Role of FcRs in Animal Model of Autoimmune Bullous Pemphigoid

Zhao, Ming-Lang; Trimbeger, Mary E.; Li, Ning; Díaz, Luis A.; Shapiro, Steven D.; Liu, Zhi

doi:10.4049/jimmunol.177.5.3398

Cited by 54 publications

(46 citation statements)

References 61 publications

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“…BP (24,45,46). More recently, it has been accepted that the FcεRI-dependent effects of IgE autoantibodies are also necessary to fully recapitulate human disease (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

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

Messingham

Srikantha

DeGueme

et al. 2011

The Journal of Immunology

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Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by IgE and IgG class autoantibodies specific for 180-kDa BP Ag 2 (BP180), a protein involved in cell-substrate attachment. Although some direct effects of BP IgG have been observed on keratinocytes, no study to date has examined direct effects of BP IgE. In this study, we use primary cultures of human keratinocytes to demonstrate Ag-specific binding and internalization of BP IgE. Moreover, when BP IgE and BP IgG were compared, both isotypes stimulated FcR- independent production of IL-6 and IL-8, cytokines critical for BP pathology, and elicited changes in culture confluence and viability. We then used a human skin organ culture model to test the direct effects of these Abs on the skin, whereas excluding the immune inflammatory processes that are triggered by these Abs. In these experiments, physiologic concentrations of BP IgE and BP IgG exerted similar effects on human skin by stimulating IL-6 and IL-8 production and decreasing the number of hemidesmosomes localized at the basement membrane zone. We propose that the Ab-mediated loss of hemidesmosomes could weaken attachment of basal keratinocytes to the basement membrane zone of affected skin, thereby contributing to blister formation. In this article, we identify a novel role for IgE class autoantibodies in BP mediated through an interaction with BP180 on the keratinocyte surface. In addition, we provide evidence for an FcR-independent mechanism for both IgE and IgG class autoantibodies that could contribute to BP pathogenesis.

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“…BP (24,45,46). More recently, it has been accepted that the FcεRI-dependent effects of IgE autoantibodies are also necessary to fully recapitulate human disease (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

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

Messingham

Srikantha

DeGueme

et al. 2011

The Journal of Immunology

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“…Increasing evidence suggests that MCs play critical roles in IgGdependent tissue-specific autoimmune diseases, including murine models of multiple sclerosis, RA, bullous pemphigoid, and glomerulonephritis (41)(42)(43)(44). In RA, circulating IgG isotype autoantibodies and immune complexes can activate synovial MCs through FcγRs (19), triggering release of inflammatory cytokines including TNF, IL-1β, and IL-17.…”

Section: Discussionmentioning

confidence: 99%

JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis

Gumá

Kashiwakura

Crain

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Rheumatoid arthritis (RA) is a chronic inflammatory disease marked by bone and cartilage destruction. Current biologic therapies are beneficial in only a portion of patients; hence small molecules targeting key pathogenic signaling cascades represent alternative therapeutic strategies. Here we show that c-Jun N-terminal kinase (JNK) 1, but not JNK2, is critical for joint swelling and destruction in a serum transfer model of arthritis. The proinflammatory function of JNK1 requires bone marrow-derived cells, particularly mast cells. Without JNK1, mast cells fail to degranulate efficiently and release less IL-1β after stimulation via Fcγ receptors (FcγRs). Pharmacologic JNK inhibition effectively prevents arthritis onset and abrogates joint swelling in established disease. Hence, JNK1 controls mast cell degranulation and FcγR-triggered IL-1β production, in addition to regulating cytokine and matrix metalloproteinase biosynthesis, and is an attractive therapeutic target in inflammatory arthritis.

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“…It was demonstrated that circulating neutrophils from DH patients show evidence of partial priming including the increased function of IgA FcRs [7] and in this way neutrophils show an increased ability to bind IgA. Literature data [10][11][12] postulated that FcRs play a crucial role in the activation and/or down-regulation of immune responses and thus, their ligation with pathogenic autoantibodies may have results in tissue damage, including blister formation in autoimmune blistering dermatoses [13]. The mechanism of inflammatory induction probably involves structural/conformation alternation of FcRs and modification of their activating/inhibitory functions.…”

Section: Introductionmentioning

confidence: 99%

IgA autoantibodies to gliadin nonapeptides, tissue transglutaminase and epidermal transglutaminase are associated, but unrelated to neutrophil elastase expression in lesional skin in human dermatitis herpetiformis

Gornowicz‐Porowska¹,

Seraszek‐Jaros²,

Kaczmarek³

et al. 2012

pdia

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A Ad dd dr re es ss s f fo or r c co or rr re es sp po on nd de en nc ce e: : Assist. Prof Original paper A b s t r a c t I In nt tr ro od du uc ct ti io on n: : In dermatitis herpetiformis (DH), activation of neutrophils via IgA Fc receptors (e.g. CD89) and immunocomplexes containing IgA1 may lead to the release of proteolytic enzymes, mainly neutrophil elastase (NE), destruction of the dermal-epidermal junction and blister formation. A Ai im m: : To analyze whether there are associations between levels of circulating IgA autoantibodies to epidermal (eTG) and tissue (tTG) transglutaminases, nonapeptides of gliadin (npG) and the intensity of cutaneous NE expression in patients with DH. M Ma at te er ri ia al l a an nd d m me et th ho od ds s: : Altogether, 31 patients with DH were studied. The levels of serum IgA autoantibodies to eTG, tTG and npG were evaluated with ELISAs. The intensity of NE expression was estimated with immunohistochemistry using NE monoclonal antibody and quantitative digital morphometry. Statistical analysis was done using Spearman's rank correlation coefficient. R Re es su ul lt ts s: : There were no statistically significant correlations between the intensity of cutaneous NE expression and the levels of serum IgA autoantibodies to eTG, tTG, npG in patients with DH. There were statistically significant correlations between the levels of IgA autoantibodies to eTG, tTG, npG. C Co on nc cl lu us si io on ns s: : It seems that in human DH the activation of neutrophils, judged by the NE expression, is unrelated to the levels of serum IgA autoantibodies to eTG/tTG/npG, but all those autoantibodies in DH are produced in a coordinated way.K Ke ey y w wo or rd ds s: : dermatitis herpetiformis, neutrophil elastase, transglutaminases, gliadin.

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Role of FcRs in Animal Model of Autoimmune Bullous Pemphigoid

Cited by 54 publications

References 61 publications

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

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

JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis

IgA autoantibodies to gliadin nonapeptides, tissue transglutaminase and epidermal transglutaminase are associated, but unrelated to neutrophil elastase expression in lesional skin in human dermatitis herpetiformis

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