FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

Messingham, Kelly A. N.; Srikantha, Rupasree; DeGueme, Amy M.; Fairley, Janet A.

doi:10.4049/jimmunol.1001753

Cited by 77 publications

(82 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…*P<0.05, **P<0.01, ***P<0.001 2013). Together with these previous observations and the recent finding that BP180-deficient epidermal keratinocytes display an abnormally high IL-8 response under various inflammatory stimuli (Van den Bergh et al 2012), our current results support the assumption that targeting BP180 directly affects the epidermal keratinocyte proinflammatory cytokine response (Schmidt et al 2000(Schmidt et al , 2001Messingham et al 2011;Van den Bergh et al 2012).…”

Section: Discussionsupporting

confidence: 78%

“…Similar to previous experiments, which showed that IgG or IgE autoantibodies from BP patients stimulated Fc receptorindependent production of IL-6 and IL-8 in primary cultures of normal human epithelial keratinocytes (NHEK) (Schmidt et al 2000(Schmidt et al , 2001Messingham et al 2011), we also observed a significant BP IgG-induced secretion of both cytokines compared to normal IgG using the HaCaT cell line. Cytokine background levels that were seen in medium containing normal IgG and which have also been reported by previous investigators may reflect the culture conditions on a plastic surface (and not human dermis) or may result from unspecific stimuli produced by keratinocytes (Schmidt et al 2000(Schmidt et al , 2001.…”

Section: Discussionsupporting

confidence: 77%

“…The rationale of our study to probe the effects of 17-DMAG on BP IgG-induced IL-6 and IL-8 production by HaCaT cells was mainly based on three documented findings: (i) both inflammatory cytokines play a key role in the pathophysiology of BP (Schmidt et al 1996a, b;Liu et al 1997;Inaoki and Takehara 1998;Schmidt et al 2000;Chen et al 2001;Schmidt et al 2001;Nelson et al 2006;Messingham et al 2011), (ii) the extensive list of Hsp90 client proteins includes many proinflammatory molecules (Salminen et al 2008;Taipale et al 2010;Henderson and Kaiser 2013), and (iii) recent evidence suggests that Hsp90 represents a novel treatment target in autoimmune bullous diseases (Kasperkiewicz et al 2011;Tukaj et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Insights into the functionally relevant pathogenic mechanisms in BP, which include complement activation, mast cell degranulation, recruitment and activation of neutrophils and eosinophils, and release of basal membrane zone-degradading proteinases from these effector cells, have been provided by in vitro studies using cultured human keratinocytes and ex vivo studies using cryosections of human skin as well as various mouse models, although the role of mast cells in models of antibody-mediated autoimmunity has recently been questioned (Kasperkiewicz and Zillikens 2007;Feyerabend et al 2011;Schmidt and Zillikens 2013). Although the precise sequence of these events is largely unknown, it has been proposed that one of the first steps leading to blister formation in BP comprise the binding of autoantibodies to BP180, thereby initiating Fc receptor-independent events leading to the release of interleukin 6 (IL-6) and IL-8 from basal keratinocytes (Schmidt et al 2000(Schmidt et al , 2001Messingham et al 2011). IL-8 is a potent chemoattractant for pathophysiologically relevant leukocyte effector cells and together with IL-6 known to be elevated in sera and blister fluids of BP patients and critical for blister formation in mouse models (Schmidt et al 1996a, b;Liu et al 1997;Inaoki and Takehara 1998;Chen et al 2001;Nelson et al 2006;Kobayashi 2008).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

View full text Add to dashboard Cite

Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFκB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose-and time-dependent fashion.

show abstract

Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

View full text Add to dashboard Cite

show abstract

“…IgE autoantibodies for atopic dermatitis and bullous pemphigoid has been previously demonstrated (7,8). These IgE autoantibodies play important roles in each disease.…”

Section: Discussionmentioning

confidence: 96%

Eosinophilic Granulomatosis with Polyangiitis Demonstrating IgE-immune Complexes and the Possible Involvement of IgE Autoantibodies

Ota

Fujiwara

Hirabayashi³

et al. 2015

Intern. Med.

View full text Add to dashboard Cite

We herein report a case of female eosinophilic granulomatosis with polyangiitis (EGPA) in which polyethylene glycol (PEG) precipitation was used to evaluate the patient's levels IgE-immune complexes (IC). Her serum IgE (7,110 IU/mL) and IgE-IC (1,880 IU/mL) levels were observed with an IgE PEG precipitated index of 26.4%. We speculate that the circulating IgE-IC were formed by anti-neutrophil IgE autoantibodies. Therefore, the large amount of IgE autoantibodies in the patient's serum appears to have induced a constant allergic pathology. This pathology may have resulted in a marked infiltration of eosinophils into the tissues, as well as intensified the EGPA pathology.

show abstract

Correlation of Serum Levels of IgE Autoantibodies Against BP180 With Bullous Pemphigoid Disease Activity

et al. 2017

View full text Add to dashboard Cite

IMPORTANCE Bullous pemphigoid (BP) is by far the most frequent autoimmune blistering disease. The presence of IgE autoantibodies against the transmembrane protein BP antigen 2 (BP180, type XVII collagen) has previously been reported in 22% to 100% of BP serum samples, and the pathogenic relevance of anti-BP180 IgE has been suggested in various experimental models and by the successful use of omalizumab in individual patients with BP. OBJECTIVES To determine the rate of anti-BP180-reactive IgE in BP, to evaluate the diagnostic relevance of anti-BP180 IgE in BP, and to correlate anti-BP180 IgE with disease activity and the clinical phenotype of patients with BP. DESIGN, SETTING, AND PARTICIPANTS This case-control cohort study examined 3 groups of patients with BP. Sixty-five patients with BP underwent an enzyme-linked immunosorbent assay for IgE antibodies against the 16th noncollagenous domain of BP180 (NC16A); 52 consecutive patients with BP underwent clinical evaluation with the Bullous Pemphigoid Disease Activity Index (BPDAI); and 36 patients with BP without anti-BP180 NC16A IgG reactivity underwent evaluation of the diagnostic importance of serum anti-BP180 IgE. In addition, 49 age-matched control individuals with noninflammatory dermatoses, 127 controls undergoing allergy testing for IgE levels, and 30 controls with pemphigus vulgaris or pemphigus foliaceus were included for comparison. Patients were seen at a university clinic from January 1, 2008, to July 31, 2014. MAIN OUTCOMES AND MEASURES Serum anti-BP180 NC16A IgE and IgG levels and BPDAI scores.RESULTS Of 117 patients with BP (69 women and 48 men), anti-BP180 NC16A serum IgE was detected in 47 (40.2%) and correlated with disease activity as measured by total BPDAI (r = 0.918; P = .06). An intraindividual correlation of anti-BP180 NC16A serum levels with the total BPDAI was observed during the course of the disease in 10 randomly selected patients with BP (r = 0.983; P = .003). Although no association of circulating BP180 NC16A IgE antibodies with urticarial or erythematous lesions was observed (r = 0.481; P = .31), the presence of IgG anti-BP180 NC16A antibodies was associated with the occurrence of erosions and blisters (r = 0.985; P = .006) but not urticarial and erythematous lesions (r = 0.632; P = .23). Assaying for anti-BP180 IgE increased the diagnostic sensitivity by only 2.2% (1 of 46 serum samples) when combined with the IgG anti-BP180 enzyme-linked immunosorbent assay. CONCLUSIONS AND RELEVANCEAlthough detection of serum anti-BP180 IgE is not of diagnostic importance, it may be relevant for therapeutic decisions (eg, the use of anti-IgE treatment). The correlation of serum anti-BP180 NC16A IgE levels with disease activity in patients with BP supports the notion that anti-BP180 IgE is of pathogenic relevance. Our observation that IgG anti-BP180 antibodies are related to the occurrence of blisters and erosions may encourage further studies on the association of fine autoantibody reactivities with clinical features of BP.

show abstract

FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

Cited by 77 publications

References 52 publications

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Eosinophilic Granulomatosis with Polyangiitis Demonstrating IgE-immune Complexes and the Possible Involvement of IgE Autoantibodies

Correlation of Serum Levels of IgE Autoantibodies Against BP180 With Bullous Pemphigoid Disease Activity

Contact Info

Product

Resources

About