Biomedical subjects

L E Munoz

Publications and source records attributed to L E Munoz.

7 recordsLinked to original sources

PubMed2006

Inefficient clearance of dying cells and autoreactivity.

Dying cells were basically unnoticed by scientists for a long time and only came back into the spotlight roughly 10 years ago. The process of recognition and uptake of apoptotic and necrotic cells is complex and failures in this process can contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we discuss the recognition and uptake molecules which are involved in an efficient clearance of dying cells in early and late phases of cell death. The exposure of phosphatidylserine (PS) is an early surface change of apoptosing cells recognized by several receptors and adaptor molecules. We demonstrated that dying cells have cell membranes with high lateral mobility of PS, which contribute to their efficient clearance. Changes of the glycoprotein composition of apoptotic cells occur later than the exposure of PS. We further observed that complement binding is an early event in necrosis and a rather late event in apoptosis. Complement, C-reactive protein (CRP), and serum DNase I act as back-up molecules in the clearance process. Finally, we discuss how the accumulation of secondary necrotic cells and cellular debris in the germinal centers of secondary lymph organs can lead to autoimmunity. It is reasonable to argue that clearance defects are major players in the development of autoimmune diseases such as SLE.

Animals↗

PubMed2006

Clearance of apoptotic cells in human SLE.

Systemic lupus erythematosus (SLE) is characterized by a diverse array of autoantibodies, particularly against nuclear antigens, thought to derive from apoptotic and necrotic cells. Impaired clearance functions for dying cells may explain accumulation of apoptotic cells in SLE tissues, and secondary necrosis of these cells may contribute to the chronic inflammation in this disease. The exposure of phosphatidylserine (PS) and altered carbohydrates on dying cells are important recognition signals for macrophages. Furthermore, serum factors such as complement, DNase I, pentraxins (e.g. C-reactive protein) and IgM contribute to efficient opsonization and uptake of apoptotic and necrotic cells. Defects in these factors may impact the development of SLE in humans and mice in a variety of ways. We observed impaired clearance of apoptotic cells in lymph nodes and skin biopsies of humans with lupus, as well as intrinsic defects of macrophages differentiated in vitro from SLE patients' CD34+ stem cells, demonstrating that apoptotic cells are not properly cleared in a subgroup of patients with SLE. This altered mechanism for the clearance of dying cells may represent a central pathogenic process in the development and acceleration of this autoimmune disease.

Animals↗

PubMed2005

SLE--a disease of clearance deficiency?

Systemic lupus erythematosus (SLE) is a multifactorial disease and its pathogenesis and precise aetiology remain unknown. Under physiological conditions, neither apoptotic nor necrotic cell material is easily found in tissues because of its quick removal by a highly efficient scavenger system. Autoantigens are found in apoptotic and necrotic material and they are recognized by autoimmune sera from SLE patients. The clearance of dying cells is finely regulated by a highly redundant system of receptors on phagocytic cells and bridging molecules, which detect molecules specific for dying cells. Changes on apoptotic and necrotic cell surfaces are extremely important for their recognition and further disposal. Some SLE patients seem to have an impaired ability to clear such apoptotic material from tissues, and this could cause the breakdown of central and peripheral mechanisms of tolerance against self-antigens. In this article, we address the cells, receptors and molecules involved in the clearance process and show how deficiencies in this process may contribute to the aetiopathogenesis of SLE.

Apoptosis↗

PubMed2005

[An impaired detection and clearance of dying cells can lead to the development of chronic autoimmunity].

Not properly cleared dead cells are dangerous for the body. The dead cells accumulate, lose their membrane integrity, danger signals are released, and nuclear antigens get accessible in an inflammatory context. In times of increased apoptosis, tolerance can be broken, a chronic inflammation results which then can lead to an autoimmune reaction against nuclear constituents. An impaired clearance of dying cells represents a central pathogenic process in the development of chronic autoimmune diseases like in systemic lupus erythematosus (SLE). Many adaptor molecules and receptors are involved in the clearance of dying cells. Complement components, serum DNase I, phosphatidylserine, and modified glycoproteins participate crucially in the clearance of apoptotic and necrotic cells. We further observed intrinsic defects of macrophages of some SLE patients. Macrophages as well as granulocytes of some SLE patients showed heterogeneous clearance defects. Furthermore, we observed an accumulation of nuclear material in germinal centres of lymph nodes of some SLE patients. The non-ingested nuclear material may provide survival signals for autoreactive B cells and consecutively antinuclear autoantibodies (ANA) will be produced. We therefore conclude that drugs promoting the phagocytosis are important candidates of specific therapies in the future which expect a more gentle and purposive treatment of patients with SLE.

Animals↗

PubMed1982

Complement activation in chronic liver disease.

Patients with HBsAg positive chronic active liver disease (CALD) and primary biliary cirrhosis (PBC) exhibit increased C3d concentrations and changes in the serum concentrations of the complement components consistent with activation of the classical and alternative pathways. In these patients the concentrations of the regulatory proteins, C3b inactivator (C3bINA) and beta IH globulin, are normal. Patients with HBsAg negative CALD and alcohol induced liver disease (ALD) exhibit no evidence of an increased level of complement system activation. In these patients diminished serum concentrations of complement components appear to be related to diminished hepatic synthetic function. C4 synthesis may be specifically reduced in autoimmune chronic active liver disease.

Complement Activation↗

PubMed1981

Is mitochondrial antibody diagnostic of primary biliary cirrhosis?

In a series of 218 patients diagnosed as having primary biliary cirrhosis only nine exhibited a negative serum mitochondrial antibody. On examining additional specimens from these patients, seven were found to be positive, giving a final incidence of greater than 99%. The two patients whose sera remained negative for the mitochondrial antibody had liver histology compatible with the diagnosis of primary biliary cirrhosis, but a firm diagnosis could not be reached. Three additional mitochondrial antibody positive subjects who were asymptomatic and exhibited normal serum alkaline phosphatase were shown on liver biopsy to have stage I primary biliary cirrhosis. The presence of a positive serum mitochondrial antibody in a patient with or without abnormalities in liver function tests strongly suggests the diagnosis of primary biliary cirrhosis.

Adult↗

PubMed1978

Spore coat protein synthesis in cell-free systems from sporulating cells of Bacillus subtilis.

Cell-free systems for protein synthesis were prepared from Bacillus subtilis 168 cells at several stages of sporulation. Immunological methods were used to determine whether spore coat protein could be synthesized in the cell-free systems prepared from sporulating cells. Spore coat protein synthesis first occurred in extracts from stage t2 cells. The proportion of spore coat protein to total proteins synthesized in the cell-free systems was 2.4 and 3.9% at stages t2 and t4, respectively. The sodium dodecyl sulfate-urea-polyacrylamide gel electrophoresis patterns of immunoprecipitates from the cell-free systems showed the complete synthesis of an apparent spore coat protein precursor (molecular weight, 25,000). A polypeptide of this weight was previously identified in studies in vivo (L.E. Munoz, Y. Sadaie, and R.H. Doi, J. Biol. Chem., in press). The synthesis in vitro of polysome-associated nascent spore coat polypeptides with varying molecular weights up to 23,000 was also detected. These results indicate that the spore coat protein may be synthesized as a precursor protein. The removal of proteases in the crude extracts by treatment with hemoglobin-Sepharose affinity techniques may be preventing the conversion of the large 25,000-dalton precursor to the 12,500-dalton mature spore coat protein.

Bacillus subtilis↗