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PubMed1991

The pathogenesis of atherosclerosis: an overview.

In this unifying hypothesis directed to the etiology and pathogenesis of atherosclerosis, the importance of focal arterial lesion-prone sites has been emphasized. Key initial participants in these sites include the focal intimal influx and accumulation of low-density lipoprotein (LDL) and a preferential recruitment of blood monocytes. Both are further enhanced in the presence of hyperlipidemia, when the quantity of intimal LDL and the oxidative potential of the intima exceed the capacity of macrophages to remove, via the non-down-regulating scavenger receptor, cytotoxic anionic (Ox-LDL) macromolecules. Foam cells, pathognomonic of the fatty streak, form during the receptor-mediated uptake of Ox-LDL by the macrophages. Interstitial free radicals and the excess of Ox-LDL particles injure and kill cells, including the foam cells, with the formation of the necrotic extracellular lipid core, a key transitional step in lesion progression. Monocyte-macrophage recruitment to the intima is likely to be regulated not only by a multiplicity of endothelial adhesive cytokines, integrins, and selectins, but also by the monocyte-specific chemoattractant, MCP-1, constitutively synthesized and secreted by intimal smooth muscle and endothelial cells. Its synthesis and secretion is augmented by mildly oxidized LDL. Free radicals, pivotal in the oxidation of LDL, and derived from activated macrophages, and also endothelial and smooth muscle cells. Smooth muscle cells migrate from the media through the intimal endothelial layer (IEL) and proliferate under the regulation of a number of mitogens, including platelet-derived growth factor (PDGF). Collagen synthesis by smooth muscle cells is substantial. Lymphocytes, as a source of interferons, invade the plaque and are present in the adventitia in substantial numbers, likely representing an autoimmune response in the later stages of plaque development. Platelets and mural thrombosis directly contribute to subsequent plaque growth, particularly after plaque rupture or fissure and disruption of the thromboresistant endothelial cells (EC). Plaque regression in all likelihood involves the conversion of the inert pool of extracellular lipid to a metabolically active intracellular pool and subsequent clearance by the high-density lipoprotein mediated reverse cholesterol transport system. The atherogenic cascades so described conceptually represent arterial inflammatory and healing processes occurring in a hyperlipidemic environment. Many components of pathogenesis are the targets for modulation by genetic, hemodynamic and selected risk factors. The prevention and treatment of the disease should logically target reduction in plasma LDL levels, the inhibition of the oxidative modification of lipoproteins, including LDL, by free radical scavengers, and augmentation of the reverse cholesterol transport system.

Animals↗
PubMedDate not supplied

Role of histone and transcription factor acetylation in diabetes pathogenesis.

Globally, diabetes (and, in particular, type 2 diabetes) represents a major challenge to world health. Currently in the United States, the costs of treating diabetes and its associated complications exceed 100 billion US dollars annually, and this figure is expected to soar in the near future. Despite decades of intense research efforts, the genetic basis of the events involved in the pathogenesis of diabetes is still poorly understood. Diabetes is a complex multigenic syndrome primarily due to beta-cell dysfunction associated with a variable degree of insulin resistance. Recent advances have led to exciting new developments with regard to our understanding of the mechanisms that regulate insulin transcription. These include data that implicate chromatin as a critical regulator of this event. The 'Histone Code' is a widely accepted hypothesis, whereby sequential modifications to the histones in chromatin lead to regulated transcription of genes. One of the modifications used in the histone code is acetylation. This is probably the best characterized modification of histones, which is carried out under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes also regulate the activity of a number of transcription factors through acetylation. Increasing evidence links possible dysregulation of these mechanisms in the pathogenesis of diabetes, with important therapeutic implications.

Acetylation↗
PubMed1994

A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice.

The tight skin (Tsk/+) mouse represents a murine model of heritable fibrosis with some similarities to the skin fibrosis seen in human scleroderma. Tsk/+ animals display alterations in connective tissue in some internal organs. Skin fibrosis can be adoptively transferred to normal recipients with Tsk/+ bone marrow or spleen cells and older Tsk/+ animals develop autoantibodies against topoisomerase suggesting that some of the pathogenesis in the Tsk/+ mouse may be mediated by autoimmunity. To determine the role of T cell subsets in the pathogenesis of fibrotic disease, Tsk/+ mice were bred with CD4- and CD8-deficient (CD4-/- and CD8-/-) mice. Tsk/+ CD4-/- mice showed a marked reduction in skin fibrosis as well as decreased cellularity and only mild collagen disorganization as compared to Tsk/+ CD4+ CD8+ control mice yet did not differ from Tsk controls in the level of serum anti-topoisomerase activity. In contrast, Tsk/+ CD8-/- mice exhibited the same histology in the skin as Tsk/+ controls yet had significantly reduced levels of serum anti-topoisomerase activity. Lung pathology, i.e. emphysema, was unaffected by both the CD4 or CD8 mutations. These data show that only some of the pathological effects of the Tsk mutation are T cell dependent and that different T cell subsets affect different parameters in this multi-organ model of fibrotic disease.

Animals↗
PubMed2004

Interleukin-5 participates in the pathogenesis of ileitis in SAMP1/Yit mice.

SAMP1/Yit mice spontaneously develop ileitis resembling Crohn's disease (CD) without chemical or genetic manipulations. Since the focus of studies were Th1 cytokines, only Th1-type T cells were thought to be responsible for intestinal inflammation in these mice. To further characterize the pathogenesis of this ileitis, we investigated the implication of Th2 cytokines in ileitis of SAMP1/Yit mice. The expression of chemokine receptors (CCR) associated with both Th1 and Th2 lymphocytes, such as CCR2, CCR3, CCR4, CCR5, and CCR8, was increased. Among cytokines, IL-5 was remarkably increased in Peyer's patches, mesenteric lymph nodes, and mucosa involved in ileitis. Furthermore, infiltration of numerous eosinophils in ileitis was histologically evident. Severe combined immunodeficiency mice injected intraperitoneally with CD4(+) cells from SAMP1/Yit mice developed colitis and ileitis, with the infiltration of eosinophils. Administration of anti-IL-5 antibodies significantly attenuated ileitis in these mice. We suggest that IL-5 participates in the pathogenesis of ileitis and that anti-IL-5 antibodies are potentially useful for immunotherapy in CD patients. This is the first demonstration that IL-5 is crucial for the development of ileitis in this mouse model of CD.

Animals↗
PubMed2004

Radiation-induced xerostomia in patients with head and neck cancer: pathogenesis, impact on quality of life, and management.

BACKGROUND: Xerostomia is a common, debilitating complication of radiation therapy (RT) for head and neck cancer. This article reviews the pathogenesis of radiation-induced xerostomia, its impact on quality of life (QOL), and treatment options. METHODS: Virtually all patients undergoing RT for head and neck cancers have xerostomia, which causes oral discomfort and pain, increased dental caries and oral infection, and difficulty speaking and swallowing. This significantly impairs QOL and can compromise nutritional intake and continuity of cancer therapy. The literature describing pathogenesis, impact on QOL of radiation-induced xerostomia, and preventive and interventional therapies was reviewed. RESULTS: Current management strategies include stringent dental and oral hygiene; parotid-sparing radiation techniques to prevent or minimize xerostomia; and pharmacotherapies, such as salivary substitutes and sialogogues. Future strategies may include advanced three-dimensional intensity-modulated RT techniques, salivary gland transfer, newer sialogogues, and gene therapy. CONCLUSIONS: New treatment approaches to xerostomia from RT for head and neck cancer may result in significant improvement in patient QOL.

Head and Neck Neoplasms↗
PubMed2002

Isotype class switching and the pathogenesis of multiple myeloma.

Translocations at the immunoglobulin heavy chain locus (14q32) are now considered the commonest karyotypic change in multiple myeloma. These translocations are thought to be intimately involved in the pathogenesis of this disease. The heavy chain locus is strongly transcriptionally active in B and plasma cells and transfer of a potential oncogene to 14q32 would result in its dysregulation. Molecular characterization suggests that the majority of these breakpoints cluster in switch regions within the heavy chain locus. Switch regions are normally involved in the regulated process of isotype switching so that in myeloma the rearrangements are believed to be a result of so-called illegitimate (aberrant) switch recombination and are likely to be an early event in myeloma development. A legitimate switch recombination event occurs between two switch regions producing a hybrid switch; this is necessary for class switching to proceed on a productive allele. In this review we describe the process of isotype switching and how illegitimate class switching may be related to the pathogenesis of multiple myeloma.

Humans↗
PubMed2006

Idiopathic myelofibrosis: pathogenesis to treatment.

Idiopathic myelofibrosis (IMF) is the least common of the chronic myeloproliferative disorders and carries the worst prognosis with a median survival of 4 years. It is a clonal haematopoietic stem-cell disorder and, although the pathogenesis remains unclear, approximately 50% of cases are known to possess an activating JAK2 V617F mutation. In contrast, the characteristic stromal proliferation is a reactive, or secondary, event that results from the aberrant release of a variety of growth factors from megakaryocytes and monocytes. Treatment for most cases is supportive, although androgens, recombinant erythropoietin, steroids and thalidomide are effective modalities for the amelioration of anaemia. Myelosuppression, splenectomy and irradiation are valuable therapeutic modalities for specific clinical situations. Prognostic scores are available to aid the identification of cases for whom bone marrow transplantation should be considered. Recently, the use of reduced intensity conditioning has resulted in prolonged survival and lower transplant-related mortality. This review summarises the recent advances in the disease's pathogenesis and discusses the role of the various therapeutic options.

Anemia↗
PubMed2006

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers.

Aberrant methylation of 5'gene promoter regions associated with gene silencing is an epigenetic phenomenon responsible for silencing of tumor suppressor genes in many cancer types. The aims of our study were to study the role of methylation of a large panel of genes during multistage pathogenesis and to correlate our findings with patient age and other clinico-pathological features. We investigated the aberrant promoter methylation profile of 19 genes in 92 colorectal cancers (CRCs) and corresponding nonmalignant epithelia (NME) (n = 57), and selected 15 genes for studying 26 colorectal adenomas (CAs). On the Basis of our results, the genes could be divided into 3 groups. Group 1 consisted of 13 genes whose methylation was tumor-specific. For 8 of these genes, the methylation frequencies in CAs were similar to those of CRCs, but significantly different from the frequencies in NME. Group 2, consisting of 2 genes demonstrating little or no methylation, were present in any sample type. In Group 3, consisting of 4 genes, relatively frequent methylation was present in both CRCs and NME, and the differences between these specimen types were not significant. Methylation of Group 1 genes were tightly correlated with each other, and these genes demonstrated increased methylation frequencies in CRCs with increasing age. Methylation was not correlated with other clinico-pathological features. In general, methylation frequencies of CAs were intermediate between CRCs and NME. Our study constitutes the most comprehensive methylation profile of CRCs, demonstrates that methylation commences early during CRC pathogenesis and is an age-related phenomenon.

Aged↗
PubMed1987

Biological function of ;pathogenesis-related' proteins: four PR proteins of tobacco have 1,3-beta-glucanase activity.

Three of the ten acidic ;pathogenesis-related' (PR) proteins known to accumulate in Nicotiana tabacum cv Samsun NN reacting hypersensitively to tobacco mosaic virus, namely -O, -N and -2, have been shown to have 1,3-beta-glucanase (EC 3.2.1.39) activity. By using sera raised against each protein purified to homogeneity close serological relationships have been demonstrated between the three proteins. The same specific sera cross-reacted with a basic protein which is also a 1,3-beta-glucanase induced by virus infection and which can be considered as a new basic pathogenesis-related protein of tobacco. Protein PR-O and the basic 1,3-beta-glucanase display about the same specific enzymatic activity, i.e. 50-fold and 250-fold higher than specific activities of proteins PR-N and -2 respectively.

Journal Article↗
PubMed1990

A major stylar matrix polypeptide (sp41) is a member of the pathogenesis-related proteins superclass.

A novel stylar-specific glycosylated protein, sp41, was characterized. Sp41 constitutes greater than 12% of the transmitting tract tissue soluble proteins and is mainly localized in the extracellular matrix. Two cDNA clones corresponding to sp41 mRNA were isolated and sequenced. The decoded sequences are, respectively, 80% and 49% homologous to acidic and basic pathogen-induced (1-3)-beta-glucanases of the leaf. Thus a subfamily of (1-3)-beta-glucanase pathogenesis-related (PR) proteins constitutes one of the major stylar matrix proteins. The accumulation of sp41 transcripts in normally developing and elicitor-treated styles and leaves was followed using an RNase protection assay. During development sp41 transcript accumulation starts well after carpel differentiation. It is first detected in styles at 8 days before anthesis. The maximal level of accumulation is reached during anthesis. Elicitor-treated styles do not accumulate the leaf-type (1-3)-beta-glucanase transcript, although they retain the capacity to synthesize leaf-type pathogenesis-related proteins such as the pathogen-induced acidic chitinase. The developmental regulation of sp41 expression points to a role for them in the normal processes of flowering and reproductive physiology.

Amino Acid Sequence↗
PubMed1995

Progressive multifocal leukoencephalopathy: a review of the pathology and pathogenesis.

Progressive multifocal leukoencephalopathy is an important viral opportunistic infection of oligodendrocytes leading to direct demyelination. Virus is likely disseminated to the brain via the blood. However, the timing of that dissemination with relationship to clinical disease is unknown. Important clues about viral pathogenesis have been learned by applying molecular in situ techniques to diseased brain. The oligodendrocyte is the primary target for JC virus infection, and its death is the primary reason for demyelination. Bizarre astrocytes show limited viral DNA replication but are abortively infected. Although lymphoid organs can be infected by JC virus, there is no definitive evidence that lymphoid cells carry virus into the brain at the time of immunosuppression. JC virus may be reactivated from a latent state in both the brain and in non-central nervous system (CNS) organs at the time of immunosuppression, leading to clinical disease. Future sensitive in situ studies will likely resolve controversies about pathogenesis.

Brain↗
PubMed2005

Molecular pathology and pathogenesis of inclusion-body myositis.

We summarize the molecular phenotype, diagnostic criteria, and the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis (s-IBM), a muscle disease usually of persons over age 50. On the basis of our research, several processes seem to be important in relation to the still-speculative pathogenesis: 1) increased transcription and accumulation of amyloid-beta precursor protein (AbetaPP), and accumulation of its proteolytic fragment Abeta; 2) abnormal accumulation of cholesterol, caveolin-1, and apolipoprotein E; 3) oxidative stress; 4) accumulations of intramuscle fiber multiprotein aggregates; and 5) evidence that unfolded/misfolded proteins participate in s-IBM pathogenesis. Our basic hypothesis is that overexpression of AbetaPP within the aging muscle fibers is an early upstream event causing a subsequent pathogenic cascade.

Aging↗
PubMed1994

Macrophage-tropic HIV-1 variants: initiators of infection and AIDS pathogenesis?

The importance of macrophage-tropic HIV-1 variants in AIDS pathogenesis becomes increasingly clear. Macrophage-tropic HIV-1 variants initiate infection, predominate in the asymptomatic phase, and persist throughout infection, even after the emergence of preferential T cell-tropic HIV-1 variants. HIV-1 infection of macrophages may contribute to the overall immune dysfunction observed in AIDS pathogenesis. Here, our knowledge of the biological variability of HIV-1, and specifically macrophage-tropic HIV-1 variants, is reviewed. Moreover, hypotheses about the mechanism of selection for macrophage-tropic variants in transmission, the mechanism by which these variants selectively persist in the asymptomatic phase, and how they may contribute to the general immune dysfunction are presented.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Chemokine immunobiology in HIV-1 pathogenesis.

The discovery of HIV-1-suppressive chemokines and the subsequent discovery of their cognate receptors as coreceptors for HIV-1 entry herald a paradigmatic shift in the study of HIV-1 pathogenesis. The presence of polymorphisms in chemokine receptor and chemokine genes associated with altered progression and susceptibility to the HIV-1 disease further underscores the potential importance that chemokines and their cognate receptors play in HIV-1 pathogenesis. It has become increasingly apparent that the immune system maintains a delicate balance between the positive and negative regulators that govern the chemokine and cytokine networks. Here we review the most recent developments in chemokine biology and relate how research into their structure, regulation, and the mechanism of their actions can shed light on the immnunopathogenesis of HIV-1 disease.

Animals↗
PubMed2000

Exploitation of host cell signaling machinery: activation of macrophage phosphotyrosine phosphatases as a novel mechanism of molecular microbial pathogenesis.

Intracellular pathogens, particularly those that target host mononuclear phagocytes, have evolved strategies to either evade or inhibit cellular mechanisms of host defense. Mycobacterium tuberculosis and Leishmania donovani exemplify a diverse group of microorganisms that have developed the ability to invade and replicate within host macrophages, leading to disease expression. Recent studies have suggested that the pathogenesis of intracellular infection may involve interference with host cell signaling. Drawing upon examples from in vitro models that focused on M. tuberculosis and L. donovani, we review evidence that activation of host cell phosphotyrosine phosphatases may contribute to pathogenesis. A leading candidate appears to be the Src homology 2 domain containing phosphotyrosine phosphatase SHP-1, the activation of which may contribute to the development of infection and disease progression.

Animals↗
PubMedDate not supplied

Modeling of receptor mimics that inhibit superantigen pathogenesis.

Staphylococcal enterotoxins SEB and SEC3 and toxic shock syndrome toxin TSST-1 act as superantigens by overstimulating the human immune system and thereby compromise host defense. The mechanism of pathogenesis is explained on the basis of superantigen binding to the MHC class II receptor on the antigen presenting cell and to the T cell receptor (TcR) on the T cell. SEB, SEC3 and TSST-1 bind as intact proteins and make contacts with the alpha1 subdomain (DRalpha) of MHC class II and Vbeta subdomain of TcR. SEB, SEC3 and TSST-1 show specificities for different TcRVbeta isoforms. We have designed three different chimeras linking the same DRalpha with different TcRVbeta isoforms to specifically target SEB, SEC3 and TSST-1 and inhibit their pathogenesis. Here, we show by molecular modeling that the DRalpha, TcRVbeta and linker of a given chimera interact with the target superantigen in a type-specific manner. An initial model of the complex is constructed on the basis of observed inter-molecular contacts between DRalpha/TcRVbeta and the superantigens. A constant temperature (300 K) 200 ps molecular dynamics is performed to sample different conformations of a chimera-superantigen complex by utilizing the flexibility of the (GSTAPPA)(2) linker while maintaining the native folds of superantigen, DRalpha and TcRVbeta and the observed intermolecular contacts. After equilibration, 100 molecular dynamic snapshots are minimized and analyzed. This provides descriptions of various pairwise interactions at the contact interface in the complex and important clues on single site mutations on the chimera that may enhance the stability of a given superantigen-chimera complex.

Antigens, Bacterial↗
PubMed2002

Viral determinants and host immune responses in the pathogenesis of HBV infection.

Hepatitis B virus (HBV) is a virus that infects about 350,000,000 people worldwide with a clinical spectrum of acute hepatitis, the healthy carrier state, cirrhosis and hepatocellular carcinoma (HCC). The outcome of HBV infection is the result of complicated viral-host interactions. As in other infections with non-cythopatic viruses, the immune response is thought to play a crucial role in disease pathogenesis but there is increasing evidence that a variety of viral mechanisms, some depending on the function of virally encoded proteins, have a profound impact on the infected hepatocytes, the liver microenvironment, and host anti-viral responses. Indeed, the virus has evolved multiple mechanisms to ensure its success in infecting a susceptible host. The essential aspects of the life cycle of HBV and the host immune response are reviewed and recent new developments in the molecular virology of HBV, including experimental animal models, in the role of accessory viral proteins in disease pathogenesis and HCC development and in the characterisation of the T cell response in the control of HBV infection, are highlighted.

Animals↗
PubMed2003

Pathogenesis of simian varicella virus.

Simian varicella virus (SVV) is closely related to varicella-zoster virus (VZV) and induces a natural varicella-like disease in nonhuman primates. Therefore, simian varicella is a useful model to investigate varicella pathogenesis and to evaluate antiviral therapies. In this report, we review recent studies on SVV pathogenesis and latency. Experimental infection of African green monkeys is followed by a 7-10 day incubation period during which a viremia disseminates the virus throughout the body. Clinical disease is characterized by fever and vesicular skin rash. Pneumonia and hepatitis may occur during more severe infections. Examination of acutely infected tissues reveals histopathology including necrosis and hemorrhage in the skin, lung, liver, and spleen. In contrast, the neural ganglia exhibit minimal histopathology. SVV DNA, immediate early, early, and late gene transcripts, and viral antigens are detected in the tissues of acutely infected monkeys. Host immune responses are induced which resolve the acute infection within 21 days. During or after acute infection, SVV establishes latent infection in the ganglia of surviving monkeys. The virus may reactivate later in life to cause secondary disease and viral transmission to susceptible monkeys.

Animals↗