Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus–associated mixed cryoglobulinemia vasculitis neuropathy

Saadoun, David; Bièche, Ivan; Maisonobe, Thierry; Asselah, Tarik; Laurendeau, Ingrid; Piette, Jean Charles; Vidaud, Michel; Cacoub, Patrice

doi:10.1002/art.21270

Cited by 78 publications

(58 citation statements)

References 23 publications

(27 reference statements)

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“…cytokines, including IFN-␥ and TNF-␣, in vasculitic nerve lesions (30). Chemokines and chemokine receptors involved in T cell and monocyte trafficking, such as Ccl3, Ccl4, and Cxcr3, were also significantly upregulated (30).…”

Section: Discussionmentioning

confidence: 99%

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

et al. 2016

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dInfectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80 ؉ macrophages, and T. cruzi tetramer-specific CD8 ؉ T lymphocytes capable of producing gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus, T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses. Vasculitis is a general term for a spectrum of diseases involving leukocyte infiltration of the blood vessel wall. Many subtypes of vasculitis are recognized based on the types of blood vessels involved and the nature of the underlying immunopathology. In some cases, an association of vasculitis with specific infectious agents has been reported; for example, polyarteritis nodosa (PAN) has been associated with hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV infections (1). However, it has been difficult to establish either causality or pathogenetic mechanisms, in part because of the low prevalence of vasculitis and the lack of good animal models (2). In this regard, while studying the chronic phase of C57BL/6J mice infected with the myotropic Colombiana strain of Trypanosoma cruzi, the infectious cause of Chagas' disease in humans, we noticed that the majority of animals developed hind limb paralysis associated with severe systemic necrotizing vasculitis affecting arteries and arterioles in skeletal muscle. Lesions were also present in many other tissues. A review of the literature identified several studies from 1970 to 2000 that described perivascular inflammation and frank arteritis in chronically T. cruzi-infected mouse skeletal muscle, aorta, nerves, and heart (3-9); however, the underlying immunologic mechanisms of disease were not defined. Interestingly, Okumura et al. reported necrotizing arteritis in small arteries beneath the peritoneal lining of the bowel and, occasionally, of the aorta and coronary arteries of T. cruzi-infected mice, which was at that time interpreted as "allergic necrotizing angiitis" (10). Dias et al. reported obliterative changes of the small and medium-sized branches of coronary...

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Section: Discussionmentioning

confidence: 99%

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

et al. 2016

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“…However, a number of T-cell abnormalities have been described, including a polarization toward Th1 subsets 17,19,38 and also a quantitative deficiency of circulating regulatory T cells. 20 B-cell depletion has been used in the treatment of patients with a number of different autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Recent investigations have shown that Th1/Th2 imbalance plays a central role in HCV-MC vasculitis. 19,38 It is important to emphasize that several factors can determine the fate of activated T cells, including type of antigen-presenting cells, costimulatory molecules, chromatin structure, and cytokines present in the local microenvironment of the cell at the time of stimulation. Interestingly, the data present here indicate that Th1 polarization can be reverted after treatment with rituximab, but only in complete responders of MC vasculitis.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis

Saadoun

Rosenzwajg

Landau

et al. 2008

Blood

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102

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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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“…The pathophysiology of HCV-related vasculitis is still controversial. Neutrophilic infiltration with leukocytoclastic changes typical of immune complex-mediated vasculitis has seldom been found, while the presence of lymphohistiocytic infiltrates suggests a T cellmediated pathogenesis and only a minor role for the humoral mechanisms in the formation of the vasculitic lesions (27)(28)(29). Along this line, relapses of HCV vasculitis after rituximab therapy were significantly higher in PAN compared to MC patients.…”

Section: Pan-type Vasculitis Associated With Hcvmentioning

confidence: 99%

Hepatitis C virus–associated polyarteritis nodosa

Saadoun¹,

Terrier²,

Semoun³

et al. 2011

Arthritis Care & Research

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Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus–associated mixed cryoglobulinemia vasculitis neuropathy

Cited by 78 publications

References 23 publications

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis

Hepatitis C virus–associated polyarteritis nodosa

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