Journal of Translational Autoimmunity最新文献

The complex pathological mechanisms of autoimmune diseases have now been discovered and described, including interactions between innate and adaptive immunity, the principal cells of which are neutrophils and lymphocytes. Neutrophil-to–lymphocyte ratio (NLR) was proposed as a biomarker for inflammation that reflects the balance between these aspects of the immune system. NLR is widely studied as a prognostic or screening parameter in quantity diseases with important inflammatory components such as malignancies, trauma, sepsis, critical care pathology, etc. Although there are still no consensually accepted normal values for this parameter, there is a proposal to consider an interval of 1–2 as a normal value, an interval of 2–3 as a grey area indicating subclinical inflammation and values above 3 as inflammation.

On the other hand, several studies have been published indicating that a particular morphological type of neutrophils, low-density neutrophils (LDNs), play a pathological role in autoimmune diseases. Probably, the LDNs detected in patients with different autoimmune diseases, mostly than normal density neutrophils, are involved in the suppression of lymphocytes through different pathways: inducing of lymphopenia through neutrophil depending overproduction of type I interferon (IFN)-α/β and direct suppression by a hydrogen-peroxide-dependent mechanism. Their functional features involvement in IFN production is of particular interest. IFN is one of the critical cytokines in the pathogenesis of many autoimmune diseases, primarily systemic lupus erythematosus (SLE). An interesting and important feature of IFN involvement in the pathogenesis of SLE is not only to be directly related to lymphopenia but also its role in the inhibition of the production of C-reactive protein (CRP) by hepatocytes. The CRP is the primary acute phase reactant, which in SLE often does not correlate with the extent of inflammation. NLR in such a case can be an important biomarker of inflammation. The study of NLR as a biomarker of inflammation also deserves attention in other diseases with established interferon pathways, as well as in hepatopathies, when CRP does not reflect the proper inflammation activity. Also, it may be interesting to study its role as a predictor of relapses in autoimmune diseases.

Immune response to vaccines and pathogens remains unclear in patients with systemic lupus erythematosus (SLE). To investigate this, a single-center retrospective study was conducted with 47 SLE patients vaccinated against COVID-19, including 13 who subsequently developed an asymptomatic/mild disease. As compared to controls, post-vaccine response against Spike was reduced in SLE patients when considering both memory T-cells in a whole blood interferon gamma release assay (IGRA-S) and IgG anti-Spike antibody (Ab) responses. The SLE-associated defective IGRA-S response was associated with a serum albumin level below 40 g/L and with the use of glucocorticoids, while a defective IgG anti-Spike Ab response was associated with lower levels of anti-dsDNA and anti-SSA/Ro 52 kDa Abs. IGRA-S and IgG anti-Spike responses were independent from SLE activity and clinical phenotype, low complement, hypergammaglobulinemia, and lymphopenia. As compared to controls, SLE patients showed a rapid decay of anti-Spike T-cell memory and stable IgG anti-Spike Ab responses. In conclusion, both T cell and humoral anti-Spike responses were independently affected in our SLE patients cohort, which supports the exploration of both responses in the follow-up of SLE patients and especially in those receiving glucocorticoids.

Systemic sclerosis (SSc) has been classically linked to interstitial lung disease (ILD) development, often in association with specific SSc autoantibodies. In the present report, we aimed to estimate the prevalence of SSc autoantibodies in 60 seropositive RA and 41 primary SS patients complicated or not by ILD. SSc autoantibodies were determined in patients’ sera by a commercial immunoblot assay. RA ILD patients displayed higher frequency of SSc-specific antibodies at strong titers compared to RA-with no lung involvement (25% vs 3.1%, p = 0.01)[OR 95% CI:10.9 (1.2–94.5)], with no differences detected between primary SS groups. These data indicate that many seropositive RA ILD patients probably represent an overlap RA/SSc entity, requiring tailored diagnostic and therapeutic approach.

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease in which the insulin-producing beta cells are destroyed. While it is clear that full-length C-peptide, derived from proinsulin, is a major antigen in human T1D it is not clear how and why C-peptide becomes a target of the autoimmune CD4⁺ T-cell responses in T1D. Neoepitopes formed by the conversion of glutamine (Q) residues to glutamic acid (E) by deamidation are central to the immune pathogenesis of coeliac disease and have been implicated in autoimmune responses in T1D. Here, we asked if the immunogenicity of full-length C-peptide, which comprises four glutamine residues, was enhanced by deamidation, which we mimicked by substituting glutamic acid for glutamine residue. First, we used a panel of 18 well characterized CD4⁺ T-cell lines specific for epitopes derived from human C-peptide. In all cases, when the substitution fell within the cognate epitope the response was diminished, or in a few cases unchanged. In contrast, when the substitution fell outside the epitope recognized by the TCR responses were unchanged or slightly augmented. Second, we compared CD4⁺ T-cell proliferation responses, against deamidated and unmodified C-peptide, in the peripheral blood of people with or without T1D using the CFSE-based proliferation assay. While, as reported previously, responses were detected to unmodified C-peptide, no deamidated C-peptide was consistently more stimulatory than native C-peptide. Overall responses were weaker to deamidated C-peptide compared to unmodified C-peptide. Hence, we conclude that deamidated C-peptide does not play a role in beta-cell autoimmunity in people with T1D.

Objective

COVID-19 outcome may be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases (RMD) receiving immunosuppressive therapy. We aimed to investigate whether RMD patients on anti-IL6 therapy prior to SARS-CoV-2 infection have less severe disease and better outcomes of COVID-19.

Methods

We conducted a retrospective national, multicentre cohort study using data from the French RMD COVID-19 cohort. We compared the severity and outcome of highly suspected or confirmed COVID-19 infection in RMD patients previously treated with tocilizumab or sarilumab (anti-IL6 group) with patients who did not receive anti-IL6 therapy (no anti-IL6 group).

Results

Data were collected for 1883 patients with mean age of 55.2 years [SD 16.7] and 1256 (66.7%) female. Two hundred ten (11.1%) developed severe COVID-19 and 115 (6.4%) died. After adjusting for potential confounding factors, severe COVID-19 was less frequent in the anti-IL6 group compared with the no anti-IL6 group (aOR for moderate vs. mild severity, 0.23 [95% CI, 0.10 to 0.54], p ≤ 0.01 and aOR for severe vs. mild, 0.29 [95% CI, 0.10 to 0.81], p ≤ 0.01). No significant differences were found for the evolution of COVID-19 between the anti-IL6 group and the no anti-IL6 group (aOR for recovery with sequelae vs recovery without sequelae, 0.78 [95% CI, 0.41 to 1.48] and aOR for death vs recovery without sequelae, 0.29 [95% CI, 0.07 to 1.30]).

Conclusion

RMD patients receiving anti-IL6 therapy prior to SARS-CoV-2 infection have less severe forms of COVID-19. No difference was observed in COVID-19 evolution, i.e., sequelae or death, between the groups.

Rationale

Effective therapies to reduce the severity and high mortality of pulmonary vasculitis and diffuse alveolar hemorrhage (DAH) in patients with systemic lupus erythematosus (SLE) is a serious unmet need. We explored whether biologic neutralization of eNAMPT (extracellular nicotinamide phosphoribosyl-transferase), a novel DAMP and Toll-like receptor 4 ligand, represents a viable therapeutic strategy in lupus vasculitis.

Methods

Serum was collected from SLE subjects (n = 37) for eNAMPT protein measurements. In the preclinical pristane-induced murine model of lung vasculitis/hemorrhage, C57BL/6 J mice (n = 5–10/group) were treated with PBS, IgG (1 mg/kg), or the eNAMPT-neutralizing ALT-100 mAb (1 mg/kg, IP or subcutaneously (SQ). Lung injury evaluation (Day 10) included histology/immuno-histochemistry, BAL protein/cellularity, tissue biochemistry, RNA sequencing, and plasma biomarker assessment.

Results

SLE subjects showed highly significant increases in blood NAMPT mRNA expression and eNAMPT protein levels compared to healthy controls. Preclinical pristane-exposed mice studies showed significantly increased NAMPT lung tissue expression and increased plasma eNAMPT levels accompanied by marked increases in alveolar hemorrhage and lung inflammation (BAL protein, PMNs, activated monocytes). In contrast, ALT-100 mAb-treated mice showed significant attenuation of inflammatory lung injury, alveolar hemorrhage, BAL protein, tissue leukocytes, and plasma inflammatory cytokines (eNAMPT, IL-6, IL-8). Lung RNA sequencing showed pristane-induced activation of inflammatory genes/pathways including NFkB, cytokine/chemokine, IL-1β, and MMP signaling pathways, each rectified in ALT-100 mAb-treated mice.

Conclusions

These findings highlight the role of eNAMPT/TLR4-mediated inflammatory signaling in the pathobiology of SLE pulmonary vasculitis and alveolar hemorrhage. Biologic neutralization of this novel DAMP appears to serve as a viable strategy to reduce the severity of SLE lung vasculitis.

Nivolumab, the programmed cell death 1 inhibitor, is a kind of immune checkpoint inhibitor commonly used to treat advanced cancers. Unfortunately, such drugs often induce various immune-related adverse events involving different body systems, with psoriasis being one of the skin toxicities. We report the clinical features of an exacerbated psoriasis induced by using nivolumab after three days in a patient with stage IIIc gastric adenocarcinoma. At the same time, we searched 27 case reports published from 2015 to 2021 over the world and systematically summarized the clinical manifestation of a total of 44 cases with psoriasis caused or exacerbated by Nivolumab. Commonly traditional treatment could be useful, and small molecule drugs such as apremilast are effective among some patients. However, more studies are needed to evaluate the efficacy and safety of biologics or small molecule drugs in treating psoriasis induced by nivolumab.

Primary biliary cholangitis (PBC) is a female-predominant liver autoimmune disease characterized by the specific immune-mediated destruction of the intrahepatic small bile duct. Although apoptosis of biliary epithelial cells (BECs) and alterations in gut microbiota are observed in patients with PBC, it is still unclear whether these events happen in the early stage and cause the breakdown of tolerance in PBC. In this study, we examined the early events in the loss of tolerance in our well-defined 2-OA-OVA-induced murine autoimmune cholangitis (AIC) model. We report herein that apoptosis of BECs was notable in the early stage of murine AIC. An altered gut microbiota, in particular, an increased percentage of gram-positive Firmicutes in AIC mice was also observed. BECs in AIC mice expressed adhesion molecule ICAM-1, cytokines/chemokines TNF-α, CCL2, CXCL9, CXCL10, and toll-like receptor (TLR) 2. Moreover, BECs treated with TLR2 ligand had elevated apoptosis and CXCL10 production. These data collectively suggest a new mechanism of tolerance breakdown in AIC. Altered gut microbiota induces apoptosis of BECs through TLR2 signaling. BECs secrete chemokines to recruit CD8 T cells to damage BECs further.

Nearly a quarter of the total number of deaths in the world are caused by unhealthy living or working environments. Therefore, we consider it significant to introduce the effect of a widely distributed component of air/water/food-source contaminants, polycyclic aromatic hydrocarbons (PAHs), on the human body, especially on immunity in this review. PAHs are a large class of organic compounds containing two or more benzene rings. PAH exposure could occur in most people through breath, smoke, food, and direct skin contact, resulting in both cellular immunosuppression and humoral immunosuppression. PAHs usually lead to the exacerbation of autoimmune diseases by regulating the balance of T helper cell 17 and regulatory T cells, and promoting type 2 immunity. However, the receptor of PAHs, aryl hydrocarbon receptor (AhR), appears to exhibit duality in the immune response, which seems to explain some seemingly opposite experimental results. In addition, PAH exposure was also able to exacerbate allergic reactions and regulate monocytes to a certain extent. The specific regulation mechanisms of immune system include the assistance of AhR, the activation of the CYP-ROS axis, the recruitment of intracellular calcium, and some epigenetic mechanisms. This review aims to summarize our current understanding on the impact of PAHs in the immune system and some related diseases such as cancer, autoimmune diseases (rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), and allergic diseases (asthma and atopic dermatitis). Finally, we also propose future research directions for the prevention or treatment on environmental induced diseases.

There are more than 100 autoimmune diseases (AD), which have a high prevalence that ranges between 5% and 8% of the general population. Type I diabetes mellitus, multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis remain the health problem of highest concern among people worldwide due to its high morbidity and mortality. The development of new treatment strategies has become a research hotspot. In recent years, the study of the ion channels presents in the cells of the immune system, regarding their functional role, the consequences of mutations in their genes and the different ways of blocking them are the subject of intense research. Pharmacological blockade of KV1.3 channel inhibits Ca2+ signaling, T cell proliferation, and pro-inflammatory interleukins production in human CD4⁺ effector memory T cells. These cells mediated most of the AD and their inhibition is a promising therapeutic target. In this review, we will highlight the biological function of KV1.3 channel in T cells, consequence of the pharmacological inhibition (through anemone and scorpion toxins, synthetic peptides, nanoparticles, or monoclonal antibodies) as well as the possible therapeutical application in AD.