Clinical Immunology and Immunopathology
Short Analytical ReviewLymphokines in Autoimmunity—A Critical Review
Abstract
The pathogenesis of autoimmunity remains an enigma; however, growing evidence points to a possible involvement of lymphokines both in the initiation phase and especially in the effector stage of many autoimmune diseases. Although no single experimental approach can accurately mimic the highly complex interplay of genetic, hormonal, and immune factors inherent in the development of autoimmunity, several lines of evidence strongly suggest a major role for lymphokines, in particular interferons (IFN), tumor necrosis factor (TNF), and interleukins 1 and 2 (IL-1, IL-2). These include the pleiotropic biologic activities of lymphokines which often synergize and interact, and can mediate several prominent clinical and laboratory manifestations of autoimmunity. Patients undergoing therapy with IFN or IL-2 may develop varied autoimmune syndromes, often an exacerbation of previously latent autoimmunity. Likewise, the administration of IFN to experimental animals can cause or accelerate autoimmune disease and, more importantly, specific lymphokine blockade was shown to be protective. Moreover, in the animal models of autoimmunity and in many patients with autoimmune diseases, increased lymphokine levels can be demonstrated either in the circulation or locally, often correlating with disease activity. Finally, aberrant MHC class II expression on nonlymphoid cells can be identified in the target organs of most autoimmune diseases and extensive data suggest that it can present autoantigen, activate autoreactive T cells, and initiate a cascade of self-propagating autoimmunity. Thus, a local release of IFN-γ, the major inducer of MHC class II, may be pivotal to the development of organ-specific autoimmunity. The central role of cytokines in lymphocyte traffic into inflammatory sites as well as a growing understanding of lymphokine production patterns by different T cell subsets important in autoimmunity lends further support for this hypothesis, at the same time revealing that certain lymphokines may have a protective inhibitory effect on autoimmunity (e.g., IL-4, TGF-β). In conclusion, varied data strongly suggest that several lymphokines, produced mainly locally and interacting with each other, have an important role in the pathogenesis of autoimmunity. Although the initiating events and complex interactions remain largely unclear, recent advances are encouraging, and may lead to specific manipulations of lymphokines in the future treatment of autoimmune diseases.
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TLR7 promotes Th1 polarization in immune thrombocytopenia
2011, Thrombosis ResearchCitation Excerpt :IFN-γ, a Th1 cytokine, has been shown to be pivotal to the development of autoimmunity. Patients undergoing therapy with IFN-γ or animals upon administration of IFN-γ develop varied autoimmune syndromes [43,50]. However, Th2 cytokines (e.g., IL-4, TGF-β) have been shown to have a protective inhibitory effect on autoimmunity and play direct role in the induction or maintenance of tolerance.
T helper 1 cell (Th1) polarization persists in the autoimmune response found in immune thrombocytopenia (ITP). Toll-like receptor 7 (TLR7) expression, which also plays an important role in autoimmune diseases, was verified to increase in ITP. However, the exact role of TLR7 in ITP is not well elucidated. Here, we explored the hypothesis that TLR7 participates in the pathophysiology of ITP by affecting Th1 polarization.
Twenty-two ITP patients and twenty-one controls were enrolled in this study. We examined the cytokine secretion of macrophages in ITP patients and controls using both TLR7 agonist (imiquimod) and antagonist (IRS 661). The influence of macrophage secretion from these groups and its effects on Th1/Th2 differentiation were subsequently studied. Effects of TLR7 on Th1/Th2 balance and platelet counts were also studied in vivo using a thrombocytopenic mouse model.
In in vitro assays, imiquimod enhanced interleukin (IL)-12 secretion in macrophages from ITP patients inducing Th1 differentiation. However, IRS 661 had the exact opposite effect and skewed Th differentiation towards the Th2 subset in ITP. Results from our in vivo studies indicated that injection of imiquimod in ITP mice resulted in elevated plasma levels of IFN-γ and decreased platelet counts. Nevertheless, injection of IRS 661 resulted in elevated plasma levels of IL-4 and platelet counts.
These findings indicate that TLR7 promotes Th1 polarization and may contribute thus in the pathogenesis of ITP.
Viruses and virus-induced lymphokines may have an important role in the pathogenesis of autoimmunity (Schattner A. Clin Immunol Immunopathol; 1994). The occurrence and significance of autoimmune manifestations after the administration of viral vaccines remain controversial.
Medline search of all relevant publications from 1966 through June 2004 with special emphasis on search of each individual autoimmune manifestation and vaccination, as well as specifically searching each viral vaccine for all potential autoimmune syndromes reported. All relevant publications were retrieved and critically analyzed.
The most frequently reported autoimmune manifestations for the various vaccinations, were: hepatitis A virus (HAV) — none; hepatitis B virus (HBV) — rheumatoid arthritis, reactive arthritis, vasculitis, encephalitis, neuropathy, thrombocytopenia; measles, mumps and rubella vaccine (MMR) — acute arthritis or arthralgia, chronic arthritis, thrombocytopenia; influenza — Guillain–Barre syndrome (GBS), vasculitis; polio — GBS; varicella — mainly neurological syndromes. Even these ‘frequent’ associations relate to a relatively small number of patients. Whenever controlled studies of autoimmunity following viral vaccines were undertaken, no evidence of an association was found.
Very few patients may develop some autoimmune diseases following viral vaccination (in particular — arthropathy, vasculitis, neurological dysfunction and thrombocytopenia). For the overwhelming majority of people, vaccines are safe and no evidence linking viral vaccines with type 1 diabetes, multiple sclerosis (MS) or inflammatory bowel disease can be found.
BCL-3 and NF-κB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages
2004, Journal of Biological ChemistryLipopolysaccharide (LPS) induces expression of tumor necrosis factor α (TNFα) and other pro-inflammatory cytokines in macrophages. Following its induction, TNFα gene transcription is rapidly attenuated, in part due to the accumulation of NF-κB p50 homodimers that bind to three κB sites in the TNFα promoter. Here we have investigated the inhibitory role of BCL-3, an IκB-like protein that interacts exclusively with p50 and p52 homodimers. BCL-3 was induced by LPS with delayed kinetics and was associated with p50 in the nucleus. Forced expression of BCL-3 suppressed LPS-induced transcription from the TNFα promoter and inhibited two artificial promoters composed of TNFακB sites that preferentially bind p50 dimers. BCL-3-mediated repression was reversed by trichostatin A and was enhanced by overexpression of HDAC-1, indicating that transcriptional attenuation involves recruitment of histone deacetylase. Analysis of macrophages from p50 and BCL-3 knock-out mice revealed that both transcription factors negatively regulate TNFα expression and that BCL-3 inhibits IL-1α and IL-1β. In contrast, induction of the anti-inflammatory cytokine IL-10 was reduced in BCL-3 null macrophages. BCL-3 was not required for the production of p50 homodimers but BCL-3 expression was severely diminished in p50-deficient cells. Together, these findings indicate that p50 and BCL-3 function as anti-inflammatory regulators in macrophages by attenuating transcription of pro-inflammatory cytokines and activating IL-10 expression.
Overview of cellular immune function in systemic lupus erythematosus
2004, Systemic Lupus Erythematosus, Fourth EditionLymphoid distribution in the migratory gull Larus ridibundus
2003, Comparative Biochemistry and Physiology - A Molecular and Integrative PhysiologyWe studied the distribution of lymphocytes in the main lymphoid tissues (blood, spleen and thymus) of the gull Larus ridibundus, searching for variations that might depend on the migratory cycle. We also looked for sex- and age-associated differences in lymphoid redistribution. In L. ridibundus, lymphocytes are the most commonly observed leukocyte subpopulation in blood. Moreover, changes in the distribution of lymphocytes in the lymphoid tissue occur, depending on the migratory period. The proportion of these cells in spleen is greater in the post-migratory and pre-migratory periods compared to the non-migratory period. The percentages of circulating lymphocytes are high in the pre-migratory period, but depletion occurs in the post-migratory period. In contrast, the age or the sex of the animals did not confer any major differences on the lymphoid distribution.
Interferon-γ-induced epithelial ICAM-1 expression and monocyte adhesion. Involvement of protein kinase c-dependent c-Src tyrosine kinase activation pathway
2002, Journal of Biological ChemistryInterferon-γ (IFN-γ) induced intercellular adhesion molecule-1 (ICAM-1) expression in human NCI-H292 epithelial cells, as shown by enzyme-linked immunosorbent assay and immunofluorescence staining. The enhanced ICAM-1 expression resulted in increased adhesion of U937 cells to NCI-H292 cells. Tyrosine kinase inhibitors (genistein or herbimycin), Src family inhibitor (PP2), or a phosphatidylinositol-phospholipase C inhibitor (U73122) attenuated the IFN-γ-induced ICAM-1 expression. Protein kinase C (PKC) inhibitors (staurosporine or Ro 31-8220) also inhibited IFN-γ-induced response. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a PKC activator, stimulated ICAM-1 expression; this effect was inhibited by tyrosine kinase or Src inhibitor. ICAM-1 promoter activity was enhanced by IFN-γ and TPA in cells transfected with pIC339-Luc, containing the downstream NF-κB and γ-activated site (GAS) sites, but not in cells transfected with GAS-deletion mutant, pIC135 (ΔAP2). Electrophoretic gel mobility shift assay demonstrated that GAS-binding complexes in IFN-γ-stimulated cells contained STAT1α. The IFN-γ-induced ICAM-1 promoter activity was inhibited by tyrosine kinase inhibitors, a phosphatidylinositol-phospholipase C inhibitor, or PKC inhibitors, and the TPA-induced ICAM-1 promoter activity was also inhibited by tyrosine kinase inhibitors. Cotransfection with a PLC-γ2 mutant inhibited IFN-γ- but not TPA-induced ICAM-1 promoter activity. However, cotransfection with dominant negative mutants of PKCα or c-Src inhibited both IFN-γ- and TPA-induced ICAM-1 promoter activity. The ICAM-1 promoter activity was stimulated by cotransfection with wild type PLC-γ2, PKCα, c-Src, JAK1, or STAT1. An immunocomplex kinase assay showed that both IFN-γ and TPA activated c-Src and Lyn activities and that these effects were inhibited by staurosporine and herbimycin. Thus, in NCI-H292 epithelial cells, IFN-γ activates PLC-γ2 via an upstream tyrosine kinase to induce activation of PKC-α and c-Src or Lyn, resulting in activation of STAT1α, and GAS in the ICAM-1 promoter, followed by initiation of ICAM-1 expression and monocyte adhesion.