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PubMed1991

Molecular mechanisms in the pathogenesis of AIDS-associated Kaposi's sarcoma.

Kaposi's Sarcoma (KS) is a tumor of mesenchymal origin of unclear etiology and pathogenesis. The epidemic form of KS (AIDS-associated) occurs in up to 30% of HIV-1 infected individuals with lesions characterized by mixed cellularity, spindle cells proliferation and neoangiogenesis. The establishment of in vitro and in vivo model systems (AIDS-KS cell cultures and nude mouse) have allowed studies toward the understanding of the pathogenesis of KS. The data presented here support the hypothesis that KS is a cytokine mediated disease and that interactions between mesenchymal cell types and HIV-1 gene products might lead to a composite lesion such as KS. In fact, in vitro and in vivo studies indicate that the HIV-1 Tat protein acts as a growth factor for cells derived from AIDS-KS lesions, thus establishing an experimental link between HIV-1 infection and the development of KS in humans. Human immunodeficiency virus (HIV-1) is implicated in various clinical manifestations associated with AIDS, including KS. KS represents the most frequent tumor arising in infected individuals, particularly homosexual and bisexual men. This form of KS (epidemic or AIDS-KS) is aggressive and often results in dissemination and invasion of lymph nodes and viscera. Histologically, KS is characterized by the proliferation of spindle-shaped cells ("KS cells"), considered to be the tumor element of the lesions, associated with endothelial cells, fibroblasts, inflammatory cells and new blood vessel formation (early stage lesions). In a later stage, the spindle cells tend to coalesce in larger tumor masses, although the slit-like spaces, which are characteristic of the lesion, usually remain evident. The histogenesis of the KS spindle cells, however, is still controversial and both types of mesenchymal cells, endothelial and smooth muscle cells, have been proposed as potential cell progenitors. Although KS is clearly associated with HIV-1 infection, little is known about the molecular events underlying its pathogenesis. Recently, however, two experimental advances (the establishment of long-term cell cultures derived from KS lesions of AIDS patients and the development of animal models) have made the study of the pathogenesis of AIDS-KS possible. Here we discuss results obtained from these new systems suggesting that the induction of the AIDS-KS lesions involves a pathway of events mediated by specific cytokines and that the HIV-1 tat gene product may play a crucial role in the development and/or progression of KS in HIV-1 infected individuals.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Lipopigments in veterinary pathology: pathogenesis and terminology.

The lipopigments are a heterogenous group of pigments whose pathogenesis and terminology is confused. Whereas there is epidemiological and observational evidence that ceroid is derived from degeneration and peroxidation of unsaturated lipid, the assumption that all so-called lipopigments are similarly formed, is questioned. In particular, recent studies have distanced the pathogenesis of the pigment found in the ceroid-lipofuscinoses from that perceived for ceroid. The importance of protein rather than lipid in the pathogenesis of the pigment of ceroid-lipofuscinosis and of age pigment from the equine thyroid is noted. In the former the essential feature is storage of the DCCD binding protein subunit c of mitochondrial ATP synthase. There is a need for more analytical studies on isolated pigments which are generally more soluble than anticipated by the literature. It is proposed that the term ceroid be limited to a family of pathological pigments where lipid degeneration and peroxidation is implied from observational and/or epidemiological factors. The term age pigment is unequivocal and preferred for age related pigment not obviously complicated by other factors. The terms lipofuscin and lipopigment retain a usefulness as generic terms, particularly where the nature of the pigment is uncertain. The term ceroid-lipofuscinosis for the inherited storage diseases of children and animals is misleading. The term "proteolipid proteinosis" has been suggested to define this group of diseases but this is perhaps premature until their full pathogenesis is known.

Aging↗

PubMed2001

Cellular receptors and hantavirus pathogenesis.

Hantaviruses cause two potentially lethal diseases, HPS and HFRS, and both diseases result in defects in vascular permeability and platelet function. Human beta 3 integrins confer cellular susceptibility to HPS- and HFRS-causing hantaviruses, a fact directly linking platelets, endothelial cells, and hantavirus diseases to the use of [figure: see text] cellular receptors that maintain capillary integrity and regulate platelet function. The role of vitronectin, PAI-1, uPAR, and complement cascades in hantavirus pathogenesis are unstudied but may contribute to specific disease syndromes effected by hantaviruses. The divergence of hantavirus surface glycoproteins and common beta 3-integrin usage provides further insight into the interaction of hantaviruses with cells. G1 and G2 glycoprotein variation is likely to contribute to additional interactions that determine pathogenic responses to individual viruses. beta 3-integrin usage also suggests that common elements exist on G1 or the more highly conserved G2 surface glycoprotein, which mediate viral attachment to integrins. Although there is currently no data defining the virion attachment protein, the development of antibodies that recognize the hantavirus attachment protein and block integrin interactions is of interest since it is likely to provide an additional point for therapeutic intervention and vaccine development. There are a plethora of effects that could be elicited by hantavirus regulation of cellular beta 3 integrins and their ligands that are consistent with hantavirus diseases. Since beta 3 integrins are critical adhesive receptors on platelets and endothelial cells and regulate both vascular permeability and platelet activation and adhesion, the use of these receptors by hantaviruses is likely to be fundamental to hantavirus pathogenesis. The lack of an animal model for hantavirus pathogenesis has prevented a systematic analysis of immune and cellular responses to hantavirus infections, and it impedes our ability to study protective or therapeutic approaches to hantavirus diseases. However, recent findings suggest that human beta 3 integrins within transgenic mice may provide animal models of hantavirus pathogenesis and have the potential to radically alter the ability to investigate hantavirus disease.

Animals↗

PubMed2000

[Role of vitreoretinal interface in the pathogenesis and therapy of macular disease associated with optic pits].

PURPOSE: Although the relationship between optic pits and macular lesions was described nearly a century ago, the pathology and pathogenesis of macular detachment remain unclear. Recent OCT studies have shown schisislike spaces in connection with the disc. None of the hypotheses of pathogenesis proposed so far could have been proven. Besides the hypothesis of exudation, the role of the vitreoretinal interface is kept in the background of discussion. We describe a case of macular detachment associated with optic pit that regained full vision after pars plana vitrectomy with laser coagulation and gas tamponade over a follow-up of 26 months. The purpose of our case report is to emphasize the role of the vitreoretinal interface in the pathogenesis of macular detachment associated with optic pits. CASE REPORT AND THERAPY: A 32-year-Caucasian woman developed macular detachment associated with an optic pit on her right eye. The vision deteriorated to 24/60. A standard three-port pars plana vitrectomy was performed. After creating a posterior vitreous detachment, all vitreoretinal adhesions were removed carefully. Peripapillary laser coagulation and gas tamponade with 15% C2F6-air mixture followed. For 26 months after surgery the macula has been flat. The vision is 60/60. CONCLUSIONS: Besides the exudative component of macular detachment, the vitreoretinal interface seems to play an underestimated role in the pathogenesis of maculopathy associated with optic pits. Tractional forces could explain the delay of macular detachment in young adulthood and the frequency of treatment failure after laser coagulation and gas tamponade. Pars plana vitrectomy with complete removal of all vitreoretinal adhesions should be a suitable technique in the treatment of macular detachment associated with optic pits.

Adult↗

PubMed1995

Maxillary sinus aspergillosis: diagnosis and differentiation of the pathogenesis based on computed tomography densitometry of sinus concretions.

PURPOSE: The efficacy of preoperative computed tomography (CT) densitometry in evaluating the origin of sinus concretions (SC) in sinus aspergillosis (SA) and its value for differentiation between a dental (endodontic) and an aerogenic pathogenesis were examined. PATIENTS AND METHODS: Thirty-two patients who demonstrated radiodense maxillary sinus concretions in standard radiography underwent an additional preoperative CT examination of the maxillary sinus and the SC. The density of the SC and the root canal filling materials was assessed. The SC were subdivided into organic (< 1,500 HU) and inorganic (> 1,500 HU) masses; this classification was useful in the differentiation between a dental and an aerogenic pathogenesis of SA. RESULTS: SA was diagnosed in 22 patients (68.8%). The SC of SA patients had a density of 2,566.5 +/- 713.6 HU, whereas those of patients without SA had a density of 1,159.9 +/- 1,008.4 HU (P < .01). A correlation between the density of inorganic SC and that of root filling materials was found (r = .78, P < .01). CONCLUSION: CT densitometry allows a classification of SC into two subgroups. The correlation between the density of root filling materials and that of radiodense sinus concretions seems to point to a "dental" origin of some concretions in SA. However, "organic" masses found in CT densitomentric examinations represent endogenous fungal products, which indicate an aerogenic pathogenesis of SA. Additional CT examinations of radiodense sinus concretions may thus be of some value for diagnosing SA and differentiating their pathogenesis.

Administration, Topical↗

PubMed1993

Pathogenesis of diabetic retinopathy--the missing link?

Release of angiogenic factors in response to the ischaemic retina is currently the most favoured hypothesis for the pathogenesis of proliferative diabetic retinopathy. Reducing the stimulus for angiogenesis by destroying the ischaemic retina also forms the basis of the most effective treatment of diabetic retinopathy by photocoagulation. Though ischaemia is undoubtedly important for neovascularization, there is recent evidence which cast doubts on ischemia being the sole mechanism for diabetic retinopathy. Many clinical observations viz. the protective effects of glaucoma, myopia, unilateral carotid stenosis on diabetic retinopathy; and its worsening after cataract extraction are not adequately explained by the present hypothesis. Moreover, the recent in vitro culture studies on retinal pigment epithelial cells have suggested an alternative explanation for the effectiveness of photocoagulation in proliferative diabetic retinopathy. Furthermore, hyperglycemia has been strongly correlated with the incidence and progression of diabetic retinopathy, but has only been indirectly indicted in its pathogenesis. These facts can be integrated into a more plausible hypothesis for the pathogenesis of diabetic retinopathy. It is hypothesized that a relative reduction in intra-ocular pressure caused by persistent or intermittent hyperglycemia may be the missing link that induces certain morphological changes in the retinal pigment epithelium. These changes, in addition to the ischaemic retina, may be important for the pathogenesis of diabetic retinopathy. Such a hypothesis also explains most of the hitherto unexplained features of diabetic retinopathy.

Animals↗

PubMed2001

Pathogenesis of alcohol-induced chronic pancreatitis: facts, perceptions, and misperceptions.

The pathogenesis of chronic pancreatitis secondary to chronic alcoholism is not fully understood. A major hurdle in the understanding of the pathogenesis is the inability to study early lesions of the pancreas and the sequential changes. Facts are few; observations are many. Each new hypothesis argues against all previous hypotheses; however, clinical chronic pancreatitis is initiated by one or more of the mechanisms. Good experimental models for alcoholic pancreatitis are not available, limiting the ability to study the pathogenesis. Additional studies on genetic markers and immunologic mechanisms might explain acinar cell injury, which seems to be the earliest lesion in most, if not all, types of chronic pancreatitis. Opie's common channel and obstruction regurgitation theories seem unrelated to chronic pancreatitis. Although biochemical changes of the pancreatic secretion in alcoholic patients promote protein-plug formation, evidence is too weak to consider protein plug as the earliest change. The theory of necrosis of the acinar cell by some unknown mechanism, subsequently leading to fibrosis, is gaining support; however, it is clear that the pathogenesis of alcoholic pancreatitis is not yet fully understood.

Humans↗

PubMed1995

Role of scatter factor and the c-met protooncogene in the pathogenesis of AIDS-associated Kaposi's sarcoma.

Kaposi's sarcoma is a highly lethal tumor in patients with sexually acquired AIDS. A number of etiologic agents have been implicated in the development of this disease in this patient population and there is ample evidence that aberrant production of and responsiveness to KS tumor and host cell-derived cytokines plays a central role in the pathogenesis of AIDS-KS. In this review we propose that aberrant expression SF and c-met is central to the pathogenesis of KS. KS is a serious and life-threatening consequence for many patients with AIDS. Unfortunately, current therapeutic strategies for the treatment of this complex neoplasm have met with only limited success. In view of the poor survival rates for AIDS-KS patients which continue to decline at an alarming rate, it is eminently clear that a better understanding of the etiology and pathogenesis of this form of KS is needed if novel therapeutic strategies designed to successfully combat this disease are to be developed. If our hypothesis is validated, one could envision several approaches whereby the modulation of SF/c-met function or production might lead to a reduction in the incidence and severity of KS lesions. Antibody therapy directed against either SF-producing tumor cells or against the c-met receptor might decrease the incidence of new tumors by limiting their clonal expansion and lead to regression of established tumors by blocking SF-mediated tumor cell proliferation and neovascularization. It might also be possible to suppress production of SF or accessory cytokines involved in the induction SF production and thus short circuit SF/c-met growth-promoting effects. We have outlined a novel hypothesis for understanding the mechanism underlying the development of AIDS-associated KS. This is most certainly not the whole story, however. Clearly, other cytokines and alterations in natural host defenses and the immune system contribute significantly to the development of AIDS-associated KS. We believe, however, that recognition of SF/c-met as a participant in this disease is necessary if we are to more fully understand the pathogenesis of AIDS-associated KS.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis.

A subset of familial cases of amyotrophic lateral sclerosis are linked to missense mutations in copper/zinc superoxide dismutase type 1. Patients with missense mutations in copper/zinc superoxide dismutase type 1 develop a paralytic disease indistinguishable from sporadic amyotrophic lateral sclerosis through an unknown toxic gain of function. Nitric oxide reacts with the superoxide anion to form the strong oxidant, peroxynitrite, which participates in neuronal injury in a variety of model systems. Peroxynitrite is an alternate substrate for copper/zinc superoxide dismutase type 1, causing catalytic nitration of tyrosine residues in other proteins. Mutations in copper/zinc superoxide dismutase type 1 may disrupt the active site of the enzyme and permit greater access of peroxynitrite to copper, leading to increased nitration by peroxynitrite of critical cellular targets. To investigate whether neuronal-derived nitric oxide plays a role in the pathogenesis of familial amyotrophic lateral sclerosis, we examined the effects of three different nitric oxide synthase inhibitors: a non-selective nitric oxide synthase inhibitor, nitro-L-arginine methyl ester; a relatively selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole; and a novel highly selective neuronal nitric oxide synthase inhibitor, AR-R 17,477, in transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 (Gly-->Ala at position 93; G93A) containing a high transgene copy number and a low transgene copy number. AR-R 17,477, but not nitro-L-arginine methyl ester or 7-nitroindazole, significantly prolonged survival in both the high and low transgene transgenic mice. To determine whether neuronal nitric oxide synthase is involved in the pathogenesis resulting from the familial amyotrophic lateral sclerosis copper/zinc superoxide dismutase type 1 mutation, we produced mice with the copper/zinc superoxide dismutase type 1 mutation which lack the neuronal nitric oxide synthase gene. The transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on neuronal nitric oxide synthase null background do not live significantly longer than transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1. Western blot analysis indicates the presence of two neuronal nitric oxide synthase-like immunoreactive bands in spinal cord homogenates of the neuronal nitric oxide synthase null mice, and residual neuronal nitric oxide synthase catalytic activity ( > 7%) is detected in the spinal cord of the transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on neuronal nitric oxide synthase null background. This amount of residual activity probably does not account for lack of protection afforded by the disrupted neuronal nitric oxide synthase gene in the familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 mice. Immunological nitric oxide synthase is not detected in the copper/zinc superoxide dismutase type 1 mutant mice at several different ages, thus excluding immunological nitric oxide synthase as a contributor to the pathogenesis of familial amyotrophic lateral sclerosis. Levels of neuronal nitric oxide synthase as well as Ca2+-dependent nitric oxide synthase catalytic activity in the copper/zinc superoxide dismutase type 1 mutant mice do not differ from wild type mice. Endothelial nitric oxide synthase levels may be decreased in the copper/zinc superoxide dismutase type 1 mutant mice. Together, these results do not support a significant role for neuronal-derived nitric oxide in the pathogenesis of familial amyotrophic lateral sclerosis transgenic mice.

Amidines↗

PubMed1999

The role of human herpesvirus-8 in the pathogenesis of multiple myeloma.

Human herpesvirus-8 has been strongly implicated in the pathogenesis of KS, BCBL, and multicentric Castleman's disease. Evidence for its role in the pathogenesis of multiple myeloma is accumulating. Human herpesvirus-8 is detectable in the nonmalignant bone marrow dendritic cells from most myeloma patients. In addition, HHV-8 is also detected in the peripheral blood of most myeloma patients. In contrast, this virus is rarely detected in close contacts of myeloma patients, healthy individuals, or patients with other malignancies. Furthermore, only about one fourth of patients with MGUS are infected with HHV-8. Sequencing of HHV-8 DNA isolated from myeloma patients shows both minor differences among patients and a conserved deletion unique to myeloma compared with HHV-8 in other malignancies. Consistent expression of both the viral homologues of IRF and IL-8R in myeloma suggests a possible role for these transforming viral genes in the pathogenesis of this disease. Although the described association between multiple myeloma and HHV-8 implies a causal role in the pathogenesis of this disease, no cause-and-effect relationship is yet demonstrated. Evidence may be obtained directly by fulfilling Koch's postulate in an animal model and indirectly through therapeutic interventions with antiviral agents or through extensive epidemiological studies. Such epidemiological studies would be greatly facilitated by the development of antibodies directed against the HHV-8 viral proteins uniquely present in myeloma. A direct or indirect causal effect of HHV-8 has potentially enormous implications for the therapeutic benefit of antiviral agents and preventative strategies using vaccines. There is, indeed, preliminary evidence that antiviral therapy in HIV-infected patients reduces the risk or development of KS. Clinical improvement in patients with KS treated with antiviral agents has also been reported. These observations suggest that future treatment strategies to combat multiple myeloma may include antiviral agents.

Antibodies, Viral↗

PubMed2001

Pathogenesis of tuberculosis in cattle.

There has been a renewed interest in the pathogenesis of bovine tuberculosis in many countries, in an attempt to understand better its transmission, to improve diagnosis and assess the potential of vaccination. This paper, which overviews current knowledge of aspects of the pathogenesis of bovine tuberculosis, draws from studies of field cases and experimental infections and highlights deficiencies in current understanding. The pathogenesis of bovine tuberculosis has not received the same level of attention as with human tuberculosis, and in many instances, the processes involved in bovine tuberculosis have been drawn from studies of human tuberculosis or from small animal models of infection. This paper however, considers the successful emulation of naturally acquired tuberculosis using experimental cattle models and identifies the complex and integrated nature of microbiological, immunological and pathological events involved. Current understanding of the initiation of infection, immune responses, and subsequent pathology, which can vary significantly in individual animals are discussed. Whilst there are aspects of M. bovis that still remain elusive to scientific investigation, further studies on the pathogenesis of bovine tuberculosis are advocated as necessary to provide a better scientific basis on which to review control and eradication strategies, which are currently less than effective in many regions.

Animals↗

PubMed1998

Pathogenesis of idiopathic calcium nephrolithiasis: update 1997.

Idiopathic calcium nephrolithiasis (ICN) is a frequent disease in Western countries. The physicochemical theory of lithogenesis, which explains stone formation by the precipitation, growth, and crystalline aggregation of lithogenic salts in the urine, has contributed greatly to the understanding of the pathogenesis of calcium urolithiasis. However, several aspects are still unexplained; the co-existence of familial occurrence, primary tubular dysfunctions with ICN, and anomalies in the systemic handling of oxalate and calcium led to the development of a cellular hypothesis of ICN. A number of cellular defects in the handling of ions has been reported that involves both anion and cation transport. These anomalies are probably the expression of a still unknown cellular defect in idiopathic calcium stone formers. We suggested that an anomaly in the cell membrane composition might be responsible for the complex array of cell ion flux abnormalities observed in ICN. Recently, a disorder in the n-6 polyunsaturated fatty acid series has been described; it is characterized by a lower linoleic acid content and a higher arachidonic acid concentration in both plasma and erythrocyte membrane phospholipids of renal calcium stone patients. This anomaly could cause an increased activity of ion carriers; furthermore, it may lead to increased prostaglandin synthesis and to secondary phenomena at the kidney, skeletal, and intestinal level. As a consequence, critical conditions for lithogenesis in the kidney may ensue. The data suggest a common pathogenesis for hypercalciuria and hyperoxaluria. The systemic defect in the phospholipid arachidonic acid level may be both of dietary or genetic origin; experimental data suggest that the increase in delta-6 desaturase activity, the limiting enzyme in the metabolic pathway of polyunsaturated fatty acids, might be relevant to the pathogenesis of lipid abnormalities observed in nephrolithiasis and to the pathogenesis of ICN and its related problems (at the kidney, intestinal, and bone level).

Calcium↗

PubMed2000

The role of podocyte injury in the pathogenesis of focal segmental glomerulosclerosis.

The podocyte has diverse functions including glomerular filtration, biosynthesis and maintenance of the glomerular capillary architecture. It discharges these functions by virtue of a unique morphology, an intimate relationship with the capillary wall, and diverse synthetic and membrane specializations. Despite the complex role that it plays in glomerular function, the clinical manifestations of podocyte dysfunction are limited to proteinuria and renal insufficiency. Recurrent focal segmental glomerulosclerosis (FSGS) in renal transplants provides a unique opportunity to study the pathogenesis of FSGS in human beings, because the patients are monitored carefully to identify the onset of disease, the recurrence is presumed to have the same etiology as the primary disease, renal biopsy is a tool to study the pathogenesis of the lesion, and therapeutic intervention provides a mechanism to test pathogenesis. Pathologic studies have identified a proliferative lesion of the podocytes as the first sign of recurrent disease. The glomerular lesions evolve to form segmental glomerular scars with time. These findings and studies in experimental models of FSGS implicate podocyte injury in the pathogenesis of the recurrent disease. The cellular lesion (similar to the proliferative lesion of podocytes in recurrent FSGS), seen early in the course of primary FSGS suggests that the pathogenic sequence in recurrent FSGS also applies to primary FSGS. A soluble circulating factor that increases glomerular permeability and correlates with recurrence of FSGS has been identified in the pretransplant serum of patients with end-stage FSGS, but the mechanism of podocyte injury by this factor remains speculative. In any case, podocytes in the cellular lesion undergo morphologic changes and lose specialized functions seen in the normal mature cell, and these structural and functional abnormalities cause the permeability changes associated with proteinuria and destruction of glomerular filtration surface by scarring associated with loss of glomerular function.

Animals↗

PubMed2000

Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis.

Insulin-dependent diabetes mellitus (IDDM) is a polygenic disease caused by progressive autoimmune infiltration (insulitis) of the pancreatic islets of Langerhan, culminating in the destruction of insulin-producing beta cells. Genome scans of families with diabetes suggest that multiple loci make incremental contributions to disease susceptibility. However, only the IDDM1 locus is well characterized, at a molecular and functional level, as alleleic variants of the major histocompatibility complex (MHC) class II HLA-DQB1, DRB1, and DPB1 genes that mediate antigen presentation to T cells. In the nonobese diabetic (NOD) mouse model, the Idd1 locus was shown to be the orthologous MHC gene I-Ab. Inheritance of susceptibility alleles at IDDM1/Idd1 is insufficient for disease development in humans and NOD mice. However, the identities and functions of the remaining diabetes loci (Idd2-Idd19 in NOD mice) are largely undefined. A crucial limitation in previous genetic linkage studies of this disease has been reliance on a single complex phenotype-diabetes that displays low penetrance and is of limited utility for high-resolution genetic mapping. Using the NOD model, we have identified an early step in diabetes pathogenesis that behaves as a highly penetrant trait. We report that NOD-derived alleles at both the Idd5 and Idd13 loci regulate a T lymphocyte-dependent progression from a benign to a destructive stage of insulitis. Human chromosomal regions orthologous to the Idd5 and -13 intervals are also linked to diabetes risk, suggesting that conserved genes encoded at these loci are central regulators of disease pathogenesis. These data are the first to reveal a role for individual non-MHC Idd loci in a specific, critical step in diabetes pathogenesis-T cell recruitment to islet lesions driving destructive inflammation. Importantly, identification of intermediate phenotypes in complex disease pathogenesis provides the tools required to progress toward gene identification at these loci.

Alleles↗

PubMedDate not supplied

Stress and pathogenesis of infectious disease.

Despite inherent difficulties in defining and measuring stress, a scientific framework has been provided in recent years for understanding how disruptive life experiences might be translated into altered susceptibility to infectious diseases. Studies of the effects of stress on pathogenesis of infectious disease are highly relevant to assessment of the biological importance of the immune impairments that have been associated with stress. With a few notable exceptions, investigations of viral infections in humans and in animal models support the hypothesis that stress promotes the pathogenesis of such infections. Similar conclusions can be drawn from studies of bacterial infections in humans and animals and from a small number of studies of parasitic infections in rodent models. While many of these studies have substantial limitations, the data nonetheless suggest that stress is a potential cofactor in the pathogenesis of infectious disease. Given recent unprecedented advances in the neurosciences, in immunology, and in the field of microbial pathogenesis, the relationship between stress and infection should be a fruitful topic for interdisciplinary research.

Animals↗

PubMed1996

Theories on the pathogenesis of endometriosis.

Although endometriosis has been known for over 100 years, its pathogenesis is still poorly understood. In this overview the literature regarding the pathogenesis of endometriosis is reviewed. The implantation or transplantation theory, that suggests implantation and subsequent growth of retrogradely shed viable endometrial cells, still remains the most widely accepted theory to explain the pathogenesis. The conditions that have to be met for the implantation theory are threefold: (i) retrograde menstruation has to occur; (ii) retrograde menstruation should contain viable endometrial cells; and (iii) adhesion to the peritoneum has to occur with subsequent implantation and proliferation. The scientific data to corroborate these conditions will be discussed. A short overview is given on cell adhesion molecules, in particular cadherins and integrins, the most important cell adhesion molecules involved in cell-cell adhesion and cell-extracellular matrix interaction. Special attention is given to the possible functional role of these cell adhesion molecules in the pathogenesis of endometriosis.

Endometriosis↗

PubMed1999

Progress in pathogenesis studies of spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder characterized by progressive loss of coordination, motor impairment and the degeneration of cerebellar Purkinje cells, spinocerebellar tracts and brainstem nuclei. Many dominantly inherited neurodegenerative diseases share the mutational basis of SCA1: the expansion of a translated CAG repeat coding for glutamine. Mice lacking ataxin-1 display learning deficits and altered hippocampal synaptic plasticity but none of the abnormalities seen in human SCA1; mice expressing ataxin-1 with an expanded CAG tract (82 glutamine residues), however, develop Purkinje cell pathology and ataxia. These results suggest that mutant ataxin-1 gains a novel function that leads to neuronal degeneration. This novel function might involve aberrant interaction(s) with cell-specific protein(s), which in turn might explain the selective neuronal pathology. Mutant ataxin-1 interacts preferentially with a leucine-rich acidic nuclear protein that is abundantly expressed in cerebellar Purkinje cells and other brain regions affected in SCA1. Immunolocalization studies in affected neurons of patients and SCA1 transgenic mice showed that mutant ataxin-1 localizes to a single, ubiquitin-positive nuclear inclusion (NI) that alters the distribution of the proteasome and certain chaperones. Further analysis of NIs in transfected HeLa cells established that the proteasome and chaperone proteins co-localize with ataxin-1 aggregates. Moreover, overexpression of the chaperone HDJ-2/HSDJ in HeLa cells decreased ataxin-1 aggregation, suggesting that protein misfolding might underlie NI formation. To assess the importance of the nuclear localization of ataxin-1 and its role in SCA1 pathogenesis, two lines of transgenic mice were generated. In the first line, the nuclear localization signal was mutated so that full-length mutant ataxin-1 would remain in the cytoplasm; mice from this line did not develop any ataxia or pathology. This suggests that mutant ataxin-1 is pathogenic only in the nucleus. To assess the role of the aggregates, transgenic mice were generated with mutant ataxin-1 without the self-association domain (SAD) essential for aggregate formation. These mice developed ataxia and Purkinje cell abnormalities similar to those seen in SCA1 transgenic mice carrying full-length mutant ataxin-1, but lacked NIs. The nuclear milieu is thus a critical factor in SCA1 pathogenesis, but large NIs are not needed to initiate pathogenesis. They might instead be downstream of the primary pathogenic steps. Given the accumulated evidence, we propose the following model for SCA1 pathogenesis: expansion of the polyglutamine tract alters the conformation of ataxin-1, causing it to misfold. This in turn leads to aberrant protein interactions. Cell specificity is determined by the cell-specific proteins interacting with ataxin-1. Submicroscopic protein aggregation might occur because of protein misfolding, and those aggregates become detectable as NIs as the disease advances. Proteasome redistribution to the NI might contribute to disease progression by disturbing proteolysis and subsequent vital cellular functions.

Animals↗

PubMed1995

Role of macrophages in the pathogenesis of human immunodeficiency virus (HIV) infection.

There are a number of machanisms by which HIV-infected macrophages contribute to the pathogenesis of the Acquired Immunodeficiency Syndrome (AIDS). Macrophage-tropic strains of HIV are present at the time of infection, and persist throughout the course of infection, despite the emergence of T cell tropic quasispecies. As HIV causes chronic infection of macrophages with only minimal cytopathology, these cells can provide an important viral reservoir in HIV-infected persons. Macrophages are more susceptible to HIV infection than freshly isolated monocytes. HIV-infected macrophages can contribute to CD4 T lymphocyte depletion through a gp120-CD4 dependent fusion process with uninfected CD4-expressing T cells. Increasing data support the role of HIV-infected macrophages and microglia in the pathogenesis of HIV-related encephalopathy and AIDS-related dementia through the production of neurotoxins. HIV infection of macrophages in vitro results in impairment of many aspects of their function. Reduced phagocytic capacity for certain opportunistic pathogens, including Toxoplasma gondii and Candida albicans, may be responsible for reactivation of these pathogens in persons with advanced HIV infection, although the mechanisms underlying reactivation of infections and susceptibility to disease from new infections are likely to be multifactorial. Our studies showing defective phagocytosis and killing provide additional information that contribute to our understanding of the pathogenesis of AIDS. Studies of in vitro efficacy of potential antiretroviral therapies should be performed in both primary lymphocyte and monocyte cultures, given the importance of both of these cell populations to HIV pathogenesis and their differing biology.

AIDS Dementia Complex↗