Autoimmunity refers to an organism’s immune response against its own healthy cells, tissues, or components, potentially leading to irreversible damage to vital organs. Central and peripheral tolerance mechanisms play crucial roles in preventing autoimmunity by eliminating self-reactive T and B cells. The disruption of immunological tolerance, characterized by the failure of these mechanisms, results in the aberrant activation of autoreactive lymphocytes that target self-tissues, culminating in the pathogenesis of autoimmune disorders. Genetic predispositions, environmental exposures, and immunoregulatory disturbances synergistically contribute to the susceptibility and initiation of autoimmune pathologies. Within the realm of immune therapies for autoimmune diseases, cytokine therapies have emerged as a specialized strategy, targeting cytokine-mediated regulatory pathways to rectify immunological imbalances. Proinflammatory cytokines are key players in inducing and propagating autoimmune inflammation, highlighting the potential of cytokine therapies in managing autoimmune conditions. This review discusses the etiology of autoimmune diseases, current therapeutic approaches, and prospects for future drug design.
Autoimmune disorders arise when the immune system erroneously attacks healthy cells, mistaking them for foreign invaders. This pathological misidentification leads to inflammation, tissue destruction, and impaired organ function. Under normal physiological conditions, the immune system adeptly identifies and eliminates potentially dangerous pathogens, such as bacteria, parasites, fungi, viruses, and even foreign tissues like tumors, without harming the body. However, the immune system can malfunction in two primary ways: first, through immune deficiency disorders, where one or more components of the immune system fail to protect the body from pathogens, and second, through autoimmune diseases. The fundamental cause of autoimmune diseases lies in the immune system’s inability to distinguish self from non-self, a phenomenon often described as a breakdown of immunological tolerance. Understanding this breakdown is central to comprehending autoimmune disorders.
The critical importance of autoimmunity in clinical disease was first elucidated approximately 50 years ago by Macfarlane Burnett. His introduction of the “forbidden clone” theory, which earned him a Nobel Prize, marked a pivotal advancement in our understanding of autoimmunity, including lymphoid cell development, thymic education, apoptosis, and the elimination of autoreactive cells. Burnett’s work laid the foundation for subsequent research in the field.
The increasing prevalence of autoimmune diseases has prompted several theories, many of which may apply to multiple disorders. The development of autoimmune diseases is a complex process involving various factors, including genetics, environmental triggers, and immune dysregulation. Genetic susceptibility plays a crucial role in the development of autoimmune diseases, as certain genes can increase the risk of these disorders. The incidence of autoimmune illness among identical twins ranges from 12% to 67%, indicating that, in addition to environmental factors, stochastic or epigenetic processes are also relevant.
Environmental factors such as infections, diet, and exposure to toxins can trigger autoimmune responses in genetically susceptible individuals. The etiology of autoimmune diseases involves a complex interplay between genetic and environmental factors. For instance, individuals with particular genetic susceptibilities may have an increased risk of developing autoimmune disorders when encountering specific environmental triggers, including infections, toxins, or stressors. The progress of autoimmune diseases has been determined in relation to the T helper 1(Th1)/Th2 cytokine balance, two T-cell subsets that cross-regulate each other. In this context, Th1 mediates responses through cytokine production, such as interleukin 2 (IL-2), tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, and through macrophage cytokines such as TNF-α, IL-1, IL-6, and IL-12. However, Th2 produces responses by IL-4, 1L-5, and IL-13. Cytokines are the main players in inflammatory responses in autoimmune conditions/diseases. Proinflammatory cytokines generally increase in autoimmune conditions and activate the cellular component of immunity at the site of inflammation. This primary inflammatory cascade helps along the progression of autoimmune pathology. The continuous activation of immune cells by cytokines can induce tissue damage and lengthen the autoimmune pathology. For example, in inflammatory bowel disease and psoriasis, IL-17 and IFN-γ produce inflammatory mediators and further matrix-degrading enzymes that cause tissue destruction and degradation. Similarly, fluctuations in cytokine levels can stimulate autoimmune flares, which are characterized by the worsening of symptoms and the intensification of disease severity. For example, a shift toward proinflammatory cytokines can magnify autoimmune responses and cause disease flares in conditions like systemic lupus erythematosus and vasculitis.
Autoimmune diseases have traditionally been categorized based on whether they target specific body tissues or cells, such as the receptors at the neuromuscular junction in myasthenia gravis or the beta cells of the pancreas in insulin-dependent diabetes mellitus. Alternatively, they may impact multiple tissues, as seen in conditions like dermatomyositis/synthetase syndromes, which affect the skin, muscle, and lungs, or systemic lupus erythematosus, which involves the skin, kidneys, joints, bone marrow, and nervous system. Typically, the autoantigens targeted in tissue-specific autoimmune responses are localized to particular tissues, such as components of the acetylcholine receptor in myasthenia gravis or islet cell autoantigens in insulin-dependent diabetes mellitus. Conversely, the autoantigens involved in systemic autoimmune processes are generally expressed in various cell types and tissues throughout the body.
In the past two decades, substantial research has advanced our understanding of the onset kinetics of autoimmune diseases. Harley and colleagues significantly contributed to this field by clarifying the timeline of autoantibody generation. They refuted the traditional notion that autoantibodies emerge only close to the onset of the disease. For instance, systemic lupus erythematosus (SLE) patients often possess autoantibodies long before the initial symptoms appear or the disease manifests. Harley’s findings categorize antibodies in patients progressing toward an SLE diagnosis into two groups: (i) those detectable long before the first symptoms, such as anti-phospholipid antibodies (APL), anti-Ro antibodies, and antinuclear antibodies (ANAs), and (ii) those that markedly increase near the time of diagnosis, including anti-RNP, Anti-Sm, and, to a lesser extent, anti-DNA. This early presence of an immune response recognizing autoantigens has also been observed in other tissue-specific and systemic autoimmune diseases, such as type I diabetes and rheumatoid arthritis (RA). These crucial insights highlight that an immune response against autoantigens can lead to persistent tissue damage, with qualitative and/or quantitative changes in the autoimmune response contributing to the development of clinical symptoms.
Overall, the development of autoimmune diseases is a complex interplay between genetic, environmental, and immunological factors. Further research is needed to fully understand their underlying mechanisms.
In central tolerance (negative selection), immature T-cells (thymocytes) that strongly bind to self-antigens presented by thymic epithelial cells, dendritic cells, and macrophages undergo apoptosis. Conversely, peripheral tolerance prevents overly sensitive T and B cells from responding inappropriately to environmental stimuli, such as microbes and allergens. All phases of autoimmune disease are associated with the breakdown of regulatory systems, which perpetuates chronic inflammation and ongoing immune responses. While some autoimmune conditions may enter a resolution phase, this phase is characterized by the partial and transient restoration of the balance between effector and regulatory responses. For assessing the risk of autoimmune diseases, a combination of genetic scores and autoantibody profiles can yield effective results, as seen in type 1 diabetes.
This review aims to provide a comprehensive overview of the mechanisms underlying autoimmunity, the breakdown of self-tolerance, predisposing genetic factors, and the current therapeutic strategies, with a focus on interleukin (IL)-related therapeutics. Recent advances in our understanding of these processes and the development of new treatment modalities underscore the importance of continued research in this field. Further elucidation of the underlying mechanisms is essential for the development of more effective therapies and the improvement of patient outcomes.
The effective functioning and maturation of the immune system depends on a complex network of signaling pathways. Disruptions in these pathways can lead to the proliferation and activation of self-reactive lymphocytes that target self-antigens, excessive cytokine production, and the release of autoantibodies. These events can result in the damage and destruction of normal tissue, causing autoimmune conditions.
Autoimmunity is triggered by a combination of genetic predisposition and environmental factors, reflecting the complexity of autoimmune diseases. Once initiated by these primary mechanisms, autoimmunity is further propagated by increasing inflammation and tissue damage, which can arise from various circumstances. Deficiencies in central or peripheral immunological tolerance may cause autoimmunity. Central tolerance, or negative selection, eliminates T or B cells reactive to the body’s own tissues, fostering self-tolerance. This occurs primarily in the thymus for T-cells and in the bone marrow for B cells, where cells that strongly bind to self-antigens are induced to undergo apoptosis. In contrast, peripheral tolerance acts to prevent the over-reactivity of T and B cells that escape central tolerance, particularly for antigens not expressed in the thymus or bone marrow during central tolerance development. Mechanisms such as allergen deletion and suppression by regulatory T-cells (Tregs) are critical for maintaining peripheral tolerance. The Th1/Th2 paradigm, introduced by Mosmann and Coffman, has significantly advanced our understanding of immune responses and autoimmune diseases by delineating the differentiation of T helper (Th) cells into Th1 or Th2 types based on their cytokine environment. This paradigm explains that Th1 responses are associated with acute-phase reactions to pathogens, whereas Th2 responses facilitate antigen elimination and disease recovery. It underscores the role of cytokines like interferon-gamma (IFNγ), produced by NK cells and Th1 cells, and IL-12 from dendritic cells in Th1 differentiation, while IL-4 is crucial for Th2 differentiation. These cytokines not only promote their own subset growth but also inhibit the development of the opposing subset, with Th1 cells enhancing immunoglobulin G2a synthesis and Th2 cells stimulating IgE and IgG1 production.
The broader context encompasses a variety of T-cell subsets, including cytotoxic T lymphocytes (CTLs), T helper (Th) cells, and regulatory T-cells (Tregs). Th cells are further subdivided into Th1, Th2, Th17, and Treg subsets, each characterized by distinct cytokine profiles and specific functions in immune regulation. Th1 cells a
