Pathogenic autoantibodies

Immune dysregulation leading to B-cell hyperactivity and subsequent production of pathogenic autoantibodies, coupled with defective clearance of apoptotic cells, followed by immune-complex formation, complement activation, and defective clearance of immune complexes all lead to inflammatory reactions that ultimately result in tissue injury and damage. An overview of the pathogenesis of SLE is illustrated in Fig. 85-1. 

Lim PL, Zouali M Pathogenic autoantibodies emerging insights into tissue injury. Immunol Lett 2006 103 17-26. 

Peng SL, Szabo SJ, Glimcher LH. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc Natl Acad Sci USA. 2002 99 5545-5550. 

A. Vincent, O. Lily and J. Palace, (1999). Pathogenic autoantibodies to neuronal proteins in neurological disorders. J. Neuroimmu-nol. 100, 169-180. 

T. Hellmark, H. Burkhardt and J. Wieslander, (1999). Goodpasture disease - Characterization of a single conformational epitope as the target of pathogenic autoantibodies. J. Biol. Chem. 274, 25862-25868. 

Systemic lupus erythematosus (SLE) is a systemic auto-immune disease of unknown cause in which tissues and cells are damaged by pathogenic autoantibodies and immune complexes. Ninety per cent of cases are in women, usually of childbearing age. Pleurisy and pleural effusions are common manifestations of SLE. Interstitial pneumonitis leading to fibrosis occurs occasionally. Pulmonary hypertension is a serious, uncommon manifestation of SLE. Many autoantibodies could be detected in SLE patients the most frequent are antinuclear antibodies (Keren) (90% of patients) the most specific antibodies are anti-DNA (70% of patients) and anti-Sm (30% of patients). 

Immunoadsorption, an advanced therapeutic modality, focuses on detoxification of patient blood rich in high-molecular-weight pathogenic substances, mostly abnormal autoantibodies such as rheumatoid factors in rheumatoid arthritis (RA) and anti-DNA autoantibodies in systemic lupus erythematosus (SLE). Detoxification of these pathogens will be accomplished through extracorporeal perfusion of the patient plasma or whole blood over an affinity column made of immunoadsorbents. These adsorbents perform their function through the same mechanism as conventional affinity adsorption, where proteins in the liquid phase are adsorbed on the specific ligands immobilized onto an insoluble support. 

Direct evidence of DNA as an antigen source to drive autoantibody production was derived from experiments using combined DNA-protein as an immunogen to immunize mice. The mice immunized with the DNA-peptide complex produce anti-dsDNA antibodies with pathogenic properties (D7). 

Anti-dsDNA antibodies are both specific and pathogenic to SLE. As mentioned previously, these autoantibodies are produced by an antigen-driven mechanism. They are organ-specific, especially kidney. We will discuss the close relationship between anti-dsDNA and lupus nephritis and the proposed mechanism by which anti-dsDNA leads to lupus nephritis. 

Neonatal lupus is caused by cross-reaction between maternal antibodies and fetal tissue. It is particularly interesting because it provides a unique opportunity for studying the pathogenic role of autoantibodies. 

Compared with anti-dsDNA, relatively fewer studies have been performed on anti-Ro/La antibodies. However, the unique ability to demonstrate the pathogenic role of autoantibodies causing disease provides us a chance to explore the mechanism of human autoimmune disease. The possibly most important task is to identify the cofactors making the infants of mothers with anti-Ro/La vulnerable to developing neonatal lupus syndromes. 

Other methods of clearing autoantibodies are extracorporeal and use the im-munoadsorption principle. Hollow fibers with dextran sulfate-coated cellulose membranes can adsorb pathogenic anti-DNA subgroups of high avidity and/or cationic antibodies, anticardiolipin, and anaphylatoxins (S35). The SLE disease activity index significantly decreased after such treatment (S35). However, the indication is still controversial. 

Baudino, L., S. Azeredo da Silveira, M. Nakata, and S. Izui. 2006. Molecular and cellular basis for pathogenicity of autoantibodies lessons from murine monoclonal autoantibodies. Springer seminars in immunopathology 28 175-184. 

Faller, G., Steininger, H., Appelmelk, B., Kirchner, T. Evidence of novel pathogenic pathways for the formation of antigastric autoantibodies in Helicobacter pylori gastritis. J Clin Pathol 51 (1998) 244-245. 

Autoimmune diseases have been reported to be more frequent in human subjects treated with several recombinant cytokines [38], For instance, increased titers or the new occurrence of autoantibodies have been observed in hepatitis C patients treated with the recombinant interferons-alpha (IFNa). Quite a few clinical case reports describe the development of organ-specific as well as systemic autoimmune diseases including systemic lupus erythematosus, insulin-dependent type I diabetes mellitus, autoimmune thrombocytopenia, autoimmune hemolytic anemia, myasthenia gravis, and autoimmune thyroiditis in patients under IFNa therapy. Although the mechanism involved is not fully elucidated, the available data support the pathogenic potential of IFNa in autoimmunity [31]. In contrast, autoimmune effects associated with IFNp therapy are thought to be of lesser concern based on the current clinical evidence [38], Thyroid autoimmunity in contrast to other autoimmune diseases is frequent in patients treated with recombinant interleukin-2 (rIL-2). Thus, among 281 previously euthyroid cancer patients treated with rIL-2, up to 41%... 

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