The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies

SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.

Targeting Regulatory T Cells for Therapy of Lupus Nephritis

Lupus glomerulonephritis (LN) is a complex autoimmune disease characterized by circulating autoantibodies, immune-complex deposition, immune dysregulation and defects in regulatory T cell (Tregs). Treatment options rely on general immunosuppressants and steroids that have serious side effects. Approaches to target immune cells, such as B cells in particular, has had limited success and new approaches are being investigated. Defects in Tregs in the setting of autoimmunity is well known and Treg-replacement strategies are currently being explored. The aim of this minireview is to rekindle interest on Treg-targeting strategies. We discuss the existing evidences for Treg-enhancement strategies using key cytokines interleukin (IL)-2, IL-33 and IL-6 that have shown to provide remission in LN. We also discuss strategies for indirect Treg-modulation for protection from LN.

Bullous pemphigoid in diabetic patients treated by gliptins: the other side of the coin

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease that affects primarily patients older than 60 years. The majority of BP cases are spontaneous, but BP can also be triggered by certain drugs’ exposures. Since 2011, a growing number of observations has been reporting cases of BP in Type 2 diabetic patients. These forms have been linked to the use of a new category of anti-diabetic drugs called dipeptidyl peptidase inhibitors (DPP-4i) or gliptins, but to date, the exact pathophysiological mechanisms underlying this association are not completely elucidated. Although conventional and gliptin-associated BP are thought to share similar clinical and histopathological features, our thorough review of the most recent literature, shows that these 2 forms are quite distinct: DPP-4-i-associated BP seems to appear at an earlier age than spontaneous BP, it may manifest either as a noninflammatory or inflammatory phenotype, while the conventional form presents with a typical inflammatory phenotype. Additionally, an important distinctive histological feature was recently shown in Gliptin-associated BP: these forms may present a less significant eosinophils infiltrate in the upper dermis of peri-blister lesions compared to the skin of patients with spontaneous BP, and this seems a specific feature of the clinically non-inflammatory forms. In accordance with previous literature, we found that the direct immunofluorescence (DIF) gives identical findings in both DPP-4i-associated and conventional forms of BP which is an IgG and complement C3 deposition as a linear band at the dermal–epidermal junction in perilesional skin. Indirect immunofluorescence shows the presence of IgG circulating autoantibodies in the patient's serum which titer does not differ between spontaneous and DPP-4i-associated BP, while the specificity of these autoantibodies, may be different in spontaneous, induced non-inflammatory and induced inflammatory forms, epitope spreading phenomenon seems to play a role in determining these specificities. Further research, based on integrated epidemiological, clinical, histo-immunological and pharmacogenomic approaches, may give more insight into these forms of BP. This combined approach will allow to better define BP endotypes and to unveil the mechanism of spontaneous or drug-induced breakage of the immunotolerance to skin self-antigens.

A rare presentation of systemic lupus erythematosus with lupus hepatitis

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation and the presence of circulating autoantibodies directed against self-antigens. Prevalence of SLE in children and adolescents is 1-6 per 100,000 population. Liver dysfunction occurs in approximately in 50-60% of the patients with SLE.And the incidence of lupus hepatitis in diagnosed SLE patients is 9.3%. We are reporting a case of 11-year-old female child who presented with fever, skin rashes, oral ulcers, irritability and positive antinuclear antibody (ANA) with deranged liver function test (LFT) in the form of elevated transaminases, bilirubin level and altered coagulation profile. Hepatitis serology was negative, with low C3 levels, diagnosed as SLE with lupus hepatitis with lupus nephritis stage IV with psychosis. Clinical improvement along with improvement in terms of laboratory findings was seen on corticosteroids therapy. It is important to differentiate lupus hepatitis from autoimmune hepatitis (AIH) as AIH presents similar to lupus hepatitis, has poor prognosis. While lupus hepatitis being rare cause for mortality in patients with SLE has good response with early intervention with corticosteroids therapy.

Immunization with desmoglein 3 induces non-pathogenic autoantibodies in mice

Background Pemphigus vulgaris (PV) is a rare autoimmune blistering disease characterized by the development of autoantibodies targeting desmoglein (Dsg) 3, but also against Dsg1 in mucocutaneous disease. Given that existing PV animal models only recapitulate aspects of the disease, we aimed to establish a more comprehensive disease model based on the immunization of mice with PV autoantigen(s). Methods The following immunization strategies were tested: (i) C57Bl/6J, B6.SJL-H2s C3c/1CyJ, DBA2/J, or SJL/J mice were immunized with recombinant murine Dsg3 (mDsg3), (ii) DBA2/J and SJL/J mice were immunized with mDsg3 and additionally injected a single non-blister inducing dose of exfoliative toxin A (ETA), and (iii) DBA2/J and SJL/J mice were immunized with human Dsg (hDsg) 1 and 3. Results Despite the induction of autoantibodies in each immunization protocol, the mice did not develop a clinical phenotype. Tissue-bound autoantibodies were not detected in the skin or mucosa. Circulating autoantibodies did not bind to the native antigen in indirect immunofluorescence microscopy using monkey esophagus as a substrate. Conclusion Immunization with PV autoantigens induced non-pathogenic Dsg1/3 antibodies, but did not cause skin/mucous membrane disease in mice. These findings, confirmed by failure of binding of the induced autoantibodies to their target in the skin, suggest that the autoantibodies which were formed were unable to bind to the conformational epitope present in vivo.

The role of serum levels of anti-phospholipase A2 receptor antibodies in the diagnosis of primary membranous nephropathy.

Introduction: Primary membranous nephropathy (PMN) is one of the most common causes of nephrotic syndrome in adults. The disease process is probably initiated by the binding of circulating autoantibodies to target podocyte antigens. In 2009, Beck et al. found that phospholipase A2 receptor (PLA2R1) was expressed on human podocytes in patients with PMN. Recent evidence suggests that PLA2R1 autoantibodies play an important role in the diagnosis of PMN. Aim: The aim of the present study was to compare the serum levels of anti-PLA2R1 in patients with PMN, second MN (SMN), other nephropathies (ON), and healthy controls (HC). Materials and methods: The study included 52 patients with PMN, 12 patients with SMN, 49 patients with ON, and 50 healthy controls. The serum concentration of anti-PLA2R1 was determined with ELISA kit (Anti-PLA2R ELISA, IgG, EUROIMMUN, L&uuml;beck, Germany) using MR-96A microplate Reader (MINDRAY). Statistical analysis was performed with SPSS v.22.0. Results: There was significant difference in the serum anti-PLA2R1 concentrations between patient groups and HC (p<0.0001). Compared to HC, the median anti-PLA2R1 level in the PMN group was significantly higher (4.8 RU/ml vs. 34.9 RU/ml, p=0.001), in the ON group it was lower (2.1 RU/ml, p=0.002) and did not differ in patients with SMN (2.9 RU/ml, p=0.193). The anti-PLA2R1 serum levels were significantly higher in the PMN group than in the SMN (p=0.015) and ON (p<0.001) groups. Conclusions: Our results showed that anti-PLA2R1 is significantly increased in patients with PMN. We can conclude that the anti-PLA2R1 serum concentration may be used as a beneficial biomarker for distinguishing PMN from other membranous nephropathies.

Anti-UBE2T antibody: a novel biomarker of progressive-fibrosing interstitial lung disease

Background Antifibrotic therapy has demonstrated efficacy against progressive-fibrosing interstitial lung disease (PF-ILD); therefore, it has become a priority to identify disease behavior before disease presentation. As autoimmunity is implicated in the pathogenesis of various ILDs, we explored the possibility of a circulating biomarker that can predict the chronic progressive behavior of ILDs. Methods A single-center retrospective cohort study was conducted to investigate a biomarker of PF-ILD. Circulating autoantibodies against 9,483 purified full-length human recombinant proteins of patients with interstitial pneumonia were screened by microarray analysis. The candidate auto-antibodies were verified their existence by multiples solution assay. In addition, enzyme-linked immunosorbent assay (ELISA) was performed in larger sample sets to evaluate accurate sensitivity, specificity and clinical significance in ILDs. Results In total, 61 healthy subjects and 87 patients with various ILDs enrolled in this study. Anti-UBE2T antibody was discovered by performing protein microarray and multiplex solution assay as a candidate biomarker of ILDs. By measuring its concentration by ELISA, anti-ubiquitin-conjugating enzyme E2T (UBE2T) antibody levels were significantly higher in patients with idiopathic interstitial pneumonias (IIPs), especially in those with PF-ILDs, than in healthy participants. The receiver operating characteristic analysis of anti-UBE2T antibody in diagnosing PF-ILD was calculated. The area under the curve was 0.85 and yielded a cut-off value of 238.1 ng/mL. Anti-UBE2T antibody-positive IIP patients demonstrated significantly higher ILD-gender age physiology scores, PF-ILD diagnosis rates and were more likely to develop honeycomb structures than anti-UBE2T-negative IIP patients after two years of follow up. The anti-UBE2T antibody positivity did not correlate with other commercial biomarkers such as KL-6 and commercial autoantibodies, suggesting the presence of anti-UBE2T antibody was independent of the others. Immunohistochemical staining of UBE2T in normal lungs was observed sparsely in the bronchiole epithelium and macrophages. Controversially, idiopathic pulmonary fibrosis lung tissue showed robust expression of the UBE2T protein in the lining epithelium of honeycomb structures. Conclusion This is the first report to describe anti-UBE2T antibody, a new biomarker that is significantly elevated in idiopathic PF-ILDs. This new antibody may constitute a sensitive biomarker to detect cases of PF-ILDs that are not currently detected by commercially available biomarkers.

Autoimmmune hepatitis

Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.