Welcome to the 13th International Congress on Autoimmunity interactive program

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ABSTRACT

The term "cytokine storm" was first proposed in 1993 by Ferrara et al. In 1991, Chatenaud described a systemic clinical picture called "Cytokine Release Syndrome", very similar to "Cytokine Storm Syndrome", so these terms can be used synonymously.

During the COVID-19 pandemic, high-risk individuals (>65 years, with comorbidities) may develop cytokine storms as a consequence of multi-organ involvement seen during the acute and post COVID-19 phases.

On the other hand, the term immune neuroendocrine system was first proposed by Besedovsky H et al. Evidence obtained during COVID-19 infection, demonstrated that SARS-CoV-2 infections can affect the immune neuroendocrine system, both in its invasion stage of different organs and tissues and in the recovery stage. This damage is caused by a viral infection and/or cytokine storm. The main stress response systems are 1. The hypothalamic-pituitary-adrenal axis (HPA). 2. The hypothalamic-pituitary-thyroid axis (HPT). 3.The hypothalamic-pituitary-gonadal axis (HPG). 4. Prolactin/growth hormone system, and 5. The autonomic nervous system. The immuno-neuroendocrine interaction is activated by stress factors such as infections, autoimmune diseases or trauma. This review analyzes the devastating effect of SARS-CoV-2 infection and the cytokine storm on the Immune neuroendocrine system. This evidence may lead to new therapeutic proposals.

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Macrophage migration inhibitory factor (MIF) is a cytokine involved in the pathogenesis of several immune-inflammatory disorders. MIF binds to the cell-surface receptor, CD74, and to the intracellular receptor, JAB1, as well as to the non-cognate receptors, CXCR2 and CXCR4. Moreover, MIF catalyzes the tautomerization of the non-naturally occurring D-dopachrome and of phenylpyruvate. Recently, a new member of the MIF superfamily has been identified, the D-dopachrome tautomerase (D-DT). The roles of MIF in immunologic response regulation are diverse, as MIF plays important roles in both innate and acquired immune response. In systemic and organ-specific autoimmune diseases, over-production of MIF can enhance the inflammatory reaction and priming of autoreactive T cells, and/or augment their pathogenetic effects to host organs. MIF affects the progression of autoimmune diseases via increased survival and clonal expansion of immunoinflammatory cells, via the promotion of immune cell migration and homing, and by stimulating the production of inflammatory mediators. MIF occurs in two redox-dependent conformational isoforms, among which the oxidized form of MIF (named, oxMIF), is selectively expressed by immune cells of autoimmune patients and correlates with disease flare-ups. Neutralizing the action of endogenous MIF with monoclonal antibodies or via small chemical inhibitors of its tautomerasic activity is effective in the control of several models of autoimmune diseases.

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One of the most challenging objectives for clinical cytometry in prospective multicenter immunomonitoring trials is to compare frequencies, absolute numbers of leukocyte populations and further the mean fluorescence intensities (MFIs) of cell markers, especially when the data are generated from different flow cytometers. In the context of the European PRECISESADS project, a multicenter, longitudinal study over a 5-year period for the collection of data on more than 3,000 individuals, we have developed an innovative standardization workflow based on: 1- preliminary harmonization of the flow cytometers using standard operating procedures, 2- the development of a R script to achieve intra-instrument normalization, 3- the collection of the data through automated file analyses using machine-learning automaton, 4- the application of Python scripts to correct intra-instrument variations over the duration of the studies and to eliminate inter-instrument disparities of MFI values. Overall, this workflow enables the comparison of all data of frequencies, absolute numbers and MFIs collected from different instruments. Although the procedure is cumbersome to implement, it allows all prospective multicenter analyzes in flow cytometry on a large scale whatever the duration, the number or the type of instruments necessary for the realization of such projects.

This work has been done thanks to the contribution of the PRECISESADS Flow Cytometry Study Group and the Clinical Consortium. It received support from the Innovative Medicines Initiative Joint Undertaking under the grant agreement number 115565, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution. LLL was supported by the Agence Nationale de la Recherche under the “Investissement d’Avenir” program with the reference ANR-11-LABX-0016-001 and the Région Bretagne.

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Genetic, environmental and hormonal factors act on various elements of the innate and adaptive immune response. The T cell response to antigen is aberrant in terms of early and late signaling events and results in misbalanced production of cytokines including decreased IL-2 and increased IL-17. Distinct molecular events account for the opposite production of these two cytokines. IL-17-producing T cells also through distinct pathways acquire increased ability to invade tissues and contribute to the inflammatory response. IL-23 is crucial for the development of various autoimmune diseases by promoting Th17 cell–mediated tissue inflammation. A human monoclonal antibody that binds to the p40 subunit which is shared by IL-23 and IL-12 in patients with lupus. IL-23 alters the function of kidney resident cells and causes their demise. Most T_reg cells develop in the thymus, while some can develop in the periphery from naïve CD4⁺ T cells. The main factor for differentiation, survival and function of T_reg cells is the IL-2. People and mice lacking elements of the control of Treg cell development, i.e. IL-2, IL-2 receptor or FoXP3 invariably develop autoimmune disease. Metabolically T_regcells can switch between fatty acid and pyruvate oxidation or glycolysis. The effect of low-dose IL-2 has extensively studied in SLE. Several studies showed biological (T_reg cell induction) as well as clinical response (different scores were used, but mostly significant improvement). Other forms of IL-2 formulations with enhanced or specified receptor-binding capacities such as muteins or complexes are in development. Restoration of immune tolerance by expanding and activating T_reg cells is now extensively used as a novel approach for treating autoimmune diseases where IL-2 is the first-in-class molecule. It needs to be identified in bigger trials how IL-2 would add-on the current therapeutic landscape in curbing a pro-inflammatory state, e.g., from monotherapy in mild disease to combination therapies with immunosuppressives in highly active inflammation.

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Vitiligo is an acquired chronic pigmentary disorder affecting the melanocytes, mainly in the skin and mucosae. It occurs due to the dynamic interaction between genetic and environmental factors leading to autoimmune destruction of melanocytes. Defects in melanocyte adhesion and increased oxidative stress further augment the immune response in vitiligo. It is a cosmetically disfiguring condition with a substantial psychological burden. Its autoimmune nature with resultant chronicity, variable responses to therapeutic modalities, and frequent recurrences have further diminished the quality of life. Hence, treatment should aim to provide more extended remission periods, prevent recurrences, provide good cosmetic outcomes and ensure patient satisfaction. These treatment goals seem plausible with the recent progress in our understanding of the complex pathogenic mechanisms underlying vitiligo. Inhibiting cytokine signaling through targeted immunotherapy with corticosteroids and other immunosuppressants and facilitating melanogenesis are the main strategies to achieve the above goals to a great extent. Immunosuppressants are mainly used to halt the disease progression, and they also induce repigmentation perhaps by allowing the existing melanocytes to work better in the milieu of reduced autoimmunity. These include-(a) systemic corticosteroids and (b) other immunosuppressants. Corticosteroids are recommended in patients with rapidly progressive vitiligo to halt disease progression. In the management of vitiligo, daily corticosteroids have mainly been replaced by the relatively safer oral corticosteroid mini pulse (OMP) therapy. OMP has been used in combination with other modalities like phototherapy, photochemotherapy, and other immunosuppressants particularly azathioprine and cyclophosphamide. Azathioprine alone is efficaceous, though having slower response and therefore used in patients where corticosteroids are contraindicated. Several other agents like methotrexate, mycophenolate mofetil are also useful, though results are variable. OMP has been safely used with NBUVB and PUVA; its combination with NBUVB results in better and earlier repigmentation than PUVA.

These can be further supplemented with surgical treatment as per the need of the individual patient. A treatment approach targeting multiple pathogenic pathways with a combination of drugs may offer even better results

Background and Aims

The aim of this study was to identify the differences in the cytokine and matrix metalloproteinases (MMP) profile between patients with COVID-19, rheumatoid arthritis (RA) and osteoarthrosis (OA) which are diseases characterized by the secretion of cytokines related to the stimulation of the inflammatory response.

Methods

Analytical cross-sectional study. RA patients under a strict follow-up program, OA patients without strict clinical follow-up and Severe (mortality) COVID-19 patients were included. Eleven proteins (cytokines, MMPs and its tissue inhibitors) were quantified through Luminex multiplex assay in serum samples. Univariate and bivariate analyzes were performed. Approval of Ethics Committee and informed consent were obtained.

Results

A total of 108 patients with RA and OA were compared with 20 severe COVID-19 patients. There were no significant differences through the method of Kruskall–Wallis, between RA and OA patients. IL1-B (P<0.0001) and MMP-2 (0.040) were significantly lower in COVID-19 patients. Levels of IL-10, IL-1RA, IL-6, MMP-1, MMP-9, and TIMP-1 were significantly higher (p<0.001) in COVID-19 patients. There were no differences in TNF-A, TIMP-2 and INF-G.

Conclusions

Compared with RA and OA patients, severe COVID-19 patients have a great impact on the cytokines and MMPs addressed in this study, proving that COVID-19 patients suffer from a cytokine storm when severely infected.

Background and Aims

Primary biliary cholangitis (PBC) is a slowly progressing, cholestatic autoimmune liver disease characterized by specific serum anti-mitochondrial (AMA) and anti-nuclear (ANAs) autoantibodies.

The aim of the study was to evaluate the serum pro-inflammatory cytokines concentration in polish patients with PBC and to determine a correlation with specific autoantibodies and biochemical and histological features.

Methods

Cytokine levels were studied in sera from 192 patients with PBC and 50 controls using commercial ELISA assays. We evaluated concentration of IL-1β, IL-6, IL-8, IL-17, IL-23, TNF-α, INF-γ and TGF-β1.

Results

Elevated concentration of pro-inflammatory cytokines were measured in over 60% patients with PBC. The levels of IL-8 (92.3 ± 20.4 vs. 4.7 ± 0.5 pg/ml, p = 0.0076), IL-6 (78.6 ± 12.0 vs. 3.9 ± 0.9 pg/ml, p < 0.0001), TNF-α (5.08 ± 1.23 vs. 0.21 ± 0.08, p = 0.0024) and INF-γ (40 vs 15 pg/ml; p < 0.01) were significantly higher in patients with PBC than in control group . Increase in the concentration of cytokines correlated with presence of specific autoantibodies. Elevated concentration of serum TNF-a, IL-8 and IL-17 is accompanied by severe liver fibrosis, as graded by liver biopsy. Also, high IL-8 serum levels were strongly related to biochemical parameters.

Conclusions

Through the pro-inflammatory effects, IL-8, IL-17 and TNF-α may be an important factors in liver pathology, especially in the development of the inflammatory process. Measurements of serum cytokine levels can be used as biomarkers of disease severity