Liver immunity,autoimmunity,and inborn errors of immunity

The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create a rapid and strong immune response,under unfavorable conditions.However,the liver's assumed immune status is anti-inflammatory or immuno-tolerant.Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance.The anatomical structure of the liver can facilitate the preparation of lymphocytes,modulate the immune response against hepatotropic pathogens,and contribute to some of its unique immunological properties,particularly its capacity to induce antigen-specific tolerance.Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane,circulating lymphocytes can closely contact with antigens,displayed by endothelial cells,Kupffer cells,and dendritic cells while passing through the sinusoids.Loss of immune tolerance,leading to an autoaggressive immune response in the liver,if not controlled,can lead to the induction of autoimmune or autoinflammatory diseases.This review mentions the unique features of liver immunity,and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.

The metabolite BH4 controls T cell proliferation in autoimmunity and cancer

Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer.The enzyme co-factor tetrahydrobiopterin(BH4)is involved in the production of monoamine neurotransmitters,the generation of nitric oxide,and pain1,2.

Stem cell-like memory T cells:Role in viral infections and autoimmunity

Stem cell-like memory T(TSCM)cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases.Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization.In case of chronic viral diseases such as human immunodeficiency virus-1,CD4+T_(SCM) cells,serve as major reservoirs of the latent virus.However,during immune activation and functional exhaustion of effector T cells,these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection.More recently,these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion.Similarly,studies are also investigating their pathological role in driving autoimmune responses.However,there are several gaps in the understanding of the role of T_(SCM) cells in viral and autoimmune diseases to make them potential therapeutic targets.In this minireview,we have attempted an updated compilation of the dyadic role of these complex T_(SCM) cells during such human diseases along with their biology and transcriptional programs.

PTPN22 and islet-specific autoimmunity:What have the mouse models taught us?

An allelic variant of the protein tyrosin phosphatase non-receptor 22(PTPN22) gene, PTPN22 R620 W, constitutes the strongest non-HLA genetic risk factor for the development of type 1 diabetes(T1D). A numberstudies using mouse models have addressed how PTPN22 predisposes to T1D. PTPN22 downmodulation, overexpression or expression of the variant gene in genetically manipulated mice has generated controversial results. These discrepancies probably derive from the fact that PTPN22 has differential effects on innate and adaptive immune responses. Moreover, the effects of PTPN22 are dependent on other genetic variables. Here we discuss these findings and try to explain the discrepancies. Exploring the mechanism by which PTPN22 contributes to islet-specific autoimmunity could help us understand its role in T1D pathogenesis and exploit it as a potential therapeutic target to prevent the disease.

miRNAs as new molecular insights into inflammatorybowel disease:crucial regulators in autoimmunity andinflammation

Inflammatory bowel disease(IBD) is characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract, and includes two major phenotypes: ulcerative colitis and Crohn's disease. The pathogenesis of IBD is not fully understood as of yet. It is believed that IBD results from complicated interactions between environmental factors, genetic predisposition, and immune disorders. mi RNAs are a class of small non-coding RNAs that can regulate gene expression by targeting the 3′-untranslated region of specific m RNAs for degradation or translational inhibition. mi RNAs are considered to play crucial regulatory roles in many biologic processes, such as immune cellular differentiation, proliferation, and apoptosis, and maintenance of immune homeostasis. Recently, aberrant expression of mi RNAs was revealed to play an important role in autoimmune diseases, including IBD. In this review, we discuss the current understanding of how mi RNAs regulate autoimmunity and inflammation by affecting the differentiation, maturation, and function of various immune cells. In particular, we focus on describing specific mi RNA expression profiles in tissues and peripheral blood that may be associated with the pathogenesis of IBD. In addition, we summarize the opportunities for utilizing mi RNAs as new biomarkers and as potential therapeutic targets in IBD.

Ethnic Differences in Preterm Birth Risks for Pregnant Women with Thyroid Dysfunction or Autoimmunity:A Meta-analysis

Objective Abnormal maternal thyroid function is associated with preterm birth.However,this association stays dubious in relevant individual studies for ethnic difference reasons and lack of direct supporting data.This study aimed to evaluate the relationship between preterm birth and thyroid dysfunction or autoimmunity based on ethnic differences.Methods Relevant studies were identified through searches of MEDLINE,Excerpta Medica,Wan Fang,China Biological Medicine disc,and China National Knowledge Infrastructure from inception to June 15,2016.Original articles in which an incidence or prevalence of thyroid dysfunction or autoimmunity before second trimester of pregnancy could be extracted were included.Results Thirty-two unique studies were included for the final meta-analysis.Patients involved were divided into two groups：Group 1（G1） and Group 2（G2） comprising of Asian and Caucasian populations,respectively.Positive thyroid antibodies were associated with the occurrence of preterm birth in both G1 [odds ratio（OR）：3.62,95% confidence interval（CI）：2.83-4.65] and G2（OR：1.35,95% CI：1.17-1.56）;hypothyroidism,only in G2（OR：1.20,CI：1.09-1.33）;and subclinical hypothyroidism or hypothyroxinemia,in neither group.Conclusion Thyroid autoimmunity may be a more favorable factor leading to preterm birth among pregnant women of different ethnicities,compared with thyroid dysfunction.

Autoantibodies to apolipoprotein A-1 as a biomarker of cardiovascular autoimmunity

Immune-driven inflammation plays an important part inatherogenesis and is therefore believed to be key to thedevelopment of cardiovascular disease(CVD), whichis currently the leading cause of death in the Westernworld. By fulfilling some of the Koch postulates, athero-genesis has even been proposed to be considered as anautoimmune disease, raising the hope that CVD couldbe prevented by immunomodulation. Nevertheless,the role of the immune system and autoimmune reac-tions in atherosclerosis appear to be a double edged-sword, with both pro-atherogenic and anti-atherogenicattributes. Hence, if immunomodulation is to becomea therapeutic option for atherosclerosis and CVD, it willbe crucial to correctly identify patients who might ben-efit from targeted suppression of deleterious autoim-mune responses. This could be achieved, for example, by the detection of disease-associated autoantibodies. In this work, we will review the currently available clini-cal, in vitro, and animal studies dedicated to autoan-tibodies against apolipoprotein A-1(anti-apoA-1 IgG), the major proteic fraction of high density lipoprotein. Current clinical studies indicate that high levels of anti-apoA-1 IgG are associated with a worse cardiovascular prognosis. In addition, in vitro and animal studies indi-cate a pro-inflammatory and pro-atherogenic role, sup-porting the hypothesis that these autoantibodies may play a direct causal role in CVD, and furthermore that they could potentially represent a therapeutic target for CVD in the future.

Role of mesenchymal stem cell derived extracellular vesicles in autoimmunity: A systematic review

BACKGROUND Mesenchymal stem cells(MSCs)have been reported to possess immune regulatory effects in innate and adaptive immune reactions.MSCs can mediate intercellular communications by releasing extracellular vesicles(EVs),which deliver functional molecules to targeted cells.MSC derived EVs(MSC-EVs)confer altering effects on many immune cells,including T lymphocytes,B lymphocytes,natural killer cells,dendritic cells,and macrophages.A large number of studies have suggested that MSC-EVs participate in regulating autoimmunity related diseases.This characteristic of MSC-EVs makes them be potential biomarkers for the diagnosis and treatment of autoimmunity related diseases.AIM To verify the potential of MSC-EVs for molecular targeted therapy of autoimmunity related diseases.METHODS Literature search was conducted in PubMed to retrieve the articles published between 2010 and 2020 in the English language.The keywords,such as“MSCs,”“EVs,”“exosome,”“autoimmunity,”“tumor immunity,”and“transplantation immunity,”and Boolean operator“AND”and“NOT”coalesced admirably to be used for searching studies on the specific molecular mechanisms of MSC-EVs in many immune cell types and many autoimmunity related diseases.Studies that did not investigate the molecular mechanisms of MSC-EVs in the occurrence and development of autoimmune diseases were excluded.RESULTS A total of 96 articles were chosen for final reference lists.After analyzing those publications,we found that it had been well documented that MSC-EVs have the ability to induce multiple immune cells,like T lymphocytes,B lymphocytes,natural killer cells,dendritic cells,and macrophages,to regulate immune responses in innate immunity and adaptive immunity.Many validated EVsdelivered molecules have been identified as key biomarkers,such as proteins,lipids,and nucleotides.Some EVs-encapsulated functional molecules can serve as promising therapeutic targets particularly for autoimmune disease.CONCLUSION MSC-EVs play an equally important part in the differentiation,activation,and proliferation of immune cells,and they may become potential biomarkers for diagnosis and treatment of autoimmunity related diseases.

Role of autoimmunity in primary biliary cirrhosis

Primary biliary cirrhosis(PBC) is an autoimmune liver disease characterized by the presence of serum autoantibodies and chronic nonsuppurative destructive cholangitis.The pathogenesis of PBC involves environmental factors,genetic predisposition and loss of immune tolerance.In recent years,it has become univocally accepted that an inappropriately activated immune response is one of the most important factors in PBC.In this study,the role of autoimmunity in PBC is summarized and a feasible research orientation is recommended.

Extremely low frequency electromagnetic fields stimulation modulates autoimmunity and immune responses：a possible immuno-modulatory therapeutic effect in neurodegenerative diseases

Increasing evidence shows that extremely low frequency electromagnetic fields（ELF-EMFs） stimulation is able to exert a certain action on autoimmunity and immune cells. In the past, the efficacy of pulsed ELFEMFs in alleviating the symptoms and the progression of multiple sclerosis has been supported through their action on neurotransmission and on the autoimmune mechanisms responsible for demyelination. Regarding the immune system, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of autoimmunity and several immunological reactions, such as increased reactive oxygen species-formation, enhanced phagocytic activity and increased production of chemokines. Transcranial electromagnetic brain stimulation is a non-invasive novel technique used recently to treat different neurodegenerative disorders, in particular Alzheimer＇s disease. Despite its proven value, the mechanisms through which EMF brain-stimulation exerts its beneficial action on neuronal function remains unclear. Recent studies have shown that its beneficial effects may be due to a neuroprotective effect on oxidative cell damage. On the basis of in vitro and clinical studies on brain activity, modulation by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative disorders reducing their severity and their onset. The objective of this review is to provide a systematic overview of the published literature on EMFs and outline the most promising effects of ELF-EMFs in developing treatments of neurodegenerative disorders. In this regard, we review data supporting the role of ELF-EMF in generating immune-modulatory responses, neuromodulation, and potential neuroprotective benefits. Nonetheless, we reckon that the underlying mechanisms of interaction between EMF and the immune system are still to be completely understood and need further studies at a molecular level.

Skin disease and thyroid autoimmunity in atopic South Italian children

AIM:To verify the prevalence of thyroid autoimmunity(TA) and the possible association between atopy and TA in children affected by skin disease.METHODS:Three hundred and twenty-four children consecutively referred due to skin disease symptoms to our Pediatric Department were enrolled.One hundred and eighty-seven were diagnosed with atopic dermatitis(AD),95 with acute urticaria,40 with chronic urticaria(CU),and 2 with alopecia areata(AA).According to the work-up for atopy,the children were divided into two groups:Atopics and non-atopics.TA was diagnosed by serum thyroid peroxidase autoantibodies and/or thyroglobulin autoantibodies levels more than twice normal values over a period of two months by immunoassay.RESULTS:In all children with skin disease,a significant prevalence of TA in atopies compared with non-atopies(13.67%vs 2.67%,P=0.0016) and a significant association between TA and atopy(OR=5.76,95%CI:1.71-19.35) were observed.These findings were confirmed as significant in children with AD:TA in atopies was 11.5%,while TA in non-atopies was2.7%(P=0.03,OR=4.68,95%CI:1.02-21.38).In addition,atopics with CU showed a significantly higher prevalence of TA(26.9%),but none of the non-atopics showed CU(P=0.0326).On the other hand,atopies with AA showed a 100%(2 out of 2) prevalence of TA,compared with none of the non-atopies.CONCLUSION:In children with skin disease,atopy seems to be associated with an increased risk of TA.

Autoimmunity as the comet tail of COVID-19 pandemic

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can give rise to different clinical manifestations that are directly related to viral tissue damage or indirectly induced by the antiviral immune response.Hyper-activation of the immune system in an attempt to eradicate the infection may trigger autoimmunity.Several immune-mediated disorders have been described in SARS-CoV-2-infected individuals.These include cutaneous rashes and vasculitis,autoimmune cytopenia,anti-phospholipid syndrome,central or peripheral neuropathy,myositis and myocarditis.On the other hand,rheumatic patients were reported to have similar coronavirus disease 2019(COVID-19)incidence,morbidity and mortality rates compared to general population.This opinion review will summarize the crucial immunologic steps which occur during SARSCoV-2-infection that may link autoimmunity to COVID-19 and provides an opportunity for further discussion regarding this association.

Effect of inflammation and autoimmunity in peripartum cardiomyopathy

Objective To explore the effect of inflammation and autoimmunity in peripartum cardiomyopathy （PPCM）. Methods A total of 82 PPCM patients and 100 normal delivery patients were randomly selected and conducted epidemiological survey. High-sensitivity C- reaction protein （hs-CRP）, troponin I, human antimyocardial antibody IgG （AMA-IgG）, Coxsackie B virus IgG （CBV-IgG） and adenovirus antibody IgG （ADV- IgG） were detected with ELISA. Results Compared with control group, PPCM patients had older age, higher pressure, higher proportion of cesarean section and infection. The levels of serum hs-CRP, cTNI, and leucocyte were markedly higher in PPCM patients compared with control. The positive proportion of AMA-IgG and CBV-IgG was signifi- cantly increased （P〈0.01） in PPCM patients compared with the control. Logistic regression showed that infection （OR=2.87, 95%CI 1.15-5.24）, increased hs-CRP （OR=1.86, 95%CI 1.08-4.02） and positive AMA-IgG （OR=2.68, 95%CI 1.19-4.85） were independent risk factors for PPCM. Conclusions Inflammation and autoimmunity play an important role in peripartum cardiomyopathy（J Geriatr Cardio12010; 7：106-109）.

Regulatory and activated effector T cells in chronic hepatitis C virus: Relation to autoimmunity

AIMTo investigate how Tregs are regulated in chronic hepatitis C virus (HCV) patients via assessment of Tregs markers (granzyme 2, CD69 and FoxP3), Teffs markers [TNFRSF4 (OX40), INFG] and CD4, CD25 genes. METHODSA prospective study was conducted on 120 subjects divided into 4 groups: Group I (n = 30) treatment naïve chronic HCV patients; Group II (n = 30) chronic HCV treated with Peg/Riba; Group III (n = 30) chronic HCV associated with non-organ specific autoantibody and Group IV (n = 30) healthy persons as a control group. Tregs and Teffs markers were assessed in peripheral blood mononuclear cells by quantitative real time reverse transcriptase-polymerase chain reaction. RESULTSChronic HCV patients exhibited significant higher levels of both Teffs and Tregs in comparison to healthy control group. Tregs markers were significantly decreased in Peg/Riba treated HCV patients in comparison to treatment naïve HCV group. In HCV patients with antinuclear antibody (ANA) +ve, Tregs markers were significantly decreased in comparison to all other studied groups. Teffs markers were significantly elevated in all HCV groups in comparison to control and in HCV group with ANA +ve in comparison to treatment naïve HCV group. CONCLUSIONElevated Tregs cells in chronic HCV patients dampen both CD4+ and CD8+ autologous T cell immune response. Interferon-α and ribavirin therapy suppress proliferation of Tregs. More significant suppression of Tregs was observed in HCV patients with autoantibodies favoring pathological autoimmune response.

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS

While the central nervous system (CNS) was once thought to be immune privileged, more recent data support that certain areas of the healthy CNS are routinely patrolled by immune cells. Further, antigen drainage is another means by which the adaptive arm of the immune system can gain information about the health of the CNS. Altogether these ensure that the CNS is not beyond the scope of immune protection against viruses and tumors. However, immune surveillance in the CNS has to be tightly regulated, as CNS autoimmune disease and inflammation may arise from increased immune cell infiltration. In this review we discuss the concept and implications of CNS immune surveillance and introduce the CNS antigen-presenting cells (APCs) that potentially regulate neuroinflammation and autoimmunity. We also discuss novel animal models in which CNS disease initiation and the role of APCs in disease regulation can be tested.

Fyn Expression Predicates Both Protective Immunity and Onset of Autoimmunity

Genomic disruption of Fyn has not been associated with an immune-deficient phenotype, notwithstanding the profound impairment in IL-2 production by T cells derived from Fyn-deficient animals observed in vitro. The results presented demonstrate that Fyn deficient animals succumb to influenza infection ahead of the protective expansion of lung infiltrating T cells and viral clearance observed in wild-type hosts. Formal proof that Fyn-dependent IL-2 production mediates T cell expansion in vivo is provided using a model of T cell induced enteropathy. Specifically, Fyn deficient naive T cells do not induce colitis in SCID animals due to their lack of expansion, and Fyn re-expression rescues both IL-2 production and its capacity to support in vivo expansion leading to colitis. These results reconcile the obligatory role of Fyn in T cell activation and autocrine IL-2 supported growth;and underscore the mechanism through which its function is integrated with and regulated by Lck.

Membrane Fluidity: About the Origin of Autoimmunity

Fluidity of cellular membranes is essential for life. Two possibilities are known to keep human membranes fluid: unsaturated fatty acids and cholesterol. Whereas liver cells can synthesize cholesterol, unsaturated fatty acids are essential. Life style in Western civilization leads to deprivation of essential fatty acids, to elevated serum-cholesterol-levels and to autoimmunity. Here the hypothesis is presented, and explains the relationship: deprivation of essential fatty acids lead to imminent quasi-crystallization of the membrane. Serum cholesterol-levels are elevated. Incorporation of cholesterol into membranes enhancing fluidity again, is able to repair the effect. At saturation, repair fails. Quasi-crystallization occurs. Proteins tilt into another conformation. This has not been learned during the “self” recognition process of the immune system during the embryonic phase. Immune system attacks the new conformation as “non-self”, autoimmunity emerges.

Vaccines and autoimmunity during the COVID-19 pandemic

To control the pandemic,efficient vaccines must be applied to the population,including patients with autoimmune diseases.Therefore,one can expect that coronavirus disease 2019(COVID-19)vaccines may influence the underlying autoimmune processes in these patients.Additionally,it is essential to understand whether COVID-19 vaccines would be effective,safe,and provide long-lasting immunological protection and memory.However,the currently available and approved COVID-19 vaccines turned out to be safe,effective,and reliable in patients with autoimmune inflammatory and rheumatic diseases.Furthermore,most patients said they felt safer after getting vaccinations for COVID-19 and reported enhanced overall quality of life and psychological wellbeing.In general,the COVID-19 vaccines have been highly tolerated by autoimmune patients.Such findings might comfort patients who are reluctant to use COVID-19 vaccines and assist doctors in guiding their patients into receiving vaccinations more easily and quickly.

Is autoimmunity in multiple sclerosis secondary to neurodegeneration？

Multiple sclerosis （MS） is characterized by neurological symptoms that are separated in time and space, which correlate with demyelination and white matter lesions. The conventional pathophysiological model is that an autoimmune reaction against the myelinated nerve sheath results in demyelination, accompanied by axon damage and the death of oligodendrocytes that produce myelin. There is no cure for MS, but current treatments are pr imar i ly aimed at suppressing the autoimmune reaction, with the goal of reducing demyelination. These treatments have limited efficacy and developing better treatments for MS remains an important goal. Here we argue that the autoimmune reaction may be secondary to neurodegeneration or neurotoxicity, and that protecting neurons from glutamate-mediated toxicity may be a better therapeutic strategy than targeting the immune system. We have recently demonstrated that a protein-protein interaction between the GluR2 subunit of the AMPA （a-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid） glutamate receptor and GAPDH （Glyceraldehyde 3-phosphate dehydrogenase） is elevated in human MS plaques and in an animal model of MS. Disrupting this interaction in a rodent model restores neurological function, preserves myelin, and protects neurons, oligodendrocytes and axons. The peptide we created to block the GluR2-GAPDH interaction also reduces immune system activation, suggesting that autoimmunity is not necessarily the primary etiology in MS. The GluR2-GAPDH interaction may promote cell death via increased calcium influx through non-GluR2- containing AMPA receptors, or through the p53 and Siahl cell death pathways.

Molecular mechanism of different viruses associated with autoimmunity

Different kinds of human chronic diseases may develop the mechanism of autoimmune diseases.As a group of disorders,in the Western world autoimmunity possess as the third most prevalent morbidity and mortality.However,the mechanism of most autoimmune diseases is still under investigation.Viral infection is the principal factor involved in the induction of autoimmune diseases other than genetic factors and cytokine activity.Different mechanisms have been proposed by which viral infection might interrupt tolerance to self and induce autoimmune cascade which eventually leads to the destruction of a specific type of cell or a whole-body organ.The autoimmune attack can be understood through the different immune systems and other possible mechanisms such as molecular mimicry,bystander activation and epitope spreading.In addition to genetic and viral factors,other environmental factors are also involved including bacterial,parasitic and fungal infections.However,different animal models have been studied which provide strong evidence that viruses induced AIDs as well as accelerated and increased lesions in conditions where self-tolerance is interrupted.In the current review,we discussed the virus-induced autoimmunity and the molecular mechanism which is associated with this phenomenon.Here we also discussed the different viruses such as rubella virus,enteroviruses,measles virus,human T-lymphotropic virus type1,human cytomegalovirus,human herpes virus-6,Epstein-Barr virus,rotavirus and some other viruses which modulate the development of AIDs.