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PubMed2004

CCTTT-repeat polymorphism of the inducible nitric oxide synthase is not associated with HIV pathogenesis.

Nitric oxide (NO) produced by the inducible form of nitric oxide synthase (iNOS) has bactericidal and virocidal effects. Although NO synthesis and iNOS expression in macrophages affect several aspects of human immunodeficiency virus (HIV) type-1 pathogenesis, their role in HIV disease remains largely unknown. In humans, the expression of iNOS is influenced by a functional CCTTT-repeat polymorphism in the promoter region of the gene. We investigated the association of this polymorphism with HIV pathogenesis in naive HIV-infected patients before the initiation of antiretroviral therapy. The allele frequencies of the iNOS CCTTT-repeat polymorphism were assessed by PCR in 857 patients from the Swiss HIV Cohort Study, including rapid progressors and long-term nonprogressors, and in 240 healthy volunteers. In HIV-infected patients, the initial viral load and the decline in total CD4 cells was calculated to estimate disease progression. Allele frequencies of the iNOS CCTTT-repeat polymorphism were similar between the HIV-infected and noninfected blood donors. In treatment-naive HIV-positive patients, there was no association of the iNOS polymorphism with viral load or with the course of CD4 cells. Regulation of iNOS expression by the functional CCTTT-polymorphism does not modify HIV pathogenesis.

Adult↗
PubMed2004

Use of proteomics to identify novel virulence determinants that are required for Edwardsiella tarda pathogenesis.

Edwardsiella tarda is an important cause of haemorrhagic septicaemia in fish and also of gastro- and extraintestinal infections in humans. Using a combination of comparative proteomics and TnphoA mutagenesis, we have identified five proteins that may contribute to E. tarda PPD130/91 pathogenesis. Lowered protein secretion, impaired autoaggregation and the absence of six proteins were observed only in three highly attenuated mutants when cultured in Dulbecco's modified eagle medium (DMEM). Five out of six proteins could be identified by their mass spectra. Three proteins were identified as putative effector proteins (EseB, EseC and EseD) that are homologous to SseB, SseC and SseD of a type III secretion system (TTSS) in Salmonella species. The other two were EvpA and EvpC, homologous to Eip20 and Eip18 in Edwardsiella ictaluri. The complete sequencing and homology studies of evpA-H indicate that similar gene clusters are widely distributed in other pathogens such as Escherichia, Salmonella, Vibrio and Yersinia species with unknown functions. Insertional inactivation and deletion of evpB or evpC led to lower replication rates in gourami phagocytes, and reduced protein secretion and virulence in blue gourami. Complementation of these deletion mutants showed partial recovery in the above three phenotypes, indicating that these genes are vital for E. tarda pathogenesis. The transport of the EvpC protein may not use the TTSS in E. tarda. The expression of EvpA and EvpC as well as EseB, EseC and EseD was temperature dependent (suppressed at 37 degrees C), and disruption of esrB affected their expression. The present study identifies two possible secretion systems (TTSS and Evp) that are vital for E. tarda pathogenesis.

Bacterial Adhesion↗
PubMed2005

The transcription factor ATAF2 represses the expression of pathogenesis-related genes in Arabidopsis.

ATAF2, a member of the plant-specific NAC-domain transcription factor family, is highly induced in leaves at a wound site and is responsive to the wound-related phytohormones methyl jasmonate and salicylic acid, but not to abscisic acid. Overexpression of ATAF2 leads to an increased biomass and yellowing of the leaves, but there is no obvious phenotype in two independent ATAF2 T-DNA insertion lines. At the transcriptome level, ATAF2 overexpression resulted in repression of a number of pathogenesis-related proteins. Conversely, four of these pathogenesis-related transcripts were increased in both ATAF2 knock-out lines. ATAF2 overexpressing plants showed a higher susceptibility to the soil-borne fungal pathogen Fusarium oxysporum. Our results indicate that ATAF2 functions as a repressor of pathogenesis-related proteins in Arabidopsis.

Amino Acid Sequence↗
PubMed1996

Proposal for a pathogenesis-based classification of tumoral calcinosis.

BACKGROUND: Deposition of calcium in skin is currently categorized into a group of disorders referred to as calcinosis cutis. Divisions between types and subtypes within this confusing classification are predominantly based on morphologic differences in the calcification and serve to obscure pathogenesis. This is especially evident in a subtype of calcinosis cutis, known as tumoral calcinosis. Calcifications in cases of tumoral calcinosis share the following characteristics, but without evidence of a common pathogenesis: large size, juxtaarticular location, progressive enlargement over time, a tendency to recur after surgical removal, and an ability to encase adjacent normal structures. The goal of this study was to formulate a pathogenesis-based classification for cases of tumoral calcinosis. METHODS: In a literature review 121 cases of tumoral calcinosis were identified. These cases, along with a case evaluated in our clinic, were reviewed retrospectively, and their features compared. RESULTS: Analysis suggests three pathogenetically distinct subtypes of tumoral calcinosis: (1) Primary normophosphatemic tumoral calcinosis: patients have normal serum phosphate, normal serum calcium, and no evidence of disorders previously associated with soft tissue calcification; (2) primary hyperphosphatemic tumoral calcinosis: patents have elevated serum phosphate, normal serum calcium, and no evidence of disorders previously associated with soft tissue calcification; and (3) secondary tumoral calcinosis: patients have a concurrent disease capable of causing soft tissue calcification. Justification for this classification is based on the presence or absence of disorders known to promote soft tissue calcification and statistically significant differences in family history, mean calcification number, mean serum phosphate level, and calcification recurrence after excision. CONCLUSIONS: A classification for tumoral calcinosis is devised that outlines potential pathogenetic mechanisms and predicts response to therapy and prognosis. Analysis of other forms of calcinosis cutis may reveal definable pathogenetic differences that suggest a coherent classification for all cutaneous calcinoses.

Adolescent↗
PubMed1989

Degradation of tomato pathogenesis-related proteins by an endogenous 37-kDa aspartyl endoproteinase.

As a response to the stress induced by different afflicting agents, tomato plants (Lycopersicon esculentum) produce the so-called 'pathogenesis-related' proteins. Here we report the degradation of some of these proteins by a constitutive endoproteolytic activity that co-distributes with pathogenesis-related proteins in the intercellular spaces of tomato leaves infected with citrus exocortis viroid. This endoproteinase was purified, showing a pH optimum of 2.5-3.5, a Mr of 37,000 and selective inhibition by pepstatin. In crude homogenates, the enzyme does not seem to degrade other cellular proteins. This specificity indicates that the proteinase might be involved in the extracellular degradative pathway of pathogenesis-related proteins and in the regulation of their biological function.

Aspartic Acid Endopeptidases↗
PubMed1995

Abomasal displacement in the bovine--a review on character, occurrence, aetiology and pathogenesis.

Literature on the subject of character, history, occurrence, causes and pathogenesis of abomasal displacement in the bovine is listed and summarized. The chapter on occurrence is subdivided according to heritibility, sex, age, season, husbandry, milk yield and concomitant diseases. In the chapter on causes special consideration is given to feeding. The chapter on pathogenesis is subdivided according to mechanical influences, disturbances of the abomasal motor activity, collection of gas and dilatation of the abomasum and artificial displacement of the abomasum. Displacement of the abomasum is seen predominantly in the spring in herds with above-average milk yield in dairy cows between the age of 4 and 7 years which have calved within the last month and have ketosis. The etiology and pathogenesis of abomasal displacement are unclear.

Abomasum↗
PubMedDate not supplied

Pathogenesis of aleutian mink disease parvovirus and similarities to b19 infection.

Aleutian mink disease parvovirus (ADV) is an unusual member of the autonomous parvoviruses in both its replication and pathogenesis. Infection of newborn mink kits results in an acute disease typified by virus replication in type II pneumocytes in the lung. This replication is permissive and cytopathic, characterized by the production of high levels of viral replicative intermediates and infectious progeny. However, infection of adult Aleutian mink leads to a chronic form of the disease termed Aleutian disease (AD). In this case, virus replication occurs predominantly in lymph node macrophages and is restricted, with viral DNA replication, RNA transcription, protein expression and production of infectious progeny occurring at low levels. B19 is the only autonomous parvovirus known to infect humans. The primary site of virus replication in both children and adults is in erythrocyte precursors in the blood and bone marrow, although viral genomes have been detected in various other tissues. B19 infection often causes a self-limiting disease although persistent infection of B19 can occur in both immuno-compromised and -competent people. Perhaps the most striking similarity between infection with ADV or with B19 is the important role the humoral immune response to infection has in pathogenesis. It can be both protective and pathogenic. Due to of the central role of antibody in the disease caused by either virus, understanding the specific roles of antibody production in protection, antibody-mediated enhancement of infection, the establishment of persistent infection and immune-mediated pathology will provide insight into the pathogenesis of these infections. A second similarity between the two viruses is the ability to establish persistent infection. Persistence of ADV is associated with restricted replication. Although many cellular factors may contribute to restricted virus replication, the interactions between the major non-structural protein, NS1, and the cells are likely to be critical. Parallels exist between the expression and post-translational modification of ADV and B19 NS1 proteins that may contribute to restriction of virus replication. Thus, a study of the regulation of NS1 expression and its interactions with cell signalling pathways may lead to increased understanding of the restricted replication of these two viruses, and perhaps of persistent infection.

Aleutian Mink Disease↗
PubMed1985

Pathogenesis of portal sclerosis in the liver with idiopathic portal hypertension. Observations of 19 autopsy cases and animal experiments.

The pathomorphological changes of intrahepatic portal veins were studied in 19 autopsy cases of idiopathic portal hypertension (IPH), and the pathogenesis of portal sclerosis was discussed by the observations on the human and experimental materials. The degree and morphological appearance of intimal lesions vary from vessel to vessel. Fibro-cellular proliferation of subendothelial tissue and incorporation of organized mural thrombi were suggested as the cause of intimal thickening in the portal veins. Animal experiment showed that injury of portal vein wall was followed by intimal hyperplasia and/or incorporation of mural thrombi, and resulted in portal sclerosis similar to that of IPH liver. The cause of portal phlebosclerosis in IPH can not be explained by passive congestion alone. There might be a certain possibility of direct injurious effect in the vessel wall in the pathogenesis of portal lesions of IPH. The following pathogenesis of portal sclerosis in IPH is postulated: phlebo-sclerotic changes of the portal veins are initiated by injury to the vessel wall due to unknown cause(s) and accelerated by secondary thrombosis and/or mechanical injury due to increased portal pressure.

Animals↗
PubMed2005

Plant models for animal pathogenesis.

Several bacteria that are pathogenic to animals also infect plants. Mechanistic studies have proven that some human/animal pathogenic bacteria employ a similar subset of virulence determinants to elicit disease in animals, invertebrates and plants. Therefore, the results of plant infection studies are relevant to animal pathogenesis. This discovery has resulted in the development of convenient, cost-effective, and reliable plant infection models to study the molecular basis of infection by animal pathogens. Plant infection models provide a number of advantages in the study of animal pathogenesis. Using a plant model, mutations in animal pathogenic bacteria can easily be screened for putative virulence factors, a process which if done using existing animal infection models would be time-consuming and tedious. High-throughput screening of plants also provides the potential for unravelling the mechanisms by which plants resist animal pathogenic bacteria, and provides a means to discover novel therapeutic agents such as antibiotics and anti-infective compounds. In this review, we describe the developing technique of using plants as a model system to study Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus aureus pathogenesis, and discuss ways to use this new technology against disease warfare and other types of bioterrorism.

Animals↗
PubMed1994

Contribution of intercellular adhesion molecule 1 (ICAM-1) to the pathogenesis of splanchnic artery occlusion shock in the rat.

1. It has been suggested that leukocytes play a key role in the pathogenesis of splanchnic artery occlusion shock. Intercellular adhesion molecule 1 (ICAM-1) is an adhesion molecule of crucial importance in the phenomenon of leukocyte accumulation. 2. We investigated the involvement of ICAM-1 in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion (SAO) shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham-operated animals were used as controls. Survival time, serum tumour necrosis factor-alpha (TNF-alpha), white blood cell (WBC) count, mean arterial blood pressure, myeloperoxidase activity (MPO; studied as a quantitative means to assess leukocyte accumulation) and the responsiveness to acetylcholine of aortic rings were investigated. SAO shocked rats had a decreased survival time (90 +/- 9.5 min, while sham-shocked rats survived more than 4 h), reduced mean arterial blood pressure, increased serum levels of TNF-alpha (201 +/- 10 mu ml-1) and MPO activity in the ileum (0.15 +/- 0.03 mu x 10(-3) per g tissue) and in the lung (1.9 +/- 0.8 mu x 10(-3) per g tissue), leukopenia and reduced responsiveness to acetylcholine (ACh, 10 nM-10 microM) of aortic rings. 3. Administration of monoclonal antibody raised against rat ICAM-1 significantly increased survival time (225 +/- 9 min), reduced leukopenia and MPO activity both in the ileum (0.031 +/- 0.003 mu x 10(-3) per g tissue) and in the lung 0.23 +/- 0.03 mu x 10(-3) per g tissue), improved the cardiovascular changes and restored the responsiveness to ACh of aortic rings. 4. Our findings are consistent with an involvement of adhesion mechanisms in vivo in the pathogenesis of SAO shock and suggest that specific adhesion mechanisms, which support leukocyte accumulation,may represent potentially important therapeutic targets in circulatory shock.

Acetylcholine↗
PubMed2005

The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites.

BACKGROUND: The role of nitric oxide (NO) in the pathogenesis of splanchnic arterial vasodilation in cirrhosis has been recently debated by some experimental studies. AIMS: We investigated the role of NO in the pathogenesis of the splanchnic arterial vasodilation along the course of CCl(4)-induced experimental cirrhosis. METHODS: We analyzed the effect on mean arterial pressure (MAP), cardiac output (CO), total peripheral resistance (TPR), and resistance in the superior mesenteric artery (RSMA), before and after the administration of a unspecific NO synthase (NOS) inhibitor (Nomega-nitro-L-arginine-methyl-ester, L-NAME) and a specific NOS2 inhibitor (L-N-(1-iminoethyl)-lysine, L-NIL) to cirrhotic rats with and without ascites, and to control rats. NOS2 and NOS3 protein expression was also assessed in systemic and splanchnic arteries of these animals. RESULTS: L-NAME in cirrhotic rats markedly improved MAP, and TPR and decreased CO regardless of whether they had ascites or not. L-NIL did not produce any significant effect on systemic haemodynamics in control and cirrhotic rats. NOS3 overexpression in the aorta of cirrhotic animals paralleled the progression of the liver disease. L-NAME increased RSMA in cirrhotic rats, but this effect was much less intense in rats with ascites. L-NIL had an effect only on RSMA in rats with ascites, which was of a similar extent to that produced by L-NAME. Western blot experiment showed a faint overexpression of NOS3 in the mesenteric artery of cirrhotic rats with and without ascites and a clear induction of NOS2 only in the mesenteric artery of rats with ascites. CONCLUSIONS: These results indicate that NO contributes significantly to the pathogenesis of arterial splanchnic circulation in the early stages of experimental cirrhosis but has only a minor role in its maintenance after the development of ascites. Furthermore, the expression of the different NOS isoforms varies along the course of the liver disease.

Analysis of Variance↗
PubMed2004

EGF-related growth factors in the pathogenesis of murine ARPKD.

BACKGROUND: Epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and their receptor, EGFR, play key roles in polycystic kidney disease (PKD) pathogenesis. Renal expression of two related growth factors, amphiregulin and heparin-binding EGF, has not been examined previously in PKD. The aims of this study of murine autosomal-recessive polycystic kidney disease (ARPKD) were (1) to characterize amphiregulin and heparin-binding EGF expression in cystic versus normal kidneys and cells; and (2) to identify the functional effects of abnormal EGF-related growth factor expression. METHODS: Amphiregulin and heparin-binding-EGF expression were examined by immunohistology and Western blot of kidneys and conditionally-immortalized collecting tubule cells obtained from cystic bpk mice (a murine model of ARPKD) and normal littermates. EGF, TGF-alpha, amphiregulin, and heparin-binding EGF in vitro effects on cystic and control collecting tubule cells were assessed by cell proliferation, cyst fluid mitogenicity, and EGFR activation. RESULTS: By immunohistology, amphiregulin and heparin-binding EGF localized to apical and basolateral surfaces of proximal tubule cysts > normal proximal tubules. In cystic collecting tubules, heparin-binding EGF (but not amphiregulin) localized to both apical and basolateral surfaces; whereas in normal collecting tubules, amphiregulin and heparin-binding EGF localized to the basolateral surface only. Increased amphiregulin and heparin-binding EGF expression by Western blot was seen in cystic vs. normal kidneys and increased heparin-binding EGF (but not amphiregulin) expression was present in cystic collecting tubule cell lines vs. controls. EGF, TGF-alpha, amphiregulin, and heparin-binding EGF were all mitogenic to cystic > control collecting tubule cells. Immunoprecipitation of EGF and TGF-alpha reduced cyst fluid mitogenicity by almost 80%, whereas heparin-binding EGF and amphiregulin immunoprecipitations had minimal effects. Differential receptor activation was also seen: Heparin-binding EGF markedly activated EGFR (>EGF = TGF-alpha > amphiregulin), with a greater effect seen in cystic vs. control collecting tubule cells. CONCLUSION: Multiple EGF-related growth factors are abnormally expressed in murine ARPKD and may have differential roles in disease pathogenesis. In particular, newly identified abnormalities in heparin-binding EGF expression in cystic kidneys and cells may have important implications for disease pathogenesis.

Amphiregulin↗
PubMed1991

Benign prostatic hyperplasia: pathogenesis and medical therapy.

Epidemiologic studies in castrates strongly support the key role of the testis in the pathogenesis of benign prostatic hyperplasia (BPH). Since the testis secretes androgen and estrogen, both of these hormones have been implicated in BPH. Much information supports the important role of dihydrotestosterone (DHT) in BPH, including intraprostatic activities of enzymes that regulate DHT. Although controversy still exists, DHT levels in BPH may be higher than in normal prostate tissue. Based upon these findings and the ability to quantitate prostate size and function with reliable new techniques, suppression of androgen-mediated action has been tested to assess the validity of the DHT theory. A variety of drugs has been demonstrated to decrease prostate size by approximately 30% by either blocking secretion of circulating testosterone and adrenal androgen, inhibiting 5 alpha-reductase to prevent DHT formation, or blocking DHT binding to androgen receptors. Accompanying these changes in size was significant improvement in clinical symptoms of prostatism in about 50% of patients, when double-blind, large multicenter studies were conducted with one of these drugs. Although these results suggest a very important role for androgen, particularly DHT, in the pathogenesis of BPH, other abnormalities may coexist since significant numbers of patients do not show a total reversal of disease. There is strong indirect evidence for a possible role for estrogen in the pathogenesis of BPH, and studies are under way to test the effects of estrogen withdrawal on prostate size and symptoms. Similarly, dynamic aspects of prostatic obstruction, which are under alpha-adrenergic regulation, may also be a component of this disease and amenable to therapy with alpha-adrenergic blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed2003

Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis?

OBJECTIVES: Obesity is a risk factor for nonalcoholic steatohepatitis (NASH). Leptin plays an important role in the regulation of food intake, body composition, energy expenditure, and body weight. It has been suggested that leptin plays a role in the pathogenesis of NASH; however, adequate studies are lacking. We therefore conducted a study to explore the role of serum leptin in the pathogenesis of human NASH. METHODS: We measured the levels of serum leptin and its anthropometric, biochemical, metabolic, and histological correlates in a cohort of patients with NASH (n = 26) and well-matched controls (n = 20). Furthermore, we measured the levels of leptin in the serum and hepatic leptin and leptin receptor messenger RNA (mRNA) expression in liver biopsy specimens of patients with NASH (n = 5) and simple steatosis (n = 5). RESULTS: Serum leptin was not statistically different between patients with NASH and their controls (21 +/- 13 vs 18 +/- 11 ng/ml, respectively, p = 0.5). There was no correlation between serum leptin and hepatic histology, serum transaminases, fasting insulin levels, or a measure of insulin resistance. After adjusting for covariates in a multiple regression analysis, only percent body fat (p = 0.04) and subcutaneous abdominal fat area (p = 0.04) had significant correlation with serum leptin. There was no expression of leptin mRNA in the cell lysate of liver biopsy specimens of subjects with NASH or steatosis. Additionally, the serum leptin levels and the hepatic leptin receptor mRNA expression were not statistically different between patients with NASH and those with simple steatosis. CONCLUSION: These data do not support a direct role for leptin in the pathogenesis of human NASH.

Adult↗
PubMed1997

Bovine attaching and effacing Escherichia coli possess a pathogenesis island related to the LEE of the human enteropathogenic Escherichia coli strain E2348/69.

Attaching and effacing Escherichia coli (AEEC) has been described as a cause of diarrhea in calves. The molecular pathogenesis of AEEC was mainly studied in human enteropathogenic E. coli strain E2348/69 in which the virulence correlated with the presence of a 35.4 kb pathogenesis island called LEE. We showed that several strains isolated from calves with diarrhea were able to produce attaching and effacing lesions in a rabbit ileal loop model and that they possess a pathogenesis island related to the LEE. Moreover, we showed that the LEE from bovine strains was inserted mainly at a different position in the chromosome compared to the human enteropathogenic E. coli strain E2348/69.

Animals↗
PubMed1997

The pathogenesis of large cell transformation in cutaneous T-cell lymphoma is not associated with t(2;5)(p23;q35) chromosomal translocation.

In 20%-50% of the advanced cutaneous T-cell lymphomas (CTCL), malignant T cells undergo large cell transformation (LCT). The malignant T cells of LCT in CTCL can share morphologic and immunophenotypic similarities with CD30 (Ki-1)-positive anaplastic large cell lymphoma (ALCL), suggesting a common mechanism of pathogenesis. The t(2;5) (p23;q35) translocation, resulting in the fusion of the nucleophosmin (NPM) gene and the anaplastic lymphoma kinase (ALK) gene, is associated with primary CD30+ ALCL. To determine whether acquisition of this chromosomal translocation is involved in the pathogenesis of LCT in CTCL, we examined 12 tumor samples from 9 CTCL patients, including 8 with LCT-CTCL and one with concurrent CTCL and Hodgkin's disease, for the presence of the t(2;5) translocation. Numerous CD30+ large cells were present in 4 LCT-CTCL consistent with secondary CD30+ ALCL; CD30 was expressed by <10% of the large cells in another case and was negative in the other 3 lymphomas. Using primers spanning the NPM/ALK fusion junction, PCR amplification following reverse transcription (RT) of mRNA failed to show the products of NPM/ALK fusion in all samples tested. Thus, the t(2;5) (p23;q35) translocation does not appear to be involved in the molecular pathogenesis of LCT in CTCL, including CD30+ cases.

Cell Transformation, Neoplastic↗
PubMed1991

Cytokine assays: role in evaluation of the pathogenesis of autoimmunity.

Cytokines are protein mediators involved in inflammation, the immune response, cell growth, repair and fibrosis. All of these processes are ongoing in active autoimmune diseases such as rheumatoid arthritis (RA), and so it would be expected that many cytokines would be actively produced in RA joints or Graves' disease (GD) thyroid glands. The cDNA cloning of cytokines has permitted the generation of pure recombinant molecules, and of newer more sensitive assays, and spurred the rapid development of knowledge in this field. Here we review the molecular strategies devised to study the possible role of cytokines in the pathogenesis of RA and GD, and describe some of the initial results. After 'cataloguing' the relative abundance of various cytokines, we sought to discover which cytokines are of major importance in pathogenesis. For that purpose we used neutralizing anti-cytokine antibodies and found that TNF alpha is one of the major signals regulating the production of IL-1 in the RA but not in the osteoarthritic (OA) joint. In order to further understand the dynamics of the cytokine network, the localization of the cytokine-producing cells by immunostaining and in situ hybridization has also been performed. The latter techniques are particularly valuable for attempting to establish the role of the target cell, such as thyroid epithelium, in the pathogenesis of disease. Cytokines act on cells via binding to high-affinity receptors. The last two years has been the cDNA cloning of many molecules encoding cytokine receptor chains, and it is now possible to begin to evaluate the other half of the cytokine pathway. Taken together, there are now exciting opportunities for the molecular dissection of the cytokine events occurring in auto-immune tissues.

Animals↗
PubMed1991

Heat-shock protein 60: implications for pathogenesis of and protection against bacterial infections.

In this review we have focused on antigenic features of hsp 60 related to: its ubiquitous distribution in the biosphere; its extraordinary homology among various bacteria; its high conservation from prokaryotic to eukaryotic cells; and its abundant expression under stress situations occurring during infection. These unique features make hsp 60 an excellent candidate antigen relevant to protection and pathogenesis of bacterial infections and, perhaps in a broader sense, to surveillance and autoimmunity. We will briefly discuss these possibilities in the following. Acquired resistance. If we assume that bacterial organisms contain some thousand different proteins which all represent potential antigens, the frequency of T cells with specificity for mycobacterial hsp 60 appears surprisingly high. Although, during the course of infection, high levels of hsp may be induced in bacteria, mere abundance appears to be an important though insufficient explanation. In addition, constant boosting by similar hsp 60 cognates from various microbes with which humans come into contact may contribute to dominance. This could easily explain the occurrence of hsp 60-specific T cells in healthy individuals with no clinical history of mycobacterial infections. Involvement of more sophisticated mechanisms, such as the affinity of hsp to other proteins, cannot be excluded (Flynn et al. 1989). Yet dominance does not necessarily mean protection and definite proof that hsp are protective antigens is lacking. Perhaps the immune response against epitopes shared by various mycobacterial pathogens represents a first line of defence preceding a more specific immune response. Such broadly reactive antigens would not qualify as prime candidates for vaccine design. Immunesurveillance. T cells with specificity for epitopes shared by bacterial and human hsp 60 are readily demonstrable and stressed host cells are recognized by hsp 60-specific T cells. Such T lymphocytes are endowed with the capacity to identify host cells stressed by a variety of assaults such as inflammation, infection, trauma, or transformation. Although it has been claimed that hsp-reactive gamma/delta T cells are particularly destined for such surveillance functions (Born et al. 1990, Asarnow et al. 1988), alpha/beta T cells could also participate. Pathogenesis. The mechanisms causing pathogenesis should be similar to those underlying protection and surveillance. In the former case bacterial hsp would be responsible for both induction of immunity and expression of pathogenic reactions; in the latter case an immune response stimulated by conserved regions of bacterial hsp 60 would be converted against a host-derived cognate.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗