453 research outputs found
The Hochberg: Rheumatology, 7e:Biology and immunopathogenesis of vasculitis Elisabeth Brouwer • Peter Heeringa • Cees G.M. Kallenberg
No full textKey Points■ The interplay between leukocytes and endothelium is important in inflammatoryprocesses in general and in the pathogenesis of vasculitis in particular.■ Cytokine-induced endothelial cell activation and leukocyte–endothelium interactionsare coordinated processes underlying differential leukocyte recruitment to sites ofinflammation■ Immune complex formation and deposition underlie the small-vessel vasculitides inimmunoglobulin A vasculitis (Henoch-Schönlein purpura), anti–glomerular basementmembrane disease, cryoglobulinemic vasculitis, and hypocomplementemic urticarialvasculitis.■ Clinical and experimental data suggest but do not prove that antineutrophilcytoplasmic antibodies (ANCAs) directed against proteinase 3, and myeloperoxidaseare pathogenic in the ANCA-associated small-vessel vasculitides.■ Toll-like receptor–mediated dendritic cell activation in the adventitia followed byinterferon-γ–producing T helper cell 1 and interleukin-17–producing T helper cell 17responses to as yet undefined antigen(s) is the major pathogenic event in themedium- and large-vessel vasculitide
The Hochberg: Rheumatology, 7e:Biology and immunopathogenesis of vasculitis Elisabeth Brouwer • Peter Heeringa • Cees G.M. Kallenberg
No full textKey Points■ The interplay between leukocytes and endothelium is important in inflammatoryprocesses in general and in the pathogenesis of vasculitis in particular.■ Cytokine-induced endothelial cell activation and leukocyte–endothelium interactionsare coordinated processes underlying differential leukocyte recruitment to sites ofinflammation■ Immune complex formation and deposition underlie the small-vessel vasculitides inimmunoglobulin A vasculitis (Henoch-Schönlein purpura), anti–glomerular basementmembrane disease, cryoglobulinemic vasculitis, and hypocomplementemic urticarialvasculitis.■ Clinical and experimental data suggest but do not prove that antineutrophilcytoplasmic antibodies (ANCAs) directed against proteinase 3, and myeloperoxidaseare pathogenic in the ANCA-associated small-vessel vasculitides.■ Toll-like receptor–mediated dendritic cell activation in the adventitia followed byinterferon-γ–producing T helper cell 1 and interleukin-17–producing T helper cell 17responses to as yet undefined antigen(s) is the major pathogenic event in themedium- and large-vessel vasculitide
The Hochberg: Rheumatology, 7e:Biology and immunopathogenesis of vasculitis Elisabeth Brouwer • Peter Heeringa • Cees G.M. Kallenberg
No full textKey Points■ The interplay between leukocytes and endothelium is important in inflammatoryprocesses in general and in the pathogenesis of vasculitis in particular.■ Cytokine-induced endothelial cell activation and leukocyte–endothelium interactionsare coordinated processes underlying differential leukocyte recruitment to sites ofinflammation■ Immune complex formation and deposition underlie the small-vessel vasculitides inimmunoglobulin A vasculitis (Henoch-Schönlein purpura), anti–glomerular basementmembrane disease, cryoglobulinemic vasculitis, and hypocomplementemic urticarialvasculitis.■ Clinical and experimental data suggest but do not prove that antineutrophilcytoplasmic antibodies (ANCAs) directed against proteinase 3, and myeloperoxidaseare pathogenic in the ANCA-associated small-vessel vasculitides.■ Toll-like receptor–mediated dendritic cell activation in the adventitia followed byinterferon-γ–producing T helper cell 1 and interleukin-17–producing T helper cell 17responses to as yet undefined antigen(s) is the major pathogenic event in themedium- and large-vessel vasculitide
Involvement of high mobility group box 1 in the auto-inflammatory process in systemic lupus erythematosus
No full textIn this thesis we investigated the role of High Mobility Group Box-1 (HMGB1), in the auto-inflammatory process in Systemic Lupus Erythematosus (SLE). HMGB1 is a nuclear protein which is present in every cell in the body, but also has immunological properties. Earlier studies have demonstrated that HMGB1 levels are increased in patients with SLE and correlate with disease activity. Collectively, studies suggest that HMGB1 is an important factor in the pathogenesis of SLE and could constitute a potential therapeutic target. However, the underlying mechanisms by which HMGB1 contributes to SLE pathogenesis are not fully understood. First, we demonstrated that addition of HMGB1 results in a more pro-inflammatory phenotype of macrophages. It has been reported that HMGB1 can contribute to a decrease in phagocytic capacity of macrophages. In particular, we demonstrated that HMGB1 contributes to the impaired phagocytosis capacity of macrophages, as seen in SLE, by interfering with recognition of apoptotic cells as well as by influencing the macrophage itself. As such, HMGB1 can be considered an important factor in sustaining the auto-inflammatory processes in SLE. We investigated whether treatment with a anti-HMGB1 antibody affects the development of lupus nephritis in lupus mice. Contrary to our expectations did not ameliorate glomerulonephritis. Also, no differences were observed with respect to other markers of disease or pro-inflammatory cytokines between mice treated with control antibody or mice treated. In summary, the results from this thesis provide further evidence that HMGB1 is involved in SLE pathogenesis but treatment with anti-HMGB1 antibodies did not alter disease development in lupus mice
Effector mechanisms of ANCA-associated glomerulonephritis
No full textThe ANCA-associated small-vessel vasculitides (ANCA-SVV) Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis are severe diseases that have a high mortality rate when left untreated. Current treatment protocols are based on non-specific immunosuppression, which is insuffi cient in preventing relapses and is characterized by severe side-eff ects. More eff ective and less toxic therapies are therefore needed. A better understanding of the pathogenic eff ector mechanisms underlying ANCA-SVV can improve the development of specific therapeutic strategies. The aim of this thesis was therefore to explore further the eff ector mechanisms involved in ANCA-associated glomerulonephritis, focusing on the discovery of targets for treatment and the testing of experimental therapies. More specifi cally, we concentrated on the importance of infl ammatory stimuli and ANCA IgG characteristics in disease and the therapeutic potential of interfering with leukocyte behaviour.
ANCA-SVV: COMPLEX MULTIFACTORIAL DISEASES
By definition, patients with autoimmune diseases have a loss of immunological tolerance towards an autoantigen, but it is usually less clear why such a break in tolerance occurs. In line with this, it is not known why ANCA autoantibodies develop in ANCA-SVV patients. In recent years, several theories have been proposed to explain the immunogenesis of ANCA-SVV.
The theory of antigen complementarity assumes that antibodies directed against a protein or peptide (antisense) that is complementary to the ANCA antigen (sense) are generated. 1 A subsequent immune response against the antigen-binding part of these antibodies generates idiotypic antibodies that cross-react with the ANCA antigen. The antisense protein or peptide in this theory may be derived from aberrant antisense transcription or from pathogens. A second theory involves molecular mimicry of exogenous proteins with ANCA antigens. This theory assumes that the initial immune response is evoked against pathogen-derived peptides that are highly homologous to peptide sequences within the ANCA-antigens, resulting in a cross-reactive immune response against the ANCA self antigens. Evidence for the occurrence of molecular mimicry in ANCA-SVV is provided by a study showing that circulating autoantibodies against lysosomal associated membrane protein 2 (LAMP-2), a heavily glycosylated type 1 membrane protein involved in cellular adhesion and homeostasis, were highly prevalent in patients with MPO-ANCA- and Pr3- ANCA-positive crescentic glomerulonephritis.2. These anti-LAMP-2 antibodies were able to activate neutrophils and endothelial cells in vitro, whereas injection of these antibodies into rats induced pauci-immune crescentic glomerulonephritis. Most interestingly, the authors showed that a major epitope recognized by anti-LAMP-2 antibodies was highly homologous to FimH-1, a bacterial adhesin of common gram-negative bacteria. When rats were immunized with FimH-1, antibodies directed against FimH-1 were generated that cross-reacted with LAMP-2. Importantly, these rats also developed necrotizing crescentic glomerulonephritis.
Review article: Pathogenic role of complement activation in anti-neutrophil cytoplasmic auto-antibody-associated vasculitis
No full textSmall-vessel vasculitides associated with anti-neutrophil cytoplasmic auto-antibodies (ANCA) are severe systemic diseases that may affect any organ. Increasing evidence from clinical, animal and in vitro studies indicates that ANCA are causally involved in disease pathogenesis mainly through activation of neutrophils resulting in endothelial cell injury. Recent studies suggest a previously unsuspected but crucial role for alternative pathway complement activation in ANCA disease pathogenesis. In this brief review, we will discuss the evidence for complement system activation in ANCA-associated vasculitides and propose a working model that links ANCA, neutrophils and complement activation in causing an inflammatory amplification loop that may explain the severe leukocytoclastic inflammation that is typical for ANCA-associated vasculitis
Metabolic inflammation in hepatic and vascular disorders: Strategies to attenuate disease development
No full textIn de afgelopen jaren is het steeds duidelijker geworden dat ontsteking – een normaal en essentieel verdedigingsmechanisme dat het lichaam beschermt tegen infectie en beschadiging – ook veroorzaakt kan worden door een overdaad aan voeding of specifieke nutriënten. Deze ontstekingstoestand wordt metabole ontsteking genoemd. Van deze laaggradige en chronische ontstekingsreactie wordt gedacht dat hij een belangrijke rol speelt in de ontwikkeling van obesitas-gerelateerde ziekten zoals type 2 diabetes, niet-alcoholische leververvetting en hart en vaatziekten. Er is echter nog veel onbekend over de oorsprong en het mechanisme van metabole ontsteking. Het doel van het onderzoek beschreven in dit proefschrift was om het ontstaan van metabole ontsteking beter te begrijpen, en om mogelijke interventies gericht op specifieke aspecten van metabole ontsteking te onderzoeken. We hebben verschillende benaderingen onderzocht, gebruikmakend van zowel farmaceutische als voedingsinterventies, en hebben de kracht van deze interventies om metabole ziekteontwikkeling te remmen beoordeeld. De focus lag op niet-alcoholische leververvetting en cardiovasculaire ziekten als primaire ziekte-eindpunten. We hebben laten zien dat interventies die de ontstekingsreactie op metabole overbelasting kunnen onderdrukken een krachtige methode bieden om ziekteontwikkeling te remmen. Deze interventies kunnen daarom waardevol zijn in de preventie en/of vertraging van metabole ziekten
Animal models of anti-neutrophil cytoplasmic antibody associated vasculitis
No full textDespite intensive reserach over the last 15 years, the etiology and pathogenesis of vasculitis associated with anti-neutrophil cytoplasmic antibodes is still far from understood. The close association with ANCA and the clinical observation that rises in the level of these autoantibodies often precede relapses in disease activity has promted the hypothesis that ANCA are intimately ivolved in the pathogenesis of these vasculitic disorders. ...
Zie: Chapter 10
Diet-induced metabolic dysfunction: Systemic views on micro- and macrovascular pathologies
No full textHoewel het onomstotelijk vast staat dat obesitas gepaard gaat met een verhoogd risico op metabole en (cardio-)vasculaire aandoeningen zoals type 2 diabetes, aderverkalking en chronische nierziekte, is er veel minder bekend over hun ontstaansgeschiedenis. De studies in dit proefschrift hebben zich toegespitst op hoe dierlijk vet en cholesterol bijdragen aan het ontstaan van een verstoord metabolisme in het vetweefsel en de lever, hoe dit bijdraagt aan verhoogde ontstekings- en lipiden waarden in het bloed en hoe dit vervolgens tot schade aan de kleine en grote vaatsystemen leidt. We leveren bewijs dat ontsteking van het vetweefsel een grotere bijdrage levert aan verhoogde ontstekingswaarden in het bloed en de ontwikkeling van type II diabetes dan de lever. Deze bevinding geeft aan dat ontstekingsremmende strategieën zich het best op dit orgaan kunnen richten. Een van de manieren om dit te bewerkstelligen is door de continue inname van natuurlijke anti-ontstekingsstoffen parallel aan de negatieve voedingstoffen. Deze stoffen, polyfenolen genaamd, komen in hoge concentraties voor in bepaalde groenten en fruit soorten en andere plantaardige producten zoals thee. In tegenstelling tot andere groepen hebben wij geen blijvende positieve effecten in het vetweefsel of bloed aan deze stoffen kunnen toeschrijven. Deze discrepantie wordt mogelijk veroorzaakt door de relatief lage dosering die gebruikt werd, alsmede het orgaan waar naar gekeken werd. Maar ook de dieettrigger blijkt van belang: zo laten we namelijk zien dat dezelfde polyfenolen wél een positief effect hebben als niet dierlijk vet maar cholesterol de trigger voor metabole dysfunctie is. Het proefschrift is een pleidooi voor een integrale, systemische kijk op dieet geïnduceerde metabole dysfunctie en ziekten
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