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PubMed2004

Pathogenesis of lesions in late age-related macular disease.

PURPOSE: To review the evidence that exists concerning the pathogenesis of lesions in late age-related macular disease (AMD). DESIGN: Review of the literature. METHODS: A review of both experimental evidence and clinical observations that address these problems. RESULTS: There is good evidence that choroidal neovascularization (CNV) is due to a change in the balance of growth factors derived from the retinal pigment epithelial basolateral plasma membrane domain (retinal pigment epithelium). Retinal angiomatous proliferation may also have a similar pathogenesis involving the apical domain. Detachment of the retinal pigment epithelium is likely to be a consequence of increased resistance of the Bruch membrane to water flow due to deposition of lipids. Geographic atrophy is preceded by accumulation of autofluorescent material in the retinal pigment epithelium and possible causal relationships between the two have been demonstrated. CONCLUSION: There is increasing understanding concerning the sequence of events that lead to those lesions causing loss of central vision in AMD. Therapeutic approaches that address the underlying mechanisms are more likely to succeed than current treatment options. Such an approach has already been initiated in the management of choroidal neovascularization.

Humans↗

PubMed2005

Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6.

PURPOSE: To determine whether correlations between vascular endothelial growth factor (VEGF) or interleukin-6 (IL-6) contribute to the pathogenesis of macular edema in eyes of patients with branch retinal vein occlusion (BRVO). DESIGN: Retrospective case-control study. METHODS: Nineteen patients with macular edema with BRVO and seven patients with non-ischemic ocular disease (control group) were studied. The degree of retinal ischemia was evaluated in terms of the area of capillary non-perfusion, and the severity of macular edema was examined by optical coherence tomography. Aqueous humor samples were obtained at the time of combined vitrectomy and cataract surgery, and VEGF and IL-6 levels in aqueous humor and plasma were determined by enzyme-linked immunosorbent assay. RESULTS: Aqueous levels of VEGF (351 +/- 273 pg/ml) and IL-6 (7.10 +/- 6.51 pg/ml) were significantly elevated in patients with BRVO compared with the control patients (119 +/- 38.7 pg/ml and 2.27 +/- 1.11 pg/ml, respectively) (P = .0017 and P = .0052, respectively). Aqueous level of VEGF was significantly correlated with that of IL-6 (P = .0396), and aqueous levels of VEGF and IL-6 were correlated with the size of the BRVO non-perfused area (P < .0001 and P = .0331, respectively). Aqueous level of VEGF was correlated with the severity of macular edema (P = .0306). CONCLUSIONS: VEGF and IL-6 may be involved in the pathogenesis of macular edema with BRVO. The increase in these cytokines might be used as a unique index of BRVO, through which we can determine the severity of the ischemic condition as being in a quiescent state or an exacerbation of macular edema.

Aged↗

PubMed2026

Novel HLA class I and II insights into the pathogenesis of systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of mortality in systemic sclerosis (SSc), yet its genetic architecture remains incompletely understood. Therefore, given the key role of the major histocompatibility complex (MHC) in SSc, we aimed to perform a comprehensive MHC-wide association study in the largest SSc-ILD cohort to date. METHODS: We analysed 2412 patients with SSc-ILD⁺, 3550 patients with SSc-ILD⁻, and 15,076 controls of European ancestry from 10 international cohorts. After quality control, the MHC region was imputed, and inverse variance weighted meta-analysis was performed. Subsequently, conditional stepwise analyses, adjustment for antitopoisomerase autoantibody (ATA) status, and functional annotation of significant single-nucleotide polymorphisms were performed. Finally, we constructed a composite score combining genetic, clinical, and demographic variables to predict SSc-ILD. RESULTS: After conditional analysis, we detected 12 significant associations within class I and class II human leukocyte antigen (HLA) genes. ATA adjustment reduced the significance of class II HLA variants, whereas class I HLA variants remained unaffected. Finally, the built composite score had an area under the curve of 0.754, significantly outperforming the models including any of the variables alone. CONCLUSIONS: In this study, we identify genetic mechanisms underlying SSc-ILD that support the potential implication of CD8+ T cells and ATAs in its pathogenesis. Moreover, we also demonstrate the enhanced efficacy of integrating genetic information into predictive models to detect patients at high risk of SSc-ILD. These findings provide new insights into disease pathogenesis and suggest potential biomarkers and therapeutic targets for improved patient management.

Humans↗

PubMed2004

Gene expression profiling in the study of the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a complex pathogenesis involving multiple genetic and environmental contributions. DNA microarray technology has recently been applied to unravel some of this complexity through genomewide profiling. Early studies using microarray analysis of peripheral blood mononuclear cells (PBMCs) from SLE patients revealed dysregulation of inflammatory cytokines, chemokines, and immune response-related genes, as well as genes involved in apoptosis, signal transduction, and the cell cycle. More recently, using arrays containing many more genes, 4 independent research groups have found that interferon (IFN)-regulated genes are highly overexpressed in the peripheral blood and kidney glomeruli of SLE patients, supporting a crucial role for interferon in SLE. Future studies focusing on target tissues or organs in lupus, including the kidney, may further contribute to our understanding of lupus pathogenesis while providing new targets for therapy.

Animals↗

PubMed2006

Pathogenesis of myelofibrosis with myeloid metaplasia: Insight from mouse models.

Myelofibrosis with myeloid metaplasia or idiopathic myelofibrosis is a myeloproliferative disease. It is known to be a stem-cell disorder that leads to a secondary and reactive stromal reaction in the bone marrow microenvironment that is responsible for impaired haematopoiesis. Although progress has been made in the elucidation of the pathogenesis of idiopathic myelofibrosis, lack of suitable models has limited our understanding of the pathology. The aim of this chapter is to address recent inferred new insights in mouse models into the pathogenesis of osteomyelofibrosis. These insights outline the role of transforming growth factor-beta1 and osteoprotegerin in the promotion of myelofibrosis and osteosclerosis, respectively, paying special regard to the role of abnormal megakaryocyte proliferation and maturation.

Animals↗

PubMed2006

Human malignant mesothelioma: molecular mechanisms of pathogenesis and progression.

The continuing identification and elucidation of the molecular defects involved in mesothelioma pathogenesis and progression should lead to better disease control and greater therapeutic options in the near future. Goal of this review article is to summarize the most recent advances in molecular pathogenesis of mesothelioma and discuss possible therapeutic implications of these findings.

Disease Progression↗

PubMed2004

Lipids and lipid peroxidation products in the pathogenesis of age-related macular degeneration.

In people over 50, age-related macular degeneration (ARMD) has become the most common cause for severe visual loss and legal blindness in all industrialized nations. Currently, there is no effective treatment for the majority of patients. To develop new and effective modes of therapy, understanding of the molecular basis of the disease in mandatory. However, the pathogenesis of ARMD is still poorly understood. Several lines of evidence suggest that aging changes of the retinal pigment epithelium (RPE), in particular the accumulation of autofluorescent lipofuscin granules in the lysosomal compartment of postmitotic RPE cells, play a key role in the pathogenesis of the disease. Recent studies indicate that lipidic compounds of lipofuscin, represented by the retinoid A2-E, and protein damage by lipid peroxidation products, in particular malondialdehyde and 4-hydroxynonenal, induce lysosomal dysfunction and lipofuscinogenesis in the RPE. The possible mechanisms underlying this lysosomal dysfunction and the resulting adverse effects on overall RPE function are discussed.

Age Factors↗

PubMed2004

Focal changes in blood supply during normal epiphyseal growth are central in the pathogenesis of osteochondrosis in pigs.

Cartilage canals are temporary vessel-containing structures within the growth cartilage. The canals gradually regress with age in a process designated chondrification, where the content of the canals is replaced by cartilage. The process of chondrification is considered physiological; however, premature regression has been associated with the formation of lesions of osteochondrosis. The purpose of the present study was to gain further insight into the nature of and relationship between chondrification of cartilage canals and the initial steps in the pathogenesis of osteochondrosis with respect to morphology, presence of factors influencing the processes, and mode of cellular death. The articular-epiphyseal cartilage complexes of the distal femur of 48 pigs were studied, combining a technique of perfusion and tissue clearing with histological and immunohistological methods. The results provided strong evidence that the process of chondrification occurs at the terminations of the cartilage canals and is characterized by disintegration of the endothelial cells and transformation of perivascular cells into matrix-producing chondrocytes. Lesions of osteochondrosis, however, are characterized by necrosis of the portion of the affected cartilage canal distal to a point of interruption, with subsequent necrosis of adjacent resting zone growth cartilage. This interruption of the cartilage canal blood supply occurs at the junction between cartilage and bone where anastomoses are formed between cartilage canal vessels and vessels from the bone marrow. It is possible that microfractures occurring secondary to minor trauma at a vulnerable time in the development of the cartilage may be the initial event in pathogenesis of osteochondrosis.

Animals↗

PubMed2006

Gallstone disease: Epidemiology, pathogenesis, and classification of biliary stones (common bile duct and intrahepatic).

Gallstones are common in Western countries and Japan. Most gallstones are found in the gallbladder, but they sometimes pass through the cystic duct into extrahepatic and/or intrahepatic bile ducts to become bile-duct stones, causing conditions known as choledocholithiasis and hepatolithiasis. Some 10-15% of gallstone patients concomitantly suffer from bile-duct stones. Bile-duct stones can also be formed in the absence of gallbladder stones, and such primary bile-duct stones are more common in East Asian countries than in the Western world. Thus pathogenesis of primary and secondary bile-duct stones is unlikely to be similar. Furthermore, the gallbladder stones are primarily cholesterol or black-pigment stones, whereas most bile-duct stones are brown-pigment stones (calcium bilirubin stones). Thus, epidemiology, pathogenesis and classification of biliary stones are very likely to differ according to stone location (intrahepatic and/or extrahepatic bile duct).

Asian People↗

PubMed2005

GADD45A and EPB41 as tumor suppressor genes in meningioma pathogenesis.

Deletions of 1p occur in approximately 30% of meningiomas. Based on loss of heterozygosity (LOH) analysis, two regions on 1p have been suspected to be carriers of tumor suppressor genes. We chose the GADD45A and EPB41 genes as tumor suppressor candidates based on their function and chromosomal localization. We analyzed 19 cases of meningioma with LOH of 1p by means of sequencing of the GADD45A gene and Western blotting of the GADD45a protein. Twenty cases of meningioma without 1p LOH were also analyzed by Western blotting to find out if changes of the GADD45a protein expression occurred. Nineteen samples with 1p LOH (12 grade I; 7 grade II, WHO classification) and 20 samples without 1p LOH (18 grade I; 2 grade II) were also analyzed by means of real-time polymerase chain reaction to find abnormalities in EPB41 mRNA levels in meningioma. LOH analysis was performed using seven microsatellite markers: D1S508 (1p36.2), D1S199 (1p36.1) D1S2734 (1p36.1), D1S2720 (1p34), D1S197 (1p32), D1S162 (1p32), D1S429 (1p11). LOH analysis confirmed previously described localization of putative tumor suppressor genes on 1p and involvement in meningioma pathogenesis (1p36 and 1p32). The open reading frame of GADD45A and intron splicing sites showed neither mutations nor polymorphisms. GADD45a protein molecular weight and expression level were unaltered in meningiomas with and without 1p LOH. We conclude that the GADD45A gene is not involved in meningioma tumorigenesis. EPB41 gene expression was unchanged in all analyzed meningiomas. This suggests that involvement of the EPB41 gene (4.1R protein) in meningioma pathogenesis should be reconsidered.

Blood Proteins↗

PubMed2004

Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury.

Neutrophils respond to myocardial ischemia-reperfusion in a manner similar to the bacterial invasion of a host. The inflammatory-like response that follows the onset of reperfusion involves intense interactions with the coronary vascular endothelium, arterial wall, and cardiomyocytes in a very well-choreographed manner. Neutrophils have been implicated as primary and secondary mediators of lethal injury after reperfusion to coronary vascular endothelium and cardiomyocytes. The involvement of neutrophils in the pathogenesis of lethal myocardial injury has been inferred from (1) their presence and accumulation in reperfused myocardium in temporal agreement with injury induced, (2) the armamentarium of toxic agents such as oxidants and proteases that are released by neutrophils in reperfused myocardium, (3) responsivity to (recruitment by and/or activation by) inflammatory factors released by reperfused myocardium, and (4) inhibition of lethal post-ischemic myocyte or endothelial cell injury by strategies that interdict neutrophil interactions at any number of stages. However, whether neutrophils are directly involved in the pathogenesis of lethal reperfusion injury in the myocardium, are just pedestrian (first) responders to inflammatory signals released after the onset of reperfusion, or are important to an early but not clinically important phase of pathology are still points of controversy. As with the general area of myocardial protection itself, the failure to reproduce the salubrious effects of anti-neutrophil therapeutic strategies and to successfully translate these strategies into clinical practice has not only fueled the debate, but has jeopardized the further pursuit of myocardial protection therapeutics to improve post-ischemic outcomes. This review will describe the molecular responses of neutrophils to ischemia-reperfusion, discuss the cellular and tissue damage inflicted either directly or indirectly by these white cells, and discuss the physiological impact of interdiction of neutrophil-mediated interactions with myocardial cells at various levels on lethal post-ischemic injury. In addition, it will discuss the arguments for and against the involvement of neutrophils in responses to ischemia-reperfusion in experimental models, and the failure to translate experimentally successful therapy into clinical practice.

Animals↗

PubMed2004

Altered cAMP-mediated signalling and its role in the pathogenesis of dilated cardiomyopathy.

Alterations in the level and function of proteins involved in cAMP-mediated signalling are important in the pathophysiology and treatment of dilated cardiomyopathy. What is unclear is the extent to which these alterations, which attenuate receptor-stimulated cAMP generation, contribute to the pathogenesis of dilated cardiomyopathy and the extent to which they constitute a beneficial compensatory response. Studies in animals involving overexpression and ablation of proteins or peptides involved in cAMP-mediated signalling have yielded disparate results that are difficult to reconcile with a simple hypothesis. Our ability to understand these differences is limited by the lack of information on how these different genetic manipulations affect the phosphorylation of individual substrates of protein kinase A (PK-A) through which cAMP signals are transduced. This is important in view of evidence that the phosphorylation of individual PK-A substrates can be regulated selectively in different intracellular compartments, and that the phosphorylation of some PK-A substrates is increased in dilated cardiomyopathy while the phosphorylation of others is reduced. Approaches that quantify changes in the phosphorylation of individual PK-A substrates in models of dilated cardiomyopathy will provide information that may allow a better understanding of the pathogenesis of the syndrome and a more rational approach to its treatment.

Animals↗

PubMed2005

Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1).

OBJECTIVE: In the hereditary long QT syndromes the commonest defect is in the K+ channel pore forming subunit, KCNQ1. In this study we investigated the role that abnormal KCNQ1 trafficking has in the pathogenesis of the hereditary long QT syndrome (LQT1). METHODS: We introduced nine missense and nonsense mutations occurring in LQT1 into the cDNA encoding KCNQ1 fused in frame to the green fluorescent protein. These mutations occur in syndromes that are inherited in both autosomal dominant and recessive fashions. We used biochemistry, electrophysiology and cell imaging to examine the behaviour of wildtype and mutant channel subunits expressed together with the auxiliary subunit KCNE1 expressed in CHO-K1 and C2C12 cells. RESULTS: We found that a number of mutations in KCNQ1 are retained in the endoplasmic reticulum and unable to translocate to the plasma membrane. Furthermore, some mutations act in a dominant negative fashion and have the ability to suppress the trafficking of wildtype channel. We use fluorescence resonance energy transfer microscopy to show that this occurs because of direct interaction between the mutant subunit and wildtype channel in the endoplasmic reticulum. Finally, a number of specific and nonspecific pharmacological tools are unable to promote the delivery of these mutants to the plasma membrane. CONCLUSIONS: Our data revealed that channel trafficking may contribute to the pathogenesis of LQT1.

Animals↗

PubMed2005

Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice.

Diffuse large B cell lymphomas (DLBCL) derive from germinal center (GC) B cells and display chromosomal alterations deregulating the expression of BCL6, a transcriptional repressor required for GC formation. To investigate the role of BCL6 in DLBCL pathogenesis, we have engineered mice that express BCL6 constitutively in B cells by mimicking a chromosomal translocation found in human DLBCL. These mice display increased GC formation and perturbed post-GC differentiation characterized by a decreased number of post-isotype switch plasma cells. Subsequently, these mice develop a lymphoproliferative syndrome that culminates with the development of lymphomas displaying features typical of human DLBCL. These results define the oncogenic role of BCL6 in the pathogenesis of DLBCL and provide a faithful mouse model of this common disease.

Animals↗

PubMed2004

Anti-fetal immune response mechanisms may be involved in the pathogenesis of placental abruption.

Placental abruption is an unpredictable severe complication in pregnancy. In order to investigate the possibility that the activation of the fetal nonadaptive immune system may be involved in the pathogenesis of this disease, IL-6 release from cord blood monocytes was examined by intracellular cytokine staining and flow cytometric analysis. Our results demonstrate that preterm placental abruption (n = 15) in contrast to uncontrollable preterm labor (n = 33) is associated with significantly (P < 0.001) increased release of IL-6 from the fetal monocytes. The same holds true for rhesus disease (n = 9, P < 0.001) that is characterized by a maternal production of antibodies against the rhesus-D antigen expressed by the fetal erythrocytes. This suggests that during rhesus disease, IL-6 release of monocytes is induced by antibody-mediated cross-linking of these cells to the erythrocytes in the fetal circulation. Hence, this assumption favors the idea that also in case of placental abruption, an increased maternal antibody production against paternal antigens leads to an elevated IL-6 release by the fetal monocytes. To elucidate this potential mechanism, the presence of anti-HLA-antibodies was assessed in the maternal circulation of patients with placental abruption (n = 17) and patients with uncontrollable preterm labor (n = 29). The percentage of women producing anti-paternal HLA-antibodies was significantly (P < 0.01) increased in the group of women with preterm placental abruption (47%) in comparison to women with uncontrollable preterm labor (14%). Therefore, our results suggest that an increased humoral immune response of the mother against the fetus may be decisively involved in the pathogenesis of placental abruption.

Abruptio Placentae↗

PubMed2004

T cells in the pathogenesis of systemic lupus erythematosus.

Recent studies in patients with systemic lupus erythematosus (SLE) have demonstrated that autoantigen-reactive T cells can be isolated from peripheral blood and that such cells can support autoantibody production ex vivo, suggesting that they may have a central role in the pathogenesis of disease. In addition, recent work has identified and characterized signaling abnormalities in T cells from SLE that may be fundamental to the disease. This review will examine the role of T cells in the pathogenesis of SLE and it will consider pathogenic mechanisms by which T cells escape normal of immunological tolerance. The focus will be on recent studies characterizing autoantigen-reactive human T cells and signaling abnormalities identified in T cells from patients with SLE.

Antigen Presentation↗

PubMed2004

DNaseI in pathogenesis of systemic lupus erythematosus.

The aberrant activation of lymphocytes causes autoimmune diseases. Although there are many candidate molecules that are involved in the pathogenesis of autoimmune diseases, it still remains unclear how immunological tolerance is disturbed in each autoimmune disease. Recently, we discovered two patients suffering from systemic lupus erythematosus (SLE) with a defect in the DNaseI gene locus. According to immunological and genetic analysis, we hypothesize that defective antigen clearance, especially accumulation of nucleosomal antigens, is responsible for the development of SLE. In this article, we review the pathogenesis of SLE from the view of defective self-antigen clearance due to low DNaseI activity.

Deoxyribonuclease I↗

PubMed2005

Virulence factors, pathogenesis and vaccine protection in cholera and ETEC diarrhea.

Recent work has provided new insights into the pathogenesis of the potentially life-threatening diarrheas caused by Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC): a new mechanism (post-translational degradation), which is involved in the control of cholera toxin expression, has been discovered. Recent evidence also suggests that vibrios upregulate cholera toxin expression in response to intestinal fluid components, and enterotoxin-carrying bacterial outer membrane vesicles might have a function in ETEC pathogenesis. An important role of the environment is supported by the correlation between cholera incidence and elevated sea surface temperature, which supports the notion that the zooplankton is a V. cholerae reservoir. Additionally, environmental lytic cholera phages could influence cholera seasonality by 'terminating' the seasonal epidemic. Finally, the strong herd immunity elicited by an oral cholera vaccine indicates that cholera vaccination could have a significant public health impact.

Animals↗