Humoral and cellular immune reactions to the myocardium in myocarditis.

Myocarditis is characterized by an infiltration of poly- and mononuclear leucocytes next to necrosis of myofibers in the heart. Various viruses induce this cardiac disorder in most cases, either by their direct cytotoxic action on the cardiocytes or by humoral and cellular immune reactions to the myocardium arising after the infection. Epidemiological and experimental and serological studies suggest, that viral myocarditis may lead to dilated heart muscle disease. Therapy consists of reducing cardiac stress by physical inactivity and drugs decreasing cardiac pre- and afterload. Immunosuppression is beneficial in some but not all patients with myocarditis.     

The molecular basis of X-linked immunodeficiency disease

Summary The molecular bases of the X-linked immunodeficiency diseases remain largely undetermined. Two of the genes involved in these diseases have been isolated, namely the genes for X-linked chronic granulomatous disease and properdin deficiency, and substantial progress has now been made in identifying the genes which are defective in the other five diseases, Wiskott-Aldrich syndrome, X-linked severe combined immunodeficiency, X-linked agammaglobulinaemia, X-linked hyper-IgM and X-linked lymphoproliferative syndrome. We review here the nature of the diseases, progress made in identifying and isolating the genes involved and the prospects for improved prenatal detection, carrier status determination and treatment of these life-threatening conditions.     

Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment

Diabetes mellitus is an important and prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs in diabetic patients independent of a recognized cause such as coronary artery disease or hypertension. The disease course consists of a hidden subclinical period, during which cellular structural insults and abnormalities lead initially to diastolic dysfunction, later to systolic dysfunction, and eventually to heart failure. Left ventricular hypertrophy, metabolic abnormalities, extracellular matrix changes, small vessel disease, cardiac autonomic neuropathy, insulin resistance, oxidative stress, and apoptosis are the most important contributors to diabetic cardiomyopathy onset and progression. Hyperglycemia is a major etiological factor in the development of diabetic cardiomyopathy. It increases the levels of free fatty acids and growth factors and causes abnormalities in substrate supply and utilization, calcium homeostasis, and lipid metabolism. Furthermore, it promotes excessive production and release of reactive oxygen species, which induces oxidative stress leading to abnormal gene expression, faulty signal transduction, and cardiomyocytes apoptosis. Stimulation of connective tissue growth factor, fibrosis, and the formation of advanced glycation end-products increase the stiffness of the diabetic hearts. Despite all the current information on diabetic cardiomyopathy, translational research is still scarce due to limited human myocardial tissue and most of our knowledge is extrapolated from animals. This paper aims to elucidate some of the molecular and cellular pathophysiologic mechanisms, structural changes, and therapeutic strategies that may help struggle against diabetic cardiomyopathy.     

The molecular and cellular basis of corticosteroid resistance

Corticosteroids (CS) can modulate gene expression and are often used to treat a range of immunological and inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis. However, a proportion of patients fail to show an adequate response. On this basis patients have been subdivided into CS-sensitive (SS) and -resistant (SR) subgroups. The ability of CS to inhibit peripheral blood T cell proliferation in vitro has also been used similarly. In rheumatoid arthritis (RA), the in vitro-defined SS and SR subgroups correlate with the clinical responses to CS therapy. The mechanisms responsible for this observation are unknown but they appear to involve a number of known molecular events related to the described mechanisms of action of CS. These include alterations in the functional status of CS receptor-alpha, perturbations of the cytokine and hormonal milieu and intracellular signalling pathways. Peripheral blood mononuclear cells (MNCs) from SR significantly overexpress activated NF-kappaB. In vitro, CS fail to significantly inhibit concanavalin A (conA)-induced NF-kappaB activation in MNCs from SR RA patients. The alterations in the intracellular signalling pathways may explain in part our observations seen in SR RA subjects, CS fail to significantly inhibit conA-induced interleukin (IL)-2 and IL-4 secretion and lipopolysaccharide-induced IL-8 and IL-1beta secretion in vitro. CS therapy fails to reduce the circulating levels of IL-8 and IL-1beta in RA patients. In asthma, CS fail to induce L10 in SR asthma patients. Other molecular mechanisms such as enhanced AP-1 expression and alterations in the MAP kinase pathway are most likely to be involved too and we are currently investigating such possibilities. A full understanding of the molecular basis of SR will lead to the development of more rational therapeutic strategies.     

The cellular and molecular basis of the ectopic ACTH syndrome

In recent years the techniques of molecular and cellular biology have made it possible to begin to dissect the origins and behaviour of the ACTH-secreting tumour cell. It is becoming apparent that these tumours represent undifferentiated neuroendocrine cells, and it may be that their peptide-secreting properties may have no more sinister oncological significance. However, an autocrine role for β-endorphin may confer a selective growth advantage on the POMC-expressing cell. It is still not clear why glucocorticoids fail to inhibit the POMC gene in these extra-pituitary tumours despite the presence of glucocorticoid receptors. This may not be resolved until the mechanism for inhibition of POMC by glucocorticoids in the normal pituitary is understood, although it is tempting to speculate that a mutation in the glucocorticoid receptor or a tissue specific interaction is responsible for the resistance of POMC observed in the ectopic ACTH syndrome. In studying the peptides secreted by the extra-pituitary tumours responsible for the ectopic ACTH syndrome it would appear that direct measurement of ACTH precursors and comparison with the circulating concentrations of ACTH can give valuable information on the percentage of tumours which do not effectively process the ACTH precursors. However, far more data have to be collected on patients with occult tumours in order to identify whether this type of processing is tissue specific. Nevertheless, these studies provide useful insights into the mechanisms of intracellular signalling and regulation in such tumours which may identify unique pharmacological tools to inhibit ACTH secretion or more importantly tumour growth.     

Update on the cellular and molecular basis of capillary permeability

The attenuated layer of endothelial cells lining the blood vessels forms the critical barrier controlling the exchange of molecules from the blood to the interstitial fluid. The interactions of normally circulating blood molecules with the endothelial glycocalyx can either restrict transcapillary exchange in general or selectively increase transendothelial transport of a specific group of ligands. Investigations into the mechanisms responsible for the effects of serum have identified specific receptors, some of which appear to be involved in receptor-mediated transcytosis and endocytosis via noncoated plasmalemma vesicles (also known as caveolae). Such studies suggest that regional differences in endothelial expression of cell surface glycoproteins can be exploited for the development of tissue-directed drug therapies.     

Classic Perspective: Discovery of the cellular and molecular basis of cholesterol control

The cellular control of cholesterol metabolism mediated by lipoproteins was first appreciated in pioneering work published in a 1974 PNAS Classic by Michael Brown and Joseph Goldstein. We know from this paper that the LDL binds to a cell surface receptor and dampens the activity of a key enzyme in cholesterol biosynthesis and that a receptor deficiency is responsible for a major genetic cause of hypercholesterolemia and premature atherosclerosis.     

Humoral and cellular immunity to intrinsic factor in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease often associated with other autoimmune disorders. A case history of MG with a coexisting atypical megaloblastic anaemia with vitamin B12 deficiency and anti Intrinsic Factor (IF) antibodies, led to a study of humoral and cellular immunity to IF in 81 MG patients. Within this series, 3 other patients had a disturbed humoral and cellular immunity to IF. These 3 patients presented no other features of pernicious anaemia. The possible origins and significance of the anti IF antibodies in MG patients are discussed.     

Thrombin and cancer: from molecular basis to therapeutic implications

The relationship between cancer and thrombosis has been recognized for nearly 150 years. Although the mechanisms underlying this association are not completely understood, there are increasing evidences suggesting a pivotal role of thrombin in cancer biology. This review will focus on the most important pathways by which thrombin may affect cancer growth and dissemination. In addition, the potential role of congenital (i.e., hemophilia) and pharmaceutical (i.e., antithrombotic agents) anticoagulation in cancer incidence and survival will be investigated through the analysis of the published experimental and clinical studies.     

Inflammatory bowel diseases： From the mystical to the cellular and now the molecular

It is of interest in an era of increasing biomedical sophistication to recall that a relatively short time ago, early in the 20th century, ‘simple‘ ulcerative colitis was an obscure ‘medicalcuriosity‘ emerging slowly from an unknown past. Crohn‘s disease was yet unidentified as a separate entity although careful review of the IBD literature documented its early presence, masquerading as‘intestinal tuberculosis‘. Into the 1930s, the etiology and pathogenesis of ulcerative colitis and Crohn‘s disease were unknown, and investigative hypotheses were scarce. Therapeutic resources were limited and treatment was primitive. At a time of limited biomedical knowledge and minimal clinical awareness, unsubstantiated views prevailed, including‘vague reactions to foods‘ (sugar,margarine, corn flakes), deficiency of a ‘protective factor‘in pig intestine, and psychiatric disease.     

Humoral and cellular immunity to Candida albicans in patients with bronchial asthma.

Delayed cutaneous reactivity to Candida albicans (C. albicans) and PPD (purified protein derivative) was examined in 52 patients with bronchial asthma in relation to the production of specific IgG4 antibodies against the antigen. 1. The frequency of a positive, immediate skin reaction to C. albicans was similar among the five age groups, ranging from 60.0% to 66.7%. 2. The incidence of a positive delayed skin reaction to C. albicans was lower in patients between the ages of 10 and 30 and tended to decrease with aging in the patients over the age of 51. 3. A delayed skin reaction to PPD was positive in patients between 31 and 50 with a higher incidence; this incidence decreased in patients over age 51. 4. The level of C. albicans-specific IgG4 antibodies was significantly higher (26.7 u/ml) in patients with a negative delayed skin reaction to the antigen than in those with a positive reaction (5.9 u/ml) (p less than 0.001). There was no correlation between delayed skin reaction to PPD and production of specific IgG4 antibodies.     

Humoral and cellular immune responses to an envelope-associated antigen of herpes simplex virus.

The humoral and cellular immune responses of rabbits and guinea pigs to the envelope-associated antigen of herpes simplex virus type I were studied. Neutralizing antibody (at high titer) and lymphocytes reactive to herpes simplex virus were detected in both guinea pigs and rabbits after immunization with the antigen. In a standard assay of cellular immunity to herpes simplex virus, the antigen stimulated blast transformation of herpes simplex virus-reactive splenic lymphocytes in vitro. Furthermore, immunization of rabbits with the envelope-associated antigen protected the animals from a lethal dose of live herpes simplex virus. Thus an antigen of herpes simplex virus can be prepared which contains neither infectious nor noninfectious viral particles and which stimulates immunity to the virus in laboratory animals.     

Humoral response to Mycobacterium tuberculosis in patients with human immunodeficiency virus infection.

The effect of the human immunodeficiency virus (HIV) on mycobacterial antibody production was investigated. Using an enzyme-linked immunosorbent assay (ELISA) for detecting IgG against Mycobacterium tuberculosis PPD, it was observed that individuals at risk of HIV infection show a pattern of humoral response to the tubercle bacillus similar to that previously found in the immunocompetent population not exposed to risk factors: 6 of 12 (50.0%) tuberculosis cases had elevated levels of antibodies to PPD and 27 of 30 (90.0%) asymptomatic individuals had antibody levels within the normal range. In an HIV-seropositive group without AIDS indicator diseases, 8 of 22 (36.4%) tuberculous patients had detectable mycobacterial antibodies whereas 156 of 164 (95.1%) non-tuberculous subjects did not. Among AIDS cases, only 1 of 20 (5.0%) patients with tuberculosis and none of 53 non-tuberculous subjects showed a positive result. The study evidenced an increasing humoral unresponsiveness to PPD in the progression of HIV infection to AIDS. Thus, a serodiagnostic method for detecting tuberculosis such as the ELISA here employed noticeably decreases its utility in the latency stage of the HIV infection, and it is practically useless in clinical AIDS.