Rebalancing Immune Homeostasis to Treat Autoimmune Diseases

Homeostatic Yin/Yang mechanisms enable the human immune system to eliminate microbes without causing autoimmunity. T cells can become positive effectors or negative regulators (e.g., Tregs) that either control immunity or maintain tolerance. DCs can become either immunogenic to induce T effectors, or tolerogenic to develop Tregs. At steady-state, tolerogenic DC populations and Tregs produce IL-10 and TGF-β. IL-2 is needed for Treg function and fitness, and its production or utilization is often impaired in some autoimmune diseases. Emerging strategies to treat autoimmunity include NPs targeted to DCs or Tregs in vivo; these have the potential to shift immunogenic DCs to tolerogenic DCs to induce and expand Tregs to numbers that might restore normal homeostasis. Biodegradable poly(lactic-co-glycolic acid) NPs loaded with rapamycin can induce tolerogenic DCs and Tregs, and protect mice against some autoimmune diseases (e.g., lupus). Other new therapeutic products to treat specific autoimmune diseases might enhance the activity of cellular regulators of immune and inflammatory responses (e.g., TNFR2 and PPAR α/γ agonists). Some commensal bacteria express cell-surface polysaccharides that can enable tolerogenic DCs to induce Tregs. Obesity alters the microbiome leading to metabolic syndrome and systemic inflammation. The prebiotic olligfructose can restore the lean gut microbiome and, thereby, reduce joint and colon inflammation. During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals. During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals. the enzyme that activates glucose and fatty acid uptake and oxidation. mechanism of immune tolerance in which lymphocytes are hyporesponsive and functionally inactive after antigen stimulation. transplantation of autologous stem cells (whose undifferentiated status allows their development into different cell types) following immunoablation (close-to-total depletion of immune cells that are replaced by transplanted stem cells). In allogenic stem cell transplantation, donor and recipient stem cells are derived from different individuals. CAR T cells are genetically engineered T cells that express a chimeric T cell receptor with antigen-binding and T cell-activating capacity, predominantly for use in immunotherapy. inhibitory costimulatory molecule expressed on both CD4+ and CD8+ T cells. immunosuppressive alkylating agent that works by forming crosslinks via guanines in DNA, effectively inducing cell apoptosis. animal model of inflammatory demyelinating disease of the central nervous system that closely resembles human multiple sclerosis (MS). transcription factor, master regulator of T regulatory cell differentiation and function. process by which the immune system maintains a normal, healthy status under normal physiological conditions and following immune responses. immunodysregulation polyendocrinopathy enteropathy X­linked syndrome; characterized by dysfunctional expression of foxp3. arbitrary nomenclature where M1 macrophages produce proinflammatory cytokines, whereas M2 macrophages are are anti-inflammatory and involved in immune regulation. protein kinase with a central role in the regulation of multiple cellular processes including cell growth, autophagy, survival, and proliferation, in addition to protein synthesis. ultra-small objects with dimensions ranging between 1 and 500 nm; they can be encapsulated with biological agents and modified to target specific cells via delivery. checkpoint inhibitor expressed in lymphoid and non-lymphoid cells; can promote apoptosis of antigen-specific T cells and simultaneously reduce regulatory T cell (Treg) apoptosis. a chronic, systemic inflammatory condition characterized by autoimmune responses that can result in many autoantibodies and can affect multiple tissues and organs. inflammatory arthritis that can recur and cause joint damage or present as a single episode of joint pain accompanied by fever and rash. Tregs that, in addition to secreting TGF-β and IL-10, suppress targets through cytotoxicity, cell-to-cell contact, and metabolic disruption. Tregs that secrete TGF-β and IL-10.