Down-regulation of Fcα receptors on blood cells of IgA nephropathy patients: Evidence for a negative regulatory role of serum IgA

Grossetête, Béatrice; Launay, Pierre; Lehuen, Agnès; Jungers, Paul; Bach, Jean‐François; Monteiro, Renato C.

doi:10.1046/j.1523-1755.1998.00885.x

Cited by 98 publications

(81 citation statements)

References 43 publications

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“…Most of the neoplasms in our patients involved the upper respiratory and digestive tracts, whose mucosa secrete IgA. It is of interest that the pathophysiology of HSP has been attributed to abnormal IgA clearance (28,29). Here, however, we found no evidence for a possible paraneoplastic origin of HSP.…”

Section: Discussionmentioning

confidence: 52%

Henoch-Scho[Combining Diaeresis]nlein Purpura in Adults

Pillebout¹,

Thervet²,

Hill³

et al. 2002

Journal of the American Society of Nephrology

496

439

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Abstract. Henoch-Schönlein Purpura nephritis (HSPN) has been extensively studied in children but, its natural history in adults is much less known. A cohort of 250 adults suffering HSP was retrospectively analyzed for a median follow-up period of 14.8 yr. All patients had biopsies consistent with HSP (predominant IgA mesangial deposits) associated with purpura, bowel angina, and/or abdominal pain. At presentation, palpable purpura was present in 96% of patients, and arthritis was reported in 61%, and gastrointestinal involvement in 48%. Thirty-two percent of the patients showed renal insufficiency (Creatinine clearance [CrCl] Ͻ50 ml/min), usually associated with proteinuria (99%) and/or hematuria (93%). Endocapillary glomerulonephritis was the most frequent lesion on renal biopsy (61%). At the end of follow-up, patient survival was only 74%. The first cause of death was carcinoma (most of them of respiratory or digestive tract). Regarding renal function, 11% of patients reached end-stage renal failure, 13% exhibited severe renal failure (CrCl Ͻ30 ml/min), and 14% moderate renal insufficiency (CrCl Ͻ50 ml/min). Clinical remission defined as the absence of proteinuria, hematuria, and a normal renal function was achieved in only 20%. This is a retrospective study; therefore, it is not possible to demonstrate any steroid and/or cyclophosphamide efficacy in diminishing the incidence of renal insufficiency. Multivariate analysis demonstrated that renal function impairment and proteinuria level at presentation and, on renal biopsy, the degree of interstitial fibrosis, percentage of sclerotic glomeruli, and presence of glomeruli with fibrinoid necrosis were associated with a poor renal prognosis. The data indicate that clinical presentation of HSPN in adults is severe and its outcome relatively poor, worse than in children. Identification of clinical and histologic prognostic factors may permit the design of appropriate therapeutic prospective studies.Henoch-Schönlein purpura (HSP) is a leukocytoclastic vasculitis involving small vessels with the deposition of immune complexes containing IgA. It is characterized by the association of skin, joint, and gastrointestinal manifestations that may occur in successive episodes (1). In addition to these manifestations, renal involvement is common, and the long-term prognosis depends on its severity.HSP primarily affects children, and its incidence is approximately 15 cases/100,000 children per yr (2); it is less common in adults. Although HSP has been extensively studied in children, much less is known about its natural history in adults. Apart from a recent multicenter Italian study (3,4), data on this disease in adults are confined to small series with relatively short follow-up (5-15). In adults, however, the incidence of HSP and the severity of its clinical manifestations appear not to be the same as in children.The incidence of renal involvement in adults varies from 45 to 85% of cases, depending on the data for patients and the definition of renal involvement (16). Among c...

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Section: Discussionmentioning

confidence: 52%

Henoch-Scho[Combining Diaeresis]nlein Purpura in Adults

Pillebout¹,

Thervet²,

Hill³

et al. 2002

Journal of the American Society of Nephrology

496

439

View full text Add to dashboard Cite

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“…Similar to FcγR, the expression of FcαRI is up-regulated by LPS, TNF-α, and other proinflammatory stimulators (33) but is downregulated by polymeric IgA (34). The regulation of FcR expression by inflammatory mediators coincides with increased serum levels of CRP during the acute-phase response, suggesting their potential involvement in pentraxin-mediated innate immunity, especially early in infection before effective antibody responses.…”

Section: Discussionmentioning

confidence: 99%

Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

Marjon

Marnell

et al. 2011

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

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C-reactive protein (CRP) is an important biomarker for inflammatory diseases. However, its role in inflammation beyond complement-mediated pathogen clearance remains poorly defined. We identified the major IgA receptor, FcαRI, as a ligand for pentraxins. CRP recognized FcαRI both in solution and on cells, and the pentraxin binding site on the receptor appears distinct from that recognized by IgA. Further competitive binding and mutational analysis showed that FcαRI bound to the effector face of CRP in a region overlapping with complement C1q and Fcγ receptor (FcγR) binding sites. CRP cross-linking of FcαRI resulted in extracellular signal-regulated kinase (ERK) phosphorylation, cytokine production, and degranulation in FcαRI-transfected RBL cells. In neutrophils, CRP induced FcαRI surface expression, phagocytosis, and TNF-α secretion. The ability of CRP to activate FcαRI defines a function for pentraxins in inflammatory responses involving neutrophils and macrophages. It also highlights the innate aspect of otherwise humoral immunity-associated antibody receptors.

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“…Our recent evidence points to the involvement of Fc␣RI, as specific cross-linking of this receptor aggravated symptoms in a mouse model of spontaneous IgA nephropathy. Given the fact that Fab A77 binds to Fc␣RI at a site different from IgA and therefore does not block IgA immune complex binding to the receptor (38,39), we examined whether Fab A77 could inhibit responses induced by its own receptor stimulated through IgA immune complex. We used Fc␣RI-humanized RBL mast cells transfected with a chimeric Fc␣RI R209L /FcR␥ that can be activated by IgA immune complex purified by precipitation with PEG from serum of an IgA nephropathy patient (24).…”

Section: Fc␣ri Monovalent Targeting Diminishes Inflammatory Signalingmentioning

confidence: 99%

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

Kanamaru

Pfirsch

Aloulou

et al. 2008

The Journal of Immunology

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Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcαRI or CD89) by anti-FcαRI Fab triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcRγ chain (FcαRI-FcRγ ITAMi) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcαRI-FcRγ ITAMi signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcαRI-Fcγ ITAMi signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcαRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcαRI-FcRγ ITAMi signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcαRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.

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Down-regulation of Fcα receptors on blood cells of IgA nephropathy patients: Evidence for a negative regulatory role of serum IgA

Cited by 98 publications

References 43 publications

Henoch-Scho[Combining Diaeresis]nlein Purpura in Adults

Henoch-Scho[Combining Diaeresis]nlein Purpura in Adults

Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

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