Breakdown Of Tolerance Research Articles

Immune response in pregnancy: An evolutionary challenge against external and internal stimuli

Immune response in pregnancy: An evolutionary challenge against external and internal stimuli

Induced Overexpression of B Cell-Activating Factor by Triiodothyronine Results in Abnormal B Cell Differentiation in Mice

Breakdown of tolerance and abnormal activation in B cells is an important mechanism in the pathogenesis of Graves’ disease (GD) and high levels of thyroid hormones (THs) can drive the progression of GD. However, the interactions between THs and abnormal activation of B cells in the context of GD are not well understood. The aim of this study was to investigate B cell-activating factor (BAFF) mediating the cross talk between THs and B cells and the possible underlying mechanisms. A high-level triiodothyronine (T3) mouse model was used to verify T3-mediated induction of overexpression of BAFF and B cell abnormal differentiation. The possible promotion of BAFF overexpression in the mice spleen macrophages during polarization to M1 by T3 was also studied. We showed that high levels of T3 can induce BAFF overexpression and lead to abnormal differentiation of B cells in the mice. While the overexpression of BAFF was observed across many tissue types in the mice, high levels of T3 could induce M1 macrophages polarization by IFN (interferon-gamma)-γ in the spleen of the mice, which in turn generated BAFF overexpression. Our findings provide a novel insight into the interactions between the endocrine and immune systems, as well as provide insight into the role of TH in the pathogenesis of GD.

Combination of Neuromyelitis Optica Spectrum Disorder with Myasthenia Gravis, Systemic Lupus Erythematosus and Hashimoto's Thyroiditis: A Case of Multiple Autoimmune Syndrome

Autoimmunity reflects an altered immune status. The coexistence of three or more autoimmune diseases in a patient constitutes multiple autoimmune syndrome. Here, an interesting case with a history of Hashimoto's thyroiditis and got the diagnosis of systemic lupus erythematosus during her evaluation, in which the clinical signs of neuromyelitis optica spectrum disorder (NMOSD) and miyasthenia gravis cooccurred will be discussed. In addition to high-dose pulse steroid, plasmapheresis and intravenous immunoglobulin treatments, rituximab treatment was started and the patient is followed up without clinical worsening and disability in the three-year follow-up. Patients with diagnosis of NMOSD need special attention as multiple immune-mediated disorders may be present simultaneously or sequentially during the course of the disease process. This case report emphasizes the importance of a multidisciplinary team approach for a better understanding of disorders related to the breakdown of immune tolerance.

Apoptotic biliary epithelial cells and gut dysbiosis in the induction of murine primary biliary cholangitis

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.

Reactivity to neural tissue epitopes, aquaporin 4 and heat shock protein 60 is associated with activated immune-inflammatory pathways and the onset of delirium following hip fracture surgery.

Activation of the immune-inflammatory response system (IRS) and a deficiency in the compensatory immunoregulatory system (CIRS), neuronal injuries, and alterations in the glutamate receptor (GlutaR), aquaporin-4 (AQP4) and heat shock protein 60 (HSP60) are involved in delirium. Increased serum levels of neurofilament protein (NFP), glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) are biomarkers of neuronal injury. This investigation delineates whether elevated IgA/IgG reactivity against those self-antigens is associated with delirium severity and IRS activation. We measured peak Delirium Rating Scale (DRS) scores on days 2 and 3 following surgery in 59 hip fractured older adults, and IgA and IgG antibody levels against MBP, NFP, GFAP and myelin oligodendrocyte glycoprotein (MOG), metabotropic glutamate receptors mGluRs 1 and 5, N-Methyl-D-Aspartate receptor (NMDAR) GLU1 (NR1) and GLU2 (NR2), APQ4 and HSP60. The IgA antibody levels against those self-antigens, especially GFAP, MBP and HSP60, strongly predict peak DRS scores on days 2 and 3 post-surgery. IgA reactivity against NMDAR and baseline DRS scores explained 40.6% of the variance in peak DRS scores, while IgA against NMDAR, IgG against MBP and age explained 29.1% of the variance in the IRS/CIRS ratio. There was no correlation between DRS scores and IgG directed against other self-antigens. Increased IgA levels against neuronal self-antigens, AQP4 and HSP60 are risk factors for delirium. Polyreactive antibody-associated breakdown of immune tolerance, IRS activation and injuries in the neuronal cytoskeleton, oligodendrocytes, astrocytes, glial cells, and myelin sheath are involved in the pathophysiology of delirium.

B Cells at the Cross-Roads of Autoimmune Diseases and Auto-Inflammatory Syndromes.

Whereas autoimmune diseases are mediated primarily by T and B cells, auto-inflammatory syndromes (AIFS) involve natural killer cells, macrophages, mast cells, dendritic cells, different granulocyte subsets and complement components. In contrast to autoimmune diseases, the immune response of patients with AIFS is not associated with a breakdown of immune tolerance to self-antigens. Focusing on B lymphocyte subsets, this article offers a fresh perspective on the multiple cross-talks between both branches of innate and adaptive immunity in mounting coordinated signals that lead to AIFS. By virtue of their potential to play a role in adaptive immunity and to exert innate-like functions, B cells can be involved in both promoting inflammation and mitigating auto-inflammation in disorders that include mevalonate kinase deficiency syndrome, Kawasaki syndrome, inflammatory bone disorders, Schnitzler syndrome, Neuro-Behçet's disease, and neuromyelitis optica spectrum disorder. Since there is a significant overlap between the pathogenic trajectories that culminate in autoimmune diseases, or AIFS, a more detailed understanding of their respective roles in the development of inflammation could lead to designing novel therapeutic avenues.

What's new in the pathogeneses and triggering factors of bullous pemphigoid.

Bullous pemphigoid (BP) is a subepidermal blistering disease induced by autoantibodies to type XVII collagen (COL17, also called BP180) and BP230. Previous studies using patients' samples and animal disease models elucidated the complement-dependent and complement-independent pathways of blister formation, the pathogenic roles of immune cells (T and B cells, macrophages, mast cells, neutrophils, eosinophils), and the pathogenicity of IgE autoantibodies in BP. This review introduces the recent progress on the mechanism behind the epitope-spreading phenomenon in BP, which is considered to be important to understand the chronic and intractable disease course of BP, and the pathogenicity of anti-BP230 autoantibodies, mainly focusing on studies that used active disease models. To clarify the pathogenesis of BP, the mechanism behind the breakdown of immune tolerance to BP antigens should be investigated. Recent studies using various experimental models have revealed important roles for regulatory T cells in the maintenance of self-tolerance to COL17 and BP230 as well as in the suppression of inflammation triggered by the binding of antibodies to COL17. Notably, physical stresses such as trauma, thermal burns, bone fractures, irradiation and ultraviolet exposure, some pathologic conditions such as neurological diseases and hematological malignancies, and the use of dipeptidyl peptidase-IV inhibitors and immune checkpoint inhibitors have been reported as triggering factors for BP. These factors and certain underlying conditions such as genetic background, regulatory T-cell dysfunction or aging might synergistically affect some individuals and eventually induce BP. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation and inflammation may expand our understanding of BP's etiology and may lead to the development of novel therapeutic approaches.

V-set domain containing T-cell activation inhibitor-1 (VTCN1): A potential target for the treatment of autoimmune diseases

Autoimmunity eventuates when the immune system attacks self-molecules as a result of the breakdown in immune tolerance. Targeting autoimmune diseases via immunomodulation has become an essential strategy in today's era. A B7 superfamily member immune checkpoint, the V-set domain containing T-cell activation inhibitor-1 (VTCN1), also known as B7-H4, B7S1, and B7x, is involved in negatively regulating T-cell activation. VTCN1 transcript has been reported in various lymphoid and non-lymphoid tissues, but its protein expression is restricted, indicating its translational regulation. Dysregulation of VTCN1 has resulted in the exacerbation of various autoimmune diseases. Moreover, increased soluble form of VTCN1 in the patient's sera positively correlates with the disease progression and severity. The current review summarizes all the reports till date, unfolding the role of VTCN1 in various autoimmune diseases and its therapeutic potential.

Destructive inflammatory reaction after an autologous retinal pigment epithelium and choroid transplantation: no detection of an auto-immune response

PurposeFive patients who underwent uncomplicated retinal pigment epithelium (RPE)-choroid transplantation for neovascular age-related macular degeneration developed a destructive inflammatory reaction causing subretinal fluid accumulation and extensive RPE atrophy in the graft. We hypothesized that this inflammation could be caused by an auto-immune response against the graft, resulting in circulating auto-antibodies. The aim of our study was to examine a potential autoimmune origin, which would allow a more targeted therapy approach.MethodsFive above-mentioned patients and four control groups of five patients each were included: 1) after uncomplicated RPE-choroid transplantation, 2) after full macular translocation, 3) treated with anti-vascular endothelial growth factor, and 4) healthy controls. Histopathology of rejected graft tissue was performed using standard procedures. Presence of RPE-choroid autoantibodies in serum was examined by indirect immunofluorescence and Western blot, and human leukocyte antigen (HLA) typing was performed.ResultsHistopathological examination of an explanted graft showed infiltration of T-lymphocytes and macrophages in the choroid and RPE, and an increased number of B-cell lymphocytes were found in the choroid. Indirect immunofluorescence showed weak RPE-choroid autoantibody immunoreactivity in three patients of different groups. Western blot did not show specific RPE-choroid autoantibody immunoreactivity and no difference of HLA genotypes between the groups was found.ConclusionsAlthough local mononuclear inflammatory cell infiltration and a high number of B-lymphocytes were observed in an explanted graft, we did not detect serological evidence of an autoimmune origin of the postoperative inflammation using direct immunofluorescence and Western Blot. Alternatively, the graft failure may have been caused by local innate inflammation, triggered by breakdown of tolerance. Based on our current findings of this small study group, we have no rationale to pursue therapies targeted towards autoreactive graft failure. More research is needed to confirm our findings.

In vitro-induced Foxp3+ CD8+ regulatory T cells suppress allergic IgE response in the gut.

Several subsets of CD8+ T cells are known to have a suppressive function in different tissues and diseases in mice and humans. Due to the lack of a consensus on the phenotype of regulatory CD8+ T cells and very low frequency in the body, its clinical use as adoptive cellular therapy has not advanced much. In the present work, using DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza), we efficiently and stably differentiated naïve CD8+ T cells (CD8+ CD25- CD44- cells) into the CD8+ Foxp3+ regulatory CD8+ T cells (CD8 Tregs). We also generated OVA peptide257-264 -specific CD8+ Foxp3+ Tregs. Compared with activated CD8 T cells, Aza plus TGF-β-induced CD8+ Foxp3+ Tregs showed significantly increased surface expression of CD39, CD73, CD122, CD62L, and CD103, and secreted TGF-βand suppressed the proliferation of effector CD4+ T cells. Interestingly, CD8+ Foxp3+ Tregs exhibited low expression of perforin and granzyme required for cytotoxic function. Analysis of chemokine receptors showed that TGF-β+Aza induced CD8+ Foxp3+ Tregs expressed gut-tropic chemokine receptors CCR6 and CCR9, and chemokine receptors CCR7 and CXCR3 required for mobilization into the spleen, lymph nodes, and gut-associated lymphoid tissues. Adoptive transfer of induced CD8+ Foxp3+ Tregs restored cholera toxin-induced breakdown of oral tolerance to OVA by regulating OVA-specific IgE and IgG1. Altogether, we showed an efficient method to generate antigen-specific CD8+ Foxp3+ Tregs, and the adoptive transfer of these cells induces oral tolerance by suppressing allergic response and maintaining intestinal homeostasis.

Immunological balance between Treg and Th17 lymphocytes as a key element of type 1 diabetes progression in children.

Type 1 diabetes (T1D) is autoimmune destruction of the beta cells of pancreatic islets. Due to complexity of that disease, the mechanisms leading to the tolerance breakdown are still not fully understood. Previous hypothesis of imbalance in the Th1 and Th2 cells as the main contributing factor has been recently changed towards role of other lymphocytes – regulatory (Treg) and IL-17A-producing (Th17). Our study aims to assess changes within Treg and Th17 cells in newly diagnosed T1D pediatric patients and their association with disease remission. Flow cytometry implementation allowed for Treg and Th17 analysis in studied groups and further combination with clinical and laboratory data. In addition, expression of diabetes-related genes was tested and evaluated in context of their association with studied lymphocytes. Initial results revealed that Treg and ratio Treg/Th17 are significantly higher in T1D than in healthy controls. Moreover, patients with lower HbA1c and daily insulin requirements demonstrated higher levels of Tregs. Similar tendency for insulin intake was also observed in reference to Th17 cells, together with high levels of these cells in patients demonstrating higher values for c-peptide after 2 years. In low-level Treg patients, that subset correlates with the c-peptide in the admission stage. In addition, higher levels of IL-10 were associated with its correlation with HbA1c and insulin dosage. In the context of gene expression, moderate associations were demonstrated in T1D subjects inter alia between CTLA4 and Treg or ratio Treg/Th17. Cumulatively, our data indicate a possible novel role of Treg and Th17 in mechanism of type 1 diabetes. Moreover, potential prognostic value of these populations has been shown in reference to diabetes remission.

Identifying key genes in CD4+ T cells of systemic lupus erythematosus by integrated bioinformatics analysis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by excessive activation of T and B lymphocytes and breakdown of immune tolerance to autoantigens. Despite several mechanisms including the genetic alterations and inflammatory responses have been reported, the overall signature genes in CD4+ T cells and how they affect the pathological process of SLE remain to be elucidated. This study aimed to identify the crucial genes, potential biological processes and pathways underlying SLE pathogenesis by integrated bioinformatics. The gene expression profiles of isolated peripheral CD4+ T cells from SLE patients with different disease activity and healthy controls (GSE97263) were analyzed, and 14 co-expression modules were identified using weighted gene co-expression network analysis (WGCNA). Some of these modules showed significantly positive or negative correlations with SLE disease activity, and primarily enriched in the regulation of type I interferon and immune responses. Next, combining time course sequencing (TCseq) with differentially expressed gene (DEG) analysis, crucial genes in lupus CD4+ T cells were revealed, including some interferon signature genes (ISGs). Among these genes, we identified 4 upregulated genes (PLSCR1, IFI35, BATF2 and CLDN5) and 2 downregulated genes (GDF7 and DERL3) as newfound key genes. The elevated genes showed close relationship with the SLE disease activity. In general, our study identified 6 novel biomarkers in CD4+ T cells that might contribute to the diagnosis and treatment of SLE.

Targets of autoantibodies in acquired hemophilia A are not restricted to factor VIII: data from the GTH-AH 01/2010 study

AbstractThe root cause of autoantibody formation against factor VIII (FVIII) in acquired hemophilia A (AHA) remains unclear. We aimed to assess whether AHA is exclusively associated with autoantibodies toward FVIII or whether patients also produce increased levels of autoantibodies against other targets. A case-control study was performed enrolling patients with AHA and age-matched controls. Human epithelial cell (HEp-2) immunofluorescence was applied to screen for antinuclear (ANA) and anticytoplasmic autoantibodies. Screening for autoantibodies against extractable nuclear antigens was performed by enzyme immunoassay detecting SS-A/Ro, SS-B/La, U1RNP, Scl-70, Jo-1, centromere B, Sm, double-stranded DNA, and α-fodrin (AF). Patients with AHA were more often positive for ANA than control patients (64% vs 30%; odds ratio [OR] 4.02, 1.98-8.18) and had higher ANA titers detected than controls. Cytoplasmic autoantibodies and anti-AF immunoglobulin A autoantibodies were also more frequent in patients with AHA compared with controls. Autoantibodies against any target other than FVIII were found in 78% of patients with AHA compared with 46% of controls (OR 4.16, 1.98-8.39). Results were similar preforming sensitivity analyses (excluding either subjects with autoimmune disorders, cancer, pregnancy, or immunosuppressive medication at baseline) and in multivariable binary logistic regression. To exclude that autoantibody staining was merely a result of cross-reactivity of anti-FVIII autoantibodies, we tested a mix of 7 well-characterized monoclonal anti-FVIII antibodies. These antibodies did not stain HEp-2 cells used for ANA detection. In conclusion, a diverse pattern of autoantibodies is associated with AHA, suggesting that a more general breakdown of immune tolerance might be involved in its pathology.

051 Exogenous IL-27 prevents disease induction in murine alopecia areata

Alopecia areata (AA) is an autoimmune disease characterized by T cell infiltration of the hair follicle. The breakdown of tolerance to the hair follicle is thought to be the driving force in the nonscarring hair loss seen in patients. There are currently no FDA approved treatments for AA. IL-27 plays a pleotropic role across many other autoimmune diseases; however, whether its immunoregulatory effects can be leveraged for therapeutic applications in AA is unknown. To address this, we used an adeno-associated virus (AAV) that drives overexpression of IL-27 in our C3H/HeJ skin graft-induction model of AA.

Transcriptional Down-Regulation of Major Histocompatibility Complex as a Possible Pathogenesis for Meniere's Disease.

ObjectivesThis study aimed to determine the underlying pathogenesis of Meniere's disease (MD) using transcriptome analysis.MethodsTotal RNA was extracted from the peripheral blood mononuclear cells of 39 patients with MD and 39 controls. Through microarray analysis for nine patients and controls, the differentially expressed genes (DEGs) of those two groups were screened based on cut-off criteria (|fold changes| > 2.0 and adjusted p-value < 0.05). The functional enrichment analysis of DEGs was performed using Gene Ontology (GO).ResultsThere were 996 DEGs identified in the MD group: 415 were upregulated and 581 were downregulated. A functional enrichment analysis indicated that the downregulated DEGs were significantly enriched in terms related to immune system processes. Among them, 17 genes were enriched in terms for the major histocompatibility complex (MHC) protein complex, and the relative messenger RNA (mRNA) levels of three markedly downregulated DEGs [fold changes < −5: human leukocyte antigen (HLA)-DMA, HLA-DRB1, and HLA-DPB1] were significantly decreased in another 30 patients with MD compared with normal controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). However, there were no correlations between the expression levels of these three genes and clinical data, such as age, onset age, time course, or hearing threshold.ConclusionsOur transcriptome analysis showed that the downregulated DEGs in MD were mainly associated with the immune system pathways including the MHC protein complex in MD. Remarkably, a breakdown in immunological tolerance mediated by MHC class II may contribute to the MD development, which has implications for targeted treatment.

Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo-Associated Paraneoplastic Cerebellar Degeneration.

Background and ObjectivesParaneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a cancer-related autoimmune disease directed against neural antigens expressed by tumor cells. A putative trigger of the immune tolerance breakdown is genetic alteration of Yo antigens. We aimed to identify the tumors' genetic and immune specificities involved in Yo-PCD pathogenesis.MethodsUsing clinicopathologic data, immunofluorescence (IF) imaging, and whole-transcriptome analysis, 22 breast cancers (BCs) associated with Yo-PCD were characterized in terms of oncologic characteristics, genetic alteration of Yo antigens, differential gene expression profiles, and morphofunctional specificities of their in situ antitumor immunity by comparing them with matched control BCs.ResultsYo-PCD BCs were invasive carcinoma of no special type, which early metastasized to lymph nodes. They overexpressed human epidermal growth factor receptor 2 (HER2) but were hormone receptor negative. All Yo-PCD BCs carried at least 1 genetic alteration (variation or gain in copy number) on CDR2L, encoding the main Yo antigen that was found aberrantly overexpressed in Yo-PCD BCs. Analysis of the differentially expressed genes found 615 upregulated and 54 downregulated genes in Yo-PCD BCs compared with HER2-driven control BCs without PCD. Ontology enrichment analysis found significantly upregulated adaptive immune response pathways in Yo-PCD BCs. IF imaging confirmed an intense immune infiltration with an overwhelming predominance of immunoglobulin G–plasma cells.DiscussionThese data confirm the role of genetic alterations of Yo antigens in triggering the immune tolerance breakdown but also outline a specific biomolecular profile in Yo-PCD BCs, suggesting a cancer-specific pathogenesis.

Anticorps anti-cytokines : quel impact clinique en pathologie humaine ?

Anti-cytokine antibodies (ACA) are an emerging cause of acquired immunodeficiency, especially in previously healthy adults. The most frequently reported are anti-IFN-γ responsible for disseminated non-tuberculous mycobacteria infections, and anti-GM-CSF mainly in mycobacteria, cryptococcosis and nocardiosis infections. The presence of anti-IFN-α in severe COVID-19 infections has recently been described. The search for and detection of these ACAs in an unusual infection situation makes it possible to set up specific therapies in addition to the anti-infective treatment. ACAs are also frequent in various autoimmune pathologies where, in addition to being indicators of the breakdown of immune tolerance, they can modulate the activity of the disease according to their cytokine target. In this review of the literature, we will focus on the epidemiology and the clinical impact of these ACAs in healthy subjects and in infectious or dysimmune diseases.

Fetal hyperhomocysteinemia is associated with placental inflammation and early breakdown of maternal-fetal tolerance in pre-term birth.

Hyperhomocysteinemia (hypHcy) due to impaired folate metabolism is shown to be a risk factor for preterm birth (PTB) and low birth weight (LBW) in mothers. However, the relationship of fetal hypHcy with adverse pregnancy outcomes is under-represented. The present study aims to investigate the association of fetal hypHcy with oxidative stress and placental inflammation that can contribute to an early breakdown of maternal-fetal tolerance in pre-term birth (PTB). Cord blood and placenta tissue were collected from PTB and term infant group. Levels of homocysteine, folic acid, vitamin B12 and oxidative stress markers (MDA, T-AOC, 8-OHdG) were measured in cord blood serum using ELISA and respective standard assay kits. Relative expression of candidate genes (TNF-α, IL-6, IL1-β, VEGF-A, MMP2 and MMP9) was also checked using RT-PCR and immunoblotting/immunohistochemistry. PTB infants showed significantly higher levels of homocysteine (P=.02) and lower levels of vitamin B12 (P=.005) as compared to term infants. We also found that PTB infants with hypHcy had lower T-AOC (P=.003) and higher MDA (P=.04) levels as compared to term infants with normal homocysteine levels. The mRNA and protein levels of TNF-α, VEGF-A, MMP2 and MMP9 were significantly higher in hypHcy PTB infants. Our results show that fetal hypHcy is associated with oxidative stress and an increase in inflammatory markers in the placenta. Thus, in conclusion, our study demonstrates that fetal hypHcy during pregnancy is a potential risk factor that may initiate an early breakdown of uterine quiescence due to activation of inflammatory processes leading to PTB.

Double Negative T Regulatory Cells: An Emerging Paradigm Shift in Reproductive Immune Tolerance?

Immune regulation of female reproductive function plays a crucial role in fertility, as alterations in the relationship between immune and reproductive processes result in autoimmune subfertility or infertility. The breakdown of immune tolerance leads to ovulation dysfunction, implantation failure, and pregnancy loss. In this regard, immune cells with regulatory activities are essential to restore self-tolerance. Apart from regulatory T cells, double negative T regulatory cells (DNTregs) characterized by TCRαβ+/γδ+CD3+CD4–CD8– (and negative for natural killer cell markers) are emerging as effector cells capable of mediating immune tolerance in the female reproductive system. DNTregs are present in the female reproductive tract of humans and murine models. However, their full potential as immune regulators is evolving, and studies so far indicate that DNTregs exhibit features that can also maintain tolerance in the female reproductive microenvironment. This review describes recent progress on the presence, role and mechanisms of DNTregs in the female reproductive system immune regulation and tolerance. In addition, we address how DNTregs can potentially provide a paradigm shift from the known roles of conventional regulatory T cells and immune tolerance by maintaining and restoring balance in the reproductive microenvironment of female fertility.

Autonomous Breakdown of the Allergen Tolerance in the Nose: A Hypothesis

The prevalence of conventional and new pathogenic types of allergies is increasing. For the last few years, new atopic disorders – local allergic rhinitis (LAR), local allergic asthma, “dual” allergic rhinitis, and local allergic conjunctivitis – have been described. In particular, LAR was identified a decade ago, whereas its immunopathogenesis is still unclear. Nevertheless, the network of immune cells and neurons determining the maintenance or breakdown of allergen tolerance has partially been studied. Therefore, this field of research is currently at the cutting edge. However, there is still not any definitive answer as to why local disorders take place. Specifically, the nasal cavity is characterized by the following prevalent neuro molecules: acetylcholine, norepinephrine, substance P, neuromedin U, vasoactive intestinal peptide, and calcitonin-gene-related peptide; some of which are pro-immunogenic and a slightly smaller part is protolerogenic. In the spotlight, the hypothesis of an autonomous breakdown of tolerance to allergens in LAR is presented. The article describes immune tolerance as the antipode of the active immune response, which does not lead to producing effector cells and molecules, and vice versa is based on active immunosuppressive processes. In addition, this article focuses on the mechanisms of the maintenance and breakdown of allergen tolerance, a form of immune tolerance, at the nasal level and throughout the body, and the essential role of various cells and molecules, including neuro molecules, in the pathogenesis of LAR.