Pemphigus Vulgaris: The Role of IL-1 and IL-1 Receptor Antagonist in Pathogenesis and Effects of Intravenous Immunoglobulin on Their Production

Bhol, Kailash; Desai, Alpesh; Kumari, Suman; Colón, José E.; Ahmed, A. Razzaque

doi:10.1006/clim.2001.5061

Cited by 46 publications

(31 citation statements)

References 38 publications

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“…The similarities between the presentation of KS and recurrent fever syndromes may suggest activation of similar pathways that trigger innate immune responses. In addition, similarities in cytokine profiles are apparent in acute KS and in recurrent fever syndromes, including elevations in the levels of tumor necrosis factor ␣ (TNF-␣), interleukin 1␤ (IL-1␤), and IL-6, and several recent studies found that IVIg increases the level of IL-1Ra, 16,17 an inhibitor of the cytokine IL-1␤ that has been shown to be important in the pathogenesis of several autoinflammatory syndromes. 18,19 As such, we hypothesize that KS and recurrent fever disorders exist together within a family of autoinflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Fever Syndromes in Patients After Recovery From Kawasaki Syndrome

et al. 2011

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The recurrence of fever in a child with a history of Kawasaki syndrome (KS) poses a dilemma for clinicians who must consider the possibility of recurrent KS. In this report we present the cases of 4 patients who presented with classical symptoms of KS, were successfully treated with intravenous immunoglobulin, and later experienced a reappearance of inflammatory symptoms in a pattern consistent with a recurrent fever syndrome. The association of these syndromes within the same patient suggests that some patients may have a genetic propensity toward altered immune responses and autoinflammatory syndromes. We propose that these 2 syndromes exist within a family of febrile disorders related to innate immune dysregulation.

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Section: Discussionmentioning

confidence: 99%

Recurrent Fever Syndromes in Patients After Recovery From Kawasaki Syndrome

et al. 2011

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“…The serum factors implicated in apoptolysis include Fas ligand (FasL) (14), tumor necrosis factor ␣ (15,16), interleukins 1, 6, 8, and 15 (15,(17)(18)(19), nitric oxide (9,20), kallikreins, and other proteases (21). Using an organ culture model of PV, it has been demonstrated that PVIgG works together with FasL and tumor necrosis factor ␣ to induce apoptolysis (22).…”

Section: Pemphigus Vulgaris (Pv)mentioning

confidence: 99%

Antimitochondrial Autoantibodies in Pemphigus Vulgaris

Marchenko

Chernyavsky

Arredondo

et al. 2010

Journal of Biological Chemistry

115

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A loss of epidermal cohesion in pemphigus vulgaris (PV) results from autoantibody action on keratinocytes (KCs) activating the signaling kinases and executioner caspases that damage KCs, causing their shrinkage, detachment from neighboring cells, and rounding up (apoptolysis). In this study, we found that PV antibody binding leads to activation of epidermal growth factor receptor kinase, Src, p38 MAPK, and JNK in KCs with time pattern variations from patient to patient. Both extrinsic and intrinsic apoptotic pathways were also activated. Although Fas ligand neutralizing antibody could inhibit the former pathway, the mechanism of activation of the latter remained unknown. PV antibodies increased cytochrome c release, suggesting damage to mitochondria. The immunoblotting experiments revealed penetration of PVIgG into the subcellular mitochondrial fraction. The antimitochondrial antibodies from different PV patients recognized distinct combinations of antigens with apparent molecular sizes of 25, 30, 35, 57, 60, and 100 kDa. Antimitochondrial antibodies were pathogenic because their absorption abolished the ability of PVIgG to cause keratinocyte detachment both in vitro and in vivo. The downstream signaling of antimitochondrial antibodies involved JNK and late p38 MAPK activation, whereas the signaling of anti-desmoglein 3 (Dsg3) antibody involved JNK and biphasic p38 MAPK activation. Using KCs grown from Dsg3؊/؊ mice, we determined that Dsg3 did not serve as a surrogate antigen allowing antimitochondrial antibodies to enter KCs. The PVIgG-induced activation of epidermal growth factor receptor and Src was affected neither in Dsg3KCs nor due to absorption of antimitochondrial antibodies. These results demonstrated that apoptolysis in PV is a complex process initiated by at least three classes of autoantibodies directed against desmosomal, mitochondrial, and other keratinocyte self-antigens. These autoantibodies synergize with the proapoptotic serum and tissue factors to trigger both extrinsic and intrinsic pathways of cell death and break the epidermal cohesion, leading to blisters. Further elucidation of the primary signaling events downstream of PV autoantigens will be crucial for the development of a more successful therapy for PV patients.Pemphigus vulgaris (PV) 3 is an IgG autoantibody-mediated disease of skin and mucosa caused by a loss of epidermal cohesion and manifested by progressive blistering and non-healing erosions. The mechanism of detachment of keratinocytes (KCs) in PV, termed acantholysis, is a subject of intensive research. Elucidation of the pathophysiologic mechanism of acantholysis should facilitate development of novel pharmacologic approaches to prevent and treat blistering without systemic corticosteroids, a mainstay of treatment of PV patients. Acantholysis can be blocked both by inhibitors of signaling kinases, such as p38 MAPK (3), mammalian target of rapamycin (4), Src, and epidermal growth factor receptor (EGFR) kinase (2, 4 -7) and by other tyrosine kinases, phospholipase C, calmodulin...

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“…The IVIg drug contains purified preparations of immunoglobulins from plasma of healthy human donors, containing predominantly polyclonal IgG, and various immunomodulatory contaminants. IVIg exhibits a plethora of biological effects, including acceleration of the clearance of autoantibod-ies, 18 modulation of serum levels of pro-inflammatory cytokines, 19 induction of immune-competent cell death, 20 and an array of anti-apoptotic effects. In addition to inactivation of lytically active Fas ligand (Fas-L) in patients' serum, 21 IVIg has been shown to protect target cells from apoptosis by up-regulating Bcl-2 expression, 22 interfering with the tumor necrosis factor-␣ (TNF-␣) 23 and interferon-␥ 24 signaling pathways, and increasing sensitivity to corticosteroid action.…”

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confidence: 99%