nutrients Review Vitamin C and Immune Function Anitra C. Carr 1,* and Silvia Maggini 2 1 Department of Pathology, University of Otago, Christchurch, P.O. Box 4345, Christchurch 8140, New Zealand 2 Bayer Consumer Care Ltd., Peter-Merian-Strasse 84, 4002 Basel, Switzerland; [email protected] * Correspondence: [email protected]; Tel.: +643-364-0649 Received: 21 September 2017; Accepted: 31 October 2017; Published: 3 November 2017 Abstract: Vitamin C is an essential micronutrient for humans, with pleiotropic functions related to its ability to donate electrons. It is a potent antioxidant and a cofactor for a family of biosynthetic and gene regulatory enzymes. Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C supports epithelial barrier function against pathogens and promotes the oxidant scavenging activity of the skin, thereby potentially protecting against environmental oxidative stress. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects. Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100–200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand. Keywords: ascorbate; ascorbic acid; immunity; immune system; neutrophil function; microbial killing; lymphocytes; infection; vitamin C 1. Introduction The immune system is a multifaceted and sophisticated network of specialized organs, tissues, cells, proteins, and chemicals, which has evolved in order to protect the host from a range of pathogens, such as bacteria, viruses, fungi, and parasites, as well as cancer cells [1]. It can be divided into epithelial barriers, and cellular and humoral constituents of either innate (non-specific) and acquired (specific) immunity [1]. These constituents interact in multiple and highly complex ways. More than half a century of research has shown vitamin C to be a crucial player in various aspects of the immune system, particularly immune cell function [2,3]. Vitamin C is an essential nutrient which cannot be synthesized by humans due to loss of a key enzyme in the biosynthetic pathway [4,5]. Severe vitamin C deficiency results in the potentially fatal disease scurvy [6]. Scurvy is characterized by weakening of collagenous structures, resulting in poor wound healing, and impaired immunity. Individuals with scurvy are highly susceptible to potentially fatal infections such as pneumonia [7]. In turn, infections can significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements. Early on, it was noted that scurvy often Nutrients 2017, 9, 1211; doi:10.3390/nu9111211 www.mdpi.com/journal/nutrients Nutrients 2017, 9, 1211 2 of 25 followedNutrientsinfectious 2016, 8, 1211 epidemics in populations [7], and cases of scurvy have been reported following2 of 24 respiratory infection [8]. This is particularly apparent for individuals who are already malnourished. reportedAlthough following the amount respiratory of infection vitamin [8]. C requiredThis is particularly to prevent apparent scurvy for isindividuals relatively who low are (i.e., ~10already mg/day) malnourished. [9], the recommended dietary intakes for vitamin C are up to one hundred-fold higher thanAlthough that forthe amount many other of vitamin vitamins C required [10]. Ato dietprevent that scurvy supplies is relatively 100–200 low mg/day (i.e., ~10 of mg/day) vitamin C provides[9], the adequaterecommended to saturating dietary intakes plasma for vitamin concentrations C are up into healthyone hundred-fold individuals higher and than should that for cover many other vitamins [10]. A diet that supplies 100–200 mg/day of vitamin C provides adequate to general requirements for the reduction of chronic disease risk [11,12]. Due to the low storage capacity saturating plasma concentrations in healthy individuals and should cover general requirements for of the body for the water-soluble vitamin, a regular and adequate intake is required to prevent the reduction of chronic disease risk [11,12]. Due to the low storage capacity of the body for the water- hypovitaminosis C. Epidemiological studies have indicated that hypovitaminosis C (plasma vitamin C soluble vitamin, a regular and adequate intake is required to prevent hypovitaminosis C. µ µ < 23Epidemiologicalmol/L) is relatively studies commonhave indicated in Western that hypovitaminosis populations, and C (plasma vitamin vitamin C deficiency C < 23 (<11μmol/L)mol/L) is is therelatively fourth leadingcommon nutrientin Western deficiency populations, in the and United vitamin States C deficiency [13,14]. There (<11 areμmol/L) several is the reasons fourth why vitaminleading C dietarynutrient recommendations deficiency in the areUnited not States met, even [13,14]. incountries There are where several food reasons availability why vitamin and supply C woulddietary be expectedrecommendations to be sufficient. are not met, These even include in countries poor where dietary food habits, availability life-stages and and/orsupply would lifestyles eitherbe expected limiting intakesto be sufficient. or increasing These micronutrientinclude poor di requirementsetary habits, life-stages (e.g., smoking and/or and lifestyles alcohol either or drug abuse),limiting various intakes diseases, or increasing exposure micronutrient to pollutants requirem and smokeents (e.g., (both smoking active and and alcohol passive), or drug and abuse), economic reasonsvarious (poor diseases, socioeconomic exposure to status pollutants and and limited smoke access (both to active nutritious and passive), food) and [15, 16economic]. Even reasons otherwise ‘healthy’(poor socioeconomic individuals in status industrialized and limited countries access to can nutritious be at risk food) due [15,16]. to lifestyle-related Even otherwise factors, ‘healthy’ such as thoseindividuals on adiet in industrialized or eating an countries unbalanced can be diet, at risk and due people to lifestyle-related facing periods factors, of excessive such as those physical on or psychologicala diet or eating stress an [unbalanced15,16]. diet, and people facing periods of excessive physical or psychological stress [15,16]. Vitamin C has a number of activities that could conceivably contribute to its immune-modulating Vitamin C has a number of activities that could conceivably contribute to its immune-modulating effects. It is a highly effective antioxidant, due to its ability to readily donate electrons, thus protecting effects. It is a highly effective antioxidant, due to its ability to readily donate electrons, thus protecting important biomolecules (proteins, lipids, carbohydrates, and nucleic acids) from damage by oxidants important biomolecules (proteins, lipids, carbohydrates, and nucleic acids) from damage by oxidants generatedgenerated during during normalnormal cell cell metabolism metabolism and andthrough through exposure exposure to toxins to and toxins pollutants and (e.g., pollutants cigarette (e.g., cigarettesmoke) smoke) [17]. Vitamin [17]. Vitamin C is also C is alsoa cofactor a cofactor for a for family a family of ofbiosynthetic biosynthetic and and gene gene regulatory regulatory monooxygenasemonooxygenase and and dioxygenase dioxygenase enzymes [18,19]. [18,19 ].The The vitamin vitamin has haslong long been beenknown known as a cofactor as a cofactor for forthe the lysyl lysyl and and prolyl prolyl hydroxylases hydroxylases required required for stabilizat for stabilizationion of the tertiary of the structure tertiary of structure collagen, of and collagen, is a andcofactor is a cofactor for the for two the hydroxylases two hydroxylases involved involved in carnitine in biosynthesis, carnitine biosynthesis, a molecule required a molecule for transport required for transportof fatty ofacids fatty into acids mitochondria into mitochondria for generation for generationof metabolic of energy metabolic (Figure energy 1) [19]. (Figure 1)[19]. FigureFigure 1. 1.The The enzyme enzyme cofactorcofactor activitiesactivities of of vitamin vitamin C. C. Vitamin Vitamin C Cis isa acofactor cofactor of ofa family a family of of biosyntheticbiosynthetic and and gene gene regulatory regulatory monooxygenase monooxygenase and dioxygenase dioxygenase enzymes. enzymes. These These enzymes enzymes are are involvedinvolved in thein the synthesis synthesis of of collagen, collagen, carnitine, carnitine, catecholaminecatecholamine hormones, hormones, e.g., e.g., norepinephrine, norepinephrine, and and amidatedamidated