Journal of Translational Autoimmunity最新文献

Introduction

Impairment of the type I interferon (IFN–I) signaling pathway is associated with increased severity of COVID-19 disease. Here we have undertaken a systematic review and meta = analysis on the association between the severity of COVID-19 and IFN-1 autoantibodies (AAbs; aIFN-1, aIFN-α, aIFN-ω, and aIFN-β).

Methods

Four databases, including Medline [PubMed], Embase, Web of Science, and Scopus, were systematically searched to find papers on the role of aIFN-1 and its subtype AAbs in the severity of COVID-19 infection. Data on the prevalence of aIFN-1, aIFN-α, aIFN-ω, and aIFN-β were pooled using random- or fixed-effects models. Subgroup analysis was performed based on disease severity. Odds ratios (OR) for COVID-19 disease outcome, including length of hospital stay, ICU admission and death, were calculated in relation to positive or negative plasma IFN-1 AAbs.

Results

A total of 33 studies with 13023 patients were included. The overall prevalence of circulating aIFN-1, aIFN-α, and aIFN-ω AAbs was 17.8 % [13.8, 22.8], 7.2 % [4.7, 10.9], and 4.4 % [2.1, 8.6], respectively, and the overall prevalence of neutralizing aIFN-1, aIFN-α, aIFN-ω, and aIFN-β AAbs was 7.1 % [4.9, 10.1], 7.5 % [5.9, 9.5], 8.0 % [5.7, 11.1] and 1.2 % [0.4, 3.5], respectively. Circulating aIFN-α (OR = 4.537 [2.247, 9.158]), neutralizing aIFN-α (O = 17.482 [8.899, 34.342]), and neutralizing aIFN-ω (OR = 12.529 [7.397, 21.222]) were significantly more frequent in critical/severe patients than in moderate/mild patients (p < 0.001 for all). Anti–IFN–1 was more common in male subjects (OR = 2.248 [1.366, 3.699], p = 0.001) and two COVID-19 outcomes including ICU admission (OR = 2.485 [1.409, 4.385], p = 0.002) and death (OR = 2.593 [1.199, 5.604], p = 0.015) occurred more frequently in patients with positive anti–IFN–1.

Conclusion: aIFN-1 and its subtypes AAbs are associated with severe and critical COVID-19 disease and may be a predictive marker for a poor prognosis, particularly in men.

Background

Patients with autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome have a worse prognosis compared to AIH or PBC alone and accurately predicting the severity and dynamically monitoring the progression of disease are therefore essential. We aimed to develop a nomogram-based model to predict advanced liver fibrosis in patients with AIH-PBC overlap syndrome.

Methods

A total of 121 patients with AIH-PBC overlap syndrome were retrospectively included and randomly assigned to a development set and a validation set. Backward stepwise regression's best model with the lowest AIC was employed to create a nomogram. Diagnose accuracy was evaluated using the area under the receiver operator characteristic curve (AUROC), calibration analysis, and decision curve analysis (DCA) and was compared with aspartate aminotransferase-to-platelet ratio (APRI) and fibrosis index based on four factors-4 (FIB-4) score.

Results

The median age of patients was 53.0 years (IQR: 46.0–63.0), and female patients accounted for 95.0 %. Platelets, globulin, total bilirubin, and prothrombin time were associated with advanced fibrosis (≥S3) and used to construct an AIH-PBC overlap syndrome fibrosis (APOSF)-nomogram (available online at https://ndth-zzy.shinyapps.io/APOSF-nomogram/). The AUROCs of APOSF-nomogram were 0.845 (95 % CI: 0.754–0.936) and 0.843 (95 % CI: 0.705–0.982) in development set and validation set respectively, which was significantly better than APRI and FIB-4. Calibration revealed that the estimated risk fits well with biopsy-proven observation. DCA outperformed APRI and FIB4 in terms of net benefit, demonstrating clinical utility.

Conclusion

This novel non-invasive web-based online APOSF-nomogram provided a convenient tool for identifying advanced fibrosis in patients with AIH-PBC overlap syndrome. Further prospective, multicenter studies with large sample size are necessary to validate the applicability of APOSF-nomogram.

Introduction

Lupus nephritis (LN) affects up to 60 % of the patients with Systemic Lupus Erythematosus (SLE) and renal damage progression is associated with proteinuria, caused in part by the integrity of the glomerular basement membrane (GBM) and by podocyte injury. The soluble urokinase plasminogen activator receptor (suPAR) and Wilms Tumor 1 (WT1) have been related to podocyte effacement and consequently with proteinuria which raises questions about its pathogenic role in LN.

Objective

Define whether suPAR levels and WT1 expression influence in podocyte anchorage destabilization in LN class IV.

Materials and methods

This is a cross-sectional study of cases and controls. We studied patients with SLE without renal involvement (n = 12), SLE and LN class IV with proteinuria ≤0.5 g/24 h (n = 12), LN class IV with proteinuria ≥0.5 g/24 h (n = 12) and compared them with renal tissue control (CR) (n = 12) and control sera (CS) (n = 12). The CR was integrated by cadaveric samples without SLE or renal involvement and the CS was integrated by healthy participants. The expression and cellular localization of WT1, urokinase-type plasminogen activator receptor (uPAR), ac-α-tubulin, vimentin, and β3-integrin was assessed by immunohistochemistry (IHC). The concentration of suPAR in serum was analyzed by enzyme-linked immunosorbent assay (ELISA).

Results

In patients with LN, the activation of anchoring proteins was increased, such as podocyte β3-integrin, as well as the acetylation of alpha-acetyl-tubulin and uPAR, in contrast to the decrease in vimentin; interestingly, the cellular localization of WT1 was cytoplasmic and the number of podocytes per glomerulus decreased. The concentrations of suPAR was increased in patients with LN.

Conclusion

The destabilization of podocyte anchorage modulated by β3-integrin activation, and tubulin acetylation, associated with decreased WT1 cytoplasmic expression, and increased suPAR levels could be involved in kidney damage in patients with LN class IV.

The spectrum and understanding of antibody-positive autoimmune encephalitis (AE) have expanded over the past few decades. In 2007, a rare subtype of AE known as anti-adenylate kinase 5 (AK5) encephalitis, was first reported. This disease is more common in elderly males, with limbic encephalitis as the core phenotype (characterized by subacute anterograde amnesia, sometimes with psychiatric symptoms, and rarely with seizures). Brain magnetic resonance imaging typically demonstrated initial temporal lobe T2/fluid-attenuated inversion recovery hyperintensities, and subsequent atrophy. No concomitant tumors have been found yet. AK5 antibody, targeting the intracellular antigen, is a biomarker for a non-paraneoplastic T-cell autoimmunity response, and can be detected in serum and cerebrospinal fluid using tissue-based and cell-based assays. Cytotoxic T-cell-mediating neuronal injury and loss play a pivotal role in the immunopathogenesis of anti-AK5 encephalitis. Patients mostly show poor response to immunotherapy and thus a poor prognosis in the long run. Herein, we review the literature and provide updated knowledge of this less-known entity, focusing on clinical characteristics, paraclinical findings, diagnosis process, and therapeutic approaches.

Introduction

Complement activation emerged as a key actor of anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV). Whether serum levels of C3 (sC3) or C3 kidney deposition may help to refine the prognosis of AAV remains elusive.

Methods

Retrospective multicentric study that included 154 patients with a first flare of AAV and sC3 (n = 143) or C3 kidney staining (n = 95) available at diagnosis. Clinical presentations, kidney pathology, and survival of patients with normal or low sC3 were compared using univariate analyses, Kaplan-Maier curves with log-rank comparison, or multivariate Cox’ model, as appropriate.

Results

20 patients (14 %) had low sC3. sC3 (as bivariate low/normal or as a continuous variable) was associated with 5-year mortality but not with kidney survival. C3 kidney deposition (C3+) was identified in 23 patients who were characterized by more frequent chronic hypertension and lower eGFR at presentation (p = 0.04). C3+ correlated with IgG, IgM, C1q deposition (p = 0.07, p < 0.0001 and p = 0.003, respectively). Chronicity and activity scores were similar in C3+ and C3- patients. Among C3+ patients, those with C3 deposition ≥2+ had lower eGFR at presentation (p = 0.006) and were more frequently classified as sclerotic using the Berden classification (p = 0.04) and as ‘high risk’ using the Brix score (p = 0.03). However, eGFR improvement following induction regimen was similar between C3+ and C3- patients, and kidney survival at 5 years was similar.

Conclusions

Correlation of sC3 with mortality confirms mechanistic links between complement pathways and AAV, but the lack of clear predictive sC3 cut-off and the similar kidney outcome irrespective of C3 deposition precludes their use as biomarkers of AAV outcomes and response to treatment.

Introduction

The impact of COVID-19 pandemic represents a serious challenge for ‘frail’ patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic.

Patients and method

This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines.

Results

The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p < 0.000), as well the COVID-19-related mortality (1.91 % vs 0.72 %, p < 0.001). As regards the putative prognostic factors of worse outcome, COVID-19 positive patients with SSc-related interstitial lung involvement showed significantly higher percentage of COVID-19-related hospitalization compared to those without (5.85 % vs 1.73 %; p < 0.0001), as well as of mortality rate (2.01 % vs 0.4 %; p = 0.002). Over half of patients (56.3 %) received the first two plus one booster dose of vaccine; while a fourth dose was administered to 35.6 %, and only few of them (1.99 %) had five or more doses of vaccine. Of note, an impaired seroconversion was recorded in 25.6 % of individuals after the first 2 doses of vaccine, and in 8.4 % of patients also after the booster dose. Furthermore, the absence of T-cell immunoreactivity was observed in 3/7 patients tested by QuantiFERON® SARSCoV-2 Starter Set (Qiagen). The efficacy of vaccines, evaluated by comparing the COVID-19-related death rate recorded during pre- and post-vaccination pandemic periods, revealed a quite stable outcome in SSc patients (death rate from 2.54 % to 1.76 %; p = ns), despite the significant drop of mortality observed in the Italian general population (from 2.95 % to 0.29 %; p < 0.0001).

Conclusions

An increased COVID-19 prevalence and mortality rate was recorded in SSc patients; moreover, the efficacy of vaccines in term of improved outcomes was less evident in SSc compared to Italian general population. This discrepancy might be explained by concomitant adverse prognostic factors: increased rate of non-responders to vaccine in SSc series, low percentage of individuals with four or more doses of vaccine, ongoing immunomodulating treatments, disease-related interstitial lung disease, and/or reduced preventive measures in the second half of pandemic. A c