FcγRIIa in autoimmunity: Unraveling pathogenic mechanisms and therapeutic opportunities.

Intravenous Immunoglobulins Suppress Antibody-Dependent Effector Functions of Human Peripheral Blood Cells

Atherosclerosis is a chronic inflammatory disease characterized by accumulation of oxidized lipoproteins, increased cell death and hypertrophic degeneration of the arterial intima. The disease process is associated with local formation of modified self antigens that are targeted by both innate and adaptive immune responses. Although it remains to be firmly established it is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful rest products from oxidized LDL and dying cells. However, studies performed on hypercholesterolaemic mice deficient in different components of the immune system uniformly suggest that the net effect of immune activation is pro-atherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease. These observations point to the possibility of developing new treatments for atherosclerosis based on modulation of immune responses against plaque antigens, an approach presently tested clinically for several other chronic inflammatory diseases with autoimmune components. Pilot studies in animals have provided promising results for both parental and oral vaccines based on oxidized LDL antigens. The time when this concept is ready for clinical testing is rapidly approaching but it will be important not to underestimate the difficulties that will be encountered in transferring the promising results from experimental animals into humans.

Knowledge about metabolism of immune cells increased almost exponentially during the last two decades and thereby created the new area immunometabolism. Increased glucose uptake and glycolysis were identified as one of the major drivers in immune cells for rapid adaptation to changes in the microenvironment or external stimuli. These metabolic switches are crucial to generate macromolecules for immune cell proliferation and activation. Glucose transporter 1 (GLUT1), a ubiquitously expressed glucose transporter, is strongly upregulated after innate and adaptive immune cell activation. Deletion or inhibition of GLUT1 blocked T cell proliferation and effector function, antibody production from B cells and reduced inflammatory responses in macrophages. Increased glucose uptake and GLUT1 expression are not only observed in proinflammatory conditions, but also in murine models of autoimmunity as well as in human patients. Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by infiltration of immune cells, hyperproliferation of fibroblast-like synoviocytes, and destruction of cartilage and bone. These processes create a hypoxic microenvironment in the synovium. Moreover, synovial samples including fibroblast-like synoviocytes from RA patients showed increased lactate level and upregulate GLUT1. Similar upregulation of GLUT1 is observed in systemic lupus erythematosus and psoriasis patients as well as in murine autoimmune models. Inhibition of GLUT1 using either T cell specific knockouts or small molecule GLUT1/glycolysis inhibitors improved phenotypes of different murine autoimmune disease models like arthritis, lupus, and psoriasis. Thereby the therapeutic potential of immunometabolism and especially interference with glycolysis was proven. This article is categorized under: Biological Mechanisms > Metabolism Translational, Genomic, and Systems Medicine > Translational Medicine Physiology > Mammalian Physiology in Health and Disease.

Metabolic flux can dictate cell fate, including immune cell effector and regulatory function. The metabolic regulation of cell function is well characterized with respect to effector, memory, and regulatory T cells. This knowledge may allow for manipulation of T cell metabolic pathways that set the stage for more effective T cell therapy. Natural Killer (NK) and T-lymphocytes have complementary roles in the defense against pathogens. However, studies of NK cell metabolism are only beginning to emerge and there is comparatively little knowledge on the metabolic regulation of NK-cell activation and effector function. Given their common lymphoid lineage, effector functions and cellular memory potential our current knowledge on T cell metabolism could inform investigation of metabolic reprogramming in NK cells. In this review, we compare the current knowledge of metabolic regulation in T cell and NK cell development, activation, effector and memory function. Commonalties in glucose transport, hypoxia-inducible factors and mTOR highlight metabolic control points in both cells types. Contrasting the glycolytic and oxidative nodes of metabolic regulation in T cells versus NK cells may provide insight into the contribution of specific immune responses to disease and promote the development of immunotherapeutic approaches targeting both innate and adaptive immune responses.

Leukocyte migration is a fundamental component of innate and adaptive immune responses as it governs the recruitment and localization of these motile cells, which is crucial for immune cell priming, effector functions, memory responses and immune regulation. This complex cellular trafficking system is controlled to a large extent via highly regulated production of secreted chemokines and the restricted expression of their membrane-tethered G-protein-coupled receptors. The activity of chemokines and their receptors is also regulated by a subfamily of molecules known as atypical chemokine receptors (ACKRs), which are chemokine receptor-like molecules that do not couple to the classical signalling pathways that promote cell migration in response to chemokine ligation. There has been a great deal of progress in understanding the biology of these receptors and their functions in the immune system in the past decade. Here, we describe the contribution of the various ACKRs to innate and adaptive immune responses, focussing specifically on recent progress. This includes recent findings that have defined the role for ACKRs in sculpting extracellular chemokine gradients, findings that broaden the spectrum of chemokine ligands recognized by these receptors, candidate new additions to ACKR family, and our increasing understanding of the role of these receptors in shaping the migration of innate and adaptive immune cells.

CD8 T cells comprise a large portion of cells in inflamed tissues in many autoimmune diseases, yet their roles in autoimmune pathogenesis have been unclear. Newer studies have demonstrated that CD8 T cells perform many effector functions that may play a vital role in autoimmune disease pathogenesis. In some autoimmune diseases, such as type 1 diabetes and polymyositis, classical cytotoxic T lymphocytes are thought to play a driving role, but in most tissues affected by autoimmune disease, granzyme K-expressing CD8 T cells are the most abundant. These cells have low cytotoxic potential and instead stimulate nearby cells by releasing cytokines and granzyme K, which can activate complement cascades. Resident memory CD8 T cells are also present in autoimmune tissues, although their roles in pathogenesis are less clear. Foxp3+ CD8 T cells exist, but regulatory functions of CD8 T cells extend beyond this population, as CD39 and GzmB expressed by other CD8 T cell subsets can suppress or kill nearby antigen-presenting cells and other pro-inflammatory cells. In this review, we describe CD8 T cell subsets and functions, their associations with human autoimmune diseases, as well as current and in-development treatments that target CD8 T cells.

From Bases to Basis: Linking Genetics to Causation in Primary Biliary Cirrhosis

Vitamin D receptor polymorphisms in primary biliary cirrhosis: A functional connection?

The aryl hydrocarbon receptor in immune regulation and autoimmune pathogenesis

Dissecting FcγR Regulation through a Multivalent Binding Model.

The most prevalent kind of acute leukemia in adults is acute myeloid leukemia (AML). While some individuals have had better effectiveness due to advancements in targeted medications, recurrence after remission and inadequate treatment specificity continue to be significant therapeutic problems. By controlling essential metabolic pathways and metabolites, metabolic reprogramming, a crucial strategy for cellular adaptability to energy needs, modifies cellular metabolic rhythms. In addition to being involved in immune cell proliferation, differentiation, and effector function, this pathway is also essential for leukemogenesis and survival signaling in AML. By altering the expression of immune molecules, the release of certain metabolites (such as lactate, ROS, glutamine, etc.) has a significant impact on the immune response to tumors. It is noteworthy that the metabolic interactions between immune cells and AML cells form a distinct pattern of energy competition in the tumor microenvironment. This study examined the new approach of targeting metabolic pathways to improve immunotherapy, systematically clarified the regulatory mechanism of metabolic reprogramming between AML cells and immune cells to counteract tumor immunity, and concentrated on the synergistic effect of current therapies and metabolic interventions. These findings offered a fresh perspective on how to fully realize the potential of metabolic therapy for AML.

Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: Perspectives and challenges

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody.

Dendritic cells (DCs) are primary antigen presenting cells in lungs that promote Th2 cell mediated immunity to house dust mite (HDM) allergen. DCs are attractive therapeutic targets to modulate allergen-induced airway inflammation and adaptive immune responses. Dimethyl fumarate (DMF) are methyl esters of fumaric acid and regulates immune cell differentiation and effector functions. However, the effect of DMF on lung DCs has not yet been addressed. Here, we investigated the effect of DMF treatment employing murine model of HDM-induced experimental allergic asthma and DC adoptive transfer experiment. We show that local DMF application attenuates airway inflammation, mucous cell hyperplasia, and airway resistance to increasing dosage of inhaled methacholine. Notably, DMF administration in the allergen challenge phase significantly inhibited the lung recruitment of CD11b+ conventional DCs (cDC2) and suppressed Th2 cytokine producing IL4, IL5, and IL13 CD4+ T cells. In lung draining mediastinal lymph node (mLNs), DMF treatment significantly induces CD4+T regulatory (Tregs) cells. Moreover, prior to administration of fluorescent-labeled HDM, single DMF application to naïve mice impeded the migration of CD11b+ cDC2 to the draining mLNs. Adoptive transfer of DMF treated CD11c+ HDM-pulsed DCs to naïve mice with subsequent intranasal HDM-challenge similarly attenuates the features of airway inflammation. Collectively, our findings suggest that local DMF application modulates lung DCs function, thereby attenuates airway inflammation and is a potent antiasthmatic therapeutic agent.

Tumor-targeting antibodies have been successful in the treatment of various types of cancers. Antibodies engage the immune system with their Fc, stimulating immune cell effector function. In the clinic, FcγRIIIa polymorphisms with higher affinity for the Fc of antibodies were shown to improve response rates and overall survival. Efforts have been made to modify the Fc to enhance affinity to Fc receptors and thereby improve effector function. An alternative for improving immune effector function may be to increase the level of tumor antigen expression. In this study, tamoxifen was used to increase HER2/neu protein level to determine whether increased tumor antigen expression could enhance NK cell-mediated antibody-dependent cytotoxicity (ADCC). Tamoxifen was found to increase HER2/neu 1.5-fold to threefold in breast cancer cell lines that were HER2/neu non-amplified. Using flow cytometry to simultaneously evaluate NK cell degranulation and tumor cell death, the increase in HER2/neu enhanced NK cell-mediated ADCC. However, in cells that had HER2/neu gene amplification and estrogen receptor expression, tamoxifen elevated HER2/neu but failed to improve NK cell function. The quantity of HER2/neu on the tumor cell surface was approximately double that of the number of Fc receptors found on NK cells. This appears to reflect a ceiling at which increasing antigen expression fails to improve NK cell effector function. This has clinical implications as trying to increase antigen expression to enhance NK cell function may be useful for patients with antigen-low tumors, but not in those whose tumors have gene amplification or high levels of antigen expression.