Inflammation is an integral part of autoimmune diseases, which are caused by dysregulation of the immune system. This dysregulation involves an imbalance between pro-inflammatory versus anti-inflammatory mediators. These mediators include various cytokines and chemokines; defined subsets of T helper/T regulatory cells, M1/M2 macrophages, activating/tolerogenic dendritic cells, and antibody-producing/regulatory B cells. Despite the availability of many anti-inflammatory/immunomodulatory drugs, the severe adverse reactions associated with their long-term use and often their high costs are impediments in effectively controlling the disease process. Accordingly, suitable alternatives are being sought for these conventional drugs. Natural products offer promising adjuncts/alternatives in this regard. The availability of specific compounds isolated from dietary/medicinal plant extracts have permitted rigorous studies on their disease-modulating activities and the mechanisms involved therein. Here, we describe the basic characteristics, mechanisms of action, and preventive/therapeutic applications of 5 well-characterized natural product compounds (Resveratrol, Curcumin, Boswellic acids, Epigallocatechin-3-gallate, and Triptolide). These compounds have been tested extensively in animal models of autoimmunity as well as in limited clinical trials in patients having the corresponding diseases. We have focused our description on predominantly T cell-mediated diseases, such as rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, ulcerative colitis, and psoriasis.
Chronic inflammation is an integral component of autoimmune diseases, which are caused by dysregulation of the immune system, such that the host mounts an immune response to body’s own component proteins and/or cells [1,2,3,4,5]. A variety of anti-inflammatory and immunomodulatory drugs are available for these disorders [6,7,8,9,10]. However, prolonged use of these drugs, which is necessary to keep persistent autoimmune reactivity in check, is frequently associated with severe adverse reactions and unavoidable high expense for the drugs. Newer drugs, such as biologics, may cause unintended systemic immune suppression, which increases the risk of severe infections and possibly, certain malignancies [6,7,10]. Furthermore, a proportion of autoimmune patients, for example, about 30–40% in case of rheumatoid arthritis (RA), fail to respond well to these drugs [11]. For these reasons, increasing proportion of patients with autoimmune diseases are resorting to the use of natural products [12,13,14]. Most popular among these products are plant-derived natural products, which have been part of various traditional systems of medicine across the world. Traditional Chinese medicine (TCM), Ayurvedic medicine, and indigenous African medicine are examples of such systems [11,13,14,15,16,17,18,19].
Accordingly, a variety of plant extracts and their bioactive components have extensively been studied for their anti-inflammatory and immunomodulatory activities, and for their applications in the treatment of autoimmune diseases [12,13,14]. These natural products are first tested in various animal models of autoimmunity and subsequently in limited clinical trials in patients with those diseases. In this article, we have focused our discussion to 5 purified compounds derived from plant extracts. These include, Resveratrol [19,20,21,22,23,24,25,26], Curcumin [12,27,28,29,30,31], Boswellic acids [15,16,32,33], Epigallocatechin-3-gallate (EGCG) [34,35,36,37,38,39,40], and Triptolide [18,41,42,43,44,45,46].
We have described below the effects of these natural products on inflammation in predominantly T cell-driven autoimmune diseases: rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), ulcerative colitis (UC; colitis), and psoriasis. For space constraints, limited number of studies for each natural product compound are discussed below.
Autoimmune diseases are manifestations of a series of events that involve an interplay between genetic and environmental factors, leading to a breakdown of self-tolerance and activation of potentially self-reactive T cells [4,5,47,48,49]. In healthy individuals, such T cells exist in the mature T cell repertoire, but their activation is kept in check by a variety of peripheral tolerance mechanisms [50]. These mechanisms include, T cell ignorance, lack of co-stimulation, activity of different types of regulatory T cells, and others [51,52]. A failure of these mechanisms results in uncontrolled activation of T cells directed against various self-antigens implicated in different autoimmune diseases [53]. These activated T cells then stimulate macrophages and/or provide help to the B cells, leading to propagation of anti-self immune responses. A variety of cytokines, chemokines and biochemical mediators of inflammation released by these immune cells trigger cascades of inflammatory pathways, tissue damage and dysfunction, and clinical manifestations [53,54]. Autoimmune diseases can either be organ-specific or systemic. Rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), ulcerative colitis (colitis) (a component of inflammatory bowel disease or IBD), and psoriasis are examples of major human autoimmune diseases [55,56,57,58,59,60] (Table 1). The organs most affected in these diseases include the synovial joints in RA, the central nervous system (CNS) in MS, the pancreatic β-islets in T1D, colon in UC, and skin in psoriasis [57,58,60,61,62]. In addition, there may be varying levels of effects on other organs, as commonly observed in RA.
Salient features of the major T cell-mediated human autoimmune diseases.
The precise etiology of autoimmune diseases is not yet fully known. It is clear that there is genetic susceptibility to several autoimmune diseases [49,65]. The major histocompatibility complex (MHC) locus is one of the important genetic factors in this regard (Table 1). There also is evidence for environmental factors, among which microbial infections are considered to be of high significance [5,65]. Microbes can contribute to the activation of self-reactive T cells via different mechanisms, including upregulation of co-stimulation in antigen-presenting cells (APCs), enhanced processing of certain antigenic determinants under inflammatory conditions, and antigenic mimicry (e.g., conformational/sequence resemblance) between microbial and host antigenic determinants (molecular mimicry) [55,56,59,63,69]. The pathogenic T cells in autoimmune diseases target subsets of self-antigens. Multiple self-antigens have been implicated in each of the above-mentioned autoimmune diseases (RA, MS, T1D, colitis and psoriasis) [57,58,60,61,62,66,67,68,70] (Table 1).
Naïve T cells that are activated by a particular self-antigen can acquire different phenotypes depending on the local milieu, particularly the type of cytokines present. Accordingly, naïve T cells can differentiate into distinct T helper (Th) type, such as Th1 or Th17 cells, which can mediate pathogenic effector functions [53,71,72]. Under another set of conditions, a naïve T cell can develop into Th2 or T regulatory cells (Treg), which can control the activity of pathogenic Th cells [53,64]. The Th cells secrete prototypic cytokines and express a distinct transcription factor [72]. Among the cytokines, interferon-γ (IFN-γ) and IL-17 are shown to promote inflammation, whereas IL-4 and IL-10 inhibit inflammation [52]. An imbalance between pro-inflammatory and anti-inflammatory cytokines, as well as that between pathogenic (Th1/Th17) and protective (Th2/Treg, respectively) T cells have been reported in various autoimmune diseases [64,73,74]. A similar imbalance can occur in macrophage subsets, such as pro-inflammatory M1 macrophages versus anti-inflammatory M2 macrophages; in dendritic cells (DCs), such as activating DCs versus tolerogenic DCs; and in B cells, such as antibody-producing B cells versus regulatory B cells that secrete IL-10 (known as B10 cells) (Figure 1). Accordingly, a deliberate re-setting of the balance between these cytokines (e.g., IFN-γ/IL-4 balance) and immune cell subsets (e.g., Th17/Treg balance) is one of the approaches under development for the treatment of these diseases [75]. This principle is also being exploited by using natural products compounds (Figure 1).
Immunomodulation by natural product compounds involves an altered balance between subsets of diverse immune cell types. The corresponding pathogenic (pro-inflammatory) (Right panel) versus protective (anti-inflammatory/immunomodulatory) (Left panel) immune cell subsets are shown: Th1 vs. Th2, Th17 vs. Treg, M1 vs. M2, activating vs. tolerogenic DC, and antibody-producing vs. regulatory B cells, respectively. (Abbreviations (Top to bottom)): Th = T helper cell; Treg = T regulatory cells; M1 = M1-type macrophage; M2 = M2-type macrophage; DC = dendritic cells (Right panel, activating DC; Left panel, tolerizing DC); B10 = B cells secreting IL-10 (a regulatory B cell subset); B cell = activated B cell for antibody production.
A dysregulation of cytokines and Th cells in turn can influence B cell activation and the type of antibody isotype produced. Thus, both cellular and humoral arms of the immune response can be affected in this manner. For simplicity, autoimmune diseases may be classified as T cell-mediated or antibody-mediated, but in reality, the disease manifestation involves the contribution of both arms of the immune system to different extents. For example, T1D is characterized by anti-insulin antibodies. In RA, rheumatoid factors (RFs) have long served as a disease marker, but their pathogenic significance is not fully validated. However, there is a correlation between smoking and RA, which involves anti-citrullinated protein antibodies (ACPAs). Here, smoking has been invoked in inducing citrullination, a type of post-translational modification, of certain self-antigens in which an arginine residue is converted into citrulline [76]. This renders that protein immunogenic because the host is tolerant to the native protein, but not to the same protein containing citrulline. Post-translational modification of antigen has also been implicated in the pathogenesis of T1D [77].
Understanding of the disease process in autoimmunity has been aided significantly by studies in animal models (Table 2). These models have also been the mainstay of testing of new drug candidates. There is no single animal model that can fully replicate all clinical features of a particular human autoimmune disease. Different rodent models are available for these diseases [57,58,60,61,62,68,78,79,80] (Table 2). Of these, some are experimentally induced, while others are spontaneous in origin. These include, for example, adjuvant-induced arthritis (AA) and collagen-induced arthritis (CIA) for RA; experimental autoimmune encephalomyelitis (EAE) for MS; non-obese diabetic (NOD) mice for T1D, chemical, spontaneous or T cell transfer models of colitis for ulcerative colitis (UC), and Imiquimod-induced psoriasis [57,58,60,61,62,68,78,79,80] (Table 2). Predominantly T cell-driven effector mechanisms are operative in these human autoimmune diseases.
Animal models of the major T cell-mediated human autoimmune diseases.
The progression of initial autoimmune reactivity to subsequent clinical disease involves inflammation driven by multiple cellular and molecular mediators [53,54,81]. The role of the T cells, macrophages and B cells is briefly discussed above. Various biochemical (e.g., leukotrienes) and immunological (e.g., cytokines) mediators released by these cells, along with others (e.g., complement components), lead to autoimmune inflammation. When uncontrolled, such inflammation can lead to tissue damage and dysfunction. Thus, the control of inflammation is one of the main tenets of treatment of autoimmunity. In this regard, we have described below 5 representative natural product compounds that have extensively been studied for controlling inflammation and re-setting the imbalanced immune system in autoimmune diseases. These include, Resveratrol [19,20,21,22,23,24,25,26], Curcumin [12,27,28,29,30,31], Boswellic acids [15,16,32,33], Epigallocatechin-3-gallate (EGCG) [34,35,36,37,38,39,40], and Triptolide [18,41,42,43,44,45,46]. A summary of these is presented below (Table 3), which also lists the biochemical molecules and pathways targeted by these 5 natural product compounds. The biochemical pathways themselves are outlined in Fig
