T-cell-mediated epineurial vasculitis and humoral-mediated microangiopathy in cryoglobulinemic neuropathy

Bonetti, Bruno; Invernizzi, F; Rizzuto, N.; Bonazzi, M. L.; Zanusso, Gianluigi; Chinaglia, G.; Monaco, Salvatore

doi:10.1016/s0165-5728(96)00191-9

Cited by 63 publications

(34 citation statements)

References 21 publications

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“…T cell involvement in the pathogenesis of HCV-MC vasculitis has been observed in previous studies (20)(21)(22)(23). Patients with HCV-MC vasculitis often have a disturbed peripheral blood T cell repertoire, with a high frequency of T cell expansions (21).…”

Section: Discussionmentioning

confidence: 60%

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

Saadoun¹,

Bièche²,

Maisonobe³

et al. 2005

Arthritis & Rheumatism

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Objective. To examine the expression profiles of a large number of genes within typical vasculitic nerve lesions in patients with mixed cryoglobulinemia (MC) vasculitis in order to better characterize the molecules involved in cellular tissue activation and trafficking.Methods. The quantitative expression of 19 genes coding for cytokines, chemokines, and their receptors in the nerve lesions of 9 patients with hepatitis C virus (HCV)-associated MC vasculitis, 7 with idiopathic polyarteritis nodosa (PAN) (rheumatic disease controls), and 8 patients with noninflammatory idiopathic neuropathy (noninflammatory neuropathy controls) was assessed using a real-time reverse transcriptasepolymerase chain reaction procedure.Results. Compared with the noninflammatory controls, HCV-MC vasculitis patients had a significantly higher expression of Th1 cytokines in vasculitic nerve lesions (mean ؎ SEM fold increase 33.7 ؎ 11.6 for interferon-␥ and 7.2 ؎ 1.9 for tumor necrosis factor ␣), whereas Th2 cytokines were absent ( Conclusion. This study is the first to demonstrate a role of cellular immunity and Th1 lymphocytes in the pathogenesis of HCV-MC vasculitic nerve lesions.Type II mixed cryoglobulinemia (MC) is a systemic vasculitis, usually associated with hepatitis C virus (HCV), that mainly involves the skin, kidneys, and nervous system (1). MC is characterized by the proliferation of B cell clones producing pathogenic IgM with rheumatoid factor activity. The neurologic complications in HCV-infected patients occur predominantly in the peripheral nervous system and are mainly associated with MC (2). The reported prevalence of peripheral nervous system involvement in patients with HCV infection varies and can be as high as 50% of cases (3,4). The most frequently described form is a distal sensory or sensorimotor polyneuropathy (3,5).The pathophysiology of HCV-MC vasculitis neuropathy is still a subject of controversy. Neutrophil 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 and only a minor role for humoral mechanisms in the formation of the vasculitic lesions (5-7). We recently obtained evidence of an important role of vascular cell adhesion molecule 1, a molecule that is exclusively involved in mononuclear cell recruitment, in the pathogenesis of severe forms of HCV-MC vasculitis (8).

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Section: Discussionmentioning

confidence: 60%

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

Saadoun¹,

Bièche²,

Maisonobe³

et al. 2005

Arthritis & Rheumatism

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“…Given the dearth of data on NSVN, the group reviewed studies that enrolled patients with SVN or NSVN. Eighteen articles were selected, six class II and twelve class III (all case-control studies, except one retrospective cohort survey) 14,34,54,60,[94][95][96][97][98][99][100][101][102][103][104][105][106][107] , which were analysed to identify variables associated with vasculitic neuropathy. By combining evidence from this review with that from class IV studies that showed active axonal degeneration to be increased in all vasculitic neuropathy series, the guideline group designed consensus diagnostic criteria for histopathologically probable vasculitic neuropathy.…”

Section: Histopathological Diagnosismentioning

confidence: 99%

The nonsystemic vasculitic neuropathies

2017

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The vasculitides are a clinically diverse group of diseases with the histopathological signature of blood vessel-centred inflammation that results in vascular damage and ischaemic injury to the affected tissues 1 . Vasculitis can be caused by drugs, infections and cancers, but diagnostic workup reveals no trigger in most patients. Autoimmune mechanisms are active in all vasculitides, except those caused by direct infection of vessel walls. Most vasculitides are systemic and involve multiple organs and tissues. Those affecting small-to medium-sized vessels often manifest with a vasculitic neuropathy. For example, neuropathies occur in 60-70% of patients with polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis and cryoglobulinaemic vasculitis, and 40-50% of those with microscopic polyangiitis and rheumatoid vasculitis 2 .Vasculitic neuropathy can also occur without systemic vasculitis. This single-organ vasculitis of the PNS has commonly been referred to as nonsystemic vasculitic neuropathy (NSVN), but other forms of clinically isolated PNS vasculitis are now recognized and can be considered variants of NSVN 3 . Although NSVN is classically an acute, relapsing, multifocal neuropathy, it can present as a slowly progressive neuropathy without distinct asymmetries. As such, it should be considered as a possible cause of any progressive axonal neur opathy. NSVN can be diagnosed only with a nerve biopsy, with or without a concomitant muscle or skin biopsy; as nerve biopsies are seldom performed, the condition is under-recognized. The disorder must be distinguished from many other causes of multifocal neuropathy, the definition of which is itself not standardized and requires clarification.A Peripheral Nerve Society guideline group reviewed the literature on vasculitic neuropathy and published consensus recommendations on the classification, diagnosis and immunosuppressive treatment of NSVN in 2010 (REF. 4) Abstract | Nonsystemic vasculitic neuropathy (NSVN) is an under-recognized single-organ vasculitis of peripheral nerves that can only be diagnosed with a nerve biopsy. A Peripheral Nerve Society guideline group published consensus recommendations on the classification, diagnosis and treatment of NSVN in 2010, and new diagnostic criteria for vasculitic neuropathy were developed by the Brighton Collaboration in 2015. In this Review, we provide an update on the classification, diagnosis and treatment of NSVN. NSVN subtypes include Wartenberg migratory sensory neuropathy and postsurgical inflammatory neuropathy. Variants include diabetic radiculoplexus neuropathy and -arguably -neuralgic amyotrophy. NSVN with proximal involvement is sometimes termed nondiabetic lumbosacral radiculoplexus neuropathy. Cutaneous polyarteritis nodosa and other skin-nerve vasculitides overlap with NSVN clinically. Three patterns of involvement in NSVN have been identified: multifocal neuropathy, distal symmetric polyneuropathy, and overlapping multifocal neuropathy (asymmetric polyneuropathy). These patterns lack standard defi...

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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.…”

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confidence: 99%

Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis

Saadoun

Rosenzwajg

Landau

et al. 2008

Blood

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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T-cell-mediated epineurial vasculitis and humoral-mediated microangiopathy in cryoglobulinemic neuropathy

Cited by 63 publications

References 21 publications

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

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

The nonsystemic vasculitic neuropathies

Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis

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