Publikationsserver der Universitätsbibliothek Marburg

Titel:Characterization of cellular and humoral immune responses in pemphigus patients and an HLA-transgenic mouse model
Autor:Hennerici, Tina
Weitere Beteiligte: Eming, Rüdiger (PD Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0199
DOI: https://doi.org/10.17192/z2017.0199
URN: urn:nbn:de:hebis:04-z2017-01997
DDC: Medizin, Gesundheit
Titel(trans.):Charakterisierung zellulärer und humoraler Immunantworten bei Pemphigus-Patienten und einem HLA-transgenen Mausmodell
Publikationsdatum:2017-03-30
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Autoimmunity, Autoantikörper, Autoantibodies, Antikörper, Autoimmunität

Summary:
The rare, but potentially fatal autoimmune disorder pemphigus is considered as a prototypical antibody-mediated organ-specific disease, in which immunoglobulin (Ig) G autoantibodies (auto-ab) mainly target the desmosomal cadherins Desmoglein 3 (Dsg3) and Dsg1 within the epidermis. This process, referred to as acantholysis, manifests clinically with the formation of flaccid blisters and erosions of the skin and mucous membranes. Still to date, therapeutic intervention is predominantly limited to unspecific immunosuppression causing severe side effects and comorbidities. Although it has long been recognized that auto-ab crucially contribute to the pathology of pemphigus, the exact immunological events leading to the loss of self-tolerance have not yet been fully identified. Aim of the first part of this doctoral thesis was to investigate antigen-presenting cells (APC) and APC-derived cytokines, as well as their relation to T helper (Th) cell subsets and the auto-ab response in the pathogenesis of pemphigus. Therefore, blood samples were obtained from 34 pemphigus patients, of which twelve clinically well characterized patients with no or minimal intake of immunosuppressive agents were selected for comprehensive analysis. This study group consisted of nine pemphigus vulgaris (PV), as well as three pemphigus foliaceus (PF) patients who were categorized according to either active or remittent state of disease. A cohort of twelve patients suffering from the autoimmune muscle weakness myasthenia gravis (MG) served as a control for a further unrelated auto-ab–mediated organ-specific disorder. Concerning the APC compartment, a major finding was reduced circulating frequencies of both myeloid and plasmacytoid dendritic cells (mDC and pDC, respectively) in active pemphigus patients. In concordance with this observation, augmented surface expression of the C-C chemokine receptor 2 (CCR2) of mDC suggest an increased migration activity to inflamed peripheral tissues, such as the skin. Similarly, active pemphigus patients displayed an upregulation of CCR2 on blood CD14+ monocytes, as well as elevated numbers of circulating CD16+ monocytes with expansion of the nonclassical subset. However, functional analysis on the cellular level could not confirm an enhanced immunogenicity status of APC in active pemphigus patients, yet we found in these patients increased plasma levels of the proinflammatory tumor necrosis factor (TNF)-α. Interestingly, plasma concentrations of interleukin (IL)-27 known to exert primarily regulatory functions were also elevated in active pemphigus patients, pointing to a rather inflammatory role of IL-27 in disease pathogenesis. Strikingly, in pemphigus patients, a significant correlation was not only found between serum IgG auto-ab titers and plasma levels of both IL-6 and TNF-α, but also between auto-ab titers and plasma concentrations of IL-27. Furthermore, similarly augmented plasma levels of IL-21 playing a crucial role in B cell activation possibly indicate the mechanism of an IL-27–mediated activation of IL-21–producing Tfh cells. Finally, as a further major finding, we observed an increase of both Th17 cells and IL-10–secreting T cells in active pemphigus patients. Aim of the second part of this doctoral thesis was to investigate Dsg3-specific cellular and humoral immune responses in a novel human leukocyte antigen (HLA)-DRB1*04:02–transgenic (tg) mouse model of PV under the genetic restriction by HLA-DRB1*04:02. Rationale for the generation of this model is the high prevalence of distinct HLA class II alleles in PV patients, such as HLA-DRB1*04:02, –DRB1*14:01, and –DQB1*05:03. The occurrence of PV being associated with the presence of specific HLA class II alleles thereby reflects the high relevance of autoreactive CD4+ T cells in disease pathogenesis. In summary, this experimental study convincingly confirmed that the PV mouse model reproduces the principle mechanisms of HLA-dependent and human Dsg3-specific induction of CD4+ T and B cell responses observed in PV patients. Accordingly, the generation of Dsg3-reactive IgG antibody responses highly depended on prior activation of Dsg3-reactive CD4+ T cells. In turn, APC-mediated activation of T cells critically relied on the recognition of epitopes of the Dsg3 ectodomain, which displayed strong binding affinity to the PV-linked HLA class II allele HLA-DRB1*04:02. Furthermore, limited cross-reactivity of human Dsg3-specific IgG antibodies with the mouse analogue protein explained lack of the clinical phenotype of PV upon immunization of HLA-DRB1*04:02–tg mice with human Dsg3 protein. Yet, this model accurately reflects that polymorphisms of peptide-binding motifs of specific PV-related HLA-class II alleles tightly regulate CD4+ T cell-mediated induction of Dsg3-reactive IgG antibodies. Therefore, this novel mouse model represents a suitable tool for further investigations of the pathoimmunological mechanisms of PV in vivo considering the strong HLA class II association of this disease.

Zusammenfassung:
Die prototypische antikörpervermittelte und organspezifische Autoimmunerkrankung Pemphigus zeichnet sich durch Autoantikörper der Immunglobulinklasse G (IgG) aus, welche vornehmlich gegen die desmosomalen Cadherine Desmoglein 3 (Dsg3) und Dsg1 in der Epidermis gerichtet sind. Dieser Prozess, der Akantholyse genannt wird, äußert sich klinisch in der Bildung von fragilen Blasen und Erosionen auf Haut und Schleimhaut. Therapiemöglichkeiten beschränken sich zurzeit überwiegend auf eine unspezifische Immunsuppression, welche mit dem Risiko schwerer Nebenwirkungen und Folgeerkrankungen einhergeht. Obwohl lange bekannt ist, dass IgG-Autoantikörper wesentlich an der Pathologie des Pemphigus beteiligt sind, ist dennoch unklar, welche immunologischen Mechanismen im Einzelnen zum Verlust der Selbsttoleranz führen. Ziel des ersten Teils dieser Dissertation war es, antigenpräsentierende Zellen (APC) und APC-assoziierte Zytokine sowie deren Beziehung zu T-Helfer (Th)-Zell-Populationen und zur Autoantikörper-Antwort in der Pathogenese des Pemphigus zu untersuchen. Zu diesem Zwecke wurden 34 Pemphigus-Patienten Blutproben entnommen und zwölf klinisch detailliert charakterisierte Patienten für eine umfassendere Analyse ausgewählt, welche keiner oder einer nur minimalen Immunsuppression unterlagen. Diese Kohorte bestand aus neun Pemphigus vulgaris (PV)- und drei Pemphigus foliaceus (PF)-Patienten, die entsprechend eines aktiven oder remittierenden Krankheitsstatus subgruppiert wurden. Als Kontrollgruppe wurden zwölf Patienten der autoimmunen Muskelschwäche Myasthenia gravis (MG) definiert, welche eine unabhängige autoantikörpervermittelte und organspezifische Autoimmunerkrankung darstellt. Im APC-Kompartiment konnte als wesentliches Ergebnis eine verminderte Anzahl zirkulierender myeloider und plasmazytoider dendritischer Zellen (DC) bei aktiven Pemphigus-Patienten festgestellt werden. Eine gleichzeitig vermehrte Oberflächenexpression des C-C Chemokinrezeptors-2 (CCR2) auf myeloiden DC weist in diesem Zusammenhang auf eine erhöhte Migration dieser Zellen in entzündete periphere Gewebe wie der Haut hin. Analog zeigte sich eine vermehrte Expression des CCR2 auf CD14+ Monozyten sowie eine erhöhte zirkulierende Population an CD16+ Monozyten mit selektiver Expansion der nichtklassischen Subpopulation. Eine funktionelle Analyse auf zellulärer Ebene konnte allerdings keinen erhöhten Immunstatus der APC bei aktiven Pemphigus-Patienten nachweisen, jedoch zeigten sich bei diesen Patienten erhöhte Plasmaspiegel des entzündungsfördernden Tumornekrosefaktors-α (TNF-α). Interessanterweise ergaben sich außerdem bei aktiven Pemphigus-Patienten erhöhte Plasmaspiegel des überwiegend immunregulatorischen Interleukin-27 (IL-27), das hauptsächlich von aktivierten APC produziert wird. Diese Beobachtung deutet auf eine entzündliche Funktion des IL-27 beim Pemphigus hin. Bemerkenswerterweise ergab sich darüber hinaus bei Pemphigus-Patienten nicht nur eine signifikante Korrelation zwischen Serum-Autoantikörpern und den Plasmaspiegeln von IL-6 und TNF-α, sondern auch eine signifikante Korrelation zwischen IgG-Autoantikörpern und der Plasmakonzentration von IL-27. Die beobachteten, ebenfalls erhöhten Plasmaspiegel des IL-21, welches eine wesentliche Funktion in der B-Zell-Aktivierung innehat, weisen auf eine mögliche Aktivierung von IL-21–produzierenden follikulären Th-Zellen in Abhängigkeit von IL-27 hin. Schließlich wurde als weiteres auffälliges Ergebnis der Studie bei aktiven Pemphigus-Patienten eine deutliche Zunahme an inflammatorischen Th-17-Zellen sowie IL-10–sezernierenden Th-Zellen festgestellt. Ziel im zweiten Abschnitt dieser Dissertation war es, Dsg3-spezifische zelluläre und humorale Immunantworten in einem neuartigen human leukocyte antigen (HLA)-DRB1*04:02–transgenen PV-Mausmodell zu untersuchen unter der genetischen Restriktion von HLA-DRB1*04:02. Dieses Modell wird definiert durch die hohe Prävalenz bestimmter HLA-Klasse-II-Allele bei PV-Patienten wie HLA-DRB1*04:02, –DRB1*14:01, und –DQB1*05:03. Der enge Zusammenhang zwischen dem Vorkommen von PV und dem Auftreten spezifischer HLA-Klasse-II-Risikoallele ist ein Indiz für die wesentliche Funktion autoreaktiver CD4+ T-Zellen in der Pathogenese der Erkrankung. Zusammenfassend geht aus dieser tierexperimentellen Studie schlüssig hervor, dass sich die in PV-Patienten identifizierten Mechanismen der HLA-abhängigen und Dsg3-spezifischen Induktion von CD4+ T– und B-Zell-Antworten in diesem Modell wiederspiegeln. Entsprechend zeigte sich in der Entstehung Dsg3-spezifischer Antikörper eine direkte Abhängigkeit von der Aktivierung Dsg3-reaktiver CD4+ T Zellen. Die APC-vermittelte Aktivierung dieser T-Zellen unterlag wiederum der Erkennung von Epitopen der Dsg3-Ektodomäne, welche eine hohe Bindungsaffinität zu dem PV-assoziierten HLA-DRB1*04:02–Allel aufwiesen. Darüber hinaus erklärte eine nur geringe Kreuzreaktivität der Antikörper zwischen humanem und murinem Dsg3-Protein das Fehlen eines klinischen Phänotyps bei HLA-DRB1*04:02–transgenen Mäusen trotz wiederholter Immunisierung mit humanem Dsg3-Protein. Jedoch gab dieses PV-Mausmodell konsequent wieder, dass die Peptidbinde-Motive spezifischer PV-assoziierter HLA-Klasse-II-Allele eine wesentliche Rolle in der CD4+-T-Zell-vermittelten Induktion von Dsg3-reaktiven Antikörpern spielen. Dieses PV-Mausmodell stellt daher ein geeignetes Instrument dar, um zukünftig immunpathologische Mechanismen des PV in vivo unter Berücksichtigung der starken HLA-Klasse-II-Assoziation dieser Erkrankung zu untersuchen.

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