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Pathogenesis of multiple sclerosis--the immune diathesis and the role of viruses.

Although the evidence of involvement of viruses in the pathogenesis of MS is largely circumstantial, the pattern of association is constant, with little evidence for direct viral infection of the CNS but with a consistent immune response to several common viruses. In parallel with these studies, epidemiological studies, while indicating genetic predisposition, favor an environmental pathogenetic factor and experimental models indicate that viruses can induce demyelination either by oligodendrolysis or by a variety of immune mechanisms with or without persistence in the CNS. In elucidating the pathogenesis of MS, the challenge is to understand the basis of the immune abnormalities, with intrathecal synthesis of viral antibodies and abnormal immune responses to some viruses, and to relate these to the MRI abnormalities which indicate periodic BBB breakdown. There is strong evidence that the breakdown is associated with inflammation. and that cytokines, particularly TNF, may play a role in demyelination. In conclusion, therefore, several factors are probably key in our understanding of MS. These include: (i) the genetic control of the immune system and its interaction with viral antigen; (ii) related effects on cerebral endothelium including cytokine and adhesion molecule regulation; and (iii) associated glial and axonal responses. Such an approach to the pathogenesis of MS may not identify a specific cause. It may, however, indicate that a pathological cascade can be "triggered" by several common viral infections and that therapy can be used to intervene at several points in the pathological response.

Animals↗

Pathogenesis of early cardiac myocyte damage after severe burns.

BACKGROUND: The importance of early cardiac myocyte damage during postburn trauma has been emphasized in recent years. However, its pathogenesis, prevention, and treatment have not been fully clarified. The aim of this study is to define its pathogenesis. METHODS: Rats with 30% third-degree burns were used. Cardiac biochemical markers reflecting cardiac myocyte damage including troponin T, cardiac myosin light chain 1, creatinine kinase and its cardiac-specific isoenzyme compound, as well as inflammatory mediators such as tumor necrosis factor, endothelin/nitric oxide ratio, malondialdehyde, and superoxide dismutase, were determined. RESULTS: Cardiac biochemical markers reflecting cardiac myocyte damage, including troponin T, cardiac myosin light chain 1, cardiac-specific isoenzyme compound, were all significantly elevated between 3 hours and 24 hours after burn. Changes in tumor necrosis factor, endothelin/nitric oxide ratio, and malondialdehyde were similar to those of cardiac biochemical markers. In contrast, levels of superoxide dismutase declined markedly after burn. CONCLUSION: The findings of this study showed that considerable amounts of myocardial constructive protein degradation and release due to destruction of cardiac myocytes occurred early after severe burns. The inflammatory mediators released after burn injury may be involved in the pathogenesis of myocardial destruction.

Animals↗

Pathogenesis of bacterial bronchitis in cystic fibrosis.

OBJECTIVE: To describe the current understanding of the pathogenesis of infections in cystic fibrosis (CF). SUMMARY: The key element in the pathogenesis of infections in CF is the abnormal mucin resulting from a defective chloride channel. Abnormal mucin and the lack of hydration of respiratory secretions entraps bacteria, permitting colonization and subsequent infection. "Normal" physiologic insults, such as microaspiration, and pollution evoke mucin secretion with bacteria-mucin aggregates causing infection of small airways. Microcolonies of pulmotropic bacteria (i.e. Haemophilus and Staphylococcus) in the trapped mucin cause mucosal injury which predisposes the patient to Pseudomonas aeruginosa infection. Eventually there is obstruction of medium-sized and small airways by inflammatory exudate and mucus. Ultimately these chronic endobronchial bacterial infections cause significant loss of pulmonary function with morbidity and a decrease in the life span of patients with CF. Although antibiotic therapy is beneficial for the management of bacterial respiratory tract infections in CF patients, gene therapy may provide the ultimate cure. CONCLUSION: New treatment strategies will emerge as the pathogenesis of cystic fibrosis is better elucidated.

Anti-Bacterial Agents↗

Adynamic bone disease: pathogenesis, diagnosis and clinical relevance.

In the past several years significant attention has been directed to the study of adynamic bone disease in uremic patients. Several reports have provided additional information about the prevalence of adynamic bone disease in different countries. It has now become clear that the pathogenesis of adynamic bone disease cannot be ascribed to one single aetiological factor, but rather to a host of complex factors. From recently published papers we have learned about the mechanism of downregulation of the parathyroid hormone/parathyroid hormone-related peptide receptor on osteoblast-like cells, which may be a very important step in the pathogenesis of adynamic bone disease. A provocative hypothesis attempts to link the widespread use of erythropoietin to the emergence of adynamic bone disease-lacking excessive aluminium accumulation. It appears from some studies that bone-specific alkaline phosphatase might become a valuable tool in differentiating high turnover from low/normal turnover bone disease; however, further studies are needed to establish the role of this marker in the diagnosis of adynamic bone disease. Several papers discussed the pros and cons of lowering the calcium concentration of the dialysate in order to prevent adynamic bone disease. The results of these studies help us to understand the pathogenesis and the clinical relevance of this lesion in attempts to provide better care for our patients.

Alkaline Phosphatase↗

Pathogenesis and the natural course of chronic pancreatitis.

This article gives an overview about current thinking in pathogenesis and natural course /therapy in chronic pancreatitis. Alcohol consumption is still the most relevant factor in the development of chronic pancreatitis, a disease with enormous personal and social impact, shortening life expectancy up to 10-20 yrs. Pathogenesis of chronic pancreatitis has to be considered for different symptoms. Particularly pain, the most bothering symptom, is most likely due to a combination of hypertension in the organ and parenchymal alterations. Pathogenesis of pancreatic head enlargement remains largely elusive. In particular it is not known what triggers growth factors to step into action. Most other symptoms like common bile duct stenosis or portal hypertension are secondary to this enlargement of the head of the pancreas.

Chronic Disease↗

Use of high-resolution, high-frequency diagnostic ultrasound to investigate the pathogenesis of pressure ulcer development.

OBJECTIVES: To investigate the pathogenesis of pressure ulcers utilizing high-resolution ultrasound and to explore the utility of this technology for the detection of incipient pressure ulcers prior to visual clinical signs. DESIGN: An observational prospective study comparing high-resolution ultrasound images obtained from 119 long-term-care facility residents determined to be at risk for pressure ulcer development (Braden Scale score of 18 or less) with images obtained from 15 healthy volunteers (medical students and medical residents). Common pressure ulcer sites were scanned, including the heels, sacrum, and ischial tuberosity. SETTING: A medical center and a long-term-care facility. INTERVENTION: Anatomic sites universally accepted as at risk for pressure ulcer development were scanned using high-resolution ultrasound; the sites did not have visual evidence of skin breakdown. The images obtained from the long-term-care facility residents were compared with images considered normal that were obtained from healthy volunteers. In addition, documentation of the clinical assessment finding for erythema was reviewed, recorded, and compared with the high-resolution ultrasound finding for each specific site. MEASUREMENTS: The images obtained were classified as not readable, normal, or abnormal. The images classified as abnormal were further classified by depth of abnormal finding: pattern 1 (deep) or pattern 2 (superficial). The images classified with the abnormal finding pattern 1 (deep) were further classified and subdivided by anatomic location of abnormal finding(s): subgroup 1, abnormal findings in the subdermal area only; subgroup 2, subdermal and dermal abnormal findings; and subgroup 3, subdermal, dermal, and subepidermal edema. Pattern 2 (superficial) included images with abnormal findings limited to the dermal/epidermal junction. RESULTS: 630 (55.3%) of the images obtained from the long-term-care residents were different from the images obtained from the healthy volunteers. The healthy volunteers' images classified as normal had the expected ultrasound findings for homogeneous pattern of ultrasound reflections, allowing for visualization of various skin layers (epidermis, superficial papillary dermis, deep reticular dermis, and hypodermis) and subcutaneous tissue (subdermal). However, many images (55.3%) obtained from the residents at risk for pressure ulcer development had patterns where areas within the various skin layers were not visible, interrupted by areas indicative of fluid or edema. Moreover, most images (79.7%) with abnormal ultrasound patterns did not have documentation of erythema. CONCLUSION: High-resolution ultrasound is an effective tool for the investigation of skin and soft tissue changes consistent with the documented pathogenesis of pressure ulcers. A progressive process for pressure ulcer development from deep subdermal layers to superficial dermal then epidermal layers can be inferred. Dermal edema was only present with subdermal edema. In other words, there was never evidence of dermal edema in the absence of subdermal edema. A better understanding of the pathogenesis of pressure ulcers through the use of high-resolution ultrasound to detect soft tissue damage and edema before visible clinical signs could lead to earlier and more focused pressure ulcer prevention programs, resulting in reduced pain and suffering for improved patient quality of life and wound care cost savings.

Case-Control Studies↗

Myositis: an update on pathogenesis.

PURPOSE OF REVIEW: The etiology and much about the pathogenesis of the inflammatory myopathies remain a mystery. In this review, we investigate recent research efforts to understand the pathogenesis of the diverse entities of polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM), diseases that result from interactions between environmental risk factors and genetic susceptibility. RECENT FINDINGS: Over the past year, there has been considerable progress toward better understanding of IBM, with relatively few developments toward understanding PM and DM. Although these diseases may share some common clinical phenotypic and serologic components, they differ on a molecular and cellular level. SUMMARY: The need for definitive, safer therapies in these diseases makes vital the search for defining detailed pathogenesis of inflammation and muscle fiber damage at the molecular level.

Animals↗

Pathogenesis of psoriatic arthritis.

PURPOSE OF REVIEW: Heterogeneity in clinical presentation and disease course has hindered understanding of disease mechanisms in psoriatic arthritis, but recent studies have provided insights into pathogenesis. This review examines relevant animal models and genetic factors implicated in disease susceptibility. Also, recent reports on mechanisms related to synovial and entheseal inflammation are discussed. RECENT FINDINGS: Two transgenic mouse models (amphiregulin, STAT-3) were reported that have features of psoriatic arthritis and psoriasis respectively. Genetic studies did not find associations between psoriatic arthritis and several class I major histocompatibility complex alleles, the caspase-activating recruitment domain 15 domain, or the major histocompatibility complex class I chain-related gene A9 allele, in sharp contrast to previous reports. The striking association of psoriatic arthritis with mutations in the killer immunoglobulin receptors on natural killer cells is particularly exciting but needs further study. Psoriatic arthritis has histopathologic features that are more characteristic of other forms of spondyloarthritis than rheumatoid arthritis. Moreover, several of these features correlate with clinical disease activity. Matrix metalloproteinases are strongly expressed in psoriatic arthritis synovium, and serum matrix metalloproteinases-3 may be a reliable biomarker for monitoring disease response. Finally, the concept of an 'enthesis organ' may explain the magnetic resonance imaging findings and clinical signs of psoriatic enthesitis and dactylitis. SUMMARY: Recent findings highlight the importance of innate immune mechanisms in disease pathogenesis. Moreover, psoriatic arthritis and rheumatoid arthritis synovium have divergent histopathologic features that indicate distinct disease mechanisms. The generation of appropriate animal models coupled with reliable biomarkers will result in a deeper understanding of disease pathogenesis and will facilitate the identification of new therapeutic targets.

Animals↗

Possible pathogenesis of painful intervertebral disc degeneration.

STUDY DESIGN: We collected the specimens of lumbar intervertebral disc (i.e., the symptomatic degenerative disc) from patients with discogenic low back pain to study the histopathologic features and growth factor expressions. OBJECTIVES: To study the pathogenesis of disc degeneration, meanwhile discriminating between common disc degeneration (aging disc) (i.e., black asymptomatic disc, not clinically relevant) and painful disc degeneration (i.e., symptomatic disc, clinically relevant). SUMMARY OF BACKGROUND DATA: The pathogenesis of intervertebral disc degeneration is poorly understood, mainly because of the difficulty to establish the experimental model with good reproducibility. Recently, the popularity of spinal fusion leads to more opportunities to obtain disc specimens, which could be applied to explore the pathogenesis of disc degeneration with modern biologic techniques. METHODS: There were 21 specimens of lumbar intervertebral discs from 15 patients with discogenic low back pain during posterior lumbar interbody fusion, 16 aging discs from patients without low back pain, and 10 normal discs as control collected for the study of their histopathologic features, as well as the expressions of basic fibroblast growth factor (bFGF) and its receptor (Flg), transforming growth factor-beta1 (TGF-beta1) and its receptor (TGF-betaRI) by immunohistochemistry. The distribution of macrophages and mast cells was also noted. Proliferating cell nuclear antigen was assessed to evaluate proliferating activities of disc cells. RESULTS: The distinct histologic characteristic of the disc from the patient with discogenic low back pain was the ingrowth of vascularized granulation tissue along torn fissures, extending from the external layer of the anulus fibrosus into the nucleus pulposus. The immunohistochemical staining showed that there were strong expressions of bFGF and TGF-beta1 and their receptors, as well as a strong expression of proliferating cell nuclear antigen in the zones of granulation tissue in the painful discs. However, there were only weak expressions in the nongranulation tissue zones in the painful discs and aging discs, and no expression in the control discs. In addition, abundant macrophages and mast cells were found in the granulation tissue zones of painful discs but absent in the nongranulation tissue zones of painful discs or aging discs and the normal control discs. CONCLUSIONS: The findings indicated that degeneration of the painful disc might originate from the injury and subsequent repair of anulus fibrosus. Growth factors, such as bFGF and TGF-beta1, macrophages and mast cells might play a key role in the repair of the injured anulus fibrosus and subsequent disc degeneration.

Adult↗

Factors predicting childhood respiratory syncytial virus severity: what they indicate about pathogenesis.

BACKGROUND: A plethora of clinical experience exists defining the factors associated with differences in severity of childhood respiratory syncytial virus (RSV) infections. These clinical severity factors reveal a wealth of information about the pathogenesis of this disease. Reviewing and interpreting the clinical risk factors to gain an insight into RSV pathogenesis is important, especially considering the relative lack of parallel between many animal models of RSV infection and observed human disease. METHODS: Existing and unpublished data on severity risk factors are reviewed and placed into a working pathogenesis model. RESULTS: Important factors discussed are: (1) the critical role of the timing of the infection; (2) its rapidity of progression to involve the lower respiratory tract; (3) factors limiting this spread; (4) the nature of the pathogenic immune response; and (5) the host genetic and other factors that alter this immune response. CONCLUSIONS: Pending new data involving these and other processes will more fully illuminate the spectrum of childhood RSV disease.

Humans↗

Chronic inflammatory demyelinating polyneuropathy--update on pathogenesis, diagnostic criteria and therapy.

PURPOSE OF REVIEW: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable but possibly underdiagnosed disorder of the peripheral nerve. This review covers the growing literature of the past years that deals with the pathogenesis, diagnostic criteria and treatment of CIDP. RECENT FINDINGS: The recent development of a biphasic animal model of experimental autoimmune neuritis may provide further insights into the pathogenesis of inflammatory demyelination of the peripheral nerve, such as in CIDP, and may allow the development of further innovative therapeutic strategies. In patients, the contribution of immune processes to the dysfunction in hereditary polyneuropathies and the association of hereditary neuropathy and CIDP has been described. Commonly used therapies remain corticosteroids, intravenous immunoglobulin and plasmapheresis; however, newer immunosuppressant approaches using mycophenolate mofetil or cyclosporin A, or immunomodulating therapies using monoclonal antibodies or interferons are presently under investigation. SUMMARY: The growing body of knowledge on the pathogenesis of CIDP and further diagnostic differentiation of subforms may help to develop more-effective therapies for CIDP in the next few years.

Anti-Inflammatory Agents↗

Evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease in cell culture and in transgenic mice expressing mutant huntingtin.

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in affected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have led to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system by comparing the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. Insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not influence their total aggregate frequency. There were also no significant differences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. These studies, together with findings in transgenic mice, suggest two phases for the pathogenesis of HD, with the initial toxicity in the cytoplasm followed by proteolytic processing of huntingtin, nuclear translocation with increased nuclear concentration of N-terminal fragments, seeding of aggregates and resultant apoptotic death. These findings support the nucleus and cytosol as subcellular sites for pathogenesis in HD.

Animals↗

Sindbis virus pathogenesis: phenotypic reversion of an attenuated strain to virulence by second-site intragenic suppressor mutations.

Monoclonal antibodies (MAbs) specific for the E2c neutralizing antigenic site on the Sindbis virus E2 glycoprotein define a pathogenesis domain that affects neonatal mouse virulence. Sequence analysis of E2c MAb escape mutants showed that the domain included E2 amino acids 62, 96 and 159. The pathogenesis domain is also influenced by changes at E2 position 114. Mutation of E2 residues Asn 62 to Asp or Lys 159 to Glu results in suppression of the attenuated phenotype conferred by a mutation from Ser to Arg at E2 position 114. Possible mechanisms of phenotypic suppression within the E2c pathogenesis domain were investigated by using site-directed mutagenesis to determine the effects of specific combinations of positively charged, negatively charged and uncharged amino acid substitutions at E2 positions 62, 114 and 159. Phenotypic reversion to virulence by second-site suppressor mutations at E2 amino acids 62 or 159 was not dependent on ionic interaction with the residue at E2 114. Rather, suppression appeared to be the result of independent virulence effects mediated by specific residues.

Animals↗

Events in the pathogenesis of experimental cholera: role of bacterial adherence and multiplication.

Pathogenic, and laboratory-derived non-adherent, non-motile, streptomycin-dependent and attenuated strains of Vibrio cholerae, were injected into the ileal loops of adult rabbits. The pattern of bacterial adherence and multiplication was studied. It was shown that all the strains multiplied to the same extent in the intestine; multiplication per se had no role in pathogenesis except when the infecting dose was low. Vibrio strains differed in their capacity to adhere to the intestine. A good correlation was found between adherence and pathogenesis. While adhesive strains were pathogenic, the poorly adhesive strains proved to be poor pathogens. There was no trace of toxin the ileal loops inoculated with poorly adhesive strains and very little in the diarrhoeal fluid produced by pathogenic strains. Adhesive strains adhered poorly to the intestine of immunised animals. It is suggested that adherence is concerned in the release of toxin and thus plays an important role in the pathogenesis of cholera.

Animals↗

Expression of Pokeweed Antiviral Protein in Transgenic Plants Induces Virus Resistance in Grafted Wild-Type Plants Independently of Salicylic Acid Accumulation and Pathogenesis-Related Protein Synthesis.

Pokeweed antiviral protein (PAP), a 29-kD protein isolated from Phytolacca americana, inhibits translation by catalytically removing a specific adenine residue from the large rRNA of the 60S subunit of eukaryotic ribosomes. Transgenic tobacco (Nicotiana tabacum) plants expressing PAP or a variant (PAP-v) were shown to be resistant to a broad spectrum of plant viruses. Expression of PAP-v in transgenic plants induces synthesis of pathogenesis-related proteins and a very weak (<2-fold) increase in salicylic acid levels. Using reciprocal grafting experiments, we demonstrate here that transgenic tobacco rootstocks expressing PAP-v induce resistance to tobacco mosaic virus infection in both N. tabacum NN and nn scions. Increased resistance to potato virus X was also observed in N. tabacum nn scions grafted on transgenic rootstocks. PAP expression was not detected in the wild-type scions or rootstocks that showed virus resistance, nor was there any increase in salicylic acid levels or pathogenesis-related protein synthesis. Grafting experiments with transgenic plants expressing an inactive PAP mutant demonstrated that an intact active site of PAP is necessary for induction of virus resistance in wild-type scions. These results indicate that enzymatic activity of PAP is responsible for generating a signal that renders wild-type scions resistant to virus infection in the absence of increased salicylic acid levels and pathogenesis-related protein synthesis.

Journal Article↗

Immunogold localization of the citrus exocortis viroid-induced pathogenesis-related proteinase p69 in tomato leaves.

Citrus exocortis viroid induces in tomato plants (Lycopersicon esculentum) synthesis and accumulation of a pathogenesis-related protein (P69) previously reported to be a proteinase (Vera P, Conejero V [1988] Plant Physiol 87: 58-63). By immunogold/transmission electron microscopy, we have studied the distribution of this protein in thin sections of parenchymatous leaf tissue. The enzyme was present intra- and extracellularly. The intracellular location was limited to the vacuole and was always associated with engulfed cell material. When extracellularly located, the enzyme was associated with a dispersed, electron-dense material in the intercellular spaces. This latter location was confirmed after analysis of intercellular washing fluids obtained by vacuum infiltration of leaves. These observations provide new data for the understanding of viroid pathogenesis and the biological role of the pathogenesis-related proteinase P69.

Journal Article↗

A harpin binding site in tobacco plasma membranes mediates activation of the pathogenesis-related gene HIN1 independent of extracellular calcium but dependent on mitogen-activated protein kinase activity.

Harpin from the bean halo-blight pathogen Pseudomonas syringae pv phaseolicola (harpin(Psph)) elicits the hypersensitive response and the accumulation of pathogenesis-related gene transcripts in the nonhost plant tobacco. Here, we report the characterization of a nonproteinaceous binding site for harpin(Psph) in tobacco plasma membranes, which is assumed to mediate the activation of plant defense responses in a receptor-like manner. Binding of 125I-harpin(Psph) to tobacco microsomal membranes (dissociation constant = 425 nM) and protoplasts (dissociation constant = 380 nM) was specific, reversible, and saturable. A close correlation was found between the abilities of harpin(Psph) fragments to elicit the transcript accumulation of the pathogenesis-related tobacco gene HIN1 and to compete for binding of 125I-harpin(Psph) to its binding site. Another elicitor of the hypersensitive response and HIN1 induction in tobacco, the Phytophthora megasperma-derived beta-elicitin beta-megaspermin, failed to bind to the putative harpin(Psph) receptor. In contrast to activation by beta-megaspermin, harpin(Psph)-induced activation of the 48-kD salicylic acid-responsive mitogen-activated protein kinase (MAPK) and HIN1 transcript accumulation were independent of extracellular calcium. Moreover, use of the MAPK kinase inhibitor U0126 revealed that MAPK activity was essential for pathogenesis-related gene expression in harpin(Psph)-treated tobacco cells. Thus, a receptor-mediated MAPK-dependent signaling pathway may mediate the activation of plant defense responses induced by harpin(Psph).

Bacterial Outer Membrane Proteins↗

Adherence and pathogenesis of Salmonella enteritidis in mice.

Adherence of many pathogenic organisms to the host cells has been associated with the presence of fimbriae. The exact role of these organelles in the adherence and pathogenesis of Salmonella enteritidis is not well established. Utilizing hemagglutination tests, S. enteritidis was shown to possess type 1 and type 3 fimbriae. Polyacrylamide gel electrophoresis of the isolated fimbriae showed that type 1 and 3 fimbriae of S. enteritidis had subunit M.r of 17 and 22 kDa, respectively. In vitro adherence assays suggested that S. enteritidis utilized type 1 fimbriae to adhere to human buccal and mouse small intestine epithelial cells. In addition, antibody produced against type 1 and type 3 fimbriae protected the mice from infection with a lethal dose of S. enteritidis. These results suggest that type 1 and possibly type 3 fimbriae are involved in the adherence and pathogenesis of S. enteritidis. The data further suggest that they may have a role in the adherence and pathogenesis of the other enteric organisms.

Animals↗