Anti-cytokine Autoantibodies Research Articles

Immunodeficiency secondary to anticytokine autoantibodies

Anticytokine autoantibodies are an important and emerging mechanism of disease pathogenesis. We will review the clinical and laboratory features of syndromes in which immunodeficiency is caused by or associated with neutralizing anticytokine autoantibodies. A growing number of patients have been described who demonstrate unique infectious phenotypes associated with neutralizing autoantibodies that target a particular cytokine known to participate in host defense against the offending organism. Examples include antigranulocyte macrophage-colony stimulating factor (GM-CSF) autoantibodies and pulmonary alveolar proteinosis; anti-interferon (IFN)-γ autoantibodies and disseminated nontuberculous mycobacteria (NTM); anti-interleukin-(IL)-6 autoantibodies and severe staphylococcal skin infection; anti-IL-17A, anti-IL-17F, or anti-IL-22 autoantibodies in patients with mucocutaneous candidiasis in the setting of both the autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) syndrome and in cases of thymoma. Anticytokine autoantibodies have manifestations that are diverse, ranging from asymptomatic to life-threatening. These emerging and fascinating causes of acquired immunodeficiency may explain some previously idiopathic syndromes.

Anti‐cytokine autoantibodies explain some chronic mucocutaneous candidiasis

have offered elegant explanations of whyCMC occurs in APECED: high-titer, neutra-lizing autoantibodies to the T-cell cytokinesthat regulate mucosal antibacterial and anti-fungal activity, IL-17 and IL-22. These cyto-kines were good targets for involvementin CMC: STAT3-deficient hyper IgE (Job’s)syndrome,

Depletion of B lymphocytes in rheumatoid arthritis patients modifies IL-8-anti-IL-8 autoantibody network

Cytokines and chemokines are key regulatory molecules involved in rheumatoid arthritis (RA). B-cell depletion therapy improves RA clinically but its mechanism is not completely understood. One possible mechanism for this therapy is the modification of the proinflammatory cytokine homeostasis of RA. We show here that the levels of the proinflammatory chemokine IL-8 in serum samples from RA patients unexpectedly increased by up to 100-fold 8 weeks after the administration of rituximab, despite clinical improvement. We also show that RA patients produced anti-IL-8 autoantibodies and that their levels dropped after RTX treatment. Moreover, we identified antibody-IL-8 immune complexes in the synovial fluid and serum of RA patients, and found that the amount of these complexes decreased after the administration of RTX. Our results indicate that B-cell depletion therapy modifies the cytokine-autoantibody network by reducing the levels of anti-cytokine autoantibodies and, consequentially, the formation of antibody-cytokine immune complexes.

Anti-interleukin-8 autoantibody:interleukin-8 immune complexes in acute lung injury/acute respiratory distress syndrome

ALI/ARDS (acute lung injury/acute respiratory distress syndrome) is a severe inflammatory lung disease associated with very high mortality. Importantly, no effective therapy has been developed to date for ALI/ARDS. Neutrophils have been implicated in the pathogenesis of ALI/ARDS, and IL-8 (interleukin-8) has been identified as the main chemotactic factor for neutrophils in lung fluids of patients with ALI/ARDS. Significantly, studies from our laboratory have revealed the presence of anti-IL-8 autoantibody:IL-8 immune complexes in lung fluids from patients with ALI/ARDS. Autoantibodies to several cytokines, including IL-8, have been found in human plasma and other tissues. The function of anticytokine autoantibodies is far from clear; however, in some instances, it has been suggested that such autoantibodies may contribute to the pathogenesis of variety of human diseases. In addition, many of these autoantibodies can form immune complexes with target cytokines. Furthermore, immune complexes consisting of anti-IL-8 autoantibodies and IL-8 are very stable due to the high affinity of autoantibodies against IL-8. These complexes are present in various human tissues, including the lung, as they have been detected in lung fluids from patients with ALI/ARDS. In this review, the significance of the latter findings are explored, and the possible involvement of anti-IL-8 autoantibody:IL-8 immune complexes in pathogenesis of ALI/ARDS is discussed.

Anti-cytokine autoantibodies are ubiquitous in healthy individuals

Anti-cytokine autoantibodies in healthy individuals have been widely reported but the occurrence is variable and inconstant. We hypothesized that cytokine-binding in vivo may explain their variable and infrequent detection. Therefore, we focused on the detection of the cytokine-autoantibody complexes and found that anti-cytokine autoantibody to IL-2, IL-8, tumor necrosis factor-α, vascular endothelial growth factor and granulocyte-colony stimulating factor were present in all 15 individuals evaluated, while those to IL-3, osteopontin and macrophage-colony stimulating factor were not detected in anyone. Autoantibodies against IL-4, IL-6, IL-10, and interferon-gamma were variously detected. Thus, we discovered that anti-cytokine autoantibodies to multiple cytokines are ubiquitous in healthy individuals.

Anti-cytokine autoantibodies in experimental autoimmune neuritis in Lewis rats

Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated, inflammatory demyelinating disease of the peripheral nervous system (PNS) that serves as a model for Guillain–Barré syndrome (GBS) in humans. Cytokine production has been suggested to act a pathogenic role for EAN. To study the potential role of cytokines in context with cytokine autoantibodies (Aabs) in EAN, we used in situ hybridization to detect mRNA expression of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-4, IL-10, and transforming growth factor (TGF)-β in lymph node mononuclear cell (MNC) and in sciatic nerve sections, as well as ELISA for detection of their autoantibodies in sera and cerebrospinal fluid (CSF) over the course of EAN. Increased mRNA expression for IFN-γ and TNF-α was registered correlating with the peak of clinical signs of EAN, and high levels of mRNA expression for IL-4, IL-10, and TGF-β were associated with EAN recovery. The levels of cytokine mRNAs were generally inversely correlated to their autoantibodies in serum and CSF, whereby the CSF levels were equal to or lower than the serum levels. Autoantibodies to IFN-γ dose-dependently inhibited IFN-γ-induced MHC expression by peritoneal macrophages proving a neutralizing biological effect of these autoantibodies. Our data demonstrate the existence of the anti-cytokine autoantibodies in the sera and CSF of rats with EAN; however, the role of anti-cytokine autoantibodies in the disease process of EAN remains to be resolved.

Induction of TNF-α Autoantibody Production by AutoVac TNF106: A Novel Therapeutic Approach for the Treatment of Allergic Diseases

Background: Cytokines play an integral role in the coordination and persistence of allergic inflammatory processes and therefore represent prime targets for novel therapies in diseases such as asthma. Multiple attempts to generate low-molecular-weight cytokine inhibitors have failed, and the main attention has focused on the development of biological agents such as neutralizing antibodies. The present work describes a simple and effective method to induce the production of therapeutic anti-cytokine autoantibodies by active immunization against a modified endogenous cytokine. Methods: Balb/c mice were subcutaneously injected with AutoVac TNF106, a recombinant murine TNF-α molecule containing a foreign immunogenic T helper epitope, and the induction of neutralizing anti-TNF-α autoantibodies was analysed. These mice were then sensitized with ovalbumin (OVA), and the effect of neutralizing anti-TNF-α autoantibodies on the allergen-induced airway inflammation was analysed. Results: AutoVac TNF106-immunized mice developed high titres of neutralizing anti-TNF-α autoantibodies, which were maintained for at least 4 weeks after the last booster injection. Mice vaccinated with AutoVac TNF106 and further immunized against OVA showed diminished TNF-α levels in the bronchoalveolar lavage (BAL) fluid after OVA challenge. Moreover, pretreatment with AutoVac TNF106 resulted in significantly reduced numbers of eosinophils and neutrophils in BAL fluid in response to single or multiple allergen exposure. Conclusion: The induction of anti-TNF-α autoantibody production by the AutoVac TNF106 technology not only confirmed the role of TNF-α in the induction of allergic inflammation but also offers a novel approach to block the activity of cytokines in order to treat allergic inflammatory conditions.

Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis.

We have screened for spontaneous anticytokine autoantibodies in patients with infections, neoplasms and autoimmune diseases, because of their increasingly reported co-occurrence. We tested for both binding and neutralizing autoantibodies to a range of human cytokines, including interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, interferon-alpha2 (IFN-alpha2), IFN-omega, IFN-beta, IFN-gamma, tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta-1 (TGF-beta1) and granulocyte-macrophage colony stimulating factor (GM-CSF), in plasmas or sera. With two notable exceptions described below, we found only occasional, mostly low-titre, non-neutralizing antibodies, mainly to GM-CSF; also to IL-10 in pemphigoid. Strikingly, however, high-titre, mainly IgG, autoantibodies to IFN-alpha2, IFN-omega and IL-12 were common at diagnosis in patients with late-onset myasthenia gravis (LOMG+), thymoma (T) but no MG (TMG-) and especially with both thymoma and MG together (TMG+). The antibodies recognized other closely related type I IFN-alpha subtypes, but rarely the distantly related type I IFN-beta, and never (detectably) the unrelated type II IFN-gamma. Antibodies to IL-12 showed a similar distribution to those against IFN-alpha2, although prevalences were slightly lower; correlations between individual titres against each were so modest that they appear to be entirely different specificities. Neither showed any obvious correlations with clinical parameters including thymoma histology and HLA type, but they did increase sharply if the tumours recurred. These antibodies neutralized their respective cytokine in bioassays in vitro; although they persisted for years severe infections were surprisingly uncommon, despite the immunosuppressive therapy also used in most cases. These findings must hold valuable clues to autoimmunizing mechanisms in paraneoplastic autoimmunity.

Induction of cytokines and anti-cytokine autoantibodies in cerebrospinal fluid (CSF) during experimental bacterial meningitis.

We have recently described the induction of anti-cytokine autoantibodies (Aabs) in the serum as a novel mechanism for cytokine regulation during bacterial infections. Here we use the infant rat-model of Haemophilus influenzae type b (Hib) meningitis to examine the induction of five potentially important cytokines and their autoantibody responses in the CSF. Protein levels of the cytokines interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), IL-4 and IL-10 were detected at day 3 post-inoculation (p.i.) with maximum induction at day 8. Thereafter, these levels of cytokines had become undetectable. Increased Aab titres to these cytokines, except IL-4, were registered with peak levels between days 7 and 9. Upon re-inoculation with Hib at day 30, regeneration of Aabs was recorded 7 days later (i.e. at day 37). To control the specificity of these Aabs, preincubation of the CSF with a cytokine inhibited the binding effects of that particular cytokine, but not those of any other cytokine. Aabs dose-dependently inhibited IFN-gamma-induced MHC expression by peritoneal macrophages and TNF-alpha-mediated L929 cytotoxicity. Our data demonstrate for the first time the existence of the anti-cytokine antibodies in the CSF of the meningitis Hib model. Furthermore, the data present a role for the Aabs in cytokine regulation, which is consistent with the previously demonstrated effects of the Aabs in the serum.

Induction of cytokines and anti-cytokine autoantibodies in cerebro-spinal fluid during experimental bacterial meningitis

Induction of cytokines and anti-cytokine autoantibodies in cerebro-spinal fluid during experimental bacterial meningitis

Cytokine autoantibodies in multiple sclerosis, aseptic meningitis and stroke.

We have recently described the induction of anti-cytokine autoantibodies during bacterial infections and autoimmune diseases as a mechanism for cytokine regulation. Herein, we study the occurrence of autoantibodies to pro- and anti-inflammatory cytokines in cerebrospinal fluid and plasma from patients with multiple sclerosis, aseptic meningitis and stroke. Increased levels of autoantibodies to interferon gamma, tumour necrosis factor alpha, interleukin 4 and interleukin 10 were detected in both compartments of multiple sclerosis and aseptic meningitis patients. Interestingly, in cerebrospinal fluid from stroke patients, only autoantibodies to interleukin 4 and interleukin 10, but not interferon alpha or tumour necrosis factor alpha were detected. No significant autoantibody levels were registered in plasma from stroke patients against all four cytokines compared with healthy control subjects. The latter revealed very low autoantibody levels in plasma and no detectable autoantibodies in cerebrospinal fluid. Our data show for the first time the occurrence of cytokine autoantibodies in these diseases, but their biological significance is unclear.

Cytokines and anti-cytokine autoantibodies during experimental african trypanosomiasis in mice with disrupted interferon-gamma and interferon-gamma receptor genes.

We studied cytokines and anti-cytokine autoantibodies (Aabs) during T.b.brucei infections in IFN-gamma-/-, IFN-gammaR-/- and wild-type mice. Increased serum levels of IFN-gamma, TNF-gamma and IL-4 with decreased Aabs to these cytokines were recorded early during infections in all mice (except IFN-gamma in IFN-gamma-/- mice). Later, these responses were reversed, and surprisingly Aabs reacting to IFN-gamma in the IFN-gamma -/- mice were detected. To examine the possibility that an IFN-ç immunoreactive molecule might be expressed due to infections and upon gene deletion, anti-IFN-gamma antibody was inoculated and resulted in abrogation of such Aabs. The scenario was different for IL-10 and TGF- since IFN-gammaR-/- and wild-type mice showed low cytokines and high Aabs early during infections, but later high cytokines and low Aabs were registered. Interestingly, IFN-gamma-/- mice exhibited reversed levels of both IL-10 and TGF-beta, and also of their Aabs. Fab fragments of purified serum immunoglobulins showed binding and neutralizing effects in biological assays. Pre-absorption of the Fab fragments with a cytokine inhibited the binding and neutralization effects of this cytokine, but not of other cytokines. These results highlight an important role for autoimmunity in cytokine regulation, and that genomic deletion of IFN-gamma modulates cytokines and their Aab responses in experimental African trypanosomiasis.

Anti-cytokine autoantibodies: epiphenomenon or critical modulators of cytokine action.

Low amounts of high-affinity autoantibodies to various cytokines have been detected in sera from healthy donors. Their levels, although highly variable, are increased in the circulation of patients subjected to cytokine therapy or suffering from a variety of immunoinflammatory diseases. It has been suggested that these autoantibodies play a regulatory role in the intensity and duration of an immune response. The antibodies may prevent the binding of a cytokine to its specific cell surface receptor thereby neutralizing its biological activity in vivo. They may also act as carrier proteins preventing the rapid elimination of a cytokine from the circulation and thus increase its bioactivity. Additionally or alternatively, autoantibodies may modulate cytokine-induced intracellular signal transduction pathways or trigger complement-mediated cytotoxicity towards cells carrying membrane-bound cytokines. The autoantibodies may exert their regulatory role in compliance with the other factors that control cytokine activity, including soluble cytokine receptors, cell surface decoy receptors, and receptor antagonists. Although not favored by many investigators, a less sophisticated role for naturally occurring anti-cytokine autoantibodies should be considered as well. Recent evidence has shown that autoantibodies are generated at a high frequency as part of a response to foreign antigens. These antibodies are produced by B cells arising from the process of somatic mutation. Thus anti-cytokine autoantibodies may be the result of a "leaky" B cell response triggered by immunoinflammatory processes. High-titered autoantibodies induced by cytokine therapy are of clinical concern since their occurrence is often associated with the loss of response to treatment. Moreover, they may also neutralize endogenously produced cytokines with possible pathological consequences. In this paper we have reviewed the available information on the biological and clinical significance of both naturally occurring and therapeutically induced anti-cytokine autoantibodies in animals and man with the emphasis on antibodies directed to interferons.

Anti-interleukin-6 autoantibodies in rheumatic diseases. Increased frequency in the sera of patients with systemic sclerosis.

To investigate the presence and the roles of anti-interleukin-6 (anti-IL-6) autoantibodies in rheumatic diseases, and to further elucidate clinical and pathophysiologic significance of anticytokine autoantibodies. Anti-IL-6 IgG autoantibodies were measured by the 125I-IL-6 binding activity of IgG, which was isolated from serum by protein A-Sepharose. Nine of 52 sera (17.3%) from patients with systemic sclerosis (SSc) contained anti-IL-6 antibodies, whereas only 1.9% of sera from normal subjects and 0-5% of sera from patients with other rheumatic diseases were positive for the antibodies. Moreover, anti-IL-6 autoantibodies were found predominantly among patients with the limited form of SSc (42.9%), compared with those with the diffuse form (7.9%). Anti-IL-6 IgG autoantibodies were detected in patients with SSc, particularly those with the limited form of the disease, at a significantly increased frequency compared with normal subjects and patients with other rheumatic diseases. These results suggest that the development of anti-IL-6 autoantibodies and IL-6 may have a role in the pathophysiology of SSc.

抗サイトカイン自己抗体と炎症

Autoantibodies against cytokines including IL-1α, IL-2, IL-6, interferons, TNF α have been recently reported by several investigators. Some of them [IL-1α, interferons (IFNs) and TNFα] are found in some normal sera. However, increased frequencies and titers of these autoantibodies have been demonstrated in certain pathological conditions. In patients with rheumatoid arthritis, the frequency of anti-IL-1α autoantibody was about 3 times (15%) more frequent than in normal subjects. Potent neutralizing activities and high affinity to IL-1α of the autoantibodies are also characteristics. Other investigators have reported the increased frequency of anti-IFNγ autoantibody in patients with recent virus infection and anti-TNF α autoantibody in patients with gram-negative bacterial infections.The mechanism by which these anti-cytokine autoantibodies are induced rematins to be determined. Antigenic stimulation of cytokines seems to be involved as a cause of the development of these autoantibodies in certain pathological states. Though pathophysiological roles of these anti-cytokine autoantibodies are still obscure, demonstration of neutralizing activities of most of these antibodies suggest a possible regulatory role in in vivo cytokine activities.