High avidity cytokine autoantibodies in health and disease: pathogenesis and mechanisms.
ABSTRACT Numerous reports have documented the presence of autoantibodies working against naturally occurring cytokines in humans in health and disease. In most instances, their physiological and pathophysiological significance remains unknown. However, recent advances in the methodologies for detecting cytokine autoantibodies and their application in research focused on specific disorders have shown that some cytokine autoantibodies play an important role in the pathogenesis of disease. Additionally, levels of cytokine autoantibodies may also correlate with disease severity and progression in certain infectious and autoimmune diseases but not in others. This suggests that cytokine-specific pathogenic differences exist. While multiple lines of evidence support the notion that high avidity cytokine autoantibodies are present and likely to be ubiquitous in healthy individuals, their potential physiological role, if any, is less clear. It is believed that they may function by scavenging pro-inflammatory cytokines and thereby inhibiting deleterious 'endocrine' effects, or by serving as carrier proteins, providing a 'reservoir' of inactive cytokines and thus modulating cytokine bioactivity. A central hypothesis is that sustained or repeated high-level exposure to cytokines triggers defects in T-cell tolerance, resulting in the expansion of existing cytokine autoantibody-producing B cells.
SourceAvailable from: Boris Gorovits[Show abstract] [Hide abstract]
ABSTRACT: The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years' editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for Large molecules bioanalysis using LBA and Immunogenicity. Part 1 (Small molecules bioanalysis using LCMS) and Part 2 (Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies' Input) were published in the Bioanalysis issues 6(22) and 6(23), respectively.Bioanalysis 12/2014; 6(24):3355-68. DOI:10.4155/bio.14.283 · 3.03 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system, which affects over 2.5 million people worldwide. Although MS has been extensively studied, many challenges still remain in regards to treatment, diagnosis and prognosis. Typically, prognosis and individual responses to treatment are evaluated by clinical tests such as the expanded disability status scale, MRI and presence of oligoclonal bands in the cerebrospinal fluid. However, none of these measures correlates strongly with treatment efficacy or disease progression across heterogeneous patient populations and subtypes of MS. Numerous studies over the past decades have attempted to identify sensitive and specific biomarkers for diagnosis, prognosis and treatment efficacy of MS. The objective of this article is to review and discuss the current literature on body fluid biomarkers in MS, including research on potential biomarker candidates in the areas of miRNA, mRNA, lipids and proteins.Expert Review of Clinical Immunology 12/2014; 11(1):1-23. DOI:10.1586/1744666X.2015.991315 · 3.34 Impact Factor
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ABSTRACT: Anti-cytokine autoantibodies (AAbs) are frequent and involve a very large panel of cytokines both in healthy subjects and in patients with various pathological conditions. In healthy individuals, anti-cytokine AAbs are described as a part of the natural AAb repertoire and are thought to contribute to the fine regulation of cytokine homeostasis. In some patients, neutralizing AAbs targeting cytokines required for the immune protection against specific microbes may induce acquired immunodeficiency leading to very specific infectious phenotypes. For instance, anti-IFNγ AAbs may induce disseminated non-tuberculous mycobacterial infections; anti-IL-17 AAbs are associated with the development of chronic mucosal candidiasis, and anti-IL-6 AAbs with severe staphylococcal or streptococcal infections. In patients with autoimmune diseases, AAbs directed against pathogenic cytokines are able to influence the course of the diseases. In lupus patients, neutralizing anti-IFNα and anti-TNFα AAbs are associated with a decreased bioactivity of the corresponding cytokine and a lower disease severity. Similarly, anti-IL-1α AAbs are associated with nondestructive forms of chronic polyarthritis. More surprisingly, neutralizing anti-BAFF AAbs are observed in the serum of lupus patients with elevated IFNα signature and higher disease activity. In this review, we summarize the current literature describing the different phenotypes and the main mechanisms associated with the occurrence of anti-cytokine AAbs. Copyright © 2015 Elsevier B.V. All rights reserved.