Autoimmune Inflammation Research Articles

B cell-mediated CD4 T-cell costimulation via CD86 exacerbates pro-inflammatory cytokine production during autoimmune intestinal inflammation

Dysregulated B cell responses have been described in inflammatory-bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here provide evidence for a detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1-/-) mice as a mouse model of chronic colitis, we identified CD86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking co-stimulatory signals mediated by CD86 through CTLA-4-Ig diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially IFN-γ and GM-CSF. Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1-/- mice, we also found CD86 mRNA and protein expression up-regulated on activated B cells isolated from inflamed tissue of human IBD patients. B cell activation and CD86 expression was boosted by soluble CD40L in vitro, which we found in the serum of mice and human IBD patients. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD.

Current opportunities for glycaemic control in children and adolescents with type 1 diabetes mellitus: the path to achieving a goal

Type 1 diabetes is a highly prevalent disorder worldwide and the commonest form of diabetes in children and adolescents. The incidence rates are steadily increasing, despite numerous efforts aimed at finding the possibility to detect and interrupt autoimmune inflammation in the pancreas at preclinical stages. Modern technologies make it possible to set metabolic control goals that are increasingly closer to physiological ones. The article presents recommendations regarding new technologies for glycaemic control and criteria for compensation of T1DM in children and adolescents in accordance with the updated guidelines of the International Society of Diabetes Mellitus in Children and Adolescents (ISPAD, 2022) and the Russian standards for self-monitoring of glycemia using an individual blood glucose meter associated with the use of continuous glucose monitoring technologies to assess the accuracy and/or calibration of monitoring data and address treatment adjustment issues. The possibilities and advantages of modern blood glucose meters are highlighted both in terms of accuracy of readings and functional expandability. Clinical cases demonstrating the importance of using blood glucose meters in decision-making by patients (adolescents) with type 1 diabetes who receive insulin pump therapy are presented. Excessive haste in decision-making by patients resulting in non-target results on glycaemic levels, which could have been avoided with timely measurement of blood glucose levels with a glucose meter was stressed. The great role of continuous education of children and adolescents with T1DM together with assessment and analysis of the significance of new and existing technologies for diagnosis, treatment, and monitoring of this chronic disease is emphasized, so that the patients and their parents can fully and effectively use constantly emerging opportunities.

Human IL-17A protein production is controlled through a PIP5K1α-dependent translational checkpoint.

The cytokine interleukin-17 (IL-17) is secreted by T helper 17 (TH17) cells and is beneficial for microbial control; however, it also causes inflammation and pathological tissue remodeling in autoimmunity. Hence, TH17 cell differentiation and IL-17 production must be tightly regulated, but, to date, this has been defined only in terms of transcriptional control. Phosphatidylinositols are second messengers produced during T cell activation that transduce signals from the T cell receptor (TCR) and costimulatory receptors at the plasma membrane. Here, we found that phosphatidylinositol 4,5-bisphosphate (PIP2) was enriched in the nuclei of human TH17 cells, which depended on the kinase PIP5K1α, and that inhibition of PIP5K1α impaired IL-17A production. In contrast, nuclear PIP2 enrichment was not observed in TH1 or TH2 cells, and these cells did not require PIP5K1α for cytokine production. In T cells from people with multiple sclerosis, IL-17 production elicited by myelin basic protein was blocked by PIP5K1α inhibition. IL-17 protein was affected without altering either the abundance or stability of IL17A mRNA in TH17 cells. Instead, analysis of PIP5K1α-associating proteins revealed that PIP5K1α interacted with ARS2, a nuclear cap-binding complex scaffold protein, to facilitate its binding to IL17A mRNA and subsequent IL-17A protein production. These findings highlight a transcription-independent, translation-dependent mechanism for regulating IL-17A protein production that might be relevant to other cytokines.

Regulatory factor X1 induces macrophage M1 polarization by promoting DNA demethylation in autoimmune inflammation.

Abnormal macrophage polarization is generally present in autoimmune diseases. Overwhelming M1 macrophage activation promotes the continuous progression of inflammation, which is one of the reasons for the development of autoimmune diseases. However, the underlying mechanism is still unclear. Here we explore the function of Regulatory factor X1 (RFX1) in macrophage polarization by constructing colitis and lupus-like mouse models. Both in vivo and in vitro experiments confirmed that RFX1 can promote M1 and inhibit M2 macrophage polarization. Furthermore, we found that RFX1 promoted DNA demethylation of macrophage polarization-related genes by increasing APOBEC3A/Apobec3 expression. We identified a potential RFX1 inhibitor, adenosine diphosphate (ADP), providing a potential strategy for treating autoimmune diseases.

A short history of nasal polyposis

Nasal polyposis was initially considered a tumor, but came to be seen as a chronic inflammatory mucosal disease during the second half of the 20th century. Although pathogenesis remains unclear, this has not prevented progress in diagnosis and treatment, both surgical and medical, based on the hypotheses of chronic rhinosinusitis with type-2 inflammation and autoimmune inflammation maintained by the vestigial olfactory mucosa of the ethmoid.

Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation.

Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNA-Seq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance.

MAP kinase inhibitor PD98059 regulates Th1, Th9, Th17, and natural T regulatory cells in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

Experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS), provides significant insights into the mechanisms that initiate and drive autoimmunity. MS is a chronic autoimmune disease of the central nervous system, characterized by inflammatory infiltration associated with demyelination. T lymphocyte cells play a crucial role in MS, whereas natural T regulatory (nTreg) cells prevent autoimmune inflammation by suppressing lymphocyte activity. This study sought to investigate the role of PD98059, a selective MAP kinase inhibitor, in Th1, Th9, Th17, and nTreg cells using the SJL/J mouse model of EAE. Following EAE development, the mice were intraperitoneally administered PD98059 (5 mg/kg for two weeks) daily. We evaluated the effects of PD98059 on Th1 (IFN-γ and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and RORγT), and nTreg (FoxP3 and Helios) cells in the spleen using flow cytometry. Moreover, we explored the effects of PD98059 on the IFN-γ, T-bet, IL-9, IRF4, IL-17A, RORγT, FoxP3, and Helios mRNA and protein levels in brain tissues using qRT-PCR and Western blot analyses. PD98059 treatment significantly decreased the proportion of CD4+IFN-γ+, CD4+T-bet+, CD4+IL-9+, CD4+IRF4+, CD4+IL-17A+, CD4+RORγT+, CD4+IL-17A+, and CD4+RORγT+ cells while increasing that of CD4+FoxP3+ and CD4+Helios+ cells. In addition, PD98059 administration decreased the mRNA and protein levels of IFN-γ, T-bet, IL-9, IRF4, IL-17A, and RORγT but increased those of FoxP3 and Helios in the brain tissue of EAE mice. Our findings suggest that PD98059 corrects immune dysfunction in EAE mice, which is concurrent with the modulation of multiple signaling pathways.

Profiling of mouse and human liver diseases identifies targets for therapeutic treatment of autoimmune hepatitis

Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and non-alcoholic steatohepatitis (NASH) are chronic liver diseases (CLDs) of distinct etiologies that represent a public health risk with limited therapeutic options. A common feature among CLDs is an aggressive T cell response resulting in destruction of liver tissue and fibrosis. Here, we assessed the presence and nature of T cell inflammation in late-stage human AIH, PSC and NASH and examined whether targeting the T cell response can improve disease pathology in a mouse model (Traf6ΔTEC) of spontaneous AIH. T cell infiltration and ensuing inflammatory pathways were present in human AIH and PSC and to a lesser extent in NASH. However, we observed qualitative differences in infiltrating T cell subsets and upregulation of inflammatory pathways among these diseases, while mouse and human AIH exhibited similar immunogenic signatures. While gene expression profiles differed among diseases, we identified 52 genes commonly upregulated across all diseases that included the JAK3 tyrosine kinase. Therapeutic targeting of chronic AIH with the JAK inhibitor tofacitinib reduced hepatic T cell infiltration, AIH histopathology and associated immune parameters in treated Traf6ΔTEC mice. Our results indicate that targeting T cell responses in established hepatic autoimmune inflammation is a feasible strategy for developing novel therapeutic approaches to treat AIH and possibly other CLDs irrespective of etiology.

SAT589 A Case Of Lymphocytic Hypophysitis In A Young Female With Unilateral Abducens Nerve Palsy

Abstract Disclosure: J.H. Yu: None. M.L. Nguyen: None. M.H. Horani: None. M. Shahlapour: None. Lymphocytic hypophysitis is a neuroendocrine disorder characterized by autoimmune inflammation of the pituitary gland. Lymphocytic hypophysitis is the most common form of hypophysitis with the cause usually unknown. It often occurs in late pregnancy or in the postpartum period with affected individuals presenting with symptoms of headaches of an intensity out of proportion to the size of the lesion and with hypopituitarism. Other manifestations include visual field defects and ocular motility disturbances. We present a case of a 24 year old Female who presents with headache, diplopia, and left-sided CN6 nerve palsy of 4 day duration. She has a known history of amenorrhea for the past year and obesity. She also presents with polydipsia and polyuria. Further workup included MRI of the brain showing a sellar mass with mass effect on optic chiasm and left cavernous sinus lesion. Pituitary hormonal workup showed ACTH 13, LH 0.42, FSH 2.1, TSH 0.442, free T4 1.0, random cortisol 6.3, and prolactin 78. Lumbar puncture with basic CSF studies showed glucose 56, protein 48, nucleated cells 38 (lymph 91%, poly 4%, mono 5%), and RBC 4. ACE, AFP, IgG4, ANA, ANCA, and CEA workup was negative. Biopsy of the mass was performed with results suggesting lymphocytic hypophysitis. Additional immunohistochemistry stains will be performed to evaluate for IgG4 related diseases. The patient would later develop diabetes insipidus and central hypothyroidism weeks later. Discussion: The lymphocytic infiltration causes inflammation, enlargement and fibrosis of the pituitary gland which can produce a mass effect on surrounding tissues. The definitive diagnosis is made via histopathology staining of biopsied sellar or suprasellar tissue. The condition predominantly affects women more than men at a ratio of 8:1.Treatment involves evaluation of pituitary function with management of any hormone deficiencies and alleviating any mass effects due to pituitary inflammation and enlargement. First line treatment usually involves high dose corticosteroids with refractory cases being treated with immunosuppressive medications. Surgery or fractionated radiotherapy can be used if medical therapy fails. In our patient, a biopsy was performed that confirmed lymphocytic hypophysitis with unmasked diabetes insipidus and hypothyroidism presenting weeks after starting on high-dose corticosteroids. Conclusion: This case highlights the unique presentation of lymphocytic hypophysitis including left-sided CN6 nerve palsy, headaches, and hypogonadotropic hypopituitarism. From our knowledge, it is one of the first presentations with unilateral CN6 nerve palsy as a mass effect from lymphocytic hypophysitis. Presentation: Saturday, June 17, 2023

Inhibition of SUMOylation promotes remyelination and reduces IL-17 mediated autoimmune inflammation: Novel approach toward treatment of inflammatory CNS demyelinating disease

Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. In the CNS, expression of myelin genes is regulated by state of SUMOylation of their respective transcription factors. In the immune system, deSUMOylation activates innate immune responses and promotes anti-viral immunity. However, the role played by SUMO in an adaptive immune response and in the development of T cell mediated autoimmune disease has not been previously described.TAK981 is a synthetic small molecule which by forming adducts with SUMO proteins prevents SUMOylation. We examined the expression of myelin genes and their transcription factors following culture with TAK981 in Oligodendrocyte Precursor Cells (OPC). We found that myelin basic protein (MBP), a key myelin protein, is upregulated in OPC in the presence of TAK981. We also found increased expression of transcription factors Sox10 and Myrf, which engage in the expression of MBP. In the Cuprizone model of demyelination/remyelination, animals which were treated with TAK981 showed increased remyelination in areas of demyelination and an increase in the number of maturing oligodendrocytes compared to vehicle treated controls. In in vitro cultures of lymphocytes, TAK981 reduced the expression of TH17 in T cells in mice immunized with MOGp35–55. Following in vivo treatment with TAK981, there was a significant reduction in the clinical and pathological severity in mice immunized to develop experimental allergic encephalitis (EAE).The dual effects of deSUMOylation on remyelination and in regulating an autoimmune adaptive response offers a novel approach to the management of human inflammatory demyelinating diseases such as multiple sclerosis.

Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells

Cognate interaction between CD4+ effector memory T (TEM) cells and dendritic cells (DCs) induces innate inflammatory cytokine production, resulting in detrimental autoimmune pathology and cytokine storms. While TEM cells use tumor necrosis factor (TNF) superfamily ligands to activate DCs, whether TEM cells prompt other DC-intrinsic changes that influence the innate inflammatory response has never been investigated. We report the surprising discovery that TEM cells trigger double-strand DNA breaks via mitochondrial reactive oxygen species (ROS) production in interacting DCs. Initiation of the DNA damage response in DCs induces activation of a cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-independent, non-canonicalstimulator of interferon genes (STING)-TNF receptor-associated factor 6 (TRAF6)-nuclear factor κB (NF-κB) signaling axis. Consequently, STING-deficient DCs display reduced NF-κB activation and subsequent defects in transcriptional induction and functional production of interleukin-1β (IL-1β) and IL-6 following their interaction with TEM cells. The discovery of TEM cell-induced innate inflammation through DNA damage and a non-canonical STING-NF-κB pathway presents this pathway as a potential target to alleviate Tcell-driven inflammation in autoimmunity and cytokine storms.

Briumvi: a breakthrough in the treatment of relapsing multiple sclerosis: a review.

Multiple sclerosis (MS) is a chronic systemic autoimmune disorder characterized by plaques of demyelination, autoimmune inflammation, and astrocytic gliosis. The primary cells involved in the pathophysiology of MS are T cells. However, B cells have recently been implicated in the pathophysiology of the disease. Therefore, researchers have been exploring B cell therapy as an alternative treatment option for MS. B cell therapy is based on the targeted depletion of CD20-positive B cells. Rituximab, ocrelizumab, and ofatumumab are anti-CD20 antibodies already approved. Briumvi, the fourth type of anti-CD20 antibody was approved by FDA in December 2022, for the treatment of relapsing types of MS, including relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis, and clinically isolated syndromes after the drug was tested in two randomized, double-blind, phase III, ULTIMATE I, and II trials which compared Briumvi (ublituximab) with Aubiago (teriflunomide). Ublituximab was found to have a much lower annual relapse rate in the ULTIMATE II trials than teriflunomide. Briumvi is a chimeric recombinant IgG1 monoclonal antibody directed against human CD20 with potential antineoplastic activity. Its mechanism of action involves several distinct processes that collectively lead to the depletion of B cells and suppression of the immune response. The primary mode of action of Briumvi is its high-affinity binding to CD20. Infusion-related reactions are the most common side effects encountered following intravenous administration of ublituximab.

Peptide-based immunotherapy in lupus: Where are we now?

In autoimmune rheumatic diseases, immune hyperactivity and chronic inflammation associate with immune dysregulation and the breakdown of immune self-tolerance. A continued, unresolved imbalance between effector and regulatory immune responses further exacerbates inflammation that ultimately causes tissue and organ damage. Many treatment modalities have been developed to restore the immune tolerance and immmunoregulatory balance in autoimmune rheumatic diseases, including the use of peptide-based therapeutics or the use of nanoparticles-based nanotechnology. This review summarizes the state-of-the-art therapeutic use of peptide-based therapies in autoimmune rheumatic diseases, with a specific focus on lupus.

ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy advances rapidly in the clinic. Despite their therapeutic benefits, ICIs can cause clinically significant immune-related adverse events (irAEs), including myocarditis. However, the cellular and molecular mechanisms regulating irAE remain unclear. Here, we investigate the function of Angiopoietin-like protein 2 (ANGPTL2), a potential inflammatory mediator, in a mouse model of ICI-related autoimmune myocarditis. ANGPTL2 deficiency attenuates autoimmune inflammation in these mice, an outcome associated with decreased numbers of T cells and macrophages. We also show that cardiac fibroblasts express abundant ANGPTL2. Importantly, cardiac myofibroblast-derived ANGPTL2 enhances expression of chemoattractants via the NF-κB pathway, accelerating T cell recruitment into heart tissues. Our findings suggest an immunostimulatory function for ANGPTL2 in the context of ICI-related autoimmune inflammation and highlight the pathophysiological significance of ANGPTL2-mediated cardiac myofibroblast/immune cell crosstalk in enhancing autoimmune responses. These findings overall provide insight into mechanisms regulating irAEs.

Differences in the skin microbiota spectrum and parameters of local immunity in the areas of inflammation in skin diseases and healthy people

Alteration of microbiota composition is a trigger, and, sometimes, an etiological factor in the development of chronic skin diseases, e.g., psoriasis or eczema. Recognition of microflora by keratinocytes and immune cells leads to the production of antimicrobial peptides, chemokines and growth factors, which contribute to the differentiation of T lymphocytes to autoaggressive effector cells of Th1, Th17 and Th22 types that implement autoimmune inflammation in the psoriatic plaque. The aim of our work was to study the differences in the skin microbiota spectrum and the parameters of local immunity in capillary blood taken near the focus of inflammation in patients with autoimmune (psoriasis) and allergic (eczema) diseases compared with the parameters of healthy people. 24 patients with psoriasis (group 1), 20 patients with eczema (group 2) and 20 healthy adults (group 3) were examined. Biological materials were taken, i.e., the smears taken with sterile dry swab to the Amies transport medium with activated carbon, and capillary blood was taken in 2 microvets, 200 µL each) from the foci of inflammation on affected skin from the hands of patients, or from the fingers of healthy people. Inoculations of diagnostic media, microscopy with Gram staining and microbial identification were performed in a microbiological analyzer. Immunophenotyping of 22 subsets of mononuclear cells was performed by four-color staining of capillary blood with erythrocyte lysis and evaluation of subsets by a flow cytometer. Cytokines in blood plasma were determined by multiplex method. The spectrum of hand skin microflora of the group 3 was more diverse in the species composition. In patients with psoriasis and eczema, the coccal flora dominated, with a shift towards pathobionts in the microbiota spectrum. Activation of T and B cells, production of pro-inflammatory cytokines, IL-23/IL-17/IL-22 axis cytokines and cytokines – markers of epithelial cell damage (IL-25 and IL-33), as well as anti-inflammatory factors insufficiency were detected. Differences in changing parameters of the local immune status in patients with autoimmune (psoriasis) and allergic (eczema) diseases were revealed, thus reflecting the distinct features of immunopathogenesis in these diseases.

LncRNA Neat1 targets NonO and miR-128-3p to promote antigen-specific Th17 cell responses and autoimmune inflammation

Long non-coding RNAs (lncRNAs) interaction with RNA-Binding proteins (RBPs) plays an important role in immunological processes. The generation of antigen-specific Th17 cells is closely associated with autoimmune pathogenesis. However, the function of lncRNA-RBP interactions in the regulation of pathogenic Th17 cell responses during autoimmunity remains poorly understood. Here, we found that lncRNA Neat1, highly expressed in Th17 cells, promoted antigen-specific Th17 cell responses. Both global and CD4+ T cell-specific knockdown of Neat1 protected mice against the development of experimental autoimmune uveitis (EAU). Mechanistically, Neat1 regulated RNA-Binding protein NonO, thus relieving IL-17 and IL-23R from NonO-mediated transcriptional repression and supporting antigen-specific Th17 cell responses. In addition, Neat1 also modulated miR-128-3p/NFAT5 axis to increase the expression of IL-17 and IL-23R, leading to augmented Th17 cell responses. Our findings elucidate a previously unrecognized mechanistic insight into the action of Neat1 in promoting antigen-specific Th17 responses and autoimmunity, and may facilitate the development of therapeutic targets for T cell-mediated autoimmune diseases.

Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition and other immune system alterations contribute to pathological changes of multiple organ systems. The vitamin D metabolite c is a critical immunomodulator playing pivotal roles in the immune system. Epidemiological evidence indicates that vitamin D deficiency is correlated with the severity of SLE. Our aim is to investigate the effects of 1,25(OH)2D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA-containing immune complex (DNA-ICs), and the effects of VitD3 on immune system balance during SLE. We purified DNA-ICs from the serum of SLE patients and isolated mDCs from normal subjects. In vitro studies showed that DNA-ICs were internalized and consumed by mDCs. VitD3 blocked the effects of DNA-ICs on RelB, IL-10 and TNF-α in mDCs. Further analysis indicated that DNA-ICs stimulated histone acetylation in the RelB promoter region, which was inhibited by VitD3. Knockdown of the histone deacetylase 3 gene (HDAC3) blocked these VitD3-mediated effects. Co-culture of mDCs and CD4+ T cells showed that VitD3 inhibited multiple processes mediated by DNA-ICs, including proliferation, downregulation of IL-10, TGF-β and upregulation of TNF-α. Moreover, VitD3 could also reverse the effects of DNA-IC-induced imbalance of CD4+ CD127- Foxp3+ T cells and CD4+ IL17+ T cells. Taken together, our results indicated that autologous DNA-ICs stimulate the activation of mDCs in the pathogenesis of SLE, and VitD3 inhibits this stimulatory effects of DNA-ICs by negative transcriptional regulation of RelB gene and maintaining the Treg/Th17 immune cell balance. These results suggest that vitamin D may have therapeutic value for the treatment of SLE.

Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice.

B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naïve B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation

Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages.

Stem-like CD4+ T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis.

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES)+ cytotoxic T cells and B cell lymphoma 6 (BCL6)+ T follicular helper-like cells. TCF1hiCD4+ T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1hiCD4+ T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4+ T cells instead of only effector T cells.