of terminal deoxynucleotidyl transferase (TdT). Finally, a comparison of the variable domains of these alpha and delta chains shows that a notable difference is the variability in length of the CDR 3 region which can be significantly longer in delta-chains than in alpha-chains.

Amino Acid Sequence↗

PubMed1992

[Diversity of T-cell antigen receptor response in individuals with sarcoidosis].

T-lymphocytes recognize specific antigen(s) through T-cell antigen receptors (TCRs). There are two classes of TCRs: those composed of alpha beta chain dimers and those formed by gamma delta dimers. Although the pathogenesis of sarcoidosis is still unclear, participation of exogenous antigen(s) is highly suggested. To investigate the mechanism of activation and accumulation of T-lymphocytes at the sites of disease, the bias of TCRs in individuals with sarcoidosis was evaluated with respect to several points. Eighteen of 51 cases of sarcoidosis showed increase of gamma delta-TCR positive T-lymphocytes in the blood. In contrast to the blood, a low number of gamma delta T-cells and evidence of T-cell stimulation through alpha beta-TCR were observed in the lung. The TCR junctional regions of V gamma 9, V delta 2 and V beta 8 gene segments were sequenced from blood and lung T-cells of individuals with sarcoidosis and normal subjects, using RT-PCR. In normals, a huge diversity of the junctional region sequences was observed in V gamma 9, V delta 2 and V beta 8 transcripts in the blood and lung. In contrast to normal subjects, a subgroup of sarcoidosis showed an increase of V gamma 9 transcripts sharing identical sequences. Although less marked than for V gamma 9, an increase in identical junctional region sequences was also observed in V delta 2 transcripts. All junctional region sequences of V beta 8 transcripts in the blood and lung were unique, indicating polyclonal activation of T-cells through TCR beta-chain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed2026

Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function.

Human protein-coding genes evolved via rearrangement of domains from ancestral genes. We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence-sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding. Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families. Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.

Humans↗

PubMed1992

Biological characteristics of CD7 positive acute myelogenous leukaemia.

We studied the biological characteristics of CD7+ acute myelogenous leukaemia (AML). We diagnosed nine out of 88 consecutive AML cases as CD7+ AML based on myeloperoxidase positivity and surface antigen expression. In eight of these nine cases more than 20% of leukaemic blasts were found to coexpress both CD7 and a myeloid-associated antigen, CD33, by a two-colour flow-cytometric assay, while in the remaining case more than 90% of blasts were positive for CD7 and myeloperoxidase. CD7+ AML was most frequently observed in M1 among AML subtypes according to the FAB classification. An early stage-specific antigen, CD34 was also expressed on leukaemic blasts from eight of these nine cases. Neither the T-cell receptor (TcR)-beta nor the TcR-gamma gene was clonally rearranged in any of the cases. We then studied the proliferative responses to stimulation by various growth factors. Among interleukin-3 (IL-3), granulocyte/macrophage colony-stimulating factor (GM-CSF), and granulocyte-CSF (G-CSF), IL-3 showed the strongest stimulatory effect on DNA synthesis and leukaemic blast colony formation in 8/9 and 6/8 CD7+ AML cases examined, respectively. On the other hand, the strongest stimulatory effect exerted by IL-3 on blast colony formation was observed in only six out of the 33 CD7- AML cases examined. Furthermore, CD7+ AML blasts could proliferate in response to stem cell factor (SCF); SCF alone showed stimulatory effects on blast colony formation (7/8 cases), and in 5/7 SCF-responding cases, stimulatory effects of SCF were more potent than those of IL-3. In addition, SCF enhanced blast colony formation synergistically with IL-3 in four of these seven cases. These data suggest that progenitor cells of CD7+ AML may possess the biological properties characteristic of immature haematopoietic stem cells.

Adolescent↗

PubMed1978

Buridan's ass: one man's view of the immune system.

This essay offers a highly biased and prejudiced interpretation of the immune response. The major points of this interpretation are: B and T lymphocyte diversity is generated by rearrangements within and among existing receptorcoding genes; the T cell receptor is a molecule genetically more closely related to immunoglobulins than to the products of the major histocompatibility complex (MHC); the course of B and T lymphocyte differentiation is largely the same except for a final processing of T lymphocytes in the thymus; the processing is directed by MHC molecules of the thymus epithelium; Ir and Ia genes are identical; and the function of MHC polymorphism is to generate diversity at the population level.

Animals↗

PubMed1992

Case report: granulocyte colony-stimulating factor overcomes severe neutropenia of large granular lymphocytosis.

Large granular lymphocytosis (LGL) is characterized by enhanced proliferation of T lymphocytes that have antibody-dependent cell-mediated cytotoxicity or natural killer cell activity and that often produce severe cytopenias, including neutropenia. When a 68-year-old man with seropositive rheumatoid arthritis and severe neutropenia was examined, he was found to have LGL with a T cell gene rearrangement, indicating the presence of a clonal population of T lymphocytes. The patient was admitted with a fever of 102 degrees F and a nonhealing ulcer over the right tibia. When the infection did not respond to intravenous antibiotics, granulocyte colony-stimulating factor (GCSF) therapy was started at 5 micrograms/kg subcutaneously each day. The neutrophil count promptly increased and the patient subsequently defervesced and was able to have a skin graft placed, which healed without difficulty. GCSF, which is known to be an effective therapeutic agent for neutropenia associated with chemotherapy and bone marrow transplantation, also was a very valuable treatment for the life-threatening neutropenia of LGL.

Aged↗

PubMed1992

Skin-infiltrating lymphocytes in normal and disordered skin: activation signals and functional roles in psoriasis and mycosis fungoides-type cutaneous T cell lymphoma.

T lymphocytes recruited into the skin can experience several different outcomes. On the one hand, they may be recruited by adhesion molecules and chemoattractants to enter the perivascular space, but never undergo activation. Other T cells undergo activation and further differentiation under the influence of the cutaneous milieu. These activated lymphocytes then coordinate specific and non-specific immune responses characteristic of inflamed tissue. We have explored two models for studying the activation and function of skin infiltrating T lymphocytes (SIL's). In the first model, we have identified a family of Langerhans cell-related professional dendritic antigen presenting cells that exist in the epidermis and dermis of normal skin, atopic skin, and mycosis fungoides skin. These have APC abilities to activate freshly recruited resting blood T cells that are distinct from another family of macrophage-related cells abnormally present in sunburned or psoriatic skin. In the second model, we examined the function of cells that have already been recruited into the skin of patients with psoriasis and mycosis fungoides. Lesional psoriasis and mycosis fungoides T cells exhibited a variety of T cell receptor gene rearrangements, conclusively demonstrating that heterogeneous populations of T lymphocytes exist in inflamed human skin. From psoriasis, clones were identified that were particularly effective at inducing normal keratinocytes to assume "psoriatic" phenotypic features and functions. Thus, lesional psoriatic SIL's could induce HLA-DR, ICAM, and CDw60 on normal keratinocytes. In addition, psoriatic SIL's induced increased keratinocyte proliferation and cytokine profile changes characteristic of psoriatic epidermis.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Presenting Cells↗

PubMed1992

T-cell receptor beta-chain gene rearrangements of T-cell populations expanded from multiple sites of synovial tissue obtained from a patient with rheumatoid arthritis.

In this study T-cell receptor (TcR) beta-chain gene rearrangements of T-cell lines prepared from multiple sites (n = 92) of synovial tissue derived from both knees of a patient with rheumatoid arthritis were analysed. In the majority of T-cell lines, dominant TcR beta-chain gene rearrangements were detected, involving C beta 1 as well as C beta 2. The dominant rearrangement patterns of T-cell lines from different tissue fragments showed significant variability, but some of the DNA restriction fragments were shared by T-cell lines from multiple sites in both knees. The latter observation suggests that identical T-cell clones may be present at different sites in the synovial tissue and in different joints. However, since many T-cell lines yielded different rearrangement patterns, these data also indicate considerable heterogeneity of T cells in the joints. Apart from theoretical implications, this TcR heterogeneity of T cells within an individual patient also has practical consequences for studies on synovial T cells obtained by biopsy.

Aged↗