Autoantibodies in COVID-19 correlate with anti-viral humoral responses and distinct immune signatures

Background: Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. Objective: We longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19. Methods: We performed highly sensitive indirect immunofluorescence assays to detect anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed-up to one year after infection, eleven vaccinated individuals, and 41 unexposed controls. Results: Compared to healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA-negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B cell compartment after recovery. Conclusion: Highly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased anti-viral humoral immune responses and inflammatory immune signatures.

Immunobiology of Gestational Diabetes Mellitus in Post-Medawar Era

Although the concepts related to fetal immune tolerance proposed by Sir Peter Medawar in the 1950s have not withstood the test of time, they revolutionized our current understanding of the immunity at the maternal-fetal interface. An important extension of the original Medawar paradigm is the investigation into the underlying mechanisms for adverse pregnancy outcomes, including recurrent spontaneous abortion, preterm birth, preeclampsia and gestational diabetes mellitus (GDM). Although a common pregnancy complication with systemic symptoms, GDM still lacks understanding of immunological perturbations associated with the pathological processes, particularly at the maternal-fetal interface. GDM has been characterized by low grade systemic inflammation that exacerbates maternal immune responses. In this regard, GDM may also entail mild autoimmune pathology by dysregulating circulating and uterine regulatory T cells (Tregs). The aim of this review article is to focus on maternal-fetal immunological tolerance phenomenon and discuss how local or systemic inflammation has been programmed in GDM. Specifically, this review addresses the following questions: Does the inflammatory or exhausted Treg population affecting the Th17:Treg ratio lead to the propensity of a pro-inflammatory environment? Do glycans and glycan-binding proteins (mainly galectins) contribute to the biology of immune responses in GDM? Our understanding of these important questions is still elementary as there are no well-defined animal models that mimic all the features of GDM or can be used to better understand the mechanistic underpinnings associated with this common pregnancy complication. In this review, we will leverage our preliminary studies and the literature to provide a conceptualized discussion on the immunobiology of GDM.

Jadassohn anetoderma: clinical observation

The article presents a clinical observation of a rare dermatosis - Jadassohn anetoderma. The described case demonstrates the important role of differential diagnostic in patients with atrophic skin changes, paying attention to the possibility of rare dermatoses. Difficulties in diagnosing such diseases are largely due not only to the low frequency of occurrence in the practice of a dermatologist, but also to the sometimes-untimely treatment of patients due to the lack of subjective sensations, especially when the rashes are located in places inaccessible for self-examination. At the same time, despite the fact that the exact pathophysiological mechanisms of the development of anetoderma remain unknown, a number of studies indicate the possibility of autoimmune diseases of the connective tissue, antiphospholipid syndrome and an increased risk of thromboembolic complications in such patients. This fact convincingly proves that the timely diagnosis of anetoderma not only makes it possible to form the correct approach to the management of such patients, but also to provide vigilance regarding the development of autoimmune pathology of the connective tissue.

Vitamin D and autoimmune thyroid diseases (part 1)

Autoimmune thyroiditis (AIT) and Graves’ disease (GD) are common autoimmune diseases, and their prevalence assessed as 5 % of general population. Currently, selective immunosuppressive agents for pathogenetic treatment of autoimmune pathology are being developed. Vitamin D with the known anti­inflammatory and immunoregulatory properties, is also of great interest. The first part of the article reviews the roles of various immune cells in the pathogenesis of autoimmune thyroid diseases, which is necessary to reveal the therapeutic potential of calcitriol in these disorders. Classically, AIT was considered to be mediated by T­helpers type 1 (Th1), and GD — by T­helpers type 2 (Th2). This misunderstanding was based on the idea that humoral immunity is controlled by Th2 cytokines, and cellular immunity — by Th1. In the past decades, the role of new subsets of immune cells in the pathogenesis of autoimmune thyroid diseases is being studied, displacing the traditional paradigm of Th1/Th2 dichotomy. It has been established that T­helpers type 17 (Th17) play an important role in the development of various inflammatory and autoimmune diseases, previously classified as Th1­dependent pathologies. The involvement of T­ and B­regulatory lymphocytes in the autoimmune process is also of particular interest. It was found that these cells accumulate in inflamed thyroid tissue in patients with thyroid pathology, but they are unable to suppress the immune response effectively. Further research will help to find out which immune cells can become targets for vitamin D agonists in the complex treatment of autoimmune diseases.

Autoantibodies are present in the bronchoalveolar lavage but not circulation in patients with fibrotic interstitial lung disease

BackgroundFibrotic interstitial lung disease (fILD) has previously been associated with the presence of autoantibody. While studies have focused on systemic autoimmunity, the role of local autoantibodies in the airways remains unknown. We therefore extensively characterised the airway and peripheral autoantibody profiles in patients with fILD and assessed association with disease severity and outcome.MethodsBronchoalveolar lavage (BAL) was collected from a cohort of fILD patients and total BAL antibody concentrations were quantified. An autoantigen microarray was used to measure IgG and IgA autoantibodies against 122 autoantigens in BAL from 40 idiopathic pulmonary fibrosis (IPF), 20 chronic hypersensitivity pneumonitis (CHP), 20 connective tissue disease-associated ILD (CTD-ILD) patients and 20 controls.ResultsA subset of patients with fILD but not healthy controls had a local autoimmune signature in their BAL that was not present systemically, regardless of disease. The proportion of patients with IPF with a local autoantibody signature was comparable to that of CTD-ILD, which has a known autoimmune pathology, identifying a potentially novel subset of patients. The presence of an airway autoimmune signature was not associated with reduced survival probability or changes in lung function in the cohort as a whole. Patients with IPF had increased BAL total IgA and IgG1 while subjects with CHP had increased BAL IgA, IgG1 and IgG4. In patients with CHP, increased BAL total IgA was associated with reduced survival probability.ConclusionAirway autoantibodies that aren't present systemically identify a group of patients with fILD and the mechanisms by which these autoantibodies contribute to disease requires further investigation.

Acute posterior reversible encephalopathy syndrome (PRES) in setting of interferon-beta use: case presentation with reduction of edema in 72 h after cessation of interferon-beta therapy with sub-clinical inflammation

Background Posterior reversible encephalopathy syndrome (PRES) represents a transient change in mental status with associated vasogenic edema of cortical and subcortical brain structures. It is often attributed to multifactorial etiology including hypertension and altered hemodynamics and disruption of vessel integrity. Patients with autoimmune disease and certain immune modulator therapies are at greater risk. Case presentation A 54-year-old female with past medical history of well-controlled multiple sclerosis on interferon-beta since 2013, presented with witnessed tonic colonic seizure. She also was noted to demonstrate left gaze deviation and left-sided hemiparesis. MRI fluid-attenuated inversion recovery sequence showed hyperintensity of the subcortical U fibers, concentrated in the occipital, parietal lobes and frontal lobes. Systolic blood pressure was 160 mmHg on arrival. The patient was started on seizure prophylxis and Interferon beta was discontinued. The patient’s mentation, seizures and hemiapresis significantly improved in next 72 h with tight blood pressure control, and had notble improvement on MRI imaging and inflammatory markers. Lumbar puncture CSF results were devoid of infectious and autoimmune pathology. Conclusions A middle-aged female with multiple sclerosis who was on chronic IFN-beta presented to the emergency room with a witnessed tonic-clonic seizure, with MRI T2 FLAIR imaging consistent with PRES. She had notable clinical improvement with decreased edema on imaging and improved inflammatory markers 72 h after cessation of IFN-beta therapy.

PRDM1 Is Sufficient for Inducing Human Primary T Cell Hyporesponsiveness and Implicates Low Gvhd Occurrence after Allo-HSCT

T cell hyporesponsiveness is crucial for functional immune system and prevent the damage induced by alloreactive T cells in autoimmune pathology and transplantation. As one of the most important regulators during B cell development, PRDM1 (also known as BLIMP-1) has been demonstrated its essential role for maintaining T cell hyporesponsiveness and homeostasis, evidenced by Prdm1 deficient mice accumulating activated T cells and developing multiorgan inflammatory disease. However, the mechanism of PRDM1 regulating T cell hyporesponsiveness is still ambiguous. In this study, we took advantage of multiomics technologies and systemic report the central role of PRDM1 in inducing human primary T cell hyporesponsiveness. Firstly, we overexpressed PRDM1 in human primary T cells and found increased ratio of CD4 +CD25 +FOXP3 + Treg cell subsets and increased IL-4 secretion. In parallel, inhibited PRDM1 expression level in human T cells decreased ratio of Treg cells and secretion of IL-4. Meanwhile, transcriptome analyses revealed that overexpressed PRDM1 enriched negative regulation of cell proliferation signaling pathway and resulted in a global reduction in IL-2 and inflammatory response signaling pathways. Furthermore, overexpressed PRDM1 in primary T cells upregulated several negative regulators of T cell function like EOMES, KLF2, LILRB1, KLRB1 and CD244, indicating a pioneer role of PRDM1 in inducing T cell hyporesponsive. To further investigate the regulation role of T cell hyporesponsiveness of PRDM1, we performed CUT&Tag and ATAC-seq in PRDM1 overexpressed primary T cells. CUT&Tag analysis showed PRDM1 could directly upregulated T cell hyporesponsiveness related gene such as KLF2, CD244 and KLRD1. Importantly, we observed consistent changes of IL-2, central regulator of T cell activation, in PRDM1 overexpressed T cell from ATAC-seq, CUT&Tag and RNA-seq data. We found PRDM1 could binding to IL-2 locus and decreased the chromatin accessibility of IL-2, consequently downregulated the expression level of IL-2 in human primary T cells. Moreover, altered open chromatin regions (OCRs) in PRDM1 overexpressed T cells enriched the similar transcription factors (TFs) with PRDM1 binding sites, indicating PRDM1 might be a pioneer TF in T cell hyporesponsiveness. These results demonstrated PRDM1 is sufficient for inducing T cell hyporesponsiveness in human primary T cells. To further validate the coexpression relationship between PRDM1 and Treg cell central TF FOXP3, we upregulated PRDM1 expression level on Jurkat T cells lines. The results also showed that elevated FOXP3 both in mRNA and protein level accompanied with upregulated PRDM1 expression level. To analyze the mechanism of PRDM1 regulating FOXP3 expression level, CUT&Tag data analyses showed that PRDM1 might upregulated FOXP3 by directly binding to the enhancer region of upstream of FOXP3 locus. Meanwhile, PRDM1 indirectly upregulated FOXP3 by upregulated KLF2, evidenced by inhibiting KLF2 in PRDM1 overexpressed primary T cells downregulated FOXP3 expression level. To further investigate the clinical implication of PRDM1 inducing T cell hyporesponsiveness, we detected the relationship of PRDM1 expression level and acute graft-versus-host disease(aGVHD) occurrence after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our results showed that patients with aGVHD (n=7) exhibited lower PRDM1 expression level than those without aGVHD in the same period after HSCT (n=7). Furthermore, we detected the expression level of PRDM1 in CD4 + T cell and CD8 + T cells from bone marrow allografts (BM) or peripheral blood allografts (PB) and followed up the occurrence of GVHD after HSCT for 2 years (n=18). There are low expression levels of PRDM1 in CD4 + T cells both from BM or PB grafts corelated with aGVHD occurrence in patients after allo-HSCT compared with those without aGVHD occurrence. In conclusion, our study provides the global regulatory model of PRDM1 in human primary T cell. We introduced PRDM1 as a sufficient regulator in T cell hyporesponsiveness induction, which is altering the chromatin accessibility and directly upregulated T cell inhibitory signals and downregulated T cell activated signals. The negative relationship between PRDM1 expression level with GVHD occurrence indicated it might be a potential biomarker for indicating HSCT prognosis. Disclosures No relevant conflicts of interest to declare.

Multiple sclerosis as one of the causes of disability at a young age

Multiple sclerosis is one of the most severe degenerative diseases of the central nervous system and is a variant of autoimmune pathology, in which demyelination and degeneration of nerve fibers occurs, against which there is a violation of their conduction. Its development occurs gradually and has a pronounced staging of the pathological process. The disease occurs as a result of the combined interaction of external factors (viruses, infection, intoxication, dietary characteristics, exposure to stressful situations, poor ecology) and hereditary predisposition. In the world, there are about 3 million patients suffering from various forms of multiple sclerosis. As a result of this pathological process, the central and peripheral nervous system is damaged mainly in young people of working age, which leads to their early disability, limitation of life opportunities, and gives reason to consider this disease a socially significant issue of our time.

EARLY DIAGNOSTICS OF AUTOINFLAMMATORY DISORDERS ASSOCIATED WITH POST-VIRAL CHRONIC FATIGUE SYNDROME AND COGNITIVE IMPAIRMENTS IN CHRONIC MIXED HERPES VIRAL INFECTIONS

The steady increase in the number of autoimmune diseases and immune-mediated autoinflammatory processes causes an increased interest of doctors of all specialties in this topic and makes the issue of early detection of autoimmune disorders / autoimmune syndrome (AS) extremely urgent. These disorders often develop against the backdrop of an atypical stream of chronic active viral infections caused by persistent viruses, in particular those of the Herpesviridae family, and remain undiagnosed due to polysymptomatic disease, and various “clinical masks” of the disorders caused by them. The semi-quantitative method developed by us for screening assessment of the content of autoantibodies in the blood serum of patients suffering from ACAI caused by herpes viruses using the ELISA method (Immunodot) is a highly specific screening method that can allow for an objective assessment of the dynamics of the autoimmune process, as well as control the effectiveness of the ongoing complex antiviral and immunomodulatory therapy. The detection of autoantibodies of various specificity in the blood serum of patients suffering from an atypical chronic active infection caused by herpes viruses (ACAI) is an early diagnostic marker, necessary, first of all, to identify autoimmune pathology of the nervous system, which is associated with a long course of the active mixed herpes-viral process.

The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis.