Summary of evaluation methods used for determining rice quality.
Rice is the staple food of half of human population globally and fulfills over 21% calorific requirement of world population. About 90% of the rice is produced and consumed in Asia. During 1960s to 1970 when the major rice producing countries relied on rice as a subsistence crop, the major emphasis was on high yield. As these countries attained food security and standard of living of the rice eating population improved, consumers became conscious about grain quality. Their potential as exporters of surplus rice produced, gave a further impetus to grain quality research. The world population is expected to reach 9.8 billion from the current 7.6 billion by 2050 (The
S. No. | Quality parameter | Recent quality evaluation method(s) |
---|---|---|
1. | Apparent amylose content | HPLC-SEC [5] DSC [6] NIRS [7, 8] |
2. | Cooking time | Measured indirectly by estimating gelatinization temperature using DSC [6] |
3. | Kernel elongation | None |
4. | Grain volume expansion | None |
5. | Gelatinization temperature | Measurement of starch gelatinization by DSC, photometric method, alkali photometry, or RVA pasting curve [9] |
6. | Pasting properties | Brabender visco-amylograph, micro Visco-analyzer [10, 11] |
7. | Gel consistency | None |
8. | Texture profiling | Instron hardness testing. Parallel plate plastometer, consistometer, texturometer, hardness tester, viscoelastograph, tensipresser, surface tensiometer, Kramer shear or texture press, extrusion and back extrusion, puncture test |
9. | Sensory evaluation | None |
10. | Aroma profiling | Detection and quantification of 2-acetyl-1-pyrroline by GC-MS [3] Detection of total volatile metabolome by GC-MS |
11. | Rancidity test | Detection of free fatty acids by titration or colorimetry [12] |
12. | Protein content | NIRS [13] |
13. | Lipid content | Metabolomics approach using LC-MS [14] or GC-MS |
14. | Resistant starch content | None |
15. | Nonstarch polysaccharide content and dietary fiber content | CE [15], HPLC coupled with mass spec detector |
16. | Micronutrients | AAS, ICP-OES, ICP-MS [16, 17], XRF |
17. | Digestibility | Time-resolved NMR [18] |
Summary of evaluation methods used for determining rice quality.
Major factors determining market value are immediately discernible by the consumers and include physical properties like, whiteness, translucence, uniform shape and yield of edible polished grain. Visual characters of rice grains like grain dimensions, chalk, color and whole grain recovery are important attributes that affect the choice of consumers’ and millers. Therefore, these are among some of the first selection criteria in varietal improvement programs [19, 20, 21]. Grain size depends on the length of the grain in its greatest dimension, while grain shape is based on length-to-breadth ratio [20]. The classification of rice samples based on size and shape is not standardized across different countries and different marketing areas [22, 23]. The routine classification system used by the International Rice Research Institute (IRRI) breeding programs for grain size is as follows: short (≤5.50 mm), medium/intermediate (5.51–6.60 mm), long (6.61–7.50 mm), and very long (>7.50 mm). Similarly, the grain shapes of rice can be described based on the length-to breadth ratio values, and the classification used in IRRI is: bold (≤2.0), medium (2.1–3.0), and slender (>3.0) [23]. Chalky areas in rice grains present on the dorsal (white belly), ventral side (white back) or in the center are opaque white parts of the endosperm and generally, associated with poor quality in many rice markets thus these grains have lower market acceptability [24]. Classification of the grains is based on the proportion of the grain that is chalky: none (0%), small (<10%), medium (10–20%), and large (>20%) [23, 25, 26]. The starch granules in the chalky areas of the grain have air spaces between them, are small and less compact compared to bigger and tightly packed granules in translucent areas and hence are more prone to breakage during milling [27, 28]. Chalk thus affects both the esthetic value and head rice yield decreasing the marketability of rice. Chalk is caused by both environment and genetic factors. Increase in nighttime air temperatures during grain filling stage can increase chalk and reduce head rice yields [29, 30]. Rice grain dimensions are conventionally measured using transparent rulers, vernier calipers and photographic enlargers [31], while the proportion of grain that is chalky is visually scored. Measuring of grain dimensions using manual methods is both labor intensive and time-consuming. Moreover, visual scoring of chalk involves subjectivity. Now-a-days, image analysis methods are being used in advanced laboratories that are very convenient and objective [31, 32, 33].
Yin et al. [34] divided the dimensions of grain shape into grain length, grain width, length-to-width ratio, grain area, grain circumference, grain diameter, and grain roundness. Several important genes have been characterized in previous studies that control grain shape traits, e.g., GS3 [35] affecting grain length, qSW5/GW5/GSE5 [14, 36, 37] affecting grain width, GL7/GW7 [38] shaping both grain length and grain width. In various studies across different environments and genetic backgrounds, a major effect quantitative trait loci (QTL) for grain length,
Milling yield is an important quality character especially from the commercial standpoint [47]. It includes milled rice yield and head rice yield. Milling yield is the estimate of the quantity of total milled rice obtained from a unit of rough rice (paddy) and produced by removing the hulls, germ, and most of the bran. It includes intact and broken kernels and generally expressed as percentage [48]. Head rice is the intact or “whole” kernels and includes milled kernels having equal to or more than three-fourth length. The economic value of broken kernels is only 50–60% that of head rice, supporting the immense impact it has on marketability. Bran consists of several layers of outer covering of the endosperm. These layers include the pericarp, testa (seed coat), the nucellus and the aleurone, including the germ, are collectively called bran. Both, the degree of milling, which is an estimate of the degree to which the bran layers are removed from the endosperm, and fissuring of grains contribute to the percentage of broken kernels and hence, determine the overall milling quality [49]. Fissures or cracks in the grains weaken the strength of the grain and predispose them to break when exposed to mechanical forces during milling process [50]. Post-harvest drying of rice is one of the greatest factors that affect the percentage of broken kernels. Alternate wetting and drying of grains, drying at high temperatures and non-equilibrated grains before polishing lead to a decrease in head rice recovery [51, 52, 53, 54, 55]. Milling quality is determined with the help of laboratory-sized mills. They include dehuskers that remove husk, polishers or Test Rice Whitening Machine and graders, indent cylinders and shaker tables to segregate broken kernels from milled rice. Lam and Proctor [56] determined that linoleic and oleic acids were the main fatty acids released during milled rice surface lipids hydrolysis. Limited number of QTLs has been identified for milling quality. Two have been fine mapped but none has been cloned so far [57].
Rice is mainly consumed as polished grain in contrast to other staple cereals like wheat and maize that are consumed after the grain is ground to flour. Therefore, the quality characters of rice grain assume greater importance. The chief component of milled rice grain is starch which constitutes approximately 78% (14% moisture) or 90% (dry weight) of the endosperm [58]. Thus, the properties of starch mainly determine the cooking and eating quality of rice grains. Three important traits of starch that determine the cooking and organoleptic properties of rice grain are: apparent amylose content (AAC), gelatinization temperature (GT) and gel consistency.
The amylose fraction, essentially the linear polymer of glucose, forms only a small component of starch. The other major form of starch is the highly branched amylopectin molecule. Amylose is an important quality trait of rice and is considered as an indirect predictor of cooking and sensory quality [59, 60, 61]. Iodine-binding assay, generally used for measuring amylose content, also detects long-chain amylopectin in addition to ‘true’ amylose [62]. Hence, amylose is referred to as apparent amylose content (AAC). AAC of starch ranges from 0.8 to 1.3% in waxy rice, whereas it constitutes 8–37% [58] in non-waxy rice, the rest being amylopectin. AAC is directly proportional to water absorption, volume expansion, fluffiness, hardness and inversely proportional to cohesiveness, tenderness, stickiness and glossiness of cooked rice. Based on AAC, rice can be classified as: waxy (0–2%), very low (3–9%), low (10–19%), intermediate (20–25%), and high (>25%) [10]. Despite overestimating the actual amylose content and other limitations, iodine—binding assay that produces blue iodine—amylose complex when iodine binds to gelatinized rice flour which is quantified using a spectrophotometer, remains the method of choice for determining AAC. The two methods approved for the estimation of amylose content in milled rice are: the AACCI Method61-03.01 and ISO Method 6647-1:2015 [63, 64]. Auto-analyzers are also being used for routine amylose estimations in several rice improvement programs [65].
In general, the AAC is related to sensory quality of cooked rice however, there are varieties that have the same AAC but differ in their cooked rice hardness [66]. To account for such differences, a complementary test called gel consistency (GC) is routinely used [32]. It measures the length moved by rice flour gel, before it sets. Rice is classified into three GC groups based on gel length: hard and very flaky (≤40 mm), medium and flaky (41–60 mm), and soft (>61 mm). The differences in GC groups are explained on the basis of the proportion of hot water soluble amylose compared to that of insoluble amylose. The varieties with higher proportion of hot water insoluble amylose exhibit hard GC [67, 68]. Studies have indicated that long-chain amylopectin that remains in the gelatinized starch granule is probably the hot water insoluble amylose [69, 70]. According to Matsue et al. [71], amylose and protein content, amylographic characteristics, and even palatability showed significant difference depending on the position of spikelets in a panicle.
Conventional genetic studies have revealed that AAC is under the control of one major gene with several modifiers [56]. Among non-waxy parents, high amylose is completely dominant over low or intermediate amylose, and intermediate is dominant over low [72]. With the advent of molecular marker technology, it is now easy to apprehend complex quantitative traits [73]. Amylose content is reported to be mainly controlled by the waxy gene locus (
Gelatinization temperature (GT) is another important physicochemical parameter that ranges from 55 to 80°C and provides information regarding the cooking time of rice and its texture [79]. The temperature at which the semi-crystalline structure of starch begins to melt in hot water with loss of birefringence is termed GT [1]. GT is classified into three classes: low (55–69°C), intermediate (70–74°C) or high (75–79°C) [27]. GT is dependent on the amylopectin fine structure of starch with higher proportion of short chains (DP 6–12) decreasing the GT [80, 81]. Consumer preferences are varied throughout the world but varieties with intermediate GT are mostly preferred [82]. The two most commonly used methods for GT determination are: alkali spreading value (ASV) and Differential Scanning Calorimetry (DSC). ASV is based on the disintegration of starch granules present in milled rice grains in dilute KOH. The extent of disintegration is numerically scored on a scale of 1–7 [31, 68]. Though ASV is a high throughput method for the determination of GT, it is an indirect and subjective test. In contrast, DSC is an instrumental method based on measuring in real time, the first peak of the endotherm as the starch granules gelatinize [6, 83, 84]. DSC is a precise but an expensive method for measuring GT and cannot be routinely used to screen thousands of breeding lines in rice improvement programs. GT is also determined by an amylograph method [85] which tracks the viscosity changes that take place when rice flour-water slurry is heated with continuous stirring and was approved as the AACCI Method 61-01.01. The temperature at which the viscosity of 20% slurry begins to rise, determines the GT. The instrument used extensively in advanced rice quality labs is Rapid Viscoamylograph (RVA) [1]. It determines the viscosity changes during the heating and cooling of relatively small rice flour samples (6 g) AACCI Method 61-02.01.
A QTL corresponding to the
Aroma is a prized sensory trait of cooked rice that increases its market value. Among more than 100 identified volatile compounds, 2-acetyl-1-pyrroline (2-AP) is the major chemical compound contributing to the fragrance of Basmati rice, Jasmine rice and Pandanus leaves [91, 92, 93, 94]. Aroma is traditionally detected by smelling after reaction with 0.1 M KOH. However, this method is subjective and is also harmful to the nasal cavity of the analyst upon continuous and prolonged exposure. To solve this problem, gas chromatography coupled with flame ionization detector (GC-FID) or mass spectrometry (GC-MS) is being used in advanced rice breeding facilities. However, these methods are expensive and involve high running and maintenance costs. Therefore, molecular markers related to 2-AP are routinely used in rice breeding programs working on aroma.
Genetics studies of aroma have been an attractive research topic and many researchers studied it by employing various sensory tests. A few scientists like Reddy and Reddy [95] described two to three recessive or dominant genes that determine the fragrance, but most researchers believe that Basmati fragrance is under the control of a single recessive gene [96, 97]. Almost two decades of attempts to know the genetics of aroma at molecular level concluded in mapping of a single locus (
Detailed studies were done by Sood and Siddiq [104] on the geological distribution of kernel elongation gene(s) in rice and reported that varieties showing high kernel elongation on cooking were known to be traditionally cultivated in the northwest part of undivided India. Kernel elongation upon cooking is an endosperm character significantly influenced by factors like environment, aging, etc. Basmati rices are characterized by doubling of kernel length upon cooking. Despite being an important trait, not many reports are available on the inheritance of kernel elongation on cooking. Among the limited number of studies on this trait, one study had reported identification of a QTL between two RFLP markers
Rice is consumed as a staple for providing sustenance to its consumers’. With improving purchasing power of the rice consumers’ post green revolution, nutritional quality of rice gained importance. As starch is the main constituent of milled rice grain, it is the major source of energy and affects its nutritional quality. It has been reported that starch is digested at different rates in human gastro-intestinal tract [106]. The digestibility of starch is measured by estimating the rise in blood glucose level of humans upon consumption of a food containing 50 g available carbohydrates compared to a standard solution containing 50 g glucose [107, 108, 109]. This glycemic response is reported as glycemic index (GI). However, estimation of GI involves low-throughput and expensive clinical assays, therefore, it is not routinely used in screening for low GI rices [110]. In vitro estimation of nutritional fractions of starch can be carried out by estimating the content of total sugars, total starch, rapidly digestible starch, slowly digestible starch and resistant starch [111, 112]. Apart from starch, the other major macronutrients present in milled rice grain are: storage proteins (7%), storage lipids (<1%) and non-starch polysaccharides (NSPs, trace amounts). These macronutrients significantly affect the nutritional quality, textural and sensory traits, and functional properties [113] even though they constitute minor components of milled rice grain. Storage proteins are major source of proteins in developing countries, are hypoallergenic and possess superior amino acid composition [114]. The Kjeldahl method with modifications to accommodate smaller sample sizes (AACCI Method 46-13.01) [63] is widely used method for the estimation of total proteins. Individual amino acids can be quantified after acid hydrolysis using pre-column derivatization with a fluorescent derivatizing reagent followed by HPLC separation [115, 116]. Rice lipids serve nutritional and functional role. They provide protection against cardiovascular diseases and cancer [117] and also affect the pasting properties. Crude fat in rice grains is routinely analyzed using a standard method (AACCI Method 30-10.01). The fatty acid composition of the bran layer can also be analyzed using gas-liquid chromatography (GLC) [118]. NSPs are concentrated in the bran layer and only trace amounts are detected in the milled rice grains but have nutritional importance because of their unique composition compared to other cereals [109].
Nutritional components such as minerals, vitamins and phytochemicals are concentrated in the bran layer and are either absent or present at low levels in milled grains. The iron and zinc content are generally low and some of which is lost during milling. So a modest increase in these levels in rice would provide a significant nutritional boost to the hundreds of millions of people who depend on it. Hence there is an imperative need for a shift in emphasis toward development of nutritionally high quality rice. This is achieved by evaluating the available germplasm lines for micro nutrient content and by generation of knowledge regarding their inheritance pattern to use in future breeding programs. Micronutrients are being quantified by using atomic absorption spectroscopy (AAS), X-ray fluorescence spectrometry (XRF), inductively coupled plasma-mass spectrometry (ICP-MS), laser-induced breakdown spectroscopy (LIBS), and inductively coupled plasma-optical emission spectrometry (ICP-OES) [16, 17].
Integration of marker assisted breeding with conventional breeding creates a possibility to track the introgression of nutritional quality associated QTLs and genes into a popular/elite cultivar from various germplasm sources [119]. Two consistent QTLs for protein content in milled rice were reported by Zhong et al. [120] as
Rice quantity and quality are directly or indirectly influenced by decrease in suitable arable land due to increase in urbanization, urban migration, soil deterioration and problems relating to climate fluctuations. Rice eating and cooking quality traits appear to be simple but the genetic machinery is too complex and needs to be deciphered. Rice appearance quality is a complex trait and involves interaction between quality and yield and also between quality and environment. Grain chalkiness is of primary concern since it affects milling, appearance, eating and cooking qualities [123]. To reduce chalkiness, genotypes with low chalk formation at high temperature after heading can be identified and utilized through MAS. Biochemical, physiological and molecular mechanisms have to be worked out by identifying and cloning chalkiness functional genes. The most challenging issue facing milling industry is to obtain high head rice recovery, since it is directly related to profitability to both the farmers and millers. Genetic understanding of milling quality is still limited [57]. Improvement of milling quality requires (i) search for QTLs with large effect (ii) robust and accurate analytical tools to measure the trait (iii) improvement in postharvest handling and storage techniques (iv) Breeding efforts through MAS. With the expeditious progress in functional genomics and development of high throughput genotyping technologies, more number of rice functional genes will be cloned in the future.
Increased awareness among the rice consuming population toward sensory and nutritional traits makes it necessary to develop evaluation techniques that can directly correlate with the consumer perception. To improve eating and sensory quality of rice it is important to integrate methods in textural analysis and rheology with taste and flavor metabolomics. Nutritional quality of rice is another trait that needs to be included in rice improvement programs. Rice has an important role to play to mitigate the impact of non-communicable diseases like diabetes. Since starch forms about 90% of milled rice grain weight, its structure (amylose content, branching pattern) and digestibility (resistant starch) affect its nutritional quality. Clinical evaluation of rice digestibility is difficult, therefore, methods for accurate
Vitamin D is a secosteroid hormone, which is known to be related to the regulation of the musculoskeletal system. It affects calcium and phosphate metabolism and is related to bone health. Recently, the extraskeletal effects of vitamin D are under intense research and have attracted the interest of the scientific community [1, 2, 3, 4, 5, 6]. In particular, the relationship of vitamin D with the immune system is in the focus of scientific evaluation [7, 8, 9]. In the chapter herein, the effects of vitamin D on the immune system will be discussed, and the relationship of vitamin D deficiency with the development of autoimmune diseases will be reviewed.
\nThe classic function of vitamin D is to enhance intestinal absorption of calcium by regulating several calcium transport proteins in the small intestine [4]. However, various cells express the vitamin D receptor (VDR) and the vitamin D activating enzyme 1-α-hydroxylase. Various cells of the immune system also express the VDR and harbor 1-α-hydroxylase [10, 11]. Thus, cells of the immune system respond to vitamin D and also activate vitamin D in a paracrine or autocrine fashion. The extra-renal 1-α-hydroxylase is not upregulated by PTH, and thus, production of 1,25(OH)2D3 is dependent on concentrations of the substrate 25(OH)D3, and it may be regulated by inflammatory signals, such as lipopolysaccharide and cytokines [12, 13]. Cells of the immune system, which express the VDR and harbor 1-α-hydroxylase, are macrophages, T cells, dendritic cells, monocytes, and B cells (Figure 1) [9]. Vitamin D is involved in the regulation of the innate immunity as it enhances the defense system of the organism against microbes and other pathogenic organisms, and it modulates the adaptive immune system through direct effects on T-cell activation and on the phenotype and function of antigen-presenting cells, particularly dendritic cells.
\nCells of the immune system regulated in part by vitamin D.
The innate immune system is a first line of defense against infection. Vitamin D is a regulator of the innate immune system [1, 14]. The first data on the effect of vitamin D on the innate immune system have been generated on the treatment of diseases caused by mycobacteria, such as tuberculosis and leprosy [15, 16, 17, 18]. Vitamin D has been used as a treatment of infections for more than 150 years. In 1849, Williams reported favorable results with the use of cod-liver-oil, an excellent source of vitamin D, in the treatment of patients with tuberculosis [19]. Fifty years later, Niels Finsen received the third Nobel Prize in Medicine for his description of using UV light, an effective method to increase vitamin D status, to treat lupus vulgaris, a cutaneous form of tuberculosis [20, 21]. Alfred Windaus contributed to the discovery of the chemical structure of vitamin D2 and vitamin D3 found in cod-liver-oil and received the Nobel prize [22, 23, 24]. Thereafter, several groups used vitamin D2 and D3 as a treatment for tuberculosis [22, 25]. Rook et al. [26] demonstrated in the 1980s that 1,25(OH)2D3 inhibited the proliferation of
Data regarding other infections also exist. Thus, children with low vitamin D status may be more prone to urinary tract infections due to low production of cathelicidin and defensin β2 [38, 39]. Also, adults with asthma may be less prone to infection after treatment with vitamin D due to increased production of cathelidicin and modulation of inflammatory cytokines [40, 41]. Low levels of vitamin D may be related to chronic obstructive pulmonary disease severity [42]. Vitamin D may increase resistance to HIV infection. Low levels of vitamin D have been associated with disease progression and mortality [43]. The ability of the immune cells to hydroxylate 25(OH)D3 locally suggests that in patients with infections, it may be better to administer 25(OH)D3 rather than hydroxylated metabolites to allow for local production and the feedback system to function.
\nThe natural history of autoimmunity remains largely unknown. However, the theory is that both genetic susceptibility and environmental factors play a role in the development of clinical autoimmune disease. Vitamin D has known immunomodulatory effects on a wide range of immune cells, including T and dendritic cells [44, 45]. Each of these immune cells expresses VDR and produces the enzymes 1-α-hydroxylase and 24-hydroxylase and is therefore capable of locally producing active 1,25(OH)2D3 [46, 47, 48, 49]. Activation of CD4+ T cells results in a significant increase in VDR expression enabling regulation of many genes responsive to 1,25(OH)2D3 [50]. 1,25(OH)2D3 suppresses T-cell receptor induced T cell proliferation and changes their cytokine expression. The overall shift is away from T helper Th1 phenotype toward a more tolerogenic Th2 response [51, 52, 53]. Vitamin D appears to directly inhibit Th1 cells and may additionally modulate a skewing toward a Th2 response [54]. Th17 cells are a subset of CD4+ T cells involved in organ-specific autoimmunity playing a role in maintaining inflammation, which can lead to tissue damage. 1,25(OH)2D3 suppresses autoimmunity and tissue destruction by inhibiting the Th17 response at several levels [55, 56]. Altogether, the evidence suggests an important role for vitamin D in influencing T-cell responses and in tempering inflammation and tissue damage.
\nVitamin D appears to have a direct effect on B cells and inhibits immunoglobulin production [57]. Additionally, differentiation of B cells is interrupted when exposed to 1,25(OH)2D3. 1,25(OH)2D3 also has effects on dendritic cells. Dendritic cells have important functions in maintaining both protective immunity and self-tolerance [58, 59]. Physiologic levels of 1,25(OH)2D3 inhibit maturation of dendritic cells and maintain an immature and tolerogenic phenotype with inhibition of activation markers such as MHC class II, CD40, and others and upregulation of inhibitory molecules [60, 61]. Thus, it appears that the maturational state of dendritic cells can be modulated by 1,25(OH)2D3, making it possible that the vitamin D status of an individual is likely to have important immunologic consequences.
\nThere are several animal models of autoimmunity, in which disease could either be prevented or ameliorated with the administration of either 1,25(OH)2D3 or one of its analogues. These animal models are models of autoimmune encephalomyelitis, collagen-induced arthritis, type 1 diabetes mellitus, inflammatory bowel disease, autoimmune uveitis, and lupus [44, 56, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76]. These studies show that treatment with active vitamin D is effective in modulating immune function and ameliorating autoimmune disease. Vitamin D deficiency is a risk factor for the development of some autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), diabetes mellitus type 1, multiples sclerosis, inflammatory bowel disease, and Hashimoto’s thyroiditis [49, 69, 74, 77, 78, 79, 80, 81, 82, 83, 84, 85] (Figure 2). Additionally, vitamin D deficiency has been observed in patients with systemic sclerosis [86].
\nAutoimmune diseases related to vitamin D deficiency.
A meta-analysis showed that low vitamin D intake is associated with the development of RA [87]. Thereafter, several studies performed in various areas all over the world showed that vitamin D deficiency is observed in patients with RA and that vitamin D deficiency is associated with disease activity [78, 82, 83, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97]. A meta-analysis of the good quality studies performed regarding the association between vitamin D deficiency and RA showed that vitamin D deficiency is observed in RA patients significantly more than in a control group and that vitamin D levels are inversely correlated with disease activity, meaning that low vitamin D levels are associated with high-disease activity [98]. Moreover, an association has been shown between VDR polymorphism and RA. Specifically, the Fokl F allele of the VDR may be a risk factor for the development of RA [99]. Further studies are needed to unravel the exact association between vitamin D deficiency and RA and to determine the best method of vitamin D supplementation and whether it may be used for the prevention of RA or for the best management of the disease [77, 100]. In addition, it has been proposed that vitamin D may contribute to the management of pain in RA and may be used along with TNF-α inhibitors in RA treatment [77, 101].
\nIn SLE, the inflammatory milieu drives the development of T cells into proinflammatory pathways, defective function of Tregs, and survival and activation of B cells, which produce autoantibodies [78, 81]. Patients with systemic lupus erythematosus have lower 25(OH)D3 levels compared to controls, suggesting that vitamin D deficiency may be a risk factor for SLE [81, 84, 102, 103, 104, 105, 106, 107]. The majority of studies have also found higher SLE disease activity associated with lower levels of 25(OH)D3 [84, 103]. As patients with SLE have often photosensitivity and are advised to avoid direct sun exposure, detecting vitamin D deficiency and replacing 25(OH)D3 with oral supplementation is critical and may impact disease activity [108].
\nType 1 diabetes mellitus is one of the most prevalent chronic diseases with onset in childhood and is the result of immune-mediated destruction of pancreatic insulin producing β cells. There appears to be a geographic variation in incidence following a gradient in latitude, which is the inverse of the global distribution of ultraviolet B irradiation, critical for the production of vitamin D within the skin [109]. Studies have shown higher incidence of vitamin D deficiency in patients with type 1 diabetes [110, 111, 112, 113]. One environmental factor thought to be protective against the development of type 1 diabetes mellitus is early supplementation with vitamin D [114]. A number of large case control studies showed that the risk of type 1 diabetes mellitus was significantly reduced in infants who were supplemented with vitamin D compared to those who were not supplemented [115, 116, 117]. Additionally, a lower incidence of type 1 diabetes was observed in infants born to mothers who were administered cod liver oil during pregnancy [118]. A birth cohort study in Finland, now more than 50 years ago, evaluated the effects of vitamin D supplementation on rickets and the development of type 1 diabetes mellitus [85]. All women due to give birth in 1966 were enrolled. There was an 80% reduction in the risk for type 1 diabetes mellitus in children having received >2000 IU vitamin D/day compared to those receiving less or not receiving supplementation with vitamin D. Evidence from both human and animal studies shows that vitamin D may be protective as far as the development of type 1 diabetes mellitus is concerned [68, 71, 76]. Thus, the administration of vitamin D may prevent diabetes mellitus type 1; however, once the destruction of pancreatic beta cells has taken place, it will not act therapeutically to reverse diabetes mellitus type 1.
\nMultiple sclerosis is characterized by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system, which can result in disability. Epidemiological studies have suggested that vitamin D insufficiency may contribute to the risk of multiple sclerosis [62, 63, 75, 119, 120]. Moreover, several genetic studies in multiple sclerosis patients have shown that diverse abnormalities in vitamin D metabolism are related to the risk of the disease. It appears that vitamin D deficiency may interact with genetic and environmental protective and risk factors, such as the allele HLA BRB1*1501, infections, obesity, smoking, and sexual hormones and may modulate the risk of the disease [63, 74, 80]. Thus, vitamin D deficiency may be a risk modulating factor for the development of multiple sclerosis. Vitamin D acts as an immunomodulatory factor affecting T and B lymphocytes, and it may exert neuroprotector and neurotrophic actions within the central nervous system. Several studies have shown that vitamin D supplementation exerts multiple beneficial immunomodulatory effects in multiple sclerosis [121, 122, 123, 124]. On the contrary, a Cochrane review states that there appears to be no benefit from vitamin D supplementation in patients with multiple sclerosis; however, the level of evidence is very low [125]. Nevertheless, it should be noted that robust statistical models used in association studies have already predicted a favorable vitamin D effect reducing relapses by 50–70% [121]. There is little doubt that vitamin D exerts a beneficial action on multiple sclerosis, the inflammatory component in particular, less so the degenerative. Until more information becomes available, vitamin D supplementation of multiple sclerosis patients, using a moderate physiological dose essentially correcting their vitamin insufficiency, is recommended.
\nVitamin D deficiency has been observed in patients with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis [126]. It was found to be related to disease activity in Crohn’s disease and ulcerative colitis. Vitamin D supports the integrity of the intestinal barrier and is related to microbiota homeostasis in this cohort of patients [127, 128]. Thus, vitamin D may contribute to the prevention of inflammatory bowel disease by supporting the integrity of the intestinal barrier, contributing to bacterial homeostasis and ameliorating disease progression via anti-inflammatory action. Vitamin D deficiency in inflammatory bowel disease is aggravated by decreased absorption of the vitamin via the gastrointestinal tract [128].
\nStudies have observed an association between autoimmune Hashimoto’s thyroiditis and low vitamin D levels [79, 129]. These studies have not observed low vitamin D levels in patients with Graves’ disease. A meta-analysis of 26 observational studies confirmed an association between vitamin D deficiency and autoimmune Hashimoto’s thyroiditis [130]. The aforementioned meta-analysis found that although there was heterogeneity between the results of the various studies performed all over the globe, studies had similar results in populations from different countries and also in populations in different age ranges, in particular pediatric and adult populations.
\nSystemic sclerosis is a chronic, inflammatory, fibrotic disorder thought to be related to autoimmune etiology. Vitamin D deficiency has been observed in patients with systemic sclerosis [86, 131], especially in patients with the diffuse type of the disease [131].
\nThe molecule used to assess vitamin D sufficiency in a population is 25(OH)D3 [9]. It appears that vitamin D has physiologic effects beyond those related to bone physiology and mineral homeostasis. It may be that the alarming prevalence of vitamin D deficiency observed all over the globe may be contributing to the development of autoimmune diseases. Based on bone-related biomarkers such as intact parathyroid hormone, calcium absorption, and bone mineral density, maintaining a 25(OH)D3 level of at least 32 ng/ml appears sufficient.
\nIt appears that vitamin D is a potent immunomodulator. It has multiple and diverse effects on the immune system. In particular, it potentiates the innate immune response enhancing the production of cathelicidin from human macrophages, monocytes, and keratinocytes, thus enhancing and potentiating the immune response against external pathogens. It affects the adaptive immune response shifting the phenotype of the adaptive immune response toward a more tolerogenic phenotype. Vitamin D deficiency is related to various autoimmune disorders. Vitamin D deficiency appears to be related to the development of RA and correlates with disease severity. Vitamin D deficiency is observed in patients with SLE. It was found to be related to disease severity and activity in some but not all studies. Vitamin D deficiency is observed in patients with multiple sclerosis, and vitamin D administration may ameliorate disease severity. Vitamin D deficiency is also observed in patients with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis, and it is related to disease activity. Vitamin D contributes to the integrity of the intestinal barrier and bacterial homeostasis. In addition, vitamin D absorption is decreased making supplementation important. Vitamin D deficiency is also observed in patients with autoimmune Hashimoto’s thyroiditis. Vitamin D deficiency is found in patients with systemic sclerosis, especially the diffuse form of the disease. It appears that optimal levels of vitamin D are important for immune function and for the prevention of autoimmunity in the human organism.
\nThe authors declare no conflict of interest.
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