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Complement and immune complex diseases.
Research during the past decade has led to a much greater understanding of the activation and control, as well as a more complete delineation, of the complement system of proteins. There has been definition of the roles of individual components in modulation of immune complex formation, the deposition of which leads to tissue injury in the autoimmune connective tissue diseases. The ability of serum to render immune complexes more soluble is complement-mediated and appears to be an important protective mechanism against immune complex diseases. Inherited deficiencies and production of non-functional variants of complement components, decreased synthesis, hypercatabolism, and the presence of serum inhibitors may all contribute to the reduced immune complex solubilisation which has been found in the connective tissue diseases. More work is required to define further the role of complement and immune complexes in the basic pathogenesis of these diseases.
Subviral DNAs associated with geminivirus disease complexes.
Ageratum conyzoides (ageratum) is a common and widespread weed species that may act as a reservoir host for geminivirus diseases. Ageratum plants growing in Singapore and exhibiting yellow vein disease are infected with a complex mixture of viral, subviral and recombinant DNA components. This whitefly-transmitted disease is caused by the monopartite begomovirus ageratum yellow vein virus (AYVV) in association with a recently discovered satellite component referred to as DNA beta. Diseased plants also contain a subviral component, referred to as DNA 1, that has probably become associated with the begomovirus and adapted to whitefly transmission during mixed infection with an aphid-transmitted nanovirus. Unlike DNA beta, the nanovirus-like component is not essential for the disease. Recombination between the viral and subviral DNAs occurs frequently and may play an important evolutionary role by generating component diversity. The identification of a similar complex associated with cotton leaf curl disease (CLCuD), a serious constraint to cotton growing in Pakistan, and the isolation of DNA beta homologues from diverse plant species growing in widespread geographical locations suggests that such disease complexes are common and may have a significant impact on agriculture in the eastern hemisphere.
Tramped teats--clinical mastitis disease complex in tied cows. Environmental risk factors and interrelationships with other diseases.
The effects of stall length, manure system, type of bedding and calving disorders on incidence rates of tramped teats, udder injuries, and clinical mastitis in Swedish Red and White tied cows, as well as interrelationships between these 3 disorders were investigated. Data used consisted of 370 herds, for a total of 45,133 cow records. Cows in herds with liquid manure system were at higher risk of udder injuries and mastitis than in herds with solid system. Lower risk of both udder injuries and mastitis was found for cows in herds with short stall size (less than 180 cm) compared to herds with stalls of 205-219 cm length. It was suggested that other factors, such as slipperiness of the stall floor and presence and type of feeding barrier, must be considered when the effect of stall characteristics on tramped teats is investigated. In farms with solid manure system cut straw or sawdust bedding increased the risk of tramped teats and mastitis relative to uncut straw. Parity and calving disorders were important risk factors for udder health and their effect was greater in herds with liquid manure system. Tramped teats and udder injuries were the most serious risk factors for clinical mastitis.
Production of cytokines in patients with primary pulmonary Mycobacterium avium-intracellulare complex disease.
To clarify the immunological state of patients with pulmonary Mycobacterium avium-intracellulare complex (MAC) disease, we compared the production of IFN-gamma, IL-10 and TNF-alpha by peripheral blood mononuclear cells (PBMC) between MAC disease patients with different levels of disease activity and healthy volunteers. The patients had no complication of systemic immunological diseases or preexisting pulmonary diseases. PBMC obtained from 46 patients and 15 healthy control volunteers were incubated with a protein antigen extracted from Mycobacterium intracellulare (PPD-B) for seven days, and IFN-gamma, IL-10 and TNF-alpha concentration in the supernatant of the cultures was measured by enzyme-linked immunosorbent assay (ELISA). We categorized the patients into 3 groups based on the findings of chest radiography or results of sputum culture for MAC: group I in a stable state of the disease activity (15 patients), group II in an unstable state (16 patients) and group III in an active state of the disease (15 patients). IFN-gamma was low in all three patient groups compared to the healthy group. There was no difference of the concentration of IFN-gamma among the three patient groups. IL-10 was high in the patient groups compared to the healthy group, and the concentration of IL-10 in the patients of groups II and III was significantly higher than in the healthy group. Although the production of TNF-alpha in group I was significantly suppressed compared to the healthy group, the production of TNF-alpha was significantly elevated in groups II and III compared to group I. There was no difference in the production of these cytokines between the patients of group III with tuberculosis-like form and with nodular-bronchietasis form. These findings suggested that the Th1-type reaction in the patients with primary pulmonary MAC disease is suppressed (lower than the healthy persons) irrespective of the disease activity state and that the Th2-type reaction is increased in parallel with disease activity.
Further evidence against preeclampsia as an immune complex disease.
Sera from 25 preeclamptic women were examined for the presence of circulating immune complexes (CICs) by the radioisotopic C1q binding assay (C1q-BA), the polyethylene glycol precipitation-complement consumption (PEG-CC) test, and the microcomplement consumption test (MCT). Five abnormal values were found by the MCT; 4 became normal after delivery, as did the preeclamptic clinical signs. Normal values were obtained by the C1q-BA and the PEG-CC test in all preeclamptic patients. In addition, maternal HLA antibodies and complement levels were investigated. There was no correlation between lymphocytotoxic activity and CICs in sera from patients with preeclampsia. Complement levels were in the normal range in all cases. It is concluded that CICs do not play a significant role in the pathogenesis of preeclampsia.
[Nontuberculous mycobacteriosis; the present status and in the future. 3-(2) Long-term prognosis of Mycobacterium avium complex disease].
This paper shows long-term course of 71 patients with Mycobacterium avium complex (MAC) disease treated in National Hiroshima Hospital between 1977 and 1991 and were observed for more than 5 years or died between 6 months and years from the onset. In the patients who were not treated with chemotherapeutic agent or treated with less than 3 drugs, about 60 per cent deteriorated and few obtained persistent negativity of bacteria. In patients treated with at least 3 drugs out of isoniazid, rifampicin, ethambutol, ethionamide, cycloserine, clarithromycin and new-quinolones for more than 12 months, 59.2 per cent deteriorated, while 29.6 per cent obtained negative conversion of bacteria by initial chemotherapy. However only 18.5 per cent remained negative during long term observation. In patients treated with at least 3 drugs including one aminoglycoside such as streptomycin for more than 12 months, 64.7 per cent obtained negative conversion and 35.5 per cent remained negative bacteriologically, while 23.5 per cent deteriorated. In twelve patients who were operated, only one patient deteriorated. The long-term prognosis of MAC disease under the chemotherapy mainly by antituberculous agents up to this time was still poor compared to that by short-term observation. Anticipated new regimens for MAC should be multidrug, to prevent secondary drug resistance.
What association analysis can and cannot tell us about the genetics of complex disease.
Human genetics researchers have been intrigued for many years by weak-to-moderate associations between markers and diseases. However, in most cases of association, the cause of this phenomenon is still unknown. Recently, interest has grown in pursuing association studies for complex psychiatric diseases, either instead of or in addition to linkage studies. However, it is one thing to detect association; the next important step is to determine why. Here we consider what a disease-marker association in the weak-to-moderate range (relative risk < 5) can tell us about disease etiology. Two distinct models (not the only possibilities) which could explain such an association are formulated. One is a linkage disequilibrium or major disease gene model, involving tight linkage with a "necessary" major gene. The other is a pure association model, involving a "susceptibility" gene that has only a minor effect on disease state. It will be shown that association analysis cannot distinguish between these two models, and hence cannot elucidate the biological mechanism behind the association. (This statement holds for traditional population-based association tests, as well as for more recent family-based association tests.) The importance of drawing the distinction between these two genetic models and the implications for understanding the genetics of complex human disease will also be discussed.
[Plasmapheresis in treating circulating immune complex diseases].
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[The analysis of angitis and nephritis in SL/Ni mouse as a model of immune complex disease--studies on SL/Ni mouse, an animal model of PN : II (author's transl)].
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[Immune complex disease of mice persistently infected with lymphocytic choriomeningitis (LCM) virus].
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[Current approaches to immunological diagnosis of autoimmune and immune complex diseases].
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Issues concerning association studies for fine mapping a susceptibility gene for a complex disease.
The usefulness of association studies for fine mapping loci with common susceptibility alleles for complex genetic diseases in outbred populations is unclear. We investigate this issue for a battery of tightly linked anonymous genetic markers spanning a candidate region centered around a disease locus, and study the joint behavior of chi-square statistics used to discover and to localize the disease locus. We used simulation methods based on a coalescent process with mutation, recombination, and genetic drift to examine the spatial distribution of markers with large noncentrality parameters in a case-control study design. Simulations with a disease allele at intermediate frequency, presumably representing an old mutation, tend to exhibit the largest noncentrality parameter values at markers near the disease locus. In contrast, simulations with a disease allele at low frequency, presumably representing a young mutation, often exhibit the largest noncentrality parameter values at markers scattered over the candidate region. In the former cases, sample sizes or marker densities sufficient to detect association are likely to lead to useful localization, whereas, in the latter case, localization of the disease locus within the candidate region is much less likely, regardless of the sample size or density of the map. The effects of increasing sample size or marker density are also investigated. Based upon a single marker analysis, we find that a simple strategy of choosing the marker with the smallest associated P value to begin a laboratory search for the disease locus performs adequately for a common disease allele. We also investigated a strategy of pooling nearby sites to form multiple allele markers. Using multiple degree of freedom chi-square tests for two or three nearby sites, we found no clear advantage of this form of pooling over a single marker analysis. Genet. Epidemiol. 20:432-457, 2001. Published by Wiley-Liss, 2001.
Thematic review series: systems biology approaches to metabolic and cardiovascular disorders. Reverse engineering gene networks to identify key drivers of complex disease phenotypes.
Diseases such as obesity, diabetes, and atherosclerosis result from multiple genetic and environmental factors, and importantly, interactions between genetic and environmental factors. Identifying susceptibility genes for these diseases using genetic and genomic technologies is accelerating, and the expectation over the next several years is that a number of genes will be identified for common diseases. However, the identification of single genes for disease has limited utility, given that diseases do not originate in complex systems from single gene changes. Further, the identification of single genes for disease may not lead directly to genes that can be targeted for therapeutic intervention. Therefore, uncovering single genes for disease in isolation of the broader network of molecular interactions in which they operate will generally limit the overall utility of such discoveries. Several integrative approaches have been developed and applied to reconstructing networks. Here we review several of these approaches that involve integrating genetic, expression, and clinical data to elucidate networks underlying disease. Networks reconstructed from these data provide a richer context in which to interpret associations between genes and disease. Therefore, these networks can lead to defining pathways underlying disease more objectively and to identifying biomarkers and more-robust points for therapeutic intervention.
Letter: Is pre-eclampsia an immune-complex disease?
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Drug-induced immune complex disease.
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The nuclear pore complex: disease associations and functional correlations.
Nuclear pore complexes (NPCs) are large protein structures spanning the double membrane of the eukaryotic nucleus that serve as sites for translocation of macromolecules between the nucleus and the cytoplasm. The vertebrate NPC has recently been found to comprise approximately 30 distinct proteins, collectively referred to as nucleoporins. Studies over the past several years have demonstrated that individual nucleoporins have unique roles in regulating NPC function and the nucleocytoplasmic transport of proteins and RNAs. The unique functions of individual nucleoporins have been made most clear through their associations with specific human diseases. Here, we highlight the relationships between individual nucleoporins and disease, with particular emphasis given to ALADIN, a nucleoporin linked to a genetically heritable human disease known as triple A syndrome.
Chronic necrotizing pulmonary aspergillosis as a complication of pulmonary Mycobacterium avium complex disease.
OBJECTIVE AND BACKGROUND: To investigate the characteristic clinical features of chronic necrotizing pulmonary aspergillosis (CNPA) as a complication of pulmonary Mycobacterium avium complex (MAC) disease. METHODS: Clinical analysis of nine cases without a history of old pulmonary tuberculosis in whom CNPA was found to be a complication during the follow-up period for MAC disease. RESULTS: The average duration from the diagnosis of pulmonary MAC disease to the diagnosis of CNPA was 36.0 months. Five patients received antituberculous therapy including clarithromycin for pulmonary MAC disease, but this treatment was ineffective in most. A positive culture for Aspergillus spp. from sputum and a bronchoscopic specimen and clinical evidence of a chronic infective process were recognized in all cases at the time of detection of CNPA. Serological fungal examinations for anti-Aspergillus IgG antibody were initially negative and became positive in all cases during the follow-up period of pulmonary MAC disease. The presence of CNPA surrounding the cavity previously caused by MAC was characterized by local thickening of the cavity with a fungus ball and the appearance of an infiltration shadow surrounding the cavity. In most of the cases, CNPA was at first treated with oral itriconazole and then with i.v. infusion of micafungin, but the clinical efficacy was generally poor. CONCLUSION: The results of this study showed that during the long follow-up period of patients with pulmonary MAC disease it is important to not only carry out serological examinations, but also perform radiological examinations using chest CT.