Increasing incidence rate of breast cancer in cystic fibrosis - relationship between pathogenesis, oncogenesis and prediction of the treatment effect in the context of worse clinical outcome and prognosis of cystic fibrosis due to estrogens.

Cystic fibrosis (CF) is the most common genetic disease in the Caucasion population. Thanks to the CFTR modulators therapy, life expectancy will significantly improve. New therapeutic challenges can be expected, including diseases associated with ageing and higher incidence of cancer, as evidenced by recent epidemiological studies. The increasing incidence of tumors includes also breast cancer. The risk of breast cancer is higher in CF patients compared to the general population. Sex hormones, especially estrogens, also affect on the pathophysiology and immunology of the CF. Previous research, has demonstrated unequivocal survival rates for female CF patients compared to their male counterparts. Is demonstrated, that chemotherapy used for breast cancer affects the CFTR channel and CFTR modulator therapy has frequent side effects on breast tissue. In this review, we focus on the effects of female sex hormones on CF disease, pathophysiological relationships between CF and breast cancer, and the impact of antitumor treatment on both, malignant disease and CF. The potential for further investigation is also discussed.

Cardiorespiratory fitness on a treadmill in an adult cystic fibrosis population.

OBJECTIVES: (1) To describe the cardiorespiratory fitness (CRF) in an adult cystic fibrosis population related to sex and age, (2) to evaluate the cause of low CRF and (3) to study the association between peak oxygen uptake (VO2peak) and forced expiratory volume in 1 s (FEV1). METHODS: A total of 204 cardiopulmonary treadmill exercise tests (CPETs) performed by 116 patients were included. VO2peak, gas exchange, heart rate, oxygen saturation and ventilatory variables were measured.A low CRF was defined as a VO2peak <80% of predicted, ventilatory limitation was defined as a breathing reserve <15%, exercise hypoxaemia was defined as an oxygen saturation <88% and ventilation-perfusion mismatch was defined as a minute ventilation/ventilatory equivalent for carbon dioxide slope ≥34. In patients who had performed three or more CPETs, the annual change in FEV1 and VO2peak were calculated using linear regression. RESULTS: The VO2peak was 40.6±11.5 and 35.2±8.9 mL kg-1 min-1, which was 87±23 and 93±20 in percentage of predicted for men and women, respectively. VO2peak was moderately affected by age, for men (r=-0.36, p<0.001) and women (r=-0.53, p<0.001), respectively. In 45 of 101 tests where CRF was low, no cardiorespiratory limiting factors were identified. The correlation coefficient between VO2peak and FEV1 was r=0.64 (p<0.001). In participants with a low CRF, FEV1 ranged from 20% to 112% of predicted. CONCLUSIONS: The correlation between VO2peak and FEV1 was moderate. The majority of the tests resulted in a VO2peak within normal limits. Interestingly, 44% of the tests with a low VO2peak could be explained by deconditioning. Thus, exercise therapy may be beneficial for these patients.

Chronic lymphocytic leukemia cells express CD38 in response to Th1 cell-derived IFN-γ by a T-bet-dependent mechanism.

Chronic lymphocytic leukemia (CLL) is a B cell malignancy associated with increased levels of inflammatory cytokines. Similarly, expression of CD38 on CLL cells correlates with CLL cell survival and proliferation, but the mechanisms that regulate CD38 expression and inflammatory cytokines remain unclear. We have recently demonstrated that patients have CLL-specific Th cells that support CLL proliferation. In this article, we show that CLL cells attract such Th cells, thereby establishing an Ag-dependent collaboration. Blocking experiments performed in vitro as wells as in vivo, using a xenograft model, revealed that secretion of IFN-γ was a major mechanism by which CLL-specific Th cells increased CD38 on CLL cells. The expression of the transcription factor T-bet in peripheral blood CLL cells significantly correlated with CD38 expression, and transient transfection of CLL cells with T-bet resulted in T-bet(hi)CD38(hi) cells. Finally, chromatin immunoprecipitation experiments revealed that T-bet can bind to regulatory regions of the CD38 gene. These data suggest that CLL cells attract CLL-specific Th cells and initiate a positive feedback loop with upregulation of T-bet, CD38, and type 1 chemokines allowing further recruitment of Th cells and increased type 1 cytokine secretion. This insight provides a cellular and molecular mechanism that links the inflammatory signature observed in CLL pathogenesis with CD38 expression and aggressive disease and suggests that targeting the IFN-γ/IFN-γR/JAK/STAT/T-bet/CD38 pathway could play a role in the therapy of CLL.

Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mice.

BACKGROUND: Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, however, is hampered by the complexity and costs due to the individualized production of protein vaccines. These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. We have here investigated whether such vaccines might elicit cross-reactive immune responses thus offering the possibility to immunize subsets of patients with the same vaccine. METHODS: Fusion vaccines targeting patient Id to mouse Major Histocompatibility Complex (MHC) class II molecules (chimeric mouse/human) or chemokine receptors (fully human) on antigen-presenting cells (APC) were genetically constructed for two Chronic Lymphocytic Leukemia (CLL) patients and one prototypic stereotyped B-cell receptor (BCR) commonly expressed by Hepatitis C Virus (HCV)-associated Non Hodgkin Lymphoma (NHL). The A20 murine B lymphoma cells were engineered to express prototypic HCV-associated B cell lymphoma BCR. Anti-Id antibody responses were studied against stereotyped and non-stereotyped BCRs on CLL patients' cells as well as transfected A20 cells. RESULTS: DNA vaccination of mice with Id vaccines that target APC elicited increased amounts of antibodies specific for the patient's Id as compared with non targeted control vaccines. Anti-Id antibodies cross-reacted between CLL cells with closely related BCR. A20 cells engineered to express patients' V regions were not tumorigenic in mice, preventing tumor challenge experiments. CONCLUSIONS: These findings provide experimental support for use of APC-targeted fusion Id DNA vaccines for the treatment of B cell lymphoma and CLL that express stereotyped BCRs.

Chronic lymphocytic leukemia cells are activated and proliferate in response to specific T helper cells.

There is increasing interest in the chronic lymphocytic leukemia (CLL) microenvironment and the mechanisms that may promote CLL cell survival and proliferation. A role for T helper (Th) cells has been suggested, but current evidence is only circumstantial. Here we show that CLL patients had memory Th cells that were specific for endogenous CLL antigens. These Th cells activated autologous CLL cell proliferation in vitro and in human → mouse xenograft experiments. Moreover, CLL cells were efficient antigen-presenting cells that could endocytose and process complex proteins through antigen uptake pathways, including the B cell receptor. Activation of CLL cells by Th cells was contact and CD40L dependent. The results suggest that CLL is driven by ongoing immune responses related to Th cell-CLL cell interaction. We propose that Th cells support malignant B cells and that they could be targeted in the treatment of CLL.

Tracking early autoimmune disease by bioluminescent imaging of NF-kappaB activation reveals pathology in multiple organ systems.

It is desirable to have an early and sensitive detection marker of autoimmune disease in intact animals. Nuclear factor (NF)-kappaB is a transcription factor that is associated with inflammatory responses and immune disorders. Previously, we demonstrated that so-called idiotypic-driven T-B cell collaboration in mice doubly transgenic for paired immunoglobulin and T cell receptor transgenes resulted in a systemic autoimmune disease with systemic lupus erythematosus-like features. Here, we investigated NF-kappaB activation by including an NF-kappaB-responsive luciferase reporter transgene in this animal model. Triply transgenic mice developed bioluminescence signals from diseased organs before onset of clinical symptoms and autoantibody production, and light emissions correlated with disease progression. Signals were obtained from secondary lymphoid organs, inflamed intestines, skin lesions, and arthritic joints. Moreover, bioluminescence imaging and immunohistochemistry demonstrated that a minority of mice suffered from an autoimmune disease of the small intestine, in which light emissions correlated with antibodies against tissue transglutaminase and gliadin. Detection of luciferase by immunohistochemistry revealed NF-kappaB activation in collaborating B and T cells, as well as in macrophages. These results demonstrate that bioluminescent in vivo imaging of NF-kappaB activation can be used for early and sensitive detection of autoimmune disease in an experimental mouse model, offering new possibilities for the evaluation of anti-inflammatory drugs.

Systemic autoimmune disease caused by autoreactive B cells that receive chronic help from Ig V region-specific T cells.

B cells present BCR V region-derived Id-peptides on their MHC class II molecules to Id-specific CD4+ T cells. Prolonged Id-driven T-B collaboration could cause autoimmune disease, but this possibility is difficult to test in normal individuals. We have investigated whether mice doubly transgenic for an Id+ Ig L chain and an Id-specific TCR develop autoimmune disease. Surprisingly, T cell tolerance was not complete in these mice because a low frequency of weakly Id-reactive CD4+ T cells accumulated with age. These escapee Id-specific T cells provided chronic help for Id+ B cells, resulting in a lethal systemic autoimmune disease including germinal center reactions, hypergammaglobulinemia, IgG autoantibodies, glomerulonephritis, arthritis, skin affection, and inflammatory bowel disease. Inflamed tissues contained foci of Id-driven T-B collaboration, with deposition of IgG and complement. The disease could be transferred with B and T cells. The results demonstrate a novel mechanism for development of autoimmune disease in which self-reactive Id+ B cells receive prolonged help from Id-specific T cells, thus bypassing the need for help from T cells recognizing conventional Ag.

Insulin sensitivity in women with coronary heart disease during hormone replacement therapy.

OBJECTIVE: The aim of the present study was to evaluate the effect on insulin secretion and insulin sensitivity of hormone replacement therapy (HRT) with short-term unopposed transdermal 17beta-estradiol and, after 1 year, when combined with intermittent medroxyprogesterone acetate (MPA). METHODS: Ninety-nine postmenopausal women with coronary artery disease (CAD), but without diabetes mellitus, consecutively recruited from patients referred for invasive coronary investigations at a tertiary university clinic, were randomized to either HRT or a control group. Unopposed estradiol was given for 3 months, and MPA was added in cycles of 14 days every 3 months. Clinical investigations were undertaken at baseline and after 3 months and 12 months. Insulin sensitivity index (HOMA-IR) and insulin secretion (HOMA-BCF) were calculated using the homeostasis model assessment. RESULTS: Compared with the control group, treatment with unopposed transdermal 17beta-estradiol caused a significant decrease in HOMA-IR, that is, improved insulin sensitivity, but after combination with MPA and 12 months of HRT, no change was observed in HOMA-IR. Similarly, a transient decrease was observed for plasma levels of C peptide after unopposed 17beta-estradiol. HOMA-BCF remained unchanged throughout the study period. Sex hormone-binding globulin (SHBG) was related to HOMA-IR but not to HOMA-BCF at baseline. The association with HOMA-IR grew stronger after unopposed transdermal estradiol. No deleterious effect of HRT on glucose metabolism was found in postmenopausal women with CAD. CONCLUSIONS: Short-term treatment with unopposed transdermal estradiol caused a decrease in insulin resistance, but long-term treatment after intermittent MPA was introduced had no effect on either insulin secretion or insulin resistance.

MHC-restricted Ig V region-driven T-B lymphocyte collaboration: B cell receptor ligation facilitates switch to IgG production.

B cells spontaneously process their endogenous Ig and present V region peptides on their MHC class II molecules. We have here investigated whether B cells collaborate with V region-specific CD4+ T cells in vivo. By use of paired Ig L chain-transgenic and TCR-transgenic mice and cell transfer into normal hosts, we demonstrate that B cell presentation of a V(L) region peptide to CD4+ T cells results in germinal centers, plasma cells, and Ab secretion. Because the transgenic B cells have a fixed L chain but polyclonal H chains, their B cell receptor (BCR) repertoire is diverse and may bind a multitude of ligands. In a hapten-based system, BCR ligation concomitant with V region-driven T-B collaboration induced germinal center formation and an IgM --> IgG isotype switch. In the absence of BCR ligation, mainly IgM was produced. Consistent with this, prolonged V region-driven T-B collaboration resulted in high titers of IgG autoantibodies against ubiquitous self-Ags, while natural-type Abs against exotic bacteria remained IgM. Taken together, V region-driven T-B collaboration may explain induction of natural IgM Abs (absence of BCR ligation) and IgG autoantibodies (BCR ligation by autoantigen) and may be involved in the development of autoimmunity.

Hormone replacement therapy does not affect plasma homocysteine in postmenopausal women with coronary artery disease. Free tissue factor pathway inhibitor antigen, a circulating anticoagulant, is related to plasma homocysteine.

OBJECTIVE: The objective was to evaluate the effect of hormone replacement therapy (HRT) on plasma homocysteine levels in postmenopausal women with coronary artery disease (CAD) and to investigate associations of homocysteine to other cardiovascular risk factors. METHODS: The women in this single-center, controlled, and randomized study were examined at baseline, and after 3 and 12 months, after they had been recruited consecutively from patients referred for investigational coronary angiography. All analyses were performed examiner blind. They were randomized to HRT consisting of transdermal application of continuous 17beta-estradiol with cyclic medroxyprogesterone acetate (MPA) tablets for 14 days every 3rd month, or to a control group. RESULTS: After 3 months of unopposed 17beta-estradiol, no significant effect on homocysteine was observed compared to the control group. The absolute decrease of 5% in median plasma homocysteine levels after 12-month HRT did not reach statistical significance. Plasma homocysteine seemed slightly higher in women with three- or four-vessel disease, but the difference was not significant. With increasing homocysteine levels, free tissue factor pathway inhibitor (TFPI) antigen increased, whereas E-selectin decreased. In women with diabetes or elevated blood glucose >6.0 mmol/l, plasma homocysteine was correlated to body mass index, C-peptide and insulin as well as age. CONCLUSION: Transdermal application of 17beta-estradiol and sequential MPA do not affect plasma homocysteine in women with established CAD. Plasma homocysteine is stable in women with CAD over time, and unless special intervention is undertaken, repetitive measurements are not necessary in this particular group of high-risk individuals. The circulating anticoagulant TEPI is related to plasma homocysteine.