Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with no known cure. It is characterized by severe and persistent inflammation that damages multiple organs. To date, treatment and prevention of disease flares have relied on long-term use of anti-inflammatory drugs where side effects are of particular concern. There is a need for better understanding of the disease and for better approaches in SLE treatment and management. In this chapter, we delineate the roles of diet and microbes in the pathogenesis of SLE.
Keywords
- diet
- microbiota
- lupus
- hygiene hypothesis
- epigenetics
1. Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disorder with complex genetic and environmental etiology. It is characterized by severe and persistent inflammation that leads to tissue damage in multiple organs. The cause is unclear, and there is currently no cure. Current standard of care treatments for SLE are primarily nonselective immunosuppressants, and not all patients respond to these regimens. Although current therapies can treat acute symptoms and reduce the risk of renal failure associated with SLE, side effects are a major cause of concern. Patients taking long-term immunosuppressants are prone to higher incidence of and more severe infections. There is an imperative need to develop new treatment strategies against SLE, for which a better understanding of disease pathogenesis is required. In this chapter, we delineate the roles of diet and microbes in the pathogenesis of SLE.
2. The hygiene hypothesis
It is most remarkable, however, that multiple infections led to complete amelioration of lupus disease in two female patients previously diagnosed with the most active form of SLE [20]. Both women were of childbearing age, where pregnancy was found to be a trigger of lupus flares. In addition, their disease was refractory to all available treatments. Due to drug-induced immunosuppression, they experienced multiple infections over several months that included CMV and
Specifically for SLE, several studies have tried to pinpoint the mechanisms by which protective infectious agents prevent lupus-like disease in mice. In response to
3. Diet and SLE
Retinoic acid has many roles in the development of both innate and cell-mediated immunity. Exposure of antigen presenting cells (APCs) to retinoic acid is critical for cell development and establishment of normal cellular function, leading to an increase in co-stimulatory molecules and induction of the expression of CD11b, a critical adhesion marker, on murine splenocytes and human monocytes [34, 35]. Retinoic acid appears to have differential effects on the induction of immune responses. 9-cis retinoic acid decreases the production of IL-12 in macrophages. However, when combined with lipopolysaccharide (LPS), it augmented the production of nitric oxide, leading to promotion of the Th2 phenotype through regulation of cytokine production by APCs [34, 36, 37].
The development and differentiation of B and T cells are also influenced by the exposure to retinoic acid. Administration of retinoic acid contributes to increased CD19+ B cell numbers in the bone marrow and spleen, accelerated B cell maturation and increased expression of Pax-5, a transcription factor promoting early B cell development and expansion [33, 34]. Conversely, retinoic acid is reported by several groups to decrease mature B cell expansion by arresting B cells in the G0/G1 phase through increased expression of p27 (Kip1). This restricted proliferation may be necessary for the increased expression of CD38 leading to increased plasma cell numbers and production of IgG1 [34, 38–40]. Retinoic acid has also been reported to increase the proliferation of memory B cells when stimulated with the TLR9 ligand CpG and retinoic acid. Stimulation of B cells with both molecules led to a threefold increase in immunoglobulin secretion compared with cells stimulated with CpG alone [34].
Vitamin A deficiency has been associated with a decrease in CD4+ T cells, a decrease in the CD4+ to CD8+ ratio, decreased splenic germinal center formation, decreased total splenocytes, as well as splenic and thymus organ mass [41–43]. Deficiency of vitamin A also contributed to an increase in a Th1-driven immune response, with increased IFN-γ and IL-12 and a decrease in IL-5 and IL-10 production [41]. Administration of retinoic acid contributed to an increase in CD4:CD8 ratio and the promotion of a Th2-driven immune response with an increase in IL-5 production, while repressing IFN-γ and the Th1 response [37, 44]. The administration of a single dose of all-
Retinoic acid administration to MRL/lpr mice contributes to the sustained function of natural T regulatory (Treg) cells and promotes the differentiation of inducible Treg cells in the peripheral tissues [36]. Enhanced differentiation of T cells to Treg cells was shown in the small intestine lamina propria, as well as upregulation of gut-homing receptors on Treg cells by the binding of retinoic acid [36, 49]. There is discrepancy as to whether DCs or macrophages are the predominant cell type to induce Treg cell differentiation in the small intestinal lamina propria, while DCs are known to contribute to Th17 cell differentiation. It has been shown that human SLE patients exhibit a defective induction of Treg cells through TGF-β induction and retinoic acid expansion [37]. This impaired induction led to increased numbers of Treg cells with defective regulatory function abilities, causing the inducible Treg cells to be ineffective at controlling the autoimmune inflammatory response. The studies described above clearly show that cells of both the innate and adaptive immune system are regulated by vitamin A/retinoic acid. Therefore, it is conceivable that vitamin A and its metabolites may have an effect on patients suffering from SLE.
D3 decreases the expression of IL-2, IFN-γ and T cell proliferation in vitro, as well as decreasing CD8+ cytotoxic activity. It is important in the regulation of many genes, including IL-2 and IFN-γ in T cells, through interaction with the vitamin D receptor-RXR heterodimer. Similar to retinoic acid, D3 inhibits the induction of the Th1-mediated immunity response in favor of the Th2 phenotype, through enhancing the production of IL-4 and decreasing IFN-γ. The Th17 cell response is also mitigated by vitamin D through the inhibition of IL-6 and IL-23 production, leading to the promotion of the Treg cell phenotype through expansion of Foxp3 [51, 52].
It has not yet been determined if D3 acts directly on B cells to decrease B cell proliferation and induction of apoptosis. D3 is also associated with decreased plasma cell differentiation and a subsequent decrease in IgG secretion. In one study, the authors showed that D3 has the ability to upregulate p27 mRNA; however, p18 and p21 were not similarly upregulated in human purified B cells from patients with SLE. The p27 gene is associated with inhibition of the cell cycle, leading to decreased proliferation in activated human B cells, especially memory B cells [53].
Mouse models of SLE have shown decreased proteinuria and prolonged survival when supplemented with D3. A commonly used therapy for human SLE patients is the administration of glucocorticoids to reduce inflammation and to broadly dampen the immune response [54]. Glucocorticoids have been shown to decrease the expression of the vitamin D receptor in multiple cell types. Conversely, D3 interferes with both glucocorticoid receptor and androgen receptor responsiveness through reduced receptor expression and impaired translocation to the nucleus due to alterations in phosphorylation status [55]. When administered as a medication, D3 can lead to adverse effects, including hypercalcemia and bone resorption [48].
Though in vitro evidence strongly supports an immune-regulatory role of vitamin D and its metabolites in the adaptive immune system, there are conflicting reports regarding vitamin D deficiency in SLE patients and the supportive role of vitamin D supplementation. The majority of studies describe decreased serum levels of D3 in patients with SLE compared to healthy patients, which correlated with increased disease activity. The current consensus is that vitamin D serum levels correlate inversely with disease activity, and vitamin D deficiency is associated with increased disease activity or severity [51, 56].
Multiple studies in mouse models of SLE have shown that the dose of vitamin E had differential effects on the disease. Low-dose α-tocopherol increases the lifespan of NZB/W F1 mice while decreasing proteinuria, anti-dsDNA autoantibody IgG in the serum, IL-6 and IFN-γ production from splenocytes [60]. In the MRL/lpr mouse model, low-dose administration of vitamin E increases lifespan and IL-2 production. In contrast, high-dose vitamin E increases anti-DNA and cardiolipin IgM, as well as IL-4 and IL-10 from activated splenocytes. The authors conclude that the decreased survival in high-dose groups was due to the imbalance of Th1/Th2 cytokines, with Th2 cytokines leading to hyperactivation of the B cells in the MRL/lpr model [61]. Vitamin E also increases the pro-inflammatory chemokine MIP-1α in MRL/lpr mice, which activates granulocytes and promotes pro-inflammatory cytokine production [62]. A study comparing plasma antioxidant status between healthy patients and patients diagnosed with SLE showed that SLE patients have impaired plasma antioxidant status as well as a decreased antioxidant intake. The study was small and did not take into account dietary restrictions or food intolerance, limiting the ability to draw firm conclusions for a large set of SLE patients [58]. The above studies demonstrate that the dose of vitamin E is a critical determinant in amelioration or exacerbation of murine lupus. Response to vitamin E supplementation in human SLE patients needs to be thoroughly investigated to determine whether vitamin E supplementation is appropriate.
In a mouse study using NZB/W F1 female mice, higher on concentrations of EPA and DHA led to increased lifespan, decreased glomerulonephritis, decreased anti-dsDNA antibodies, as well as a reduction in pro-inflammatory cytokines IL-1β, IL-6 and TNFα in splenocytes, relative to controls. The authors also demonstrated a reduction in nuclear factor-κB (NF-κB) and p65 nuclear translocation in mice fed higher concentrations of both EPA and DHA [66]. In studies using the MRL/lpr mouse model, fish oil altered pro-inflammatory chemokine production, leading to a decrease in RANTES and MCP-1 from splenocytes [62]. In NZB/W F1 mice, omega-6 PUFAs, conversely, led to an increase in IL-6 and TNFα production as well as prostaglandin E2 from macrophages, a decrease in TGF-β mRNA from splenocytes and lower anti-dsDNA IgG in the serum [67].
There is evidence that n-3 PUFAs remodel the lipid rafts in T cells, which can lead to a decrease in intracellular signaling through the T cell receptor, as well as binding to multiple PPARs. Omega-3 PUFAs bind to PPARα in T and B cells, whereas they bind to PPARγ in cells of myeloid lineage, leading to alterations in gene expression. The binding capacity to PPARs by n-3 and n-6 PUFAs is equal, suggesting that gene modulation between the different families is unlikely, though the possibility exists for differences in cellular metabolism of n-3 and n-6 PUFAs to allow for distinct PPAR activation [65]. In certain instances, the evidence is contradictory between ex vivo and in vivo studies, and cytokine levels have been shown to be opposite in mouse models compared to human data [65]. While there is inconclusive evidence for the anti-inflammatory effects of n-3 PUFAs in human clinical trials, it is still recommended by some that rheumatic patients supplement their diet with long-chain n-3 PUFA and gamma linoleic acid [65].
Supplementation with CLA leads to a reduction in the loss of body mass during end-stage disease, along with an increase in survival after the onset of proteinuria in the NZB/W F1 mouse model [69, 70]. In a non-autoimmune mouse model and cell lines, CLA has a profound effect on macrophage functions. In BALB/c mice, CLA ameliorates LPS-induced body wasting and anorexia in vivo, decreases the production of nitric oxide from macrophages, and decreases the serum concentration of TNFα. Splenocytes from BALB/c mice fed the CLA supplement also have a lower level of IL-4 production and an increase in IL-2 production after stimulation with concanavalin A [71]. CLA also decreases macrophage adhesion as well as downregulating multiple atherogenic genes associated with leukocyte adhesion, while inducing the antagonist IL-1Rα in human umbilical cord vein endothelial cells and the RAW macrophage cell line [72].
CLA is able to exert immune-modulatory effects on dendritic cells and subsequent differentiation of T cells in mice. DCs produce multiple cytokines after activation and express MHC II on the cell surface to facilitate interactions with T cells and B cells. Exposure of DCs to CLA led to a decrease in IL-12 and an increase in IL-10 production, along with decreased migration to the lymph nodes [73]. CLA decreased the expression of MHC II and costimulatory molecules CD80 and CD86 on the surface of DCs, reducing the DC’s ability to trigger T cell and B cells responses [74]. When exposed to LPS stimulation in mice fed a CLA rich diet, serum levels of IFN-γ, IL-1β and IL-12p40 were decreased [75]. CLA decreases the ability of DCs to induce the T helper cell differentiation into Th1 and Th17 cells, as well as directly suppressing the production of IL-17 and IL-2 by Th17 cells [74]. The mechanism for CLA influencing the DC response after activation with LPS was shown to be through suppression of both NF-κB and IRF3 downstream of TLR4 [75]. The immune-modulatory effects have been well described in mouse models, though data for the effects of CLA in human SLE patients are lacking at this time.
The connection between obesity and the development of SLE is complex, and contradictory information exists among studies. There was no correlation found in Danish women between obesity and the incidence of SLE after 11 years [77, 78]. This cohort study had multiple limitations, such as reliance on survey questionnaires regarding pre-pregnancy weights and diagnoses, potential socio-economic bias with women of lower socioeconomic status being underrepresented in the Danish National Birth Cohort, and the confounding factor of pregnancy and childbirth during the study, which do not allow for conclusions to be drawn regarding the link between obesity and SLE [78]. Childhood obesity rates correlated positively with incidence of childhood-onset SLE. The adipokine leptin has been extensively studied and exerts multiple effects on the body [79]. Leptin promotes satiety and stimulation of energy expenditure, by acting on the hypothalamic nuclei, as well as contributing to fertility, bone metabolism and having a profound effect on the immune system. Lack of leptin, due to starvation, testosterone or glucocorticoids, can lead to immunosuppression, while upregulation of leptin by inflammatory cytokines or female sex hormones, 17β-estradiol and progesterone, can lead to inflammation [79]. Leptin can induce the production of IL-6, IL-12 and TNFα pro-inflammatory cytokines from macrophages, while stimulating the proliferation of naïve T cells and promoting a Th1 immune response. Leptin inhibits the production of Th2 cytokines IL-4 and IL-10, along with inhibiting T regulatory cell proliferation [80]. The formation of a pro-inflammatory state through increased leptin levels may contribute to autoimmune disease development.
Leptin is commonly elevated in obese patients as well as SLE patients, which contributes to the survival of autoreactive T cells, and a decrease in the functional T regulatory cells, while promoting the proliferation of Th17 cells in a mouse model of SLE [81, 82]. Circulating serum leptin levels as well as leptin secretion have been shown to be higher in females compared to males, both in obese and non-obese subjects. The sex difference in leptin secretion may be a contributing factor in the development of female-predominant SLE. Leptin deficiency in murine models of SLE has led to decreased anti-dsDNA and a decrease in severity of SLE symptoms [83, 84]. The increased level of circulating leptin may also contribute to the exacerbation of cardiovascular damage in some SLE patients [85, 86]. Adiponectin deficiency was correlated with an increase in SLE disease severity [87, 88]; however, another study found increased levels of adiponectin in the serum and urine of human patient with lupus nephritis [89]. Little information is available regarding other adipokines and their involvement with SLE development.
Obesity is correlated with a predisposition to metabolic syndrome, with increased rates of hypertension, dyslipidemia and atherosclerosis, as well as subsequent cardiovascular disease. Atherosclerosis and cardiovascular disease are highly prevalent in patients with SLE, and a significant number of patient deaths occur due to cardiovascular disease, while obesity has been linked to worsening renal disease and cardiovascular disease in patients suffering from SLE [77]. High levels of inflammatory markers and elevated leptin concentrations found in SLE patients, and mice have been correlated with decreased cognitive function, increased renal damage and increased cardiovascular risks [90, 91].
Diets high in salt (sodium chloride) are found in multiple regions throughout the world, mainly in developed countries where processed foods and “fast food” are prevalent. Excess sodium intake has been attributed to cardiovascular disease and hypertension, as well as stroke, and is now being studied in the development of autoimmune diseases [76]. T cells in a hyperosmotic environment show an increase in p38/MAPK as well as transcription factor NFAT5, leading to an altered cellular response [92]. Sodium can be stored in the human body in various tissues, leading to hyper-osmotic environments in multiple tissues during high-dietary salt intake. Human and murine T cells were investigated under high salt conditions
Phytoestrogens are plant compounds that exert an estrogenic or an anti-estrogenic effect on the human body through interaction with both estrogen receptor α and β, with a preferential binding to ERβ [97]. Phytoestrogens can also block the binding of more potent estrogenic compounds to the ER and regulate target genes. Many types of phytoestrogens are found naturally, with soy-based phytoestrogens, isoflavones, present in many of the foods consumed in industrialized societies. Due to the ubiquity of phytoestrogens in normal diets, controlled human trials are lacking with regard to the specific effects of phytoestrogens on SLE disease development. Data from mouse experiments involving supplementation of isoflavones to MRL/lpr mice show a decrease in IFN-γ from splenocytes with a decrease in anti-dsDNA and cardiolipin levels in the serum, along with a reduction in proteinuria and renal damage through preferential binding of the ERβ [98]. Exclusion of dietary isoflavones through diets using casein as the protein source rather than soy led to amelioration of glomerulonephritis [99]. Alfalfa sprout extract supplementation to MRL/lpr mice produced similar results with decreased renal damage and increased survival, while decreasing IFN-γ and IL-4 production by splenocytes. Alfalfa sprout extract was also able to reduce TNFα, IL-6 and IL-1β pro-inflammatory cytokines in a mouse model of endotoxic shock [100]. Coumestrol, one phytoestrogen in alfalfa, was able to decrease anti-dsDNA IgG and decrease proteinuria in the NZB/W F1 mouse model [101]. However, these findings have not been observed in human SLE patients, where ingestion of alfalfa tablets, which contain all phytoestrogen components of the alfalfa plant, exacerbated disease severity [102].
Multiple phytoestrogens have been shown to upregulate VDR expression in various human cell lines. Genistein and glycitein upregulated VDR transcription and translation in colon cancer cells, while resveratrol and genistein also increased VDR expression in breast cancer cells [103, 104]. Along with receptor expression, genistein decreased CYP24, an enzyme responsible for metabolism of the vitamin D metabolite D3 [105]. Phytoestrogens are abundant in many diets throughout the world and are able to contribute to the modulation of the immune system through interaction with estrogen receptors, potentially ameliorating or exacerbating patients’ clinical signs.
4. The role of gut microbiota
The host’s genetic make-up is the primary factor in determining the composition of one’s adult microbiota. Other contributing factors include mother’s health in utero, the method of delivery during birth, if one is either breast fed or fed formula, the use of antibiotics during early childhood and types of foods consumed prior to, and during, weaning. The adult microbiota is not a static entity, however, and can be modified through many different environmental factors, and the composition will also change with age. Many of the previously discussed contributions to SLE are associated with alterations in the microbiota. Obese patients have an increased
Murine studies on how the microbiota affects the immune system have emerged recently. At the level of the intestinal lamina propria, bacteria compete with host defenses and establish homeostasis. T cells are kept in check between pro-inflammatory Th1, Th2 and Th17 cells as well as innate lymphoid cells, and the anti-inflammatory T regulatory cells [118–120]. Specific bacterial groups can elicit distinct immune responses, as evidenced by mice colonized with segmented filamentous bacteria developed elevated levels of Th17 cells in the lamina propria [121, 122]. Colonization of previously germ-free mice with clostridial strains from cluster IV and XIVa resulted in an expansion of the T regulatory cell population in the lamina propria and systemically [123]. Polysaccharide A derived from
There have been few human trials to determine the impact on intestinal microbiota specifically on SLE development. In 20 human SLE patients in remission compared to healthy controls, a decreased
5. Bacterial metabolites and mechanisms of action
In addition to their initial relevance in cancer biology [151], HDAC enzymes are now increasingly being investigated as regulators of inflammation and immunity [147]. As reviewed by Shakespear et al., HDACs are documented to play a role in myeloid development, toll-like receptor (TLR) and interferon (IFN) signaling in innate immune cells, antigen presentation and development and function of B and T lymphocytes [147]. Subsequently, pharmacologic inhibition of HDACs has been evaluated as a possible treatment modality in a wide spectrum of diseases, including inflammatory and autoimmune diseases [152].
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