Predominance of type 1 (Th1) cytokine production in the liver of patients with HCV-associated mixed cryoglobulinemia vasculitis

Saadoun, David; Boyer, Olivier; Trébeden-Nègre, Hélène; Limal, Nicolas; Bon-Durand, Véronique; Andreu, Marita; Klatzmann, David; Piette, Jean Charles; Cacoub, Patrice

doi:10.1016/j.jhep.2004.08.011

Cited by 49 publications

(35 citation statements)

References 37 publications

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“…22 A higher proinflammatory cytokine production (i.e., tumor necrosis factor ␣) has been observed in the peripheral blood and liver of HCV-cryoglobulinemic patients compared with their cryoglobulin-negative couterparts. 23,24 Hence, upregulation of low-density lipoprotein receptors associated with inflammation may result in lipid accumulation in the liver of HCV-cryoglobulinemic patients. Among 437 patients with chronic hepatitis C, 55% had steatosis.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidence suggests that patients with HCV-related mixed cryoglobulin display a particular immune response to HCV infection. 23,24,38 Tumor necrosis factor ␣, which induces the recruitement of inflammatory cells and stimulates oxidative stress in hepatocytes, 39 is highly produced in the liver of HCV-cryoglobulinemic patients 24 and may account for a more severe course of liver disease. A recent study showed that B cells play an important role in the development of liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C†

et al. 2006

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The relationship between cryoglobulin and severity of liver lesions is debated. No study has focused on the relationship between cryoglobulin, liver steatosis, and fibrosis. The aim of this study was to determine the relationship between cryoglobulins and liver lesions (necroinflammation, fibrosis, and steatosis) in patients with hepatitis C virus (HCV) infection. Four hundred and thirty-seven consecutive patients with untreated chronic hepatitis C who had been admitted for liver biopsy were included in the study. Risk factors for fibrosis and steatosis were assessed. The mean age was 50.9 ؎ 13.8 years, and 49% were male. Cryoglobulin was present in 286 patients, 103 of whom had vasculitis. One hundred and eighty-six patients (43%) had steatosis greater than 10%, and 110 (25%) had advanced fibrosis (Metavir score F3-F4). On multivariate analysis, cryoglobulin increased by nearly threefold the risk of having advanced fibrosis and steatosis greater than 10%. Steatosis greater than 10% was associated with a higher body mass index (P < .001), HCV genotype 3 (P < .001), cryoglobulin (P ‫؍‬ .002), and advanced liver fibrosis (P ‫؍‬ .009). Advanced fibrosis (F3-F4) was associated with a higher level of ␥-glutamyltransferase (P ‫؍‬ .04), cryoglobulin (P < .001), a high grade of necroinflammation (Metavir score A2-A3) (P < .001), and steatosis higher than 10% (P ‫؍‬ .04). In conclusion, our study shows an independent association between cryoglobulin and steatosis as well as advanced fibrosis. (HEPATOLOGY 2006;43: 1337-1345.)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C†

et al. 2006

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“…Neutrophilic infiltration with leukocytoclastic changes, typical of immune complex-mediated vasculitis, has seldom been found, while the presence of lymphohistiocytic infiltrates suggests a T cell-mediated pathogenesis. [16][17][18][19] Patients with HCV-MC vasculitis display a disturbed peripheral blood T-cell repertoire. 20 CD4 ϩ CD25 ϩ regulatory T cells, which have been shown to control autoimmunity, are significantly reduced in HCV-MC vasculitis patients.…”

Section: Introductionmentioning

confidence: 99%

Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis

Saadoun

Rosenzwajg

Landau

et al. 2008

Blood

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Rituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as mixed cryoglobulinemia (MC). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of peripheral blood B-and T-cell subsets, the clonal VH1-69 cells, as well as the cytokine profile following rituximab therapy. The study involved 21 patients with hepatitis C-related MC who received rituximab, of whom 14 achieved a complete response.Compared with healthy and hepatitis C virus (HCV) controls, pretreatment abnormalities in MC patients included a decreased percentage of naive B cells (P < .05) and CD4 ؉ CD25 ؉ FoxP3 ؉ regulatory T cells (P ‫؍‬ .02) with an increase in memory B cells (P ‫؍‬ .03) and plasmablasts (P < .05). These abnormalities were reverted at 12 months after rituximab. Clonal VH1-69 ؉ B cells dramatically decreased following treatment (32% ؎ 6% versus 8% ؎ 2%, P ‫؍‬ .01). Complete responders of rituximab exhibited an expansion of regulatory T cells (P < .01) accompanied with a decrease in CD8 ؉ T-cell activation (P < .01) and decreased production of interleukin 12 (IL-12; P ‫؍‬ .02) and interferon-␥ (IFN-␥; P ‫؍‬ .01). Our IntroductionChronic infection with hepatitis C virus (HCV) is the main cause of mixed cryoglobulinemia (MC) vasculitis, a potentially lifethreatening, systemic vasculitis. 1 MC reflects the expansion of B cells producing a pathogenic IgM with rheumatoid factor (RF) activity. MC may lead to clinical manifestations ranging from an MC syndrome (purpura, arthralgia, asthenia) to a more serious vasculitis with neurologic and renal involvement. 2 Oligoclonal or monoclonal B-cell expansions are significant molecular features of MC. 3,4 It is estimated that almost 10% of patients with MC progress to frank B-cell non-Hodgkin lymphoma (NHL). The overall risk of NHL in patients with HCV-MC is estimated to be 35 times higher than in the general population. 5 HCV is capable of infecting B-lymphocytes through LDL receptors or CD81. 6,7 The E2 envelope glycoprotein of HCV can bind CD81 B-cell surface protein. 6 CD81 has been demonstrated to play a costimulatory role in T-cell activation and an inhibitory role on natural killer (NK) cell on binding to E2 glycoprotein. 8,9 CD81 on B-cell surface may provide a strong stimulatory signal if activated as a part of a complex (CD19/CD21/CD81 complex) together with BCR activation. 10 The ability of E2 to directly engage CD81 alongside the binding of specific anti-E2 BCR may create a powerful stimulatory signal, promoting proliferation. Clonal B-cell expansion has been demonstrated in liver, blood, and bone marrow of patients with chronic HCV infection in the absence of overt B-cell malignancy. 3,4 The B-cell repertoire in cryoglobulinemic vasculitis is highly restricted. B-cell clones in HCV-MC often use the VH1-69 gene and VkA27 segment, which is also used by anti-E2 antibodies elicited by HCV. 11,12 Sequencing of these Ig variable regions has also revealed that they are the product o...

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“…Patients with HCV-induced MC vasculitis have decreased numbers of circulating Treg cells, increased numbers of effector T cells, and a predominant Th1 differentiation compared with patients with HCV infection without MC vasculitis (13,(27)(28)(29). It has also been shown that CD8ϩ cells from patients with chronic HCV infection may express FoxP3 after stimulation with HCV-derived peptides, which indicates that there is likely a wide heterogeneity of FoxP3-expressing cells in response to viral infection (30).…”

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Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

Landau¹,

Rosenzwajg²,

Saadoun³

et al. 2008

Arthritis & Rheumatism

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Objective. Mixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder associated with chronic hepatitis C virus (HCV) infection. We previously reported that MC vasculitis is associated with a quantitative defect of peripheral blood regulatory T cells. The aim of this study was to prospectively evaluate the evolution of this defect during the course of antiviral treatment.Methods. Treg cell frequencies and numbers were analyzed in 131 patients with chronic HCV infection (including 66 with MC vasculitis) and 20 healthy volunteer donors. Measurements were taken before, during, and after treatment with PEGylated interferon alfa-2b plus ribavirin.Results. At baseline, patients with MC vasculitis had a significantly lower frequency and number of Treg cells than did patients without MC vasculitis. Complete remission of MC vasculitis following antiviral treatment was associated with a significant increase in Treg cell levels compared with baseline. In contrast, Treg cell levels in nonresponders or partial responders, which did not differ from those in complete responders at baseline, remained unchanged over the course of the study. Conclusion. The strong positive correlation between clinical responses and Treg cell levels provides further support for the central role of Treg cells in the pathogenesis of HCV-induced MC vasculitis and emphasizes the dual role of Treg cells in chronic HCV infection: while Treg cells may hinder viral elimination, they also limit autoimmune injury.Chronic infection with hepatitis C virus (HCV) is the main cause of mixed cryoglobulinemia (MC) vasculitis, a potentially life-threatening systemic vasculitis (1). MC is a B cell proliferative disorder characterized by polyclonal or monoclonal activation and autoantibody production. MC may lead to clinical manifestations ranging from an MC syndrome (purpura, arthralgia, asthenia) to a more serious vasculitis with nervous system and renal involvement (1). The observation of T cells in the vascular infiltrates and the presence of autoantibodies, together with the observation that some HLA groups confer susceptibility to MC vasculitis in HCV-infected patients, suggest that autoimmune processes are implied in this virus-induced disease (2,3). It has been demonstrated that antiviral treatment can lead to the disappearance of symptoms and can induce an immunologic response, i.e., a significant decrease in plasma cryoglobulin levels (4). Furthermore, the clinical response is closely related to effective viral elimination (4,5), supporting the causal link between chronic HCV infection and the autoimmune process.During the past several years, CD4ϩCD25 high immunoregulatory T cells have been identified in

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Predominance of type 1 (Th1) cytokine production in the liver of patients with HCV-associated mixed cryoglobulinemia vasculitis

Cited by 49 publications

References 37 publications

Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C†

Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C†

Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

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