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We investigated 23 hepatitis C virus (HCV)-infected patients with overt lymphoproliferative diseases (15 cases) or monoclonal B lymphocytosis (8 cases) treated with direct agent antiviral (DAAs) per clinical practice. DAA therapy yielded undetectable HCV-RNA, the complete response of cryoglobulinemia vasculitis and related signs, whilst the presence of B-cell clones (evaluated by flow cytometry, IGHV, and BCL2-IGH rearrangements), detected in 19/23 cases at baseline, was maintained (17/19). Similarly, IGHV intraclonal diversification, supporting an antigen-driven selection mechanism, was identified in B-cell clones at baseline and end of follow-up. DAA therapy alone, despite HCV eradication and good immunological responses, was less effective on the pathological B-cell clones.
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PURPOSE: Mixed cryoglobulinemia syndrome (MCs) is a rare immunoproliferative systemic disorder with cutaneous and multiple organ involvement. Our multicenter survey study aimed to investigate the prevalence and outcome of COVID-19 and the safety and immunogenicity of COVID-19 vaccines in a large MCs series. METHODS: The survey included 430 unselected MCs patients (130 M, 300 F; mean age 70 ± 10.96 years) consecutively collected at 11 Italian referral centers. Disease classification, clinico-serological assessment, COVID-19 tests, and vaccination immunogenicity were carried out according to current methodologies. RESULTS: A significantly higher prevalence of COVID-19 was found in MCs patients compared to Italian general population (11.9% vs 8.0%, p < 0.005), and the use of immunomodulators was associated to a higher risk to get infected (p = 0.0166). Moreover, higher mortality rate was recorded in MCs with COVID-19 compared to those without (p < 0.01). Patients' older age (≥ 60 years) correlated with worse COVID-19 outcomes. The 87% of patients underwent vaccination and 50% a booster dose. Of note, vaccine-related disease flares/worsening were significantly less frequent than those associated to COVID-19 (p = 0.0012). Impaired vaccination immunogenicity was observed in MCs patients compared to controls either after the first vaccination (p = 0.0039) and also after the booster dose (p = 0.05). Finally, some immunomodulators, namely, rituximab and glucocorticoids, hampered the vaccine-induced immunogenicity (p = 0.029). CONCLUSIONS: The present survey revealed an increased prevalence and morbidity of COVID-19 in MCs patients, as well an impaired immunogenicity even after booster vaccination with high rate of no response. Therefore, MCs can be included among frail populations at high risk of infection and severe COVID-19 manifestations, suggesting the need of a close monitoring and specific preventive/therapeutical measures during the ongoing pandemic.
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Vacinas contra COVID-19 , COVID-19 , Crioglobulinemia , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Anticorpos Antivirais , COVID-19/complicações , COVID-19/epidemiologia , Vacinas contra COVID-19/efeitos adversos , Crioglobulinemia/diagnóstico , Crioglobulinemia/epidemiologia , Fatores Imunológicos , Prevalência , Vacinação/efeitos adversos , VacinasRESUMO
Studies from high endemic areas, mostly China, indicate that surface antigen positive (HBsAgpos) chronic hepatitis B virus (HBV) infection is associated with an increased risk of developing diffuse large B-cell lymphoma (DLBCL), whereas studies in low endemic areas have provided conflicting results. Past infection, serologically defined by negative HBsAg and positive anti-core antibody (HBsAgnegHBcAbpos), has also been suggested to increase the risk of B-cell non-Hodgkin's lymphoma (NHL) in high endemic areas. We retrospectively reviewed unselected clinical records of 253 patients with DLBCL (54% male, aged 60.3 ± 14.6 years at diagnosis) and 694 patients with different types of indolent B-cell NHL (46% male, aged 61.7 ± 12.8 years). Patients were seen at a single center in Italy between 2001 and 2022 and HBV serological status (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb, and HBV DNA) was analyzed through enzyme-linked immunosorbent assays and molecular assays; patients infected with hepatitis C virus or human immunodeficiency virus were excluded. We used an unconditional multiple logistic regression model including as matching variables gender, age at diagnosis, immigrant status, and HBV serological status. Patients with DLBCL had, compared to indolent NHL, a higher prevalence of HBsAgpos active infection (odds ratio (OR) 2.8, 95% confidence interval (95% CI) 1.2-6.3, p = 0.014). Strikingly, patients with DLBCL had also a significantly higher prevalence of past infection (OR 2.4, 95% CI 1.5-4.0, p = 0.0006). Male gender was associated with increased risk of DLBCL independently of the HBV serological status. These findings suggest that both past and active HBV infection may increase the risk of DLBCL in a low endemic area. Our study needs confirmation by studies in areas or populations with different rates of chronic or past HBV infection.
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Hepatite B Crônica , Hepatite B , Linfoma Difuso de Grandes Células B , Humanos , Masculino , Feminino , Vírus da Hepatite B/metabolismo , Estudos Retrospectivos , Antígenos de Superfície da Hepatite B , Hepatite B Crônica/complicações , Hepatite B Crônica/epidemiologia , Prevalência , Hepatite B/epidemiologia , Hepatite B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico , Anticorpos Anti-Hepatite BRESUMO
OBJECTIVES: Mixed cryoglobulinaemic vasculitis (MCV) is an immune-complex-mediated systemic vasculitis characterised by heterogeneous clinical manifestations mainly involving lymphatic system, skin, kidney and peripheral nervous system. Although MCV patients have been included in priority programs for vaccination against SARS-CoV-2 in Italy, limited information is available for these patients. The aims of this multicentre Italian study were to investigate SARS-CoV-2 vaccination rate in MCV patients and its safety profile. METHODS: All MCV patients referring to participating centres were assessed with an interview-based survey about vaccination, reasons for not getting vaccinated, adverse events (AE), and disease flares within a month after vaccination. RESULTS: A total of 416 patients were included in the study. Among participants, 7.7% did not get vaccinated, mainly for fear related to vaccine side-effects (50%) or medical decision (18.8%). They were more frequently treated with chronic glucocorticoids or rituximab (p=0.049 and p=0.043, respectively). Mild and self-limiting AE were recorded in 31.7% of cases, while post-vaccination vasculitis flares were observed in 5.3% of subjects. Disease relapses were mainly observed in patients with peripheral neuropathy or skin vasculitis (40% and 25%, respectively). CONCLUSIONS: Vaccination against SARS-CoV-2 has been performed in a high percentage of MCV patients with encouraging safety profile. Vasculitis flares rate was in line with that observed for other autoimmune diseases, despite patients with purpura or peripheral neuropathy seem to be at risk for symptoms' exacerbation. Patients' hesitancy, rituximab and glucocorticoids treatment were the main reasons for delaying vaccination.
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Vacinas contra COVID-19 , COVID-19 , Crioglobulinemia , Arterite de Células Gigantes , Granulomatose com Poliangiite , Poliarterite Nodosa , Humanos , COVID-19/complicações , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Glucocorticoides , Itália/epidemiologia , Rituximab , SARS-CoV-2 , Vacinação/efeitos adversosRESUMO
INTRODUCTION: Direct-acting antiviral agents (DAAs) have modified the management of chronic hepatitis C virus (HCV) infection, including HCV-related cryoglobulinemic vasculitis (CryoVas). However, patients might experience vasculitis relapse, and no reliable predictors of CryoVas relapse after sustained virologic response (SVR) have been established. We aimed to describe HCV-CryoVas relapse rates and factors associated with it. METHODS: An international multicenter cohort where patients with HCV-CryoVas from Egypt, France, and Italy treated with DAA were analyzed retrospectively. Factors associated with relapse-free survival were evaluated in a multivariate-adjusted model. RESULTS: Of 913 patients, 911 (99.8%) obtained SVR. After 35 months of the median follow-up, 798 patients (87.4%) had sustained remission of vasculitis, while 115 (12.6%) experienced CryoVas relapse. By the time of relapse, skin involvement was present in 100%, renal involvement in 85.2%, and peripheral neuropathy in 81.7%. Relapses were treated with glucocorticoids in 90.9%, associated with plasma exchange, cyclophosphamide, or rituximab in 50%, 37.3%, and 6.4%, respectively. The cumulative incidence of CryoVas relapse was 0.7% (95% CI 0.3-1.4), 12.3% (95% CI 10.2-14.6), and 13.1% (95% CI 11.0-15.5) at 12, 24, and 36 months after DAA treatment, respectively. Independent baseline risk factors associated with CryoVas relapse were male sex, skin ulcers, kidney involvement at baseline, and peripheral neuropathy at the end of DAA treatment. Death occurred in 11 relapsers, mainly due to infections. DISCUSSION: A substantial proportion of patients with CryoVas experience relapse after DAA-induced SVR. Relapses are moderate-to-severe and affect survival after 24 months, mainly due to infections. Independent risk factors for relapse or death were found.
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Crioglobulinemia , Hepatite C Crônica , Hepatite C , Vasculite , Antivirais/uso terapêutico , Crioglobulinemia/complicações , Crioglobulinemia/etiologia , Hepacivirus , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferons/uso terapêutico , Masculino , Recidiva , Estudos Retrospectivos , Resposta Viral Sustentada , Vasculite/tratamento farmacológicoRESUMO
Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable.
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Vacinas contra COVID-19 , COVID-19 , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Humanos , Imunização Secundária , VacinaçãoRESUMO
The objective of this study was to evaluate the predictive role of CD21low B cells as markers of new digital ulcers in systemic sclerosis patients. Peripheral blood B cell subpopulations and clinical assessments have been evaluated in 74 systemic sclerosis patients at baseline and after a 12-month follow-up. After a 12-month follow-up, 23 (31.1%) systemic sclerosis patients developed new digital ulcers. The median percentage of CD21low B cells was significantly higher in patients with than without new digital ulcers [10.1 (4.3-13.6) versus 4.8 (3.5-7.4); p < 0.01]. The 10% cut-off shows good diagnostic accuracy [area under the curve (AUC) = 0.732, confidence interval (CI) = 0.587-0.878; P = 0.01]. Kaplan-Meier curves show a significantly reduced free survival from new digital ulcers in systemic sclerosis patients with CD21low B cells ≥ 10% (p < 0.0001). In multivariate analysis, CD21low B cells ≥ 10%, modified Rodnan skin score (mRSS) and systolic pulmonary arterial pressure (sPAP) are associated with the development of new digital ulcers. We hypothesize that CD21low B cells are a predictive marker of new digital ulcers in systemic sclerosis patients.
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Linfócitos B/imunologia , Biomarcadores/metabolismo , Receptores de Complemento 3d/metabolismo , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Úlcera Cutânea/imunologia , Úlcera Cutânea/metabolismo , Linfócitos B/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Circulating free light chains (FLCs), considered biomarkers of B cell activity, are frequently elevated in patients affected by systemic inflammatory autoimmune diseases. As the systemic sclerosis (SSc) clinical course can be variable, this study is aimed at evaluating FLCs levels in affected individuals as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72 SSc patients and 30 healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of κ and λ FLC in serum significantly higher than HC (p = 0.0001) alongside the mean values of free κ/λ ratio and κ + λ sum (p = 0.0001). SSc patients showed increased free κ in urine with a κ/λ higher than HC (p = 0.0001). SSc patients with increased κ + λ in serum showed that erythro-sedimentation rate (p = 0.034), C-reactive protein (p = 0.003), DAI (p = 0.024) and DSS (p = 0.015) were higher if compared to SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free κ and DAI (r = 0.29, p = 0.014). In addition, SSc patients with increased free κ in urine had higher DAI (p = 0.048) than SSc patients with normal κ levels. Our results strengthen the role of serum FLC as useful biomarker in clinical practice to early diagnosis and monitor disease activity, showing for the first time that also urine FLC levels correlated with disease activity in SSc patients.
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Biomarcadores/sangue , Biomarcadores/urina , Cadeias Leves de Imunoglobulina/sangue , Cadeias Leves de Imunoglobulina/urina , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/urina , Idoso , Linfócitos B/imunologia , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Feminino , Humanos , Cadeias kappa de Imunoglobulina/sangue , Cadeias kappa de Imunoglobulina/urina , Cadeias lambda de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/urina , Masculino , Pessoa de Meia-IdadeRESUMO
Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53-1203) vs 825 (451-1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.
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Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Feminino , Humanos , Itália , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2/imunologia , Escleroderma Sistêmico/imunologia , Vasculite Sistêmica/imunologia , Vacinação , Potência de VacinaRESUMO
OBJECTIVES: The biomarkers of an immunological dysregulation due to a chronic HBV infection are indeed understudied. If untreated, this condition may evolve into liver impairment co-occurring with extrahepatic involvements. Here, we aim to identify a new panel of biomarkers [including immunoglobulin G (IgG) subclasses, RF, and Free Light Chains (FLCs)] that may be useful and reliable for clinical evaluation of HBV-related cryoglobulinemia. METHODS: We retrospectively analysed clinical data from 44 HBV-positive patients. The patients were stratified (according to the presence/absence of mixed cryoglobulinemia) into two groups: 22 with cryoglobulins (CGs) and 22 without CGs. Samples from 20 healthy blood donors (HDs) were used as negative controls. Serum samples were tested for IgG subclasses, RF (-IgM, -IgG, and -IgA type), and FLCs. RESULTS: We detected a strikingly different distribution of serum IgG subclasses between HDs and HBV-positive patients, together with different RF isotypes; in addition, FLCs were significantly increased in HBV-positive patients compared with HDs, while no significant difference was shown between HBV-positive patients with/without mixed cryoglobulinemia. CONCLUSION: The immune-inflammatory response triggered by HBV may be monitored by a peculiar profile of biomarkers. Our results open a new perspective in the precision medicine era; in these challenging times, they could also be employed to monitor the clinical course of those COVID-19 patients who are at high risk of HBV reactivation due to liver impairment and/or immunosuppressive therapies.
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Biomarcadores/sangue , COVID-19/imunologia , Crioglobulinemia/imunologia , Crioglobulinemia/virologia , Vírus da Hepatite B/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , SARS-CoV-2RESUMO
Several studies have suggested that hepatitis C virus (HCV) may be the causative agent of some B-cell non-Hodgkin lymphomas (B-NHL). Several authors have demonstrated that pegylated interferon (Peg-IFN) plus ribavirin (RBV) can revert indolent low-grade B-NHL by inducing HCV eradication. Presently, the combination therapy (IFN plus RBV) has been abandoned since the direct antiviral agents (DAAs) have shown very high efficacy in achieving sustained virologic response (SVR) (range: 95%-100%). This review analyzed DAAs efficacy in HCV-associated indolent low-grade NHL, providing a detailed literature review. Overall, 122 B-cell NHL patients were treated with DAAs: complete/partial hematological response, particularly in those with marginal zone lymphoma, was obtained in most cases. Hematological response, obtained either with DAAs or IFN-based therapy, was similar. Nonetheless, DAAs therapy showed better tolerability and higher SVR. A fraction of the patients, despite SVR, underwent hematologic relapse or progression. In these cases, a recovery treatment with immunotherapy, or chemoimmunotherapy, had to be planned. In conclusion, data obtained from published studies mostly agree that HCV eradication with DAAs should be considered as the first-line treatment in HCV-related NHL. In fact, the chronic viral stimulation of the immune system might be the primary pathogenic mechanism in disease development and progression.
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Antivirais/uso terapêutico , Hepatite C/complicações , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/etiologia , Antivirais/farmacologia , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/patologia , Pessoa de Meia-IdadeRESUMO
Sustained virological response (SVR) obtained with interferon (IFN) or with direct-acting antivirals (DAAs) is commonly followed by response of hepatitis C virus (HCV)-associated mixed cryoglobulinemia vasculitis (MCV), but relapse of MCV despite SVR has been reported in several patients after DAAs and rarely after IFN. Since relapses could have been overlooked in studies with IFN, we retrospectively compared the outcomes of MCV in SVR patients treated with DAAs (n = 70) or IFN (n = 39) followed-up, respectively, for 30.5 (range 11-51) or 48 months. Groups were comparable for demographics and clinics and response rates of MCV were similar (92% and 86%); however, DAA-treated patients less efficiently reduced cryoglobulins (P = .006) and circulating B-cell clones (P = .004), and had more frequently relapses of MCV (18% vs 3%, P = .028) and need for rituximab therapy (P = .01). Although largely inferior on an intention-to-treat basis, IFN may be superior to DAAs on clinico-immunological outcomes possibly owing to its antiproliferative activity.
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Crioglobulinemia , Hepatite C Crônica , Hepatite C , Antivirais/uso terapêutico , Crioglobulinemia/tratamento farmacológico , Hepacivirus , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferons/uso terapêutico , Recidiva , Estudos RetrospectivosRESUMO
People with cryoglobulinaemic vasculitis (CV) have an increased risk of infections, attributed to different causes: impairment of the immune system due to the disease itself, comorbidities, and immunosuppressive therapy. Therefore, these patients may be at high risk for a more severe course of COVID-19, including hospitalisation and death. Concerns about efficacy, immunogenicity and safety of vaccines, as well as doubts, not yet fully clarified in patients with systemic autoimmune diseases, represent other important factors for a low vaccination rate in people with (CV). Indeed, providing an expert position on the issues related to SARS-CoV-2 vaccination in patients suffering from CV is of critical relevance in order to help both patients and clinicians who are treating them in making the best choice in each case. A multidisciplinary task force of the Italian Group for the Study of Cryoglobulinaemia (GISC) was convened, and through a Delphi technique produced provisional recommendations regarding SARS-CoV-2 vaccination in cryoglobulinaemic patients.
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COVID-19 , Crioglobulinemia , Vasculite , Vacinas contra COVID-19 , Humanos , Itália , SARS-CoV-2 , VacinaçãoRESUMO
Cryoglobulinaemia consists of circulating monoclonal and/or polyclonal immunoglobulins with rheumatoid factor (RF) activity that precipitate at temperatures <37°C. Cryoglobulinaemic syndrome, characterised by clinical signs of systemic vasculitis, is associated with chronic infection of hepatitis C virus (HCV) and might evolve in B-cell malignancies. In about one third of all HCV infection cases, serum autoantibodies are commonly found. This is probably due directly to the transformation of infected B cells but, also, indirectly, to the viral chronic stimulation of a pool of autoreactive B cells. The pattern of IgG subclasses seems to contribute to the worsening progression of HCV infection into lymphoproliferative and/or autoimmune diseases. Many evidences showed that B cells circulating in patients with HCV-associated mixed cryoglobulinaemia (MC) are profoundly abnormal; moreover, in most of cases, normal B cells are replaced by expanded clonal B cells characterized by the low expression of CD21. After viral eradication, these cells persist in circulation and their occurrence does not correlate with serum cryoglobulins nor with vasculitis response or relapse. It is probably due to the persistence of monoclonal B cells producing RF, that in course of MC can be reactivated by circulating immune complexes, highly produced during infections or tumours. Here, we aimed to review current literature focusing the pathogenesis of MC referring to specificity and immunochemical characteristics of the immunoglobulins involved in cryoprecipitation.
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Crioglobulinemia , Hepatite C , Imunidade Adaptativa , Crioglobulinas , Hepacivirus , HumanosRESUMO
Hepatitis C virus (HCV) represents the major risk factor for mixed cryoglobulinemia (MC), a small-vessel vasculitis that may evolve into an overt B-cell non-Hodgkin's lymphoma. Here, we aimed to identify a biomarker signature for the early diagnosis of minimal residual disease (MRD). We assessed free light chains (FLCs), IgM k,and IgM λ heavy/light chain (HLC) pairs, and vascular endothelial growth factor (VEGF) in sera from 34 patients with MC vasculitis (32 HCV- and 2 HBV-related), treated with low-dose rituximab (RTX). FLCs and IgM HLCs were measured by turbidimetric assay; VEGF by an enzyme-linked immunosorbent assay. After RTX, the positive (complete + partial) clinical and laboratory responses were of 85.29% and 50%, respectively; in contrast, the mean levels of FLCs, IgM HLCs, and VEGF were substantially unaffected in most patients and still above the normal range. In those achieving a reduction of FLCs and IgM k and λ chains values within the range of normality, we found that post-treatment free λ chains and IgM k values correlated with clinical and laboratory response. Our results suggest that high levels of FLCs, IgM HLCs, and VEGF could represent the signature of "dormant" B cell clones' activity that could be very useful to identify MRD indicative of possible relapse or worsening outcome.
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Crioglobulinemia , Imunoglobulina M/sangue , Cadeias kappa de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/sangue , Rituximab/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Crioglobulinemia/sangue , Crioglobulinemia/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Hepatitis C virus (HCV) causes B-cell lymphoproliferative disorders (LPDs) expressing stereotyped B-cell receptors (BCRs) endowed with rheumatoid factor (RF) activity and putatively recognizing the HCV E2 protein. To further untangle the shaping and function of these BCRs, we analyzed immunoglobulin gene rearrangements of monoclonal B cells from 13 patients with HCV-associated LPDs and correlated their features with the clinical outcomes of antiviral therapy. While only two patients shared a stereotyped heavy-chain complementarity determining region 3 (CDR3) sequence, two kappa chain CDR3 stereotyped sequences accounted for 77% of BCRs. Light chains were enriched in sequences homologous to anti-HCV E2 antibodies compared with heavy chains (7/13 vs. 0/13; p = 0.005). Anti-HCV E2 homology was uniquely associated (7/7 vs. 0/6; p = 0.0006) with a stereotyped CDR3 sequence encoded by IGKV3-20/3D-20 gene(s) accounting for 54% of BCRs. An IGKV3-15/IGKJ1-encoded stereotyped sequence homologous to WA RF accounted for 23% of BCRs. LPDs expressing KCDR3s homologous to anti-HCV E2 antibodies responded more frequently to the eradication of HCV by antiviral therapy (6/6 vs. 1/6; p = 0.015). These findings, although limited by the small sample size, suggest that a stereotyped KCDR3 may predominantly shape anti-HCV specificity of BCRs, possibly providing a signature that may help identifying bona fide HCV-dependent LPDs.
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Cadeias Leves de Imunoglobulina/genética , Receptores de Antígenos de Linfócitos B/genética , Idoso , Sequência de Aminoácidos/genética , Linfócitos B/metabolismo , Regiões Determinantes de Complementaridade/genética , Feminino , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/complicações , Humanos , Cadeias Leves de Imunoglobulina/metabolismo , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Transtornos Linfoproliferativos , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos B/metabolismo , Fator Reumatoide/imunologiaRESUMO
OBJECTIVES: To evaluate expansion of CD21low B cells and their role in B cell homeostasis, apoptosis, clinical manifestations and serum vascular endothelial growth factor (VEGF) in systemic sclerosis (SSc). MATERIALS AND METHODS: B-cells subpopulations and apoptosis have been assessed in 74 SSc patients and 20 healthy donors. Renal Doppler ultrasound, echocardiography, pulmonary function test and VEGF were performed. RESULTS: SSc patients with expanded CD21low B cells (SSc-CD21low) show a distinct B cell profile with increased memory B cells compared to patients without CD21low B cells (SSc-CD21+). Renal resistive index, systolic pulmonary arterial pressure and FVC/DLCO ratio were significantly higher in SSc-CD21low group than SSc-CD21+, DLCO was lower in SSc-CD21low group than SSc-CD21+. We found a positive linear correlation between CD21low and sPAP, RI and FVC/DLCO ratio whereas a negative correlation was observed between CD21low and DLCO and VEGF levels. CONCLUSIONS: CD21low B cells are increased in SSc patients with visceral vascular manifestations.
Assuntos
Subpopulações de Linfócitos B/imunologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Doenças Vasculares/etiologia , Idoso , Feminino , Cardiopatias/etiologia , Humanos , Nefropatias/etiologia , Pneumopatias/etiologia , Masculino , Pessoa de Meia-Idade , Receptores de Complemento 3d/imunologia , Escleroderma Sistêmico/patologia , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
OBJECTIVES: Essential mixed cryoglobulinaemia (EMC) is a disorder of B-cells producing rheumatoid factor (RF), and is clinically and immunologically similar to mixed cryoglobulinaemia (MC) related to hepatitis C virus (HCV-MC). We report here the first comprehensive analysis of B-cell clonality, phenotype and function in EMC. METHODS: The study population included 16 patients with EMC and 24 patients with HCV-MC. Molecular analysis was done for the detection of circulating clonal B cells and for B cell receptor sequencing. B-cell phenotype, proliferative response, apoptosis and ERK signaling were analysed by flow cytometry. RESULTS: Molecular analysis of immunoglobulin genes rearrangements revealed circulating B-cell clones in about half of patients, on average of smaller size than those found in HCV-MC patients. Sequence analysis showed usage of the same stereotyped RF-encoding B-cell receptors frequently expressed in HCV-MC and in primary Sjögren's syndrome. B-cells with low expression of CD21 (CD21low) and unusual homing and inhibitory receptors were increased in EMC and in HCV-MC, but at a significantly lower extent in the former. The CD21low B-cells of EMC and HCV-MC patients shared functional features of exhaustion and anergy, namely reduced proliferation upon ligation of Toll-like receptor 9, high constitutive expression of phosphorylated ERK, and proneness to spontaneous apoptosis. CONCLUSIONS: Our findings suggest a common pathogenetic mechanism in EMC, HCV-MC and primary Sjögren's syndrome, consisting of autoantigen-driven clonal expansion and exhaustion of selected RF-producing B-cells. The more massive clonal expansion in HCV-MC may be due to co-stimulatory signals provided by the virus.
Assuntos
Autoantígenos/imunologia , Linfócitos B/imunologia , Crioglobulinemia/patologia , Hepatite C/patologia , Fator Reumatoide , Linfócitos B/patologia , Crioglobulinemia/virologia , Hepacivirus , HumanosRESUMO
Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of IgM+CD27+ B cells. These cells display both the features of anergy induced by continual engagement of the B-cell receptor (BCR), such as high expression of phosphorylated extracellular signal-regulated kinase (pERK) and reduced lifespan, and of virus-specific exhaustion, such as CD21low phenotype and a defective response to ligation of BCR and Toll-like receptor 9 (TLR9). MC usually regresses after eradication of HCV with interferon, whose immunomodulatory activity might contribute to this effect. We investigated the phenotypic and functional changes in clonal B cells of MC patients with sustained virologic responses to direct-acting antivirals (DAAs), which lack immunomodulatory properties. We found that high pERK expression and accelerated apoptosis revert within 4 weeks after beginning therapy, whereas clonal B cells unresponsive to TLR9 stimulation persist for at least 24 weeks, although they may partially rescue normal CD21 expression. Thus, similar to mouse models, features of anergy in MC B cells rapidly revert after disengagement from HCV, whereas virus-specific exhaustion imparts a durable inhibitory imprint on cell function. Treatment of HCV+ MC with DAAs provides a valuable tool for untangling the molecular mechanisms of anergy and exhaustion in human B cells.
Assuntos
Linfócitos B/imunologia , Anergia Clonal , Crioglobulinemia/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Receptores de Complemento 3d/imunologia , Viremia/imunologia , Crioglobulinemia/etiologia , Feminino , Regulação da Expressão Gênica/imunologia , Hepatite C/terapia , Humanos , MasculinoRESUMO
Depletion of B cells is beneficial in rheumatoid arthritis (RA) patients with autoantibodies to citrullinated proteins (ACPA) and/or the Fc portion of immunoglobulins (rheumatoid factor [RF]), suggesting a role for B cells in disease pathogenesis. To date, however, the identity of specifically pathogenic B cell subsets has not been discovered. One candidate population is identified by the low expression or absence of complement receptor 2 (CD21-/low B cells). In this study, we sought to determine whether there was any correlation between CD21-/low B cells and clinical outcome in patients with established RA, either ACPA+ /RF+ (n = 27) or ACPA- /RF- (n = 10). Healthy donors (n = 17) were included as controls. The proportion of the CD21-/low CD27- IgD- memory B cell subset in peripheral blood (PB) was significantly increased in ACPA+ /RF+ RA patients compared with healthy donors, and the frequency of this subset correlated with joint destruction (r = 0.57, P < 0.04). The levels of the chemokines CXCL-9 and CXCL-10 were higher in synovial fluid than in plasma, and PB CD21-/low cells expressed the receptor, CXCR3. In synovial fluid, most of the B cells were CD21-/low , approximately 40% of that population was CD27- IgD- , and a third of those expressed the pro-osteoclastogenic factor receptor activator of the nuclear factor κB ligand (RANKL). This subset also secreted RANKL, in addition to other factors such as IL-6, even in the absence of stimulation. We interpret these data as reason to propose the hypothesis that the CD27- IgD- subset of CD21-/low B cells may mediate joint destruction in patients with ACPA+ /RF+ RA.