Autoantibodies in immune-mediated neuropathies.

PURPOSE OF REVIEW: Over the past 25 years, many autoantibodies directed against peripheral nerve glycan and protein antigens have been described. Principally through this area of research, significant advances have been achieved in the understanding of the pathophysiology of inflammatory neuropathies. More evidence constantly continues to emerge supporting the role of antibodies in pathogenesis. This review reports the recent studies highlighting the complex association between autoantibodies directed against various peripheral nerve antigens and immune polyneuropathies. RECENT FINDINGS: The discovery of serum antibodies directed against ganglioside and glycolipid complexes has generated huge interest in this area of research. The expectation that nodal proteins are important targets continues to be pursued in line with the improvements in detection methodology. Basic studies continue to support a direct role for autoantibodies in neuropathy pathogenesis. SUMMARY: Discovery of new target epitopes has not only raised hopes for further improvement in our understanding of pathophysiology and availability of new diagnostic markers, but also for future targeted therapies. Further studies are required to elucidate the precise pathological and clinical significance of these new antibodies.

Mycobacterium leprae phenolglycolipid-1 expressed by engineered M. bovis BCG modulates early interaction with human phagocytes.

The species-specific phenolic glycolipid 1 (PGL-1) is suspected to play a critical role in the pathogenesis of leprosy, a chronic disease of the skin and peripheral nerves caused by Mycobacterium leprae. Based on studies using the purified compound, PGL-1 was proposed to mediate the tropism of M. leprae for the nervous system and to modulate host immune responses. However, deciphering the biological function of this glycolipid has been hampered by the inability to grow M. leprae in vitro and to genetically engineer this bacterium. Here, we identified the M. leprae genes required for the biosynthesis of the species-specific saccharidic domain of PGL-1 and reprogrammed seven enzymatic steps in M. bovis BCG to make it synthesize and display PGL-1 in the context of an M. leprae-like cell envelope. This recombinant strain provides us with a unique tool to address the key questions of the contribution of PGL-1 in the infection process and to study the underlying molecular mechanisms. We found that PGL-1 production endowed recombinant BCG with an increased capacity to exploit complement receptor 3 (CR3) for efficient invasion of human macrophages and evasion of inflammatory responses. PGL-1 production also promoted bacterial uptake by human dendritic cells and dampened their infection-induced maturation. Our results therefore suggest that M. leprae produces PGL-1 for immune-silent invasion of host phagocytic cells.

[Molecular pathogenesis of mycobacterial diseases].

Mycobacterial diseases, including tuberculosis, leprosy, and disease due to nontuberculous mycobacteria, are the major cause of death from infectious diseases around the world. About one-third of the world population is latently infected with Mycobacterium tuberculosis. Over 8 million new cases and nearly 2 million deaths occur each year. Tuberculosis presents a significant health threat to the world. The pathogenicity of mycobacteria is related to their ability to escape killing by ingested macrophages, latent infection, and induce delayed type hypersensitivity. This has been attributed to several components of the mycobacterial cell wall, such as surface glycolipids, lipoarabinomannan, complement activation factor, heat-shock protein, and mycobacterial DNA binding protein. From the aspect of my research interests, I have focused on mycobacterial glycolipids and mycobacterial DNA binding protein in this article. Surface molecules of mycobacteria exert pleiotropic activities in both the microbe and host, and thus participate in the pathogenesis of mycobacterial diseases. The better understanding of mycobacterial pathogenicity may open the new avenue for the development of therapeutic and prophylactic interventions.

Phenolic glycolipid-1 of Mycobacterium leprae binds complement component C3 in serum and mediates phagocytosis by human monocytes.

Previous studies from this laboratory have demonstrated that Mycobacterium leprae, an obligate intracellular bacterial parasite, enters human mononuclear phagocytes via complement receptors on these host cells and bacterium-bound C3. The present study investigates the role of M. leprae surface molecules in C3 fixation and phagocytosis. By enzyme-linked immunosorbent assay, C3 binds selectively to phenolic glycolipid-1 (PGL-1), a major surface molecule of the leprosy bacillus. C3 fixation to PGL-1 is serum concentration dependent and is abolished in heat-inactivated serum or serum containing ethylenediaminetetraacetic acid. C3 fixation is also abolished in serum containing ethyleneglycol-bis (beta-aminoethyl ether)N,N,N'-tetraacetic acid and MgCl2 indicating that isolated PGL-1 fixes C3 via the classical complement pathway. The capacity of PGL-1 to fix C3 is dependent upon its terminal trisaccharide since sequential removal of monosaccharide units of the trisaccharide results in a stepwise reduction in C3 fixation. Deacylation of PGL-1 also abolishes C3 fixation. C3 fixes to the trisaccharide of PGL-1 that is chemically linked to bovine serum albumin via the chemical carrier, 8-methoxycarbonyloctanol. PGL-1 mediates C3 fixation to polystyrene microspheres, and PGL-1 and C3 together mediate ingestion of polystyrene microspheres by human monocytes, wherein these inert test particles reside in membrane-bound phagosomes. Thus, complement receptors on mononuclear phagocytes, complement component C3, and PGL-1 comprise a three-component receptor-ligand-acceptor molecule system for mediating phagocytosis of M. leprae.

Microbial glycolipids: possible virulence factors that scavenge oxygen radicals.

Two important pathogens of developing countries, Mycobacterium leprae, the etiologic agent of leprosy, and Leishmania donovani, the protozoal parasite that causes kalaazar, persist in the human host primarily in mononuclear phagocytes. The mechanisms by which they survive in these otherwise highly cytocidal cells are presently unknown. Since the best understood cytocidal mechanism of these cells is the oxygen-dependent system that provides lethal oxidants including the superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH), and singlet oxygen (1O2), we sought specific microbial products of these organisms that might enable them to elude oxidative cytocidal mechanisms. Phenolic glycolipid I of M. leprae and lipophosphoglycan of L. donovani are unique cell-wall-associated glycolipids produced in large amounts by the organisms. In this study, phenolic glycolipid I derivatives and lipophosphoglycan were examined for their ability to scavenge potentially cytocidal oxygen metabolites in vitro. Electron spin resonance and spin-trapping indicate that phenolic glycolipid I derivatives and lipophosphoglycan are highly effective in scavenging hydroxyl radicals and superoxide anions. The results suggest that complex glycolipids and carbohydrates of intracellular pathogens that can scavenge oxygen radicals may contribute to their pathogenicity and virulence.