The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris—Analysis of Four Different Ethnic Cohorts

Recke, Andreas; Konitzer, Sarah; Lemcke, Susanne; Freitag, Miriam; Sommer, Nele Maxi; Abdelhady, Mohamed; Amoli, Mahsa M.; Benoit, Sandrine; Elchennawy, Farha A.; El-Darouti, Mohammad Ali; Eming, Rüdiger; Gläser, Regine; Günther, Claudia; Hadaschik, Eva; Homey, Bernhard; Lieb, Wolfgang; Peitsch, Wiebke K.; Pföhler, Claudia; Robati, Reza M.; Saeedi, Marjan Ghazi; Sárdy, Miklós; Sticherling, Michael; Uzun, Soner; Worm, Margitta; Zillikens, Detlef; Ibrahim, Saleh M.; Vidarsson, Gestur; Schmidt, Enno

doi:10.3389/fimmu.2018.01788

Cited by 18 publications

(10 citation statements)

References 28 publications

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“…Overexpression of ST18 is able to heighten the susceptibility to deletion of keratinocytes adhesion, and enhanced extracellular signal-regulated kinase (ERK) signaling is a possible mechanism [ 16 ]. A p.Arg435His variation in IgG3 has been reported to be associated with PV in cohorts including German, Turkish, Egyptian and Iranian patients [ 17 ].…”

Section: Pemphigusmentioning

confidence: 99%

The pathogenesis of bullous skin diseases

Yang

Zhao

et al. 2019

Journal of Translational Autoimmunity

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Bullous skin diseases are a group of dermatoses characterized by blisters and bullae in the skin and mucous membranes. The etiology and pathogenesis of bullous skin diseases are not completely clear. The most common are pemphigus and bullous pemphigoid (BP). Autoantibodies play critical roles in their pathogenesis. Abnormalities in the adhesion between keratinocytes in patients with pemphigus leads to acantholysis and formation of intra-epidermal blisters. Anti-desmoglein autoantibodies are present both in the circulation and skin lesions of patients with pemphigus. The deficient adhesion of keratinocytes to the basement membrane in BP patients gives rise to subepidermal blisters. Autoantibodies against the components of hemidesmosome can be detected in BP patients. Many novel therapeutics based on knowledge of the pathogenesis have emerged in recent years.

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Section: Pemphigusmentioning

confidence: 99%

The pathogenesis of bullous skin diseases

Yang

Zhao

et al. 2019

Journal of Translational Autoimmunity

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“…In this study, blocking of FcRn abolished the capacity of PV sera to cause detachment of keratinocytes in vitro (284). In another study, Recke et al (285) found that an allelic variant harboring an amino acid replacement of His435 to Arg favoring high affinity of IgG3 to FcRn was associated with an increase risk of PV. Altogether these studies raise evidence for a potential benefit of targeting FcRn in pemphigus.…”

Section: Emerging Therapiesmentioning

confidence: 99%

Pemphigus: Current and Future Therapeutic Strategies

et al. 2019

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Pemphigus encompasses a heterogeneous group of autoimmune blistering diseases, which affect both mucous membranes and the skin. The disease usually runs a chronic-relapsing course, with a potentially devastating impact on the patients' quality of life. Pemphigus pathogenesis is related to IgG autoantibodies targeting various adhesion molecules in the epidermis, including desmoglein (Dsg) 1 and 3, major components of desmosomes. The pathogenic relevance of such autoantibodies has been largely demonstrated experimentally. IgG autoantibody binding to Dsg results in loss of epidermal keratinocyte adhesion, a phenomenon referred to as acantholysis. This in turn causes intra-epidermal blistering and the clinical appearance of flaccid blisters and erosions at involved sites. Since the advent of glucocorticoids, the overall prognosis of pemphigus has largely improved. However, mortality persists elevated, since long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants portend a high risk of serious adverse events, especially infections. Recently, rituximab, a chimeric anti CD20 monoclonal antibody which induces B-cell depletion, has been shown to improve patients' survival, as early rituximab use results in higher disease remission rates, long term clinical response and faster prednisone tapering compared to conventional immunosuppressive therapies, leading to its approval as a first line therapy in pemphigus. Other anti B-cell therapies targeting B-cell receptor or downstream molecules are currently tried in clinical studies. More intriguingly, a preliminary study in a preclinical mouse model of pemphigus has shown promise regarding future therapeutic application of Chimeric Autoantibody Receptor T-cells engineered using Dsg domains to selectively target autoreactive B-cells. Conversely, previous studies from our group have demonstrated that B-cell depletion in pemphigus resulted in secondary impairment of T-cell function; this may account for the observed long-term remission following B-cell recovery in rituximab treated patients. Likewise, our data support the critical role of Dsg-specific T-cell clones in orchestrating the inflammatory response and B-cell activation in pemphigus. Monitoring autoreactive T-cells in patients may indeed provide further information on the role of these cells, and would be the starting point for designating therapies aimed at restoring the lost immune tolerance against Dsg. The present review focuses on current advances, unmet challenges and future perspectives of pemphigus management.

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“…The H435-IgG3 allele is most common in Africans (30%-60%), suggesting a possible role for positive selection, given its relatively high frequency in malaria endemic areas [9]. However, the G3m15 and G3m16 allotypes have also been associated with increased susceptibility to the autoantibody-mediated disease pemphigus vulgaris (PV), a severe blistering skin disorder, and thus, IgG3 might play a role in the pathogenesis of PV; alternatively, there may be a genetic association between H435-IgG3 alleles and PV in Middle Eastern and North African countries [101]. More research on IgG3 polymorphism frequencies in endemic populations may aid in the identification of potential selective advantages and disadvantages of these IgG3 polymorphisms [9].…”

Section: Parasitic Infectionsmentioning

confidence: 99%

Role of IgG3 in Infectious Diseases

Damelang

Rogerson

Kent

et al. 2019

Trends in Immunology

157

126

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Immunoglobulin IgG3 comprises only a minor fraction of IgG in human plasma and has remained relatively understudied until recent years. Key physiochemical characteristics of IgG3 include an elongated hinge region, greater molecular flexibility, extensive polymorphisms and additional glycosylation sites not present on other IgG subclasses. These characteristics make IgG3 a uniquely potent immunoglobulin, with the potential for triggering effector functions including complement activation, antibody-mediated phagocytosis or antibody-mediated cellular cytotoxicity. Recent studies underscore the importance of IgG3 effector functions against a range of pathogens and have provided approaches to overcome IgG3-associated limitations, such as allotype-dependent short antibody half-life and excessive pro-inflammatory activation. Understanding the molecular and functional properties of IgG3 may facilitate the development of improved antibody-based immunotherapies and vaccines against infectious diseases. IgG3 allotypic variations can have structural and functional consequences, such as a shorter hinge regions and extended half-life compared to other allotypes [23, 24]. In addition, polymorphisms in the CH3 domain affect the CH3-CH3 interdomain interactions [25], with potential consequences for C1q binding in complement activation [25, 26]. Specific allotypes also contribute to underappreciated difficulties in purifying human IgG3 from serum samples, where only allotypes containing a histidine residue at position 435 can be purified by protein A [27]. Glycosylation of IgG3Glycosylation is a post-translational modification of IgG Abs, which can be regulated by a range of B-cell stimuli, including environmental factors, such as stress or diseases, cytokines and innate immune signaling receptors, such as Toll-like receptors. Hence, exposure to specific pathogens, antigens, or vaccination has the potential to skew Ab glycan profiles [28]. Glycosylation is an inherent mechanism of Ab diversification, on top of V(D)J recombination, somatic hypermutation (SHM) and class switch recombination (CSR), and thereby contributes to the extent of the Ab repertoire of B-cells [29].IgG3 Abs can include up to three potential glycosylation sites. The most well-described glycosylation site is found in all human IgG subclasses, where carbohydrate groups are attached to asparagine 297 in the CH2 domain (Fig. 1c). The glycans at this Nglycosylation site can influence Ab stability [30], binding to Fcγ-receptors (FcγRs)and complement [31], consequently modulating effector functions, such as complement-dependent cytotoxicity (CDC) and Ab-dependent cell cytotoxicity (ADCC) [32][33][34][35][36]. For instance, it has been shown that monoclonal IgG3 Abs expressed

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The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris—Analysis of Four Different Ethnic Cohorts

Cited by 18 publications

References 28 publications

The pathogenesis of bullous skin diseases

The pathogenesis of bullous skin diseases

Pemphigus: Current and Future Therapeutic Strategies

Role of IgG3 in Infectious Diseases

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