The Infectious Etiology of Chronic Diseases Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary (2004) / Chapter Skim
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3 Obstacles and Opportunities for Framing Future Research
3 Obstacles and Opportunities for Framing Future Research
Pages 135-173
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From page 135... ...
The damage has been done, however, resulting in chronic disease. For some chronic diseases of this type, such as Reiter's syndrome, Guillain-Barré syndrome, or rheumatic heart disease, it is very difficult to find a fingerprint of the organism in the disease tissue.
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From page 136... ...
The significance of studying neonatal exposure derives from the fact that the effects of many genetic and environmental risk factors are evident either prior to or around the time of birth, and the interaction between them often is apparent well before the onset or diagnosis of the chronic disease condition. Thus, studying the effects of neonatal BDV infection across the entire postnatal period in genetically different strains of rats will aid in understanding the course and time-dependent character of the interaction of genetic background features and the virus infection.
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From page 137... ...
, and Helicobacter pylori infection (gastric carcinoma and MALT lymphoma) .In addition, new disease associations are being made with respect to previously known pathogens, such as the association of chronic hepatitis C virus infection with nonHodgkin's lymphoma in certain populations.
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From page 138... ...
Toward this aim, clinicians should be increasingly encouraged to identify patients who have recently developed or seem to be developing various suspect chronic diseases, to collect in an orderly manner a range of clinical specimens, and then to follow the course of the disease in order to identify tell-tale early clinical features. Calls were made for more effort devoted to developing animal models of chronic diseases, and to teaching health professionals about their value and their limitations.
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From page 139... ...
This may be an opportunity for multiple institutions and multiple governments, domestic and foreign, to cooperate in devising a system of patient consent that operates more smoothly, protects patient rights, and allows for expanded research on infections and chronic diseases. Given the magnitude of the outstanding scientific questions, and of the health consequences at stake, an increasing share of future research likely will involve groups of investigators representing a variety of disciplines, or groups of institutions working collaboratively.
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From page 140... ...
PATHOGENS AND DISEASE: ISSUES IN DETERMINING CAUSALITY Patrick S Moore University of Pittsburgh Pittsburgh, PA Successful new pathogen discovery requires the talents of multiple disciplines, including epidemiology, clinical medicine, molecular biology, and pathology.
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From page 141... ...
141 patient. same the from adaptor)
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From page 142... ...
The two aforementioned RDA fragments of the KSHV genome facilitated the identification of infected cell lines to serve as source material for viral DNA and as a reagent for biologic studies (Cesarman et al., 1995b)
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From page 143... ...
The importance of new pathogen discovery is illustrated by a timeline of KS research. This would be equally true also for hepatocellular carcinoma and hepatitis C or a wide range of diseases where a new pathogen has been found.
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From page 144... ...
It can be said that the remaining negative 5 percent is probably spurious due to technical difficulties in detection or misdiagnosis, and in fact the virus is absolutely necessary for disease. Though this cannot be proven at present, it can be argued that the situation is very similar to that of papillomavirus and cervical cancer 5 years ago.
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From page 145... ...
Now let's consider issues where causality is more problematic. First, KSHV has been claimed not only to cause Kaposi's sarcoma, but also a wide variety of diseases that don't fit its epidemiologic pattern, such as multiple myeloma and sarcoidosis.
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From page 146... ...
So Hill's criteria cannot be used to determine that EBV causes nasopharyngeal carcinoma since it is likely to be a composite risk factor and additional causal factors have to be used in conjunction with EBV infection. These factors are unknown for NPC, but it is easy to see that rather than using EBV infection alone as an exposure variable, it may be more valuable to measure exposure as EBV infection at a certain susceptible age or EBV infection in a cell having a specific mutation.
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From page 147... ...
For example, not too long ago the idea that a bacteria could cause stomach ulcers would have been considered laughable. Helicobacter pylori and peptic ulcer disease had a pathogenic mechanism that was poorly understood and thus there was no framework to gauge whether or not a bacteria was the possible cause.
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From page 148... ...
1995. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma lesions from persons with and without HIV infection.
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From page 149... ...
1999. Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma.
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From page 150... ...
However, the evidence is now clear that genes and environment are interactive as well, and several important issues of the gene-environment interaction are illustrated here with data obtained on the animal model of neurodevelopmental damage in rats neonatally infected with an experimental teratogen, Borna disease virus (BDV)
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From page 151... ...
The significance of the neurodevelopmental perspective is substantiated by the fact that effects of many genetic and environmental risk factors are evident either prior to or around the time of birth, and the interaction between them is apparent well before the identified onset/diagnosis of the classical, chronic disease condition. For this reason, we study effects of neonatal BDV infection across the entire postnatal period in genetically different strains of rats in order to understand the course and time-dependent character of the interaction of genetic background features and the virus infection.
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From page 152... ...
However, the outcome of this virus infection in these two different strains is not identical. Neonatal BDV infection produces a more profound thinning of the neocortex in Fisher344 rats compared to Lewis rats, while a similar reduction in granule cells in the dentate gyrus of the hippocampus and the comparable hypoplasia of the cerebellum was observed in two rat strains (Pletnikov et al., 2002a)
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From page 153... ...
1999. Neonatal Borna disease virus infection in the rat causes a loss of Purkinje cells in the cerebel lum.
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From page 154... ...
2002a. Effects of genetic back ground on neonatal Borna disease virus infection-induced neurodevelopmental damage.
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From page 155... ...
. These include a common bacterial pathogen (Helicobacter pylori infection with gastric carcinoma and MALT lymphoma)
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From page 156... ...
Kaposi's sarcoma, body cavity lymphoma Human immunodeficiency virus Kaposi's sarcoma, and non-Hodgkin's lymphoma, cutaneous and mucosal papillomas and carcinomas SV-40 Possible associations with mesothelioma and ependymoma PROTOZOA Strongyloides stercoralis T-cell leukemia (with HTLV) Plasmodium falciparuma Burkitt's lymphoma Schistosoma hematobium Squamous cell carcinoma of the urinary bladder S
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From page 157... ...
pylori infection with gastric cancer was an important landmark, because it provided the first definitive link between a chronic bacterial infection, chronic inflammation originating within the target tissue, and the ultimate development of a human cancer. Perhaps even more provocative has been the association of H
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From page 158... ...
hematobium causes chronic inflammation, fibrosis, and increased proliferation of squamous cells; malignant squamous cell carcinomas usually arise from this premalignant proliferative lesion. In contrast, most malignant tumors of the bladder that arise outside of the context of infection with S
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From page 159... ...
Malignancy associated with viral infection has in some cases been attributed to direct effects of viral gene products, as described above for the human papillomavirus, or it may be associated with increased cellular proliferation of a target tissue, as described for the bacterial infections above. In both settings, host immune responses are likely to play an important role in the tolerance of persistent viral infection.
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From page 160... ...
. This EBV-specific IgA response may be an indirect, albeit diagnostically important, indication of EBV infection on mucosal surfaces which itself serves as a proferative stimulus of epithelial cell populations accompanied by lymphocytic infiltration (lymphoepithelioma)
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From page 161... ...
Defects in immune surveillance may contribute to the evolution of KSHVassociated lesions in a manner similar to its more highly prevalent cousin, EBV; these defects may be acquired or intrinsic in nature. Recently, KSHV was recognized in dendritic cells of the bone marrow from patients with multiple myeloma and a smaller number of patients with monoclonal gammopathy of unknown significance (MGUS)
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From page 162... ...
Further work will be necessary to determine whether the sequences of these exogenous and endogenous viruses play a significant role in human cancers or other malignancies. Malignancies associated with HIV infection include increased susceptibility to cervical dysplasia, squamous cell carcinoma, B cell lymphomas, Kaposi's sarcoma, and possibly seminomas and testicular cancer.
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From page 163... ...
A reduction in levels of antigen-specific cytotoxic T cell responses are associated with activation of infection or disease progression in all of these cases, and a reduction in the efficiency of immune surveillance has been proposed as a factor in tumorigenesis. Consistent with this hypothesis, patients on immunosuppressive therapy following transplantation appear to be at increased risk for the same spectrum of malignancies with the exception of a lower incidence of KS; accordingly, KSHV appears to be much less prevalent in transplant patients compared to HIV patients, presumably because of the risk factors associated with the predominantly sexual transmission of KSHV (Chang and Moore, 1996)
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From page 164... ...
In this respect, the genesis of neoplasia may be similar to that described for Helicobacter pylori-related MALT lymphoma. The relative disparity in the frequency of nonHodgkin's lymphoma associated with HCV infection in the United States compared to that in Europe may conceivably reflect differences in duration of infection within the population, immunogenetic differences, or exposure to other oncoviruses including KHSV.
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From page 165... ...
Archetypal "oncogenic" subtypes of HPV appear capable of infecting different anatomical sites, and associations of HPV infection with squamous cell carcinomas of the head and neck are reasonably well established. The involvement of HPV in the pathogenesis of skin cancer, the most common malignancy in the world, was suggested recently and a new family of HPV types has now been described in recurrent squamous cell carcinomas of the skin in transplant patients (Shamanin et al., 1996)
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From page 166... ...
Several studies have now indicated that failure to mount cytotoxic T cell (CTL) responses to human papillomavirus-infected cells may significantly predispose to the development of cervical cancer (Tsukui et al., 1996)
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From page 167... ...
. The Role of Humoral and Cellular Immune Responses As illustrated vividly by HIV infection, infection with one pathogen may lead to a predisposition toward other infectious processes as well as cancer; a key feature of the immune suppression associated with HIV infection and pharmacologically-produced immunosuppression following transplantation is a reduction of cytotoxic T-cell (CTL)
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From page 168... ...
. Humoral immune responses to cancer-specific antigens often occur in cancer patients and are undetectable in patients without cancer (Disis et al., 1997)
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From page 169... ...
Since early generation of such responses appears to be a critical step in the resolution of human papillomavirus infections, patients harboring functionally similar mutations may be uniquely predisposed to the development of cervical and other cancers linked to HPV infection. By focusing on unusually severe outcomes of relatively common infectious diseases, we may be able to identify critical immunogenetic factors in the formation of protective immune responses, and to tailor patient management and cancer chemoprevention efforts (in some cases directed against the pathogens themselves)
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From page 170... ...
1995. Human papillomavirus type 18 DNA and E6-E7 mRNA are detected in squamous cell carcinoma and adenocarcinoma of the lung.
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From page 171... ...
1994. Transitional cell carcinoma of the bladder: evaluation of the role of human papillomaviruses.
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From page 172... ...
1996. Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients [see comments]
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From page 173... ...
Journal of Cancer Research and Clinical Oncology 122:313. zur Hausen H and Rosl F
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