Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model.

B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain.

Interleukin-10 promoter polymorphisms in patients with systemic lupus erythematosus from the Canary Islands.

The purpose of this study was to examine whether several allelic variants in the polymorphic interleukin (IL)-10 promoter region were related with an increased risk of developing systemic lupus erythematosus (SLE) in Spanish patients from Canary Islands. Microsatellites (MS) at positions -4000 and -1200 (IL10R and IL10G, respectively) and single nucleotide polymorphisms (SNPs) (MS) at positions -1082G/A, -819C/T and -592C/A of the IL-10 promoter were analysed in patients with SLE and healthy controls from Canary Islands (Spain). We found that SNPs but not MS were associated with SLE.

Expression of human leukocyte antigen-G in systemic lupus erythematosus.

The purpose of this study was to examine the expression of human leukocyte antigen-G (HLA-G) in patients with systemic lupus erythematosus (SLE) and its relation with interleukin-10 (IL-10) production. The study included 50 female SLE patients and 59 healthy female donors. HLA-G expression in peripheral blood and cutaneous biopsies was determined by flow cytometry and immunohistochemistry, respectively.

Prognostic irrelevance of HLA-G in B-cell chronic lymphocytic leukemia.

In the last few years, it has been suggested that the involvement of human leukocyte antigen-G (HLA-G) in several tumoral processes and its likely participation as a factor of immune tolerance in malignant cells. Recently, positive HLA-G surface expression has been associated with a poor prognosis in a small group of patients with B-cell chronic lymphocytic leukemia (B-CLL), a lymphoproliferative disorder characterized by a heterogeneous clinical course. In the present work, 169 patients suffering from B-CLL were analyzed for the expression of HLA-G by flow cytometry in order to verify its prognostic value in a larger cohort.

Association of the microsatellite in the 3' untranslated region of the CD154 gene with rheumatoid arthritis in females from a Spanish cohort: a case-control study.

CD40-CD154 interaction is an important mediator of inflammation and has been implicated in T helper type 1-mediated autoimmune diseases including rheumatoid arthritis (RA). Linkage studies have shown association of markers in the proximity of the CD154 gene. In the present work we investigated whether specific allele variants of the microsatellite in the 3' UTR of the CD154 gene might modulate the risk of RA.

CD5 does not regulate the signaling triggered through BCR in B cells from a subset of B-CLL patients.

CD5 is a transmembrane protein expressed on all T lineage cells and a subset of B cells. It is known that CD5 is physically associated with the T-cell receptor and B-cell receptor (BCR), inhibiting the signaling triggered by both of them. CD5 is also characteristic of B-chronic lymphocytic leukemia (B-CLL) B cells, although its implication in the development of this lymphoproliferative disorder has not been studied.

CD5 provides viability signals to B cells from a subset of B-CLL patients by a mechanism that involves PKC.

B-chronic lymphocytic leukaemia (B-CLL) is a heterogeneous disease characterized by an accumulation of B lymphocytes expressing CD5. To date, the biological significance of this molecule in B-CLL B cells remains to be elucidated. In this study, we have analysed the functional consequences of the binding of an anti-CD5 antibody on B-CLL B cells.

Polymorphism in the CD5 gene promoter in B-cell chronic lymphocytic leukemia and mantle cell lymphoma.

Despite the low incidence of microsatellite instability (MSI) in lymphoid malignant neoplasms, it has been reported that the CD5 promoter MSI was relatively frequent among B-cell chronic lymphoproliferative disorders. We studied the presence of MSI in the CD5 promoter in 134 cases of B-cell chronic lymphocytic leukemia (B-CLL) and 47 of mantle cell lymphoma (MCL) by comparing the pattern of microsatellite repeats on autologous germline and tumor DNA samples. Microsatellite alterations were not observed in any case.

A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells.

The progressive rise of mature CD5+ B lymphocytes, despite the low proportion of proliferating cells, has led to the notion that B cell chronic lymphocytic leukemia (B-CLL) is primarily related to defective apoptosis. The microenvironment likely plays a prominent role because the malignant cells progressively accumulate in vivo, whereas they rapidly undergo spontaneous apoptosis when cultured in vitro. To assess microenvironment-mediated survival signals, B-CLL cells were cultured with a murine fibroblast cell line, Ltk-, with and without an agonistic antibody to CD40.

The dinucleotide repeat polymorphism in the 3'UTR of the CD154 gene has a functional role on protein expression and is associated with systemic lupus erythematosus.

Objective: To investigate the association of the (CA)n dinucleotide repeat in the 3' untranslated region (3'UTR) of the CD154 gene with systemic lupus erythematosus (SLE), and its functional role in protein expression.

Methods: The allelic and genotypic distributions of the polymorphism were compared in 80 patients with SLE and 80 controls. A complete clinical and analytical database was recorded in each patient in order to correlate the clinical manifestations in SLE with different alleles.

Mannose binding lectin polymorphisms as a disease-modulating factor in women with systemic lupus erythematosus from Canary Islands, Spain.

Objective: To determine whether mannose binding lectin (MBL) polymorphisms are associated with clinical characteristics and with susceptibility to systemic lupus erythematosus (SLE) in women from the Canary Islands, Spain.

Methods: MBL alleles and genotypes were determined by polymerase chain reaction in 89 female patients and 188 female controls.

Results: No differences in the allelic or genotypic frequencies were observed between patients and controls.

IL4-R1 (5q31-q33) and FcepsilonRI-betaca (11q13) markers and atopy: a case/control study in a spanish population.

Background: Rhinoconjunctivitis and bronchial asthma are atopic diseases with a high prevalence in the Canary Islands (Spain). Given that the most prevalent allergen is the house-dust mite Dermatophagoides pteronyssinus, early detection of genetically susceptible subjects would allow the application of preventive measures. The objective was to investigate the possible association of IL4-R1 (chromosome 5q31-q33) and FcepsilonRI-betaca (chromosome 11q13) markers with the atopic disease in our population.

CD154 polymorphism in Spanish populations. Differences in the allelic distribution between Canary islanders and Peninsulars.

The CD154 gene contains a dinucleotide repeat (CA)n in the 3' untranslated region. Allelic distribution in Spanish populations from two areas with different genetic background, the Canary Islands and Peninsula, are described. Seven alleles with different allelic distribution between the two groups, were found.

Pocket 4 in the HLA-DRB1 antigen-binding groove: an association with atopy.

Background: Many studies have attempted to identify an association between HLA genes and atopy, given the role of HLA molecules in the regulation of the immune response. In the case of house-dust mites, it is difficult to find an association with a particular HLA allele, due to the complexity of the allergen. The objective was to investigate whether HLA-DRB1 functional groups are better correlated with the atopic disease in our population than DRB1 alleles.

Association of HLA-DR11 with the anaphylactoid reaction caused by nonsteroidal anti-inflammatory drugs.

Background: Several HLA alleles have been associated with asthma induced by nonsteroidal anti-inflammatory drugs (NSAIDs). The existence of HLA markers linked to other NSAID-induced reactions, such as cutaneous and anaphylactoid reactions, has not been established.

Objective: The purpose of our work was to study the HLA-DRB1 and HLA-DQB1 alleles in patients with cutaneous and anaphylactoid reactions caused by NSAIDs.

Linkage of house dust mite allergy with the HLA region.

Background: Atopy is a multifactorial disease, the pathogenesis of which is influenced by both genetic and environmental conditions. Genes in the HLA region have been involved in the control of the IgE response.

Objective: In order to investigate whether allergy to house dust mite is associated with HLA in our population, we performed sib-pair analysis in 18 families and a case/control study of 161 non-related individuals.

Clinical and immune aspects of idiopathic acute tubulointerstitial nephritis and uveitis syndrome.

Five patients with idiopathic interstitial nephritis and uveitis without bone marrow granulomas were followed-up for 1 year. Ophthalmological examination revealed bilateral anterior uveitis. Light microscopy of the renal tissue revealed predominant lymphocyte infiltration of the interstitium.

Selective disbalances of peripheral blood T lymphocyte subsets in human CD3 gamma deficiency.

The selection of T lymphocytes in the thymus and their activation upon the encounter with foreign antigens in the periphery require the aggregation and signals of the T cell receptor (TcR)/CD3 complex and several surface molecules termed coreceptors (notably CD4 or CD8 and CD45). The spatial arrangement and interactions of the different molecules in the resulting multimolecular recognition structure are mostly unknown. Here we report, from studies on a healthy human CD3 gamma deficiency, that the lack of the CD3 gamma component of the TcR/CD3 complex is associated with a long-term severe defect of peripheral blood CD4+ CD45RA+ and CD8+ lymphocytes, whereas CD4+CD45RO+, B and natural killer lymphocytes are unaffected.

From pathology to physiology of the human T-lymphocyte receptor.

The recent description of a selective human CD3 gamma deficiency and other T-cell receptor (TCR)/CD3 structural and functional defects, together with previous biochemical data on the structure and interactions of the TCR/CD3 complex, may aid in elucidating the physiology of this multi-subunit membrane ensemble. CD3 gamma seemed to be required for the commitment and thymic maturation of an important fraction of T lymphocytes to the CD8 (but not CD4) lineage, perhaps by participating with the CD8 co-receptor in the instructive signal delivered through the alpha beta TCR during intrathymic positive selection by HLA class I molecules. The homologous CD3 delta component would, in contrast, be necessary for the selection of CD4 lymphocytes by HLA class II molecules.

High frequency of the HLA-DRB1*0405-(Dw15)-DQw8 haplotype in Spaniards and its relationship to diabetes susceptibility.

A study of DR4 subtypes has been done in Spanish unrelated controls and insulin-dependent diabetics by using dot blot hybridization with specific DR4B1 exon-2 oligonucleotides and automated dideoxy DNA sequencing. Dw15-DQw8 is the predominant DR4 subtype present in our normal population (37%); this DR4 frequency characteristic singles out our population from all other Caucasoids tested so far and may also be a marker of the original Iberian paleo-North African population. Dw15-DQw8 is not significantly increased in our insulin-dependent diabetics sample and despite its relative high frequency in the control population it does not have a bearing in lowering insulin-dependent diabetes mellitus frequency of DR4-positive Spaniards.

T-lymphocyte dysfunctions occurring together with apical gut epithelial cell autoantibodies.

Gut epithelial cell autoantibodies have been considered a hallmark of autoimmune enteropathy, a disorder occurring in children with protracted diarrhea of unknown etiology. Four patients (two male and two female) with such autoantibodies were studied. Immunofluorescence analysis showed two different disjunctive staining patterns: complement-fixing apical (three of four) and cytoplasmic (the remaining fourth one), which are shown to be directed against different structures.

Immunogenetics of systemic lupus erythematosus in Spanish patients: differential HLA markers.

HLA-DR3 antigen included in the compound phenotype B18BfF1 (but not the one linked to the B8BfS compound phenotype) was found to be significantly increased in our SLE patients. It is remarkable that in our Southern-Mediterranean population, B18BfF1DR3 individuals (but not B8BfSDR3) are prone to SLE with renal disease, in contrast with other Northern European and Caucasoid populations. Also, patients with autoantibodies to Ro/La have a significant increase of the B8DR3 compound phenotype.

Expression and function of a variant T cell receptor complex lacking CD3-gamma.

A T cell line termed DIL2 has been derived from an infant with a polyclonal T cell receptor (TCR)/CD3 cell surface expression defect. Indirect immunofluorescence showed that the expression of certain TCR/CD3 epitopes (like those detected by WT31 and BMA031 monoclonals) was strongly reduced (around five-fold) on DIL2, whereas other epitopes (like those detected by SP34 and Leu4) were only around two-fold lower than in normal T cell lines. Specific immunoprecipitates of surface-radioiodinated DIL2 cells contained TCR-alpha, TCR-beta, CD3-delta, CD3-epsilon and TCR-zeta chains, but lacked CD3-gamma.

Biochemical basis of a novel T lymphocyte receptor immunodeficiency by immunohistochemistry. A possible CD3 gamma abnormality.

Necropsic lymphoid tissues obtained from an infant with a novel type of immunodeficiency consisting of a peripheral blood T lymphocyte antigen receptor (TCR) surface expression defect, were analyzed by immunohistochemistry for the expression of various TCR-associated epitopes. The work was aimed to characterize the biochemical basis of this kind of disorder and confirm the defect in different lymphoid tissues. Within an assessed lymphoid depletion, the patient's tissues showed a normal expression of several TCR epitopes (those associated to CD3 epsilon, CD3 delta and the clonotypic -Ti- alpha and beta chains).