Dietary practices can influence immune tolerance and disease. Indeed, dietary components, including micronutrients and macronutrients, can affect both innate physical defenses such as epithelial barrier integrity (61–64), antimicrobial peptides (65), and pro/anti-inflammatory cytokines (66–68), as well as adaptive immune cell functionality (69–72). The high incidence of immune-mediated diseases such as autoimmune and allergic disorders in the Western world, where common themes of dietary behaviors exist including increased caloric (fat and carbohydrate) intake with much less fibers and imbalanced dietary fatty acid consumption, pinpoint the immunomodulatory capacities of these macronutrients and their potential causal implications on autoimmune development (47). In contrast, dietary patterns that are mostly plant-based such as Mediterranean or DASH diets have been shown to contain anti-inflammatory and antioxidant components (73, 74) that could impose protective effects against autoimmunity (75). Among these, plant-derived phytochemicals including polyphenols (76) such as flavonoids (77–79) and isoflavones (80, 81) have been extensively investigated for healthful modulation of autoimmunity.

To this end, the upside of the COVID-19 pandemic is its impact on the unprecedented dietary shifts to less processed and more plant-based dietary sources (82). Interestingly, plant-based diets are associated with lower odds of moderate-to-severe COVID-19 and may provide protective support against severe COVID-19 infection (83). Indeed, such dietary trends with COVID-19 emergence can not only benefit to restrain COVID-19 infection in normal people but also be supportive strategies for the vulnerable populations with autoimmune conditions. For example, quercetin is a natural flavonoid derived from different plant sources that has various anti-inflammatory and antioxidant immunomodulatory capacities (84, 85). Based on pharmacology and molecular docking, quercetin has been proposed as a potential protective treatment against acute renal injury, one of the most serious complications reported in hospitalized patients with COVID-19 infection (86–88). At the same time, quercetin has been shown to attenuate various autoimmune pathologies in human and murine rheumatoid arthritis (RA) (89–92), and in experimental models of inflammatory bowel diseases (IBD) (93, 94) and SLE (95). In the following section, we review how different micronutrients and macronutrients modulate immune health and autoimmune outcomes and discuss the potential advantageous roles of dietary manipulation in mitigating the risks of COVID-19 infection in autoimmune patients.

Vitamins have important functions in maintaining immune health through their antioxidant capacities (97). There is a huge body of literature supporting the notion that oxidative stress plays a crucial role in autoimmune pathogenesis (98–100). For instance, oxidative degradation of lipids that occur in the cellular membrane in a process known as lipid peroxidation is mediated by free radicals (101, 102), which could impair the integrity of the cell membrane (103), induce cellular death (101) and accumulate apoptotic products, subsequently initiating autoimmunity (104–106). In addition, intracellular oxidative signaling could increase the responsiveness of autoreactive immune cells such as T lymphocytes and drive their autoimmune pathogenicity (107). Moreover, the extracellular release of oxidative products including reactive oxygen species (ROS) and proteases by innate immune cells such as neutrophils could initiate autoreactivity and lead to collateral tissue damage (108). Interestingly, oxidative stress has also been proposed to be associated with COVID-19 pathogenesis (109–111). Therefore, antioxidant vitamins could provide potentially beneficial supportive care for autoimmune patients with COVID-19. Here, we review the immunomodulatory functions of vitamins E, A, and D in autoimmunity and discuss their potential implications in COVID-19.

Vitamin E (VE) as an antioxidant can diminish the secretion of ROS (e.g., by monocytes) (112), thereby protecting against oxidative cell stress and indirectly maintaining immune cell functionality. Therefore, it has been suggested that the relative deficiency of VE could initiate autoimmunity (113). Although data from human studies are not conclusive—where some reports showed that VE levels were increased in patients with systemic autoimmunity of primary Sjögren’s syndrome (114), while others correlated VE deficiency with the development of neurological complications of celiac disease (115) or showed no difference in VE levels in patients with IBD (116)—murine studies more decisively support the potential beneficial effect of VE in the treatment of autoimmune conditions such as RA (117, 118). Importantly, based on data from murine lupus, VE is proposed as a safe treatment option for SLE (119, 120) where the supplementation reduces hallmarks of SLE such as the levels of anti-double-stranded DNA (anti-dsDNA) IgG antibodies (121) and counteracts oxidative stress (and lipid peroxidation) that would otherwise contribute to more debilitating SLE manifestations (122, 123). In human studies, VE supplementation as part of a treatment regime improved the oxidative and nitrosative biomarkers and disease activity in SLE patients (124).

Vitamins A and D (VA and VD, respectively) are known to modulate the differentiation of immune cells, their tissue homing, and effector functions. On the innate arm, VD and VA have context/tissue-dependent functions that may antagonize each other. VD has been shown to mitigate the maturation of DCs, inhibiting their expression of maturation markers MHCII and CD80/86 (125), as well as reducing their production of the pro-inflammatory cytokine IL-12 (126), collectively inducing the tolerogenic phenotype of DCs (127, 128). In contrast, VA has context-dependent effects on DCs. Although VA is a key player in the induction of mucosal tolerance (129), it can also enhance DC maturation and their antigen-presenting capacities in the presence of pro-inflammatory stimuli (130). In addition, VA can increase the expression of matrix metalloproteinase-9 (MMP9) to enhance the migration of inflammatory DCs to lymph nodes (131). Together, these immunomodulatory capacities of VD and VA could represent a tango for in-vivo tuning of DC functions. Importantly, since DCs could modulate self-tolerance and the development of autoimmune disease such as SLE as we previously reviewed (132), VD (133)-, and VA (134, 135)-mediated regulation of DC function could indirectly impact the development of tolerance and disease. On the adaptive arm, both VD and VA can affect the differentiation of T cell subsets, including T helper (Th)1 (proinflammatory) vs. Th2 (anti-inflammatory), and T regulatory (Treg; immunosuppressive) vs. Th17 (proinflammatory) as depicted in Figure 2 . For example, VD (67, 125, 136–138) and VA (139–141) have been shown to inhibit Th1 differentiation and responses while supporting the development and responses of Th2 lymphocytes. In addition, both VD (142, 143) and VA (144–146) potentiate the development of Treg over Th17. Importantly, the imbalance between these different T cell subsets is a driving force for autoimmune development (147, 148).

Ecological associations between low VD levels and the incidence of different autoimmune conditions such as IBD, MS, T1D, and RA have been reported in areas with limited sun exposure (149–151). It is widely hypothesized that deficiency of VD is associated with the development of different autoimmune conditions where polymorphism in VD receptors (VDR) are implicated among the causal risks for autoimmune conditions including AITD (152, 153), T1D (154), MS (155), RA (156) and SLE (157). In addition, VD deficiency is associated with more aggravated autoimmune flares in SLE (158–161) by promoting memory B cells responses (162) and subsequent autoantibody production (163). These observations strengthen the potential use of VD supplementation to control autoimmune disease (164). Importantly, plasma (165) and serum (166) levels of VD have been shown to be depleted in COVID-19 patients. Additionally, low levels of VD are also correlated with the severity of COVID-19 progression in those patients (166). Meanwhile, VD supplementation during or just before COVID-19 contraction can mitigate disease progression and enhance the survival rate in infected patients (167). Together these reports support the potential healthful effect of VD in autoimmune patients to combat COVID-19 severity and fatality.

In contrast, it remains to be determined if VA deficiency or polymorphisms in VA receptors are causally associated with autoimmune development. Although serum retinol levels have been negatively correlated with MS activity (168), and hypovitaminosis A has been detected proceeding the clinical diagnosis of SLE (169, 170), it is still to be elucidated whether VA deficiency is a driving factor for autoimmunity. Due to their immunomodulatory capacities, retinoids have been proposed as potentially beneficial adjuvants controlling autoimmune disorders (171). The most active metabolite of VA, all-trans-retinoic acid (tRA), has been shown to control pathogenic T cell subsets such as IL-17 secreting γδ T cells and sufficiently ameliorate experimental autoimmune encephalitis (EAE), a murine model of MS. Similarly, we and others have shown the protective effects of VA on murine SLE especially during the active stage of the disease (172–174). In future investigations, we propose to (1) investigate the potentially detrimental effects of VA deficiency on the progression of renal inflammation in genetically-prone SLE, and (2) delineate the molecular and transcriptional mechanisms by which hypovitaminosis A promotes systemic autoimmunity. Importantly, a recent study conducted in hospitalized COVID-19 patients with respiratory failure showed that serum retinol levels were significantly lower compared to healthy controls (175). This report’s findings support the idea that COVID-19 infection is associated with retinoic acid depletion syndrome (176) and that VA supplementation might be a beneficial approach especially in areas of limited medical resources (177). Therefore, considering its complex roles in modulating autoimmunity, VA might be a crucial element to be considered for monitoring and supplementation as needed for autoimmune patients with COVID-19 infection.

It is important to note that for clinical applications, optimal levels of these vitamins as combinations may be crucial for achieving the harmony of their action. Future investigations on the vitamins’ modulation of autoimmunity as an overlapping circuit rather than solo-induced effects will shed more light on their therapeutic potential in clinical settings.

Minerals, or specifically trace elements such as selenium, copper, and zinc, modulate immune functions in various indirect ways. Generally, minerals can have antioxidant capacities and consequently maintain the structural integrity of essential biological molecules (e.g., maintaining cell membrane stability) (178), participate in enzymatic activities (179), and potentiate energy production and use during cellular metabolism (180). Importantly, some trace elements are needed to facilitate cell signaling (181, 182), where their binding to target ligands/receptors regulates essential processes including gene expression and protein synthesis (183, 184). Selenium, for example, acts as an antioxidant, eliminating free radicals and subsequently maintaining immune system functions (185). It also has catalytic activities and is essential for the enzymatic activity of glutathione peroxidase to inhibit lipid peroxidation (186). This is particularly important for protecting cell membrane phospholipids, consequently maintaining cell membrane structure and preventing oxidative mitochondrial damage in immune cells such as macrophages (187–189). Therefore, selenium deficiency is associated with increased inflammation (190, 191) and autoimmunity as in celiac disease and AITD (192). Similarly, meta-analysis of genome-wide association studies (GWAS) have predicted high selenium levels to be associated with a decreased risk for SLE (193). Indeed, selenium supplementation in murine models of SLE has been shown to improve survival (194) and mitigate various hallmarks of the disease including splenomegaly and autoantibody production (195). In addition, a recent cohort study has shown that severe COVID-19 patients exhibit a pronounced deficit in total serum selenium and selenoprotein levels, and that selenium status is significantly higher in COVID survivors compared to non-survivors, suggesting the therapeutic potential of selenium supplementation in severely diseased and/or selenium-deficient COVID-19 patients (196).

Aside from these non-specific immunomodulatory capacities, minerals can directly modulate both innate and adaptive immune cell activities and be involved in the activation of key signaling molecules such as NF-κB. Zinc, for example, can be both pro- and anti-inflammatory and plays an essential role in maintaining both innate and adaptive cellular responses (197). Zinc promotes NF-κB signaling and subsequently the production of pro-inflammatory cytokines from macrophages (198, 199). The utilization of zinc by macrophages enhances their phagocytic activities (200, 201). Therefore, lower circulatory levels of zinc could be linked to macrophage-related autoimmune diseases such as RA (202). Meanwhile, zinc can also induce tolerogenic DCs in both in-vivo and in-vitro settings (203). Thus, zinc deficiency could compromise the interface between innate and adaptive immunity leading to skewing of Th cell balance (203). Zinc is essential for T lymphocyte proliferation (204) and activation (205) through promoting IL-2 signaling. It also promotes the upregulation of IL-12 signaling and Th1 transcription regulator T-bet (206). Consistently, zinc deficiency reduces the levels of Th1-polarizing cytokines (e.g., IFNγ) (207). Therefore, a shift of Th1/Th2 balance to Th2 has been linked to zinc deficiency. However, zinc can enhance the differentiation of Treg cells through upregulating FOXP3, where it increases the phosphorylation of Smad proteins, allowing for its binding to the Foxp3 promoter (208). Furthermore, zinc can suppress Th17 differentiation through inhibiting signal transducer and activator of transcription 3 (STAT3) signaling (209) as well as memory Th17 responses via inhibition of the IL-1β/IL‐1 receptor‐associated kinase 4 (IRAK4) phosphorylation (210). Thus, zinc can benefit by tuning T cell-driven autoimmunity as shown in EAE (211, 212). In human studies, lower systemic zinc levels have been reported in different autoimmune conditions (213) including MS (214) and SLE (215, 216). Interestingly, COVID-19 patients also have lower zinc levels that are correlated with disease complications and prolonged hospital stays (217). Together, these studies warrant further investigation on the immunomodulatory capacities of zinc in autoimmune and/or other high-risk patients for COVID-19.

In summary, micronutrients are essential for fine-tuning the development and function of immune cells. Altered homeostasis of micronutrients as seen in various autoimmune diseases could critically influence immunity and promote autoimmune dysregulations.

It is noteworthy that although evidence-based findings are still being uncovered on the causal relationship between micronutrient deficiencies and more severe COVID-19, as well as the potential healthful effects of micronutrients on COVID convalescence, the immunomodulatory functions of micronutrients may support their roles in combating COVID-19 infection (218–220). Therefore, for autoimmune patients in the COVID-19 pandemic, the potential benefits of micronutrients as discussed above urge for regular monitoring of their levels and if deemed necessary, supplementations in individuals with specific micronutrient deficiencies.

Dietary carbohydrates are usually in the form of polysaccharides, oligosaccharides (e.g., fructo-oligosaccharides), disaccharides (e.g., lactose), and monosaccharides (e.g., glucose and fructose) (226). Carbohydrates, especially non-digestible polysaccharides and oligosaccharides (e.g., in prebiotics), exert both direct and indirect immunomodulatory capacities. Indirectly, they act as a source of energy for gut microbiota which, in turn, could modulate immune responses via different mechanisms as previously reviewed (227, 228). Directly, they could modulate both innate and adaptive effector immune functions involving epithelial tight junctions, cytokine/chemokines, and antibody production as reviewed elsewhere (229). Indeed, dietary polysaccharides are sensed by different immune cell receptors including complement receptor 3 (CR3), Toll-like receptor (TLR) as well as dectins (carbohydrate-binding proteins) (230); subsequently, they act as immunogens to stimulate immune responses. Notably, plant polysaccharides can be the interface linking innate and adaptive immune cell activation. They primarily stimulate the proliferation and activation of innate cellular components such as natural killer (NK) cells (enhancing their cytotoxic activities) and macrophages (augmenting their production of TNFα and IL-6 as well as their lysosomal activities and nitric oxide production) (231). In turn, these innate components activate their adaptive counterparts, inducing Th cell differentiation and antibody production from B cells as previously detailed (231).

The effector functions of immune cells rely primarily on glucose (232). Therefore, it is not surprising that high carbohydrate intake could exacerbate the hyperactivation of immune cells in chronic inflammatory and autoimmune conditions. Indeed, modern diets containing high levels of processed fructose-rich carbohydrates increase the incidence of chronic inflammation (233, 234). High glucose intake augments ROS-dependent activation of TGFβ and consequently the induction of Th17, thereby exacerbating autoimmune conditions as reported in murine models of MS (i.e., EAE) and colitis (235). In addition, excessive carbohydrate intake increases the levels of circulatory inflammatory markers such as IL-6 and C-reactive proteins (CRP) in SLE patients (236). In contrast, natural glucose derived from plant-based carbohydrates such as cell wall-based cellulose (which is an insoluble fiber and composed of unbranched β-1,4-linked glucose monomers) has been shown to reduce the frequency and number of pro-inflammatory T cells and promote autoimmune suppressive Th2 responses in EAE (237). These findings illustrate the pivotal effects of dietary carbohydrates on immune cell functions and warrant further investigations towards more mechanistic insights with a specific emphasis on autoimmune modulation.

It is also crucial to maintain a balance between carbohydrates and other macronutrients including dietary fats and proteins. Although plant-based lipids (e.g., phytosterol from vegetable oils) could beneficially modulate autoimmune inflammation as reported in EAE (238, 239), it is controversial how fat-modulated diets precisely shift immune responses and subsequently autoimmune progression. If only the level of fat consumption is changed, reduced dietary fat levels increase the proliferation of human peripheral blood mononuclear cells (PBMCs) following both mitogens and inflammatory cytokine stimuli (240), suggesting better responses to pathogenic invaders (241). However, recent studies propose that ketogenic diets of low carbohydrate and high fat intake potentiate more protective γδ T cell responses against infectious triggers (242). This emphasizes the importance of considering the levels of all macronutrients together when assessing immune modulation under steady-state conditions.

Under autoimmune conditions, on the other hand, a large pool of evidence proposes that a high-fat diet (HFD) adversely impacts the immunopathogenesis of different autoimmune diseases as widely investigated in SLE (243). For example, high fat intake resulted in defective phagocytic and cytotoxic activities of macrophages and NK cells, respectively, and this was associated with earlier onset and exacerbated autoimmunity in lupus-prone NZB/W F1 mice (244). In addition, HFD further increased TLR7 expression and signaling in TLR8 knockout mice (a spontaneous murine lupus model characterized by increased TLR7 signaling) leading to exacerbated kidney inflammation due to increased production and renal deposition of autoantibodies (245). Furthermore, HFD-induced obesity increased the T follicular helper (Tfh) cell activity in MRL/lpr mice and consequently the activation of B cells, exacerbating SLE-associated splenomegaly and potentiating IgG production and their glomerular deposition (246). In contrast, a low-fat, isoenergetic diet designed to provide no more than 20% energy from fat a day, together with supplementation of 1 g of fish oil, effectively attenuated disease activity in SLE patients (247). Although it is yet to be tested whether high fat/low carbohydrate ketogenic diets are beneficial in SLE patients, a potential positive effect of ketogenic diets has been reported for some autoimmune patients with MS (248) or T1D (249). Interestingly, a ketogenic diet may also provide supportive care for COVID-19 patients (250), reducing their need for the intensive care unit (251). This again emphasizes the importance of considering the levels of all macronutrients together on immune modulation under autoimmune status and highlights the importance of personalized care plans for autoimmune individuals with COVID-19 infection.

Not only the quantity but also the type of consumed fat could differentially affect the immunopathogenesis of autoimmunity. Dietary fats could be in the form of saturated fat, trans-fat and unsaturated fat. Increased intake of saturated fat accelerates the disease relapse in children with MS (252). Increased consumption of trans-fat increases the levels of free radicals that damage the integrity of immune cell membranes and contribute to autoimmunity (243). In contrast, the incorporation of Mediterranean diets that significantly increases the ratio of unsaturated to saturated fats has been linked to improved autoimmune pathologies (e.g., alleviating RA symptoms) (253). Notably, a diet rich in polyunsaturated fatty acids (PUFA) can improve the overall clinical scores and elicit anti-inflammatory effects in SLE (254). Similarly, a recent report has shown a negative correlation between adherence to Mediterranean diets and COVID-19 cases in Spain and other countries (255), supporting a potential protective role of PUFA-rich Mediterranean diets against COVID-19 (256, 257).

Indeed, supplementation of PUFA such as omega-3 (ω−3) augment the activities of antioxidant enzymes and diminish autoimmunity (243). Several studies have shown that ω−3 enriched diets dramatically reduce SLE-associated inflammatory markers, lupus progression (mitigating glomerulonephritis) and improve survival in different mouse models of SLE (258–262). This is achieved mostly through potentiating the effects of antioxidant enzymes (such as superoxide dismutase and glutathione peroxidase) which, in turn, potentiate the ability of renal cells to eliminate harmful free radicals (e.g., reactive oxygen intermediates) (259, 261). Moreover, a diet rich in ω−3 (e.g., with fish oil) reduces the level of anti-dsDNA antibodies (258, 261), circulating immune complexes, and their renal deposition (258). Furthermore, fish oil can reduce the expression of renal pro-inflammatory cytokines including IFNγ, IL-12, TNFα (259, 261), and renal profibrotic molecules such as TGFβ and fibronectin-1 (261). By downregulating these molecules, fish oil diminishes the age-associated activation of NF-κB signaling in lupus mice, thereby mitigating lupus nephritis (259). Indeed, fish oil is a dietary source for ω−3 PUFA that exerts anti-inflammatory capacities through dampening immune cell responsiveness to IFNγ (263). Recent findings have shown that ω−3 PUFA could also downregulate biomarkers associated with T and B cell activation and/or differentiation and leukocyte recruitment such as CD80, CTLA-4, IL-18, CCL5, CXCR3, IL-6, TNFα (264). Similarly, they mitigate inflammatory markers associated with intestinal inflammation/colitis such as IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and leukotriene B₄ (LTB₄) (265). Collectively, these beneficial actions of ω-3 PUFA on autoimmune development (especially SLE) could be targeted in future human intervention studies. Interestingly, for their immunomodulatory capacities, ω−3 PUFA have been recently proposed as part of the supportive care for COVID-19 patients (266, 267), as recent pilot data suggest that a higher ω-3 index may lower the risk of COVID-19 fatality (268). Therefore, diets rich in PUFA might confer benefits for autoimmune patients with SARS-CoV-2 infection.

Dietary proteins are the third component of macronutrients in a balanced diet and are hydrolyzed in the gut to generate amino acids and peptides. Proteins can, directly and indirectly, modulate immune functions. Directly, dietary proteins-derived amino acids can serve as major energy sources for leukocytes, enhance the development of immune cells from hematopoietic progenitors, and modulate their effector functions as previously reviewed (269). Indirectly, proteins are utilized through gut microbiota which in turn mediates the interplay between protein metabolites and the host immune system as detailed elsewhere (270). Indeed, exposure to dietary protein antigens is necessary for the maturation of the immune system (271, 272). Feeding of weanling mice a protein-deficient diet that had only free amino acids resulted in a poorly developed immunological profile that resembled that of newborn or germ-free (GF) mice (271, 273), which is characterized by reduced secretory IgA and systemic Ig levels as well as less-developed gut-associated lymphoid tissues (271, 273). Moreover, in addition to playing an integral role in the development of oral tolerance (273, 274), early-life intake of protein antigens is crucial for Th1 differentiation (271), B cell responses, and class switching (275), thereby helping to augment the immunity against infectious invaders later in life (272). Together, these studies suggest that dietary protein malnutrition (PM) could adversely impact immunity. Interestingly, both PM and excessively high protein intake could exacerbate inflammation. PM could potentiate intestinal mucosal damage following inflammatory stimulation (e.g., zymosan-induced systemic inflammation), allowing bacterial translocation and gut-induced septicemia (276). In parallel, in contrast to proteins from plant origins that could mitigate inflammation (277), a high-protein diet, especially from animal origin, aggravates both acute and chronic dextran sulfate sodium (DSS)-induced colitis via promoting the pro-inflammatory responses of macrophages (278). Furthermore, high protein intake has been associated with deterioration of renal disease involving glomerular hyperfiltration (279). Meanwhile, a low-protein diet could help the management of chronic kidney diseases (280). As kidney inflammation, namely lupus nephritis is the most life-threatening manifestation of SLE, modulation of protein intake could be of great importance. Indeed, moderate dietary protein intake of 0.6 g/kg daily improves renal functions in SLE patients (281). Restriction of protein intake in NZB/W F1 mice improved the disease outcome, inhibited splenomegaly, and maintained immune cell responsiveness to mitogenic stimulation (282).

Together, these observations suggest that dietary protein modulation can influence immune components in the pathogenesis of autoimmune disorders such as SLE, therefore warranting further studies to elucidate the underlying cellular and molecular mechanisms.

Epidemiological association between obesity and autoinflammatory disorders (283) suggests that excessive caloric/energy intake could lead to the breakdown of immunological tolerance. Excess caloric intake in early life increases the incidence of IBD (284) and autoimmune thyroiditis (285) in adulthood. In contrast, caloric/energy intake restriction (EIR) can improve the autoimmune/inflammatory outcomes as have been reported in experimental models of SLE (286–291), EAE (292–295), and Sjogren’s syndrome (296).

Immune responses are high energy-dependent to fuel the biosynthetic needs of activated immune cells. The bioenergetic demand of immune cells is achieved via three interconnected metabolic pathways including oxidative phosphorylation (which occurs in the mitochondria of naïve cells), glycolysis (which occurs in the cytoplasm of activated and proliferating cells), and tricarboxylic acid (TCA) cycle (which occurs in the mitochondria of activated and proliferating cells) (232). The immune system is dynamically active with continuous changes in cellular activities such as those between resting naïve cells and proliferating effector cells, and those of memory/long-lived cell populations that might be quiescent but ready to undergo rapid proliferation upon stimulation. Therefore, the cellular energy demand is variable based on the phases and activities of immune cells (297–299). For instance, for a cell in a resting state (e.g., naïve T or B cells), the need for energy will be towards maintaining its minimal metabolic and biosynthetic requirements that are directed for building cellular components. Therefore, the cellular energy expenditure is met through oxidative phosphorylation and targets preserving cellular integrity. In contrast, effector immune cells undergo rapid proliferation and have a wide range of effector functions as represented in the production of effector molecules such as cytokines, chemokines, inflammatory mediators, and immunoglobulins. This will require upregulation of fuel uptake and aerobic glycolysis to satisfy higher metabolic configurations needed for both bioenergetic and biosynthetic pathways (297–299). Importantly, these shifts of cellular energy phases could be largely dependent on nutrient and energy supplies in the microenvironment. Moreover, energy/caloric intake can influence cellular metabolism as well as phenotypic and functional capacities of immune cells (300–302). For instance, due to chronic metabolic stress leading to ATP depletion, chronically activated T cells in SLE patients fulfill their need for ATP through oxidative phosphorylation rather than upregulating the aerobic glycolysis (303). In parallel, continuous low-grade inflammation due to excess energy intake (as in obesity) exacerbates the proinflammatory phenotype of different immune cells, favoring the differentiation of Th1 and Th17 subsets while diminishing the frequency of Treg cells (304), thereby predisposing individuals to autoimmunity (283).

Furthermore, energy intake can shape the fate of immune cells (e.g., differentiation and effector functions) through modulating key signaling pathways and transcription factors which in turn contribute to autoimmune pathogenesis. For instance, activation of T cells through TCR signaling and CD28 co-stimulation leads to activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt pathway (305–307), which subsequently turns on the mammalian target of rapamycin (mTOR) pathway, where mTOR is of two functional complexes, mTORC1 and mTORC2 (308). mTOR is a central regulator for T cell differentiation and homeostasis (309, 310). Under normal nutrient and energy conditions, mTOR (especially mTORC1) senses the microenvironment and upregulates the expression of glycolytic genes (311), allowing for biosynthetic anabolic processes needed for cell proliferation (309). However, excessive functions of mTOR can disrupt cellular differentiation and predispose individuals to autoimmune conditions such as RA (312) and SLE (313). Augmented mTOR activities under autoimmune conditions are not limited to T cells, where mTORC1 expands pathogenic T cell populations including Th17 and the CD4^-CD8^- double-negative T (DN-T cells) while suppressing Treg cells (313); but also B cells (314–316), DCs and macrophages (317, 318). Activation of mTORC1 precedes the onset of SLE as a result of chronic metabolic stress with long-term ATP depletion and mitochondrial hyperpolarization (319, 320). In contrast, during energy restriction, rapid inhibition of mTOR occurs, allowing the shift to catabolic processes to maintain the energy required for cell survival (321, 322); at the same time, Treg cells become responsive to TCR stimulation, thus enhancing their proliferation (323). Therefore, optimizing the cellular metabolic shifts could open new therapeutic avenues for the treatment of autoimmunity (324, 325).

Consistent with this notion, EIR can suppress the immunopathogenic responses associated with autoimmunity and chronic inflammation including hyperactivation of cellular and humoral responses (326). For instance, EIR reduces antigen processing by macrophages as well as the T cell-dependent activation of B cells (326). Similarly, EIR diminishes the inflammatory activities of circulating monocytes and their mobilization from the bone marrow without compromising their emergency egression during acute infection and tissue repair (327). Through these mechanisms, EIR has been shown to modify the autoimmune/inflammatory pathogenesis of various disorders (286–296). For example, EIR can dampen the SLE progression. Early dietary modulation through caloric restriction by the time of weaning reduces SLE-associated lymphadenopathy in mice (328). Caloric restriction significantly reduces B cell frequencies and their activation (291), reduces circulatory anti-dsDNA antibodies, and prevents the increase of possibly pathogenic T cell subsets such as DN-T cells (329), while maintaining a higher percentage of naïve T cell subsets (291) as well as the responsiveness of lymphocytes to mitogenic stimulation (329). In addition, lupus-prone NZB mice with chronic energy/calorie intake restriction (CEIR; fed a 40% caloric reduction diet that was relatively low in fat and high in carbohydrates) prolongs the survival and delays the disease initiation (286). In NZB mice as well as other lupus-prone murine models including MRL/lpr and BXSB, CEIR diminishes proliferation of lymphoid cells in the spleen, thymus, and mesenteric lymph node (MLN) (287), downregulates the transcript levels of proinflammatory cytokines such as IFNγ and IL-12, reduces IgA and IgG2a autoantibodies (288), and decreases molecules associated with fibrinogenesis such as platelet-derived growth factor (PDGF) (289), subsequently ameliorates lupus-associated kidney inflammation or glomerulonephritis. These observations emphasize the potential use of EIR in the treatment of SLE.

In summary, calorie restriction (e.g., intermittent fasting) and fat/carbohydrate modulation (e.g., ketogenic diets) may provide novel opportunities against autoimmunity by regulating both adaptive and innate immune activation pathways (242, 330). However, further studies are warranted to establish the safety and clinical efficacy of immunometabolic treatment strategies in autoimmunity. In parallel, it is essential to ensure that the modulated diets do not lead to malnutrition that promotes immune dysfunction and increases the risk and severity of infections (331). Notably, malnutrition predisposes COVID-19 patients to more severe disease in an age-dependent manner (332) and increases the odds of their fatality (333). Indeed, COVID-19 patients may require higher energy intake and increased protein consumption (334), and it is a necessity to consider the immunomodulatory influence of macronutrients for proper supportive managements of autoimmune patients with COVID-19 infection.

In Table 1 , we present a short list of several nutrients that have shown beneficial effects in murine models of SLE where human studies are warranted.