Superantigens in autoimmune disease

The recent identification of superantigens (of retroviral origin in mice and bacterial origin in humans) has given rise to several hypotheses linking superantigens to autoimmune responses. The most compelling argument in support of such a link is restricted V beta gene usage by lymphocytes in rheumatoid joint fluid and Sj?gren's syndrome salivary tissue. However, a substantial body of evidence from mouse models militates against a link between the presence of self-superantigen-reactive T-cells and the development of autoimmune disease. Nevertheless, superantigens are powerful instruments for investigating tolerance.     

Superantigens: new data

The paper pertains novel data on action of bacterial and viral superantigens on the immune system. Against the background, new morbid conditions have been described, which may result from the action of superantigens. In the context of superantigen action on the immune system, antigen pathways in the system have been described. The review has been based on laboratory results obtained during recent 5 years in various scientific centers in the world.     

Beta-amyloid peptide interacts specifically with the carboxy-terminal domain of human apolipoprotein E: relevance to Alzheimer's disease

Growing evidence indicates the involvement of apolipoprotein E (apoE) in the development of late-onset and sporadic forms of Alzheimer's disease, although its exact role remains unclear. We previously demonstrated that beta-amyloid peptide (Abeta) displays membrane-destabilizing properties and that only apoE2 and E3 isoforms inhibit these properties. In this study, we clearly demonstrate that the carboxy-terminal lipid-binding domain of apoE (e.g., residues 200-299) is responsible for the Abeta-binding activity of apoE and that this interaction involves pairs of apoE amphipathic alpha-helices. We further demonstrate that Abeta is able to inhibit the association of the C-terminal domain of apoE with lipids due to the formation of Abeta/apoE complexes resistant to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. On the contrary, the amino-terminal receptor-binding domain of apoE (e.g., residues 129-169) is not able to form stable complexes with Abeta. These data extend our understanding of human apoE-dependent binding of Abeta by involving the C-terminal domain of apoE in the efficient formation of apoE/Abeta complex.     

Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease

Elevated homocysteine (Hcy) levels are observed in two apparently unrelated diseases: neural-tube defects (NTD) and premature vascular disease. Defective human methionine synthase (MS) could result in elevated Hcy levels. We sequenced the coding region of MS in 8 hyperhomocysteinaemic patients (4 NTD patients and 4 patients with pregnancies complicated by spiral arterial disease, SAD). We identified only one mutation resulting in an amino acid substitution: an A-->G transition at bp 2756, converting an aspartic acid (D919) into a glycine (G). We screened genomic DNA for the presence of this mutation in 56 NTD patients, 69 mothers of children with NTD, 108 SAD patients and 364 controls. There was no increased prevalence of the GG and AG genotypes in NTD patients, their mothers or SAD patients. The D919G mutation does not seem to be a risk factor for NTD or vascular disease. We then examined the mean Hcy levels for each MS genotype. There was no correlation between GG- or AG-genotype and Hcy levels. The D919G mutation is thus a fairly prevalent, and probably benign polymorphism. This study, though limited, provides no evidence for a major involvement of MS in the aetiology of homocysteine-related diseases such as NTD or vascular disease.     

Interaction of tacrine and velnacrine with neocortical synaptosomal membranes: relevance to Alzheimer's disease

The acridine-based, potential Alzheimer's disease therapeutic agents, tacrine and velnacrine, were incubated with rat or gerbil neocortical synaptosomal membranes. Electron paramagnetic resonance employing a protein-specific spin label was used to monitor this interaction. Analogous to their effects in erythrocyte membranes [Butterfield and Rangachari (1992) Biochem. Biophys. Res. Commun. 185: 596-603], in the present studies both agents decreased segmental motion of spin labeled synaptosomal membrane proteins, consistent with increased cytoskeletal protein-protein interactions (0.001 < P < 0.005), and tacrine was more potent than velnacrine. These results are discussed with possible relevance to molecular actions of the agents and molecular alterations in Alzheimer's disease.     

Oral ulcerations in individuals infected with human immunodeficiency virus: clinical presentations, diagnosis, management, and relevance to disease progression

Oral ulcerations can be both a localized disease entity and a manifestation of an underlying systemic condition. In individuals infected with the human immunodeficiency virus, oral ulceration may serve as a marker for a specific systemic illness, early immunosuppression, and disease progression. This article reviews clinical manifestations, diagnosis, and management of oral ulcerations in individuals with the human immunodeficiency virus.     

Apoptosis: regulation and relevance to toxicology

1. Apoptosis is a remarkably stereotyped morphological event across all tissues in response to a vast array of damaging agents. 2. Our very existence depends upon a willing exchange of old life for new: apoptotic cell death is our guardian and saviour from genetic damage. 3. There is a close link between cell proliferation and apoptosis: When a cell picks up the machinery to proliferate it also acquires an abort pathway--'better dead than wrong'. 4. A wide variety of highly conserved genes have been implicated in triggering apoptosis. 5. The release of DNA loops from the nuclear scaffold is a more crucial intracellular event than DNA 'laddering' in apoptotic cells. 6. The manipulation of apoptotic rates in many of the common diseases in man will be a major therapeutic strategy in the future.     

Modulation of intestinal immune system by dietary fat intake: relevance to Crohn's disease

Gut-associated lymphoid tissue is the major inductive site of the mucosal immune system, which is functionally independent of the systemic immune system. Both the amount and type of dietary fat modulate intestinal immune function. Absorption of long-chain fatty acids stimulates lymphocyte flux and lymphocyte blastogenesis in intestinal lymphatics. Long-chain fatty acid absorption also significantly enhances migration of T lymphocytes to Peyer's patches, possibly due to up-regulation of adhesion molecules, such as alpha4-integrin and L-selectin. Lipoproteins are involved in stimulation of lymphocyte function by both receptor-dependent and independent mechanisms. However, unsaturated fatty acids at higher concentrations have a suppressive effect on cell-mediated immunity via eicosanoid release, receptor affinity changes or interactions with intracellular signal transduction. Fat absorption also influences various other cells in the intestinal mucosa: increased cytokine release from intestinal epithelial cells follows long-chain fatty acid absorption. In Crohn's disease, elemental diets and total parenteral nutrition often induce remission, possibly by reducing antigenic load on activated immune cells in the intestine and, thus, down-regulating hyperreactive CD4 cells. Dietary oleic acid supplements caused an immunological reversal effect in the intestinal immune system of animals fed an elemental diet. An excess of long-chain fatty acids in an elemental diet, therefore, may negate its beneficial effect on gut-associated lymphoid tissues in Crohn's disease. In contrast, supplemental dietary fish oil apparently tends to prevent relapse of Crohn's disease. Because dietary fat intake is closely associated with immunological function of the intestinal mucosa, careful manipulation of dietary fat can be important in management of this disease.     

Superantigens and experimental SLE induced by idiotypic dysregulation

Electroacupuncture (EA) has been reported to induce changes in skin temperature; however, it is not clear whether high- and low-frequency EA produce similar effects. Therefore, the purpose of this study was to investigate the effects of EA on the skin temperature of the hand and finger in normal subjects. Twenty-one subjects received high-frequency EA (100 Hz) and low-frequency EA (4 Hz) at the Large Intestine 4 and Small Intestine 3 acupuncture points, as well as a no-treatment control condition. The results showed that the skin temperature following high- and low-frequency EA produced significant cooling effects at both sites as compared with the no-treatment control condition during the stimulation period (p < 0.05). These data show that EA produces significant changes in skin temperature that may be of benefit in pathologic conditions that are accompanied by an increase in local circulation.     

Impaired innervation of cultured human muscle overexpressing betaAPP experimentally and genetically: relevance to inclusion-body myopathies

To investigate whether abnormally accumulated betaAPP may be responsible for denervation of muscle fibers that are present in hereditary inclusion-body myopathy (h-IBM) and sporadic inclusion-body myositis (s-IBM), we cultured five h-IBM and eight normal muscle biopsies. In eight other experiments, a 3 kb human 751-betaAPP-cDNA was transferred, using adenovirus vector, into cultured normal myotubes immediately after myoblast fusion. In all experiments, cultured muscle fibers were co-cultured with fetal rat spinal cord. Controls had no detectable betaAPP epitopes, whereas betaAPP epitopes were greatly increased in cultured h-IBM muscle and in cultured normal muscle after betaAPP-gene transfer. Innervated normal cultured muscle fibers were continuously contracting and fully cross-striated, and they had acetylcholine receptors (AChRs) and acetylcholinesterase (AChE) accumulated only at the neuromuscular junctions (NMJs). By contrast, both groups of betaAPP-overexpressing cultured muscle fibers were not contracting and not cross-striated; and did not have NJMs containing AChRs and AChE. Our results suggest that over-expression of betaAPP in cultured muscle fibers inhibits their innervation, and that the accumulation of betaAPP in muscle fibers of both h- and s-IBM patients may be responsible for their not becoming or remaining properly innervated or reinnervated, i.e. a 'myogenous-dysinnervation' mechanism.     

DNA adducts in human carcinogenesis: etiological relevance and structure-activity relationship

Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(epsilon)-DNA adduct-forming chemicals were developed and applied to humans and animal models. The aims were to identify hitherto unknown sources and mechanisms of exogenous and endogenous DNA damage, to examine the effect of drug polymorphism on BP adduct levels, and to develop QSAR between tumorigenic potency, heritable genetic damage and structural elements of alkylating carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13-32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring (+)-anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248-6253). In smokers, a positive correlation was found between pulmonary CYP1A1-related catalytic activity (AHH) and the level of lung BPDE-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carcinogenesis, 16, 1373-1376). (ii) 3-Alkyladenines (3-alkAde): Alkylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3-alkAde in urine, for which a detection method was developed (Friesen et al. (1991) Chem. Res. Toxicol., 4, 102-106; Prevost et al. (1990) Carcinogenesis, 11, 1747-1751), using immunoaffinity purification and GC-MS analysis. The usefulness of 3-alkAde analysis for the determination of the whole-body dose of alkylating agents derived from exogenous and endogenous sources was demonstrated. (iii) Etheno-DNA adduct-forming agents: Etheno(epsilon)-DNA base adducts (epsilon A, epsilon dC, epsilon dG) are promutagenic DNA lesions that are formed by occupational (vinyl halides) and environmental (urethane) carcinogens. An ultrasensitive detection method was developed (Nair et al. (1995) Carcinogenesis, 16, 613-617), based on immunoaffinity purification and 32P-postlabelling of epsilon-nucleoside 3'-monophosphates. Liver DNA from unexposed rats, mice and from human samples contained background levels of epsilon dA and epsilon dC (Bartsch et al. (1994) Drug. Metab. Rev., 26, 349-371). As formation of epsilon dA and epsilon dC adducts by lipid peroxidation products was demonstrated (El Ghissassi et al. (1995) Chem. Res. Toxicol., 8, 278-283), they may serve as markers for oxidative stress. Results from testing this hypothesis are presented.     

Cognitive impairment following frontal lobe damage and its relevance to human amnesia.

Whether frontal lobe pathology can account for some of the cognitive impairment oberved in amnesic patients with Korsakoff's syndrome was investigated. Various cognitive and memory tests were given to patients with circumscribed frontal lobe lesions, patients with Korsakoff's syndrome, non-Korsakoff amnesic patients, and control Ss. Patients with frontal lobe lesions were not amnesic. Nevertheless, they exhibited 2 deficits that were also exhibited by patients with Korsakoff's syndrome but not by other amnesic patients: (a) impairment on the Wisconsin Card Sorting Test and (b) impairment on the Initiation and Perseveration subscale of the Dementia Rating Scale. Thus, frontal lobe pathology can explain some of the cognitive deficits observed in patients with Korsakoff's syndrome. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Superantigens but not mitogens are capable of inducing upregulation of E-selectin ligands on human T lymphocytes

A cDNA clone derived from the Trypanosoma cruzi alpha-tubulin gene was isolated and sequenced (Tc alpha tub; L37345). Tc alpha tub revealed an 87.79% and an 85.36% identity with the DNA sequence of T. brucei and Leishmania, respectively. This clone was used to study, by Northern blots, alpha-tubulin gene expression in epimastigotes, cell-cultured derived trypomastigotes and extracellular amastigotes. alpha-tubulin MRNA levels were the same in epimastigotes and trypomastigotes, however, there was a drastic decrease in amastigotes. This clone could be useful to elucidate the regulatory mechanisms of alpha-tubulin gene expression during the differentiation of T. cruzi.     

Glycoproteins and their relationship to human disease

Glycoproteins are proteins that carry N- and O-glycosidically-linked carbohydrate chains of complex structures and functions. N-glycan chains are assembled in the endoplasmic reticulum and the Golgi by a controlled sequence of glycosyltransferase and glycosidase processing reactions involving dolichol intermediates. The assembly of O-glycans occurs in the Golgi and does not involve dolichol. For most reactions, families of glycosyltransferases exist; the expression of the individual enzymes within a family is often subject to complex regulation. The biosynthesis of N- and O-glycan is controlled at the level of gene expression, mRNA, enzyme protein activity and localization, and through substrate and cofactor concentrations at the site of synthesis. This complex regulation results in many hundreds of structures, the range of which varies in different species, cell types, tissue types, states of development and differentiation. In diseased cells, the relative proportions of these structures are often characteristically different from normal, and may be useful for the assessment of the stage of the disease and for diagnosis. Knowledge of disease-specific glycoprotein structures and their functions may be used therapeutically, in immunotherapy, in blocking cell adhesion or interfering with other binding or biological processes. Recently, some of the mechanisms underlying glycoprotein alterations in disease have been elucidated. This opens the possibility of an active interference in the disease process. The functions of glycans in diseased cells will become more clear with the tools of molecular biology and transgenic animal models.     

A novel MspI PCR-RFLP in the human cytosine 5-methyltransferase gene: lack of relevance for malignant lymphoproliferative disease and breast cancer

A 72 year-old man underwent a Bentall procedure for aortic regurgitation secondary to annulo-aortic ectasia and ascending aortic aneurysm. On the 11th postoperative day, the C-reactive protein (CRP) level and white blood cell (WBC) count rose. Echocardiography and a computed tomographic scan showed the appearance of pericardial effusion. A diagnosis of mediastinitis and composite graft infection was made, and mediastinal drainage and irrigation were performed. Methicillin-resistant coagulase negative staphylococcus (MRCNS) was identified as the causative organism. Vancomycin, arbekacin and minocycline were used intravenously. Additionally, a continuous mediastinal irrigation was performed through the chest tubes. CRP level and WBC count were gradually reduced to normal range. He has now been free from signs of infection for more than 3 years. Because MRCNS is considered less virulent than methicillin-resistant Staphylococcus aureus, mediastinitis and composite graft infection due to MRCNS might be treatable by such conservative therapy even in patients with prosthetic implants. Since MRCNS often becomes ubiquitous, preventing infections by strict attention to asepsis is important.     

Ecologic studies of rodent reservoirs: their relevance for human health

To gain insight into the immunomodulatory effects of vitamin E (VE), immune cell population analyses were conducted using thymus and spleen from male broilers fed diets with various levels of VE supplementation (0, 17, 46, and 87 mg dl-alpha-tocopherol acetate/kg of feed). At 2 and 7 wk of age, the percentages of B cells, macrophages, and T cell subsets, delineated by the expression of CD4, CD8, and T cell receptor (TCR) isotype, in thymus and spleen were determined by flow cytometry. The percentages of thymic and splenic B cells and macrophages from 2- and 7-wk-old chickens, as well as the percentage of thymic T cells in 2-wk-old chickens, were unaffected by VE treatment. However, 7-wk-old broilers maintained on 87 mg VE/kg feed had a higher percentage of CD4+CD8- thymocytes, a higher CD4+CD8- to CD4-CD8+ thymocyte ratio, and a lower percentage of CD4+CD8+ thymocytes than chickens receiving no dietary VE supplementation. The VE-induced increase in the percentage of CD4+CD8- thymocytes was due to an increase in the TCR2+CD4+CD8- thymocyte subset, whereas the decrease in the percentage of CD4+CD8+ thymocytes involved all TCR defined T cell subsets. In the spleen, the percentage of CD4+CD8- T cells was lower in 2-wk-old chickens and higher in 7-wk-old chickens maintained on 87 mg/kg feed than in chickens receiving no dietary VE supplementation. The decrease in CD4+CD8- splenocytes at 2 wk of age was due to a decline in the percentage of TCR2+CD4+CD8- splenocytes, whereas the increase in CD4+CD8- splenocytes in 7-wk-old chicks was due to an increase in the percentages of all TCR defined CD4+CD8- T cell subsets. These data support an immunomodulatory effect of VE on CD4+CD8- T cells.