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High avidity cytokine autoantibodies in health and disease: Pathogenesis and mechanisms

https://doi.org/10.1016/j.cytogfr.2010.03.003Get rights and content

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.

Introduction

In 1981, antibodies against interferon (IFN)-α or IFN-β were reported in participants of clinical trials evaluating administration of these exogenous recombinant human cytokines [1], [2]. Less than a decade later, naturally occurring autoantibodies against endogenous interleukin-1α (IL-1α) were reported [3], [4]. Cytokine autoantibodies have been identified in pharmaceutical preparations of intravenous immunoglobulin (IVIG) and in the healthy subjects from whom IVIG were derived [5], [6], [7], [8], [9]. Numerous studies have additionally demonstrated that cytokine autoantibodies are detectable in health and disease in various tissues, including blood [3], [4], [7], [10], [11], [12], [13], [14], lung [10], [15], [16], [17], pleural fluid [18], central nervous system [19], gums [20] and synovial fluid [21], [22]. In some cases, specific autoantibodies have been implicated in disease pathogenesis or predisposition [10], [14], [16], [17], [18], [23], [24], [25], [26], [27]. Others appear to be responsible for the associated physical manifestations of disease [28], [29], [30]. In addition to blocking specific cytokine function, cytokine autoantibodies may play an important role in health and disease by virtue of their ability to form immune complexes [12], [13], [16], [17], [31], [32], [33], which can interfere with their detection by conventional cytokine ‘antigen-capture’ methods [12], [13]. The recent development of novel methods has improved our ability to detect cytokine autoantibodies and has enhanced our understanding of their role and function. In this report, we review the current literature relating to the presence, biological function, potential mechanisms of production and significance of cytokine autoantibodies.

Section snippets

Cytokine autoantibodies in disease

Cytokine autoantibodies have been detected in patients with various diseases (Table 1). In order to explore the pathogenic roles of cytokine autoantibodies in each of these diseases, we discuss (1) the role of each cytokine in the given disease, (2) the incidence of autoantibody detection in the disease, (3) the mechanism of their function in disease pathogenesis, and (4) reports detailing the association of autoantibodies with certain therapies or clinical manifestations. In each case, the

Cytokine autoantibodies in healthy individuals

A broad range of cytokine autoantibodies have been reported in fresh frozen plasma (FFP) or IVIG of healthy individuals (Table 2). Their occurrence has been reported to vary with age [60], [61], gender [60], [61], and history of infection [18], depending on the specific autoantibody.

As one batch of IVIG is usually a product of pooled plasma IgG from several thousand individuals, we can assess the properties of cytokine autoantibodies in the healthy state through their characteristics in IVIG [7]

Potential mechanism(s) of cytokine autoantibody production

Most cytokine autoantibodies reported previously were high-affinity IgG autoantibodies, suggesting that plasma cells differentiated from cytokine-reactive B-cells in the germinal center are present. As differentiation into such IgG plasma cells in germinal centers requires the support of T-cells targeting self-cytokines, dysregulation in T-cell tolerance is also thought to be a crucial event that leads to inappropriate autoantibody production. However, such cytokine targeting T-cell clones have

Clinical perspective

Here we review the ability of cytokine autoantibodies to mediate cytokine activities by combining multiple mechanisms (scavenger, reservoir, and FcR-mediated signal transmitter). Based on numerous publications, it has been suggested that cytokine autoantibodies may contribute to homeostasis but are also causative in certain disease conditions. Recently, therapeutic targeting of cytokines using monoclonal antibodies has been applied in clinical settings, and this has called for a more detailed

Conclusions

Multiple lines of evidence support the concept that certain cytokine autoantibodies play an important role in disease pathogenesis by neutralizing cytokine activity. This includes:

  • (1)

    GM-CSF autoantibodies are critical for disruption of surfactant homeostasis in patients with the common form of PAP.

  • (2)

    G-CSF autoantibodies cause neutropenia in FS.

  • (3)

    EPO autoantibodies cause anemia in patients with PRCA.

  • (4)

    IFN-γ, type I IFNs and IL-6 autoantibodies cause increased susceptibility to microbial infections.

In

Contributors

Masato Watanabe, Koh Nakata, and Bruce Trapnell conceptualized and wrote the review; Kanji Uchida conducted some of the original work described herein and helped write the review; and Kazuhide Nakagaki helped to write the review.

Conflict of interest statement

The authors declare no competing financial interests related to this review.

Acknowledgement

We thank Dr. John A. Hamilton (University of Melbourne) for critically reviewing the manuscript.

Masato Watanabe MD, PhD is an assistant professor in the Department of Respiratory Medicine at the Kyorin University in Tokyo. He obtained his MD from Kyorin University in 1999. He completed a medical residency at Niigata University Hospital, and he is a Board Certified Member of the Japanese Respiratory Society. He obtained his PhD from Kyorin University in 2007. During the course of PhD degree, he analyzed the pathogenesis of autoimmune pulmonary alveolar proteinosis in which GM-CSF

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    Masato Watanabe MD, PhD is an assistant professor in the Department of Respiratory Medicine at the Kyorin University in Tokyo. He obtained his MD from Kyorin University in 1999. He completed a medical residency at Niigata University Hospital, and he is a Board Certified Member of the Japanese Respiratory Society. He obtained his PhD from Kyorin University in 2007. During the course of PhD degree, he analyzed the pathogenesis of autoimmune pulmonary alveolar proteinosis in which GM-CSF autoantibodies play a central role, and then he has extended his focus to the pathophysiological functions of autoantibodies against multiple cytokines. His research interest includes analysis of autoantibodies against cytokines and cytokine-autoantibody complexes in healthy subjects and their role in immune mediation. More recently, his interest in experimental respirology turned to investigating the role of cytokine autoantibodies in bacterial pneumonia, which is an important infectious disease related with cytokine biology.

    Kanji Uchida earned his PhD from Tokyo University Graduate School of Medicine in 2004 where he characterized GM-CSF autoantibodies purified from patients with pulmonary alveolar proteinosis. During his post-doctoral research in Cincinnati Children's Hospital Medical Center, Cincinnati Ohio, he focused on GM-CSF biology in health and disease including naturally occurring GM-CSF autoantibodies. His recent study suggested the possible role of anti-GM-CSF autoantibody that regulates GM-CSF bioactivity and thus modulates myeloid cell immune function.

    Kazuhide Nakagaki is a sole veterinarian in our team. He received his PhD degree, on his birthday in1986, from the University of Tokyo for his studies investigating the pathological mechanism of canine filarial glomerulonephritis and how it could serve as a model for immune complex nephritis. In 1988, he pursued a 4-year post-doctoral fellowship, joining Dr. Bruce Hammerberg's laboratory at the North Carolina State University College of Veterinary Medicine. His main research interest was parasite–host interaction, particularly the immunoprophylaxis of nematodes through vaccine development and implementation. In 1999, he took a 2-year sabbatical from teaching by joining Dr. Gaetan Faubert's laboratory at the Institute of Parasitology, McGill University becoming a team member working on the development of a Giardia transmission blocking vaccine strategy. Presently, his current interests lie in the development of DNA vaccines against parasitic nematodes.

    Bruce C. Trapnell is the Francis R. Luther Endowed Chair and Professor of Medicine and Pediatrics at the University of Cincinnati and attending physician at the Cincinnati Children's Hospital and University Hospital Medical Centers in Cincinnati, Ohio. He is Director of Translational Pulmonary Research, Director of the Rare Lung Diseases Network, Co-Director of the Cincinnati Cystic Fibrosis (CF) Therapeutics Development Network Center, and Assistant Director of the Adult Cystic Fibrosis Center. An ardent supporter of patient advocacy, Dr. Trapnell previously served as Scientific Director for the Alpha-1 Foundation and currently serves as the Scientific Director of the Pulmonary Alveolar Proteinosis Foundation. His research is focused to the pathogenesis and therapy of rare lung diseases and mechanisms by which GM-CSF regulates innate immunity and lung host defense. He has published more than 130 scientific manuscripts, reviews and chapters, trained more than 16 post-doctoral fellows, and has been continuously funded by the NIH since 2001, shortly after coming to Cincinnati.

    Koh Nakata, MD, PhD is the professor & Chairman of Bioscience Medical Research Center in Niigata University Medical & Dental Hospital. Bioscience Medical Research Center was established in 2003 for promotion of translational research in Niigata University, the biggest city along Japan Sea side in the Honshu Island. The Center is consisted of three divisions; Clinical Trial Center, Division of Genetic Affairs, and Division of Regenerative Medicine. He was born in Tokyo in 1954 and awarded the BSC degree of agriculture from Tokyo University in 1977. He then entered faculty of Medicine, Kyoto University and graduated in 1983. He trained and worked at hospitals in Tokyo for five years and then started basic research on differentiation and proliferation of human alveolar macrophages under the member of Dr. Kiyoko Akagawa, a macrophage biologist. In 1999, He and his colleagues discovered high-affinity GM-CSF autoantibody in the blood and lung of patients with idiopathic pulmonary alveolar proteinosis (J. Exp. Med. 1999). Soon after he developed a method for serological diagnosis of the disease and characterized GM-CSF autoantibody from the patients. During 2002–2008, he organized multi-center phase II trial of GM-CSF inhalation therapy for autoimmune pulmonary alveolar proteinosis, resulting in overall response rate of 69% (n = 35).

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