Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid

Chen, Ruoyan; Ning, Gang; Zhao, Ming-Lang; Fleming, Matthew G.; Díaz, Luis A.; Werb, Zena; Li, Zhi

doi:10.1172/jci200111494

Cited by 74 publications

(98 citation statements)

References 43 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have previously shown that anti-mBP180-mediated complement activation is essential for PMN recruitment to the cutaneous BMZ (37,38). One finding that demonstrated this link is that C5 -/-mice injected i.d.…”

Section: Figurementioning

confidence: 96%

“…with the suboptimal and optimal doses of pathogenic IgG and examined at 2, 12, 24, and 48 hours after injection. At 2 hours, when MC degranulation triggered by pathogenic IgG reaches its peak (38), toluidine blue staining revealed extensive MC degranulation in the dermis of WT and Fb -/-mice ( Figure 4, A and C). In contrast, C4 -/-mice exhibited a minimal level of MC degranulation in the dermis ( Figure 4B).…”

Section: Pathogenic Anti-mbp180 Antibodies Induce Subepidermal Blistementioning

confidence: 99%

“…C5a could carry out this role directly (by functioning as a PMN chemoattractant itself), indirectly (by stimulating local cells to release proinflammatory mediators such as IL-8), or through a combination of these 2 mechanisms (40). Recently, we have shown that in experimental BP, MC degranulation, which leads to PMN recruitment, mainly depends on complement activation (38). Our present data further demonstrate that MC degranulation and subsequent PMN infiltration triggered by pathogenic anti-mBP180 antibodies was severely impaired in mice deficient in the classical pathway component C4.…”

Section: Figurementioning

confidence: 99%

“…Skin sections (approximately 3 × 3 mm) of IgG-injected mice were fixed in 10% formalin. Paraffin sections (6 μm thick) were prepared and stained with toluidine blue and H&E. Dermal MCs were counted by 2 individuals in the laboratory in a blinded fashion and classified as degranulated (>10% of the granules exhibiting fusion or discharge) or normal in 5 random fields under a light microscope at ×400 magnification (38,51). There was no significant difference between the 2 individual countings (for total MCs, 32.20 ± 6.52 versus 36.97 ± 11.55; P = 0.082).…”

Section: Figurementioning

confidence: 99%

“…Subepidermal blistering triggered by anti-mBP180 IgG depends on complement activation, mast cell (MC) degranulation, and polymorphonuclear neutrophil (PMN) infiltration (37)(38)(39). In this study, we investigated the role of these 3 pathways of complement activation in the disease development of experimental BP by using mice genetically deficient in pathway-specific components.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Role of different pathways of the complement cascade in experimental bullous pemphigoid

Nelson¹,

Zhao²,

Schroeder³

et al. 2006

J. Clin. Invest.

Self Cite

101

View full text Add to dashboard Cite

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies directed against the hemidesmosomal proteins BP180 and BP230 and inflammation. Passive transfer of antibodies to the murine BP180 (mBP180) induces a skin disease that closely resembles human BP. In the present study, we defined the roles of the different complement activation pathways in this model system. Mice deficient in the alternative pathway component factor B (Fb) and injected with pathogenic anti-mBP180 IgG developed delayed and less intense subepidermal blisters. Mice deficient in the classical pathway component complement component 4 (C4) and WT mice pretreated with neutralizing antibody against the first component of the classical pathway, C1q, were resistant to experimental BP. These mice exhibited a significantly reduced level of mast cell degranulation and polymorphonuclear neutrophil (PMN) infiltration in the skin. Intradermal administration of compound 48/80, a mast cell degranulating agent, restored BP disease in C4 -/-mice. Furthermore, C4 -/-mice became susceptible to experimental BP after local injection of PMN chemoattractant IL-8 or local reconstitution with PMNs. These findings provide the first direct evidence to our knowledge that complement activation via the classical and alternative pathways is crucial in subepidermal blister formation in experimental BP. IntroductionBullous pemphigoid (BP) is a subepidermal blistering skin disorder of the elderly (1). Lesional skin of BP patients is characterized by a detachment of the basal keratinocytes of the epidermis from the dermis, resulting in tense, fluid-filled vesicles. Similar skin lesions were noted in herpes gestationis (HG), a nonviral disease of pregnancy (2). Immunofluorescence (IF) studies demonstrated that these patients exhibit circulating and tissue-bound autoantibodies directed against antigens of the basement membrane zone (BMZ) (3-8).BP and HG autoantibodies recognize 2 antigens, BP230 and BP180, that are localized in the hemidesmosome, the main epidermal structure involved in dermal-epidermal adhesion (4-6, 9). The BP230 antigen is restricted to the cytoplasmic plaque of the hemidesmosome and appears to interact directly with the intermediate filament network (10, 11). The BP180 antigen is a type II transmembrane protein with an aminoterminal endodomain and an extended carboxyterminal ectodomain that spans the lamina lucida, projecting into the lamina densa of the BMZ (12-16). The ectodomain of human BP180 contains a series of 15 interrupted collagen domains (complement components 1-15 [C1-C15]) with the typical Gly-X-Y repeat (14). It has recently been shown that the BP180 extracellular domain forms a collagen triple helix (17, 18). The extracellular noncollagenous stretches are designated NC1 (located at the carboxyl terminus) through NC16A (adjacent to the membrane-spanning domain). The NC16A domain of human BP180 harbors major extracellular antigenic sites recognized by BP and HG sera (19,20).Complement can be activated...

show abstract

Section: Figurementioning

confidence: 96%

Section: Pathogenic Anti-mbp180 Antibodies Induce Subepidermal Blistementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Role of different pathways of the complement cascade in experimental bullous pemphigoid

Nelson¹,

Zhao²,

Schroeder³

et al. 2006

J. Clin. Invest.

Self Cite

101

View full text Add to dashboard Cite

show abstract

Usefulness of BP230 and BP180-NC16a Enzyme-Linked Immunosorbent Assays in the Initial Diagnosis of Bullous Pemphigoid

Charneux¹,

Lorin²,

Vitry³

et al. 2011

Arch Dermatol

106

View full text Add to dashboard Cite

Objective: To investigate the diagnostic value of commercially available BP230 and BP180-NC16a enzyme-linked immunosorbent assays (ELISAs) in routine practice in patients with bullous pemphigoid (BP).Design: Single-center retrospective study.Setting: French academic dermatology department. Patients:The study population comprised 138 patients, Interventions: Sera samples were analyzed by ELISA; clinical and immunopathological data were recorded from the patients' medical charts.Main Outcome Measures: BP230 and BP180-NC16a ELISA scores were evaluated with respect to clinical characteristics (number of blisters, mucosal involvement, localized or generalized disease, and outcome) and routine indirect immunofluorescence (IF).Results: Of the 138 study patients, 81 (59%) had a positive BP230 ELISA result and 119 (86%) had a positive BP180 ELISA result. There was no relationship between a positive ELISA BP230 result and the disease extent at diagnosis or the presence of mucosal involvement. Serum antibasement membrane zone autoantibodies (indirect IF) were more frequently detected when the BP230 ELISA result was positive (P Ͻ .001). The median anti-basement membrane autoantibody titer as detected by indirect IF was higher in patients with a positive BP230 result (PϽ.001). The BP180 ELISA result was associated with disease extent at diagnosis as estimated by both the percentage of patients with extensive BP (P=.01) and the mean number of blisters (P=.03) but was not associated with mucosal involvement. Conclusions:The currently available BP230 ELISA is a reliable although less-sensitive test than BP180 ELISA in BP, and its diagnostic added value compared with BP180 ELISA alone is approximately 5%. Our results support the predominant contribution of the BP230-specific autoantibodies to anti-basement membrane zone antibody titer as detected by indirect IF.

show abstract

Lymphocyte‐independent connective tissue mast cells populate murine synovium

Shin¹,

Gurish²,

Friend³

et al. 2006

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. Mast cells (MCs) are a heterogeneous population of tissue-resident bone marrow-derived cells; distinct MC subpopulations are situated at specific microanatomic locations. The phenotype of the murine synovial MC remains undefined. Since MCs have been implicated in the pathogenesis of inflammatory arthritis, we sought to define the phenotype of the murine synovial MC population in normal and arthritic joints. We also examined the contribution of lymphocytes to synovial MC physiology.Methods. The MC phenotype in healthy and K/BxN serum transfer-induced arthritic synovial tissue was defined using immunohistochemical staining of prototypic MC-specific proteases (murine MC proteases [mMCP] 1, 2, 4, 5, 6, and 7) (chymases and tryptases). MC numbers and density were determined by histomorphometry in healthy and arthritic synovia. The lymphocyte contribution to MC populations was assessed using RAG-null mice.Results. We found that synovial MCs display a connective tissue mast cell (CTMC) phenotype in both normal and arthritic synovial tissue, which expresses mMCP-4, -5, -6, and -7, but not mMCP-1 or mMCP-2. In addition, MC hyperplasia was seen in the arthritic synovium. In RAG-null mice, the phenotype and degree of MC hyperplasia were identical to those observed in normal mice with and without arthritis. Furthermore, in contrast to skin CTMCs, all synovial MCs expressed mMCP-6, demonstrating discrete differences between synovial CTMCs and other anatomic CTMC populations.Conclusion. Our findings demonstrate that the murine synovial MC population is composed of lymphocyte-independent CTMCs and identify arthritic synovium as a model system by which to gain insight into the poorly understood physiology of CTMCs in chronic inflammation.

show abstract

Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid

Cited by 74 publications

References 43 publications

Role of different pathways of the complement cascade in experimental bullous pemphigoid

Role of different pathways of the complement cascade in experimental bullous pemphigoid

Usefulness of BP230 and BP180-NC16a Enzyme-Linked Immunosorbent Assays in the Initial Diagnosis of Bullous Pemphigoid

Lymphocyte‐independent connective tissue mast cells populate murine synovium

Contact Info

Product

Resources

About