Ascorbic Acid and the Immune SystemFred Ottoboni, M.P.H., Ph.D.;' Alice Olloboni. Ph.D.'

BackgroundOur introduction to the benefit of vi-

tamin C for preventing head colds was astudy reported by Cowan. Diehl, and Bakerin 1942 in which 200 mg/day reduced theincidence and severity of the common coldin a group of university students.' At thattime, approximately 30 mg/day of vitaminC was considered to be all that was neces-sary to prevent scurvy, the only illness ac-cepted by the nutrition establishment asbeing related to vitamin C deficiency. Thus,200 mg was considered a megadose andlooked upon with skepticism by many phy-sicians. Such a radical notion was bound tostir a lot of interest in the medical commu-nity and stimulate further investigations.

Over the succeeding decades hundredsof studies of the effects of vitamin C (here-after referred to as ascorbic acid), ratherthan settling the matter, only added fuel toa growing controversy; studies showingbenefits were countered with studies thatshowed no benefit. The medical and nu-trition communities endorsed the negativestudies because they confirmed their pro-fessional opinion that ascorbic acid had novalue, except for prevention of scurvy.Pauling surmised that perhaps the "'lack ofenthusiasm" for ascorbic acid on the partof physicians and nutritionists might bedue to their mistaken idea that ascorbicacid was a drug and, like drugs, was toxic.Thus, it was to be administered only insmall quantities.-* As a result, these smallquantities assured failure in studies of ef-fects of ascorbic acid because they were toosmall to give positive results. PerhapsPauling's most intuitive surmise was a "lackof interest of the drug companies in a natu-ral substance that is available at a low priceand cannot be patented."

1. Public health .scientist, retired. 4956 Santa Barbara Ave.,Sparks, NV 89436-3607. USA.

Despite the naysayers, a few coura-geous and dedicated physicians exploredthe therapeutic use of large and frequentdoses ascorbic acid, orally and intrave-nously, for a wide variety of infectious andnoninfectious diseases, often with miracu-lous results."' These valuable contribu-tions to the fund of knowledge on thetherapeutic benefits of ascorbic acid re-mained largely ignored until Pauling en-tered the field in the late lQbOs." The posi-tive experience he and his wife had hadwith an ascorbic acid regime, in the facethe prevailing medical opinion that ascor-bic acid was of no value in treating thecommon cold, led him to examine the sub-ject for himself."

As the recipient of two Nobel Prizes(Chemistry, 1954; Peace 1962). Pauling wasa well-known public figure; thus, his writ-ings on any subject were widely read. Thoseon ascorbic acid spread the word amongthe general public and scientists outside ofthe medical community about the use ofascorbic acid for preventing and treatingthe common cold. Although his writingsgreatly increased public awareness andinterest in ascorbic acid, they did little to stemthe controversy, primarily because of opposi-tion from the medical and nutrition estab-lishments. The situation seems little changedtoday from the time that Pauling first broughtascorbic acid to public attention, except thatsales of orange juice have experienced a greatincrease and vitamin C supplements arewidely available in drug stores.

Ascorbic Acid RevisitedDespite the fact that the general pub-

lic and the medical and nutrition commu-nities still think of ascorbic acid as only avitamin, a considerable amount of research.both theoretical and practical, has beenconducted on ascorbic acid during the pastseveral decades. The vast amount of infor-

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mation produced by this research, whichdemonstrates that ascorbic acid is not justa vitamin but an indispensable therapeu-tic agent, is well summarized by Levy.'

In 1959. Burns reported that the hu-man requirement for ascorbic acid is theresult of an inborn error of carbohydratemetabolism."* In most animal species, glu-cose is converted through a series of fourreactions to ascorbic acid In a tew mammalianspecies, most notably the human, tlie enzymefor the fourth step, L-gulonolactone oxidase.is inactive. As a result, the conversion ofglucose to ascorbic acid cannot be com-pleted. It has been calculated that if hu-mans had intact glucose/ascorbic acidpathways, they would produce about twoto four grams of ascorbic acid per day un-der normal conditions and at least 15grams per day under stress."

Studies of ascorbic acid at the molecu-lar, cellular, and clinical levels conductedby a host of scientists from a variety of dis-ciplines have revealed that ascorbic acidplays multiple biochemical roles. In addi-tion to its participation in immunity, whichis described below, ascorbic acid also servesimportant enzymatic, antioxidant, andregulatory functions. However, from theviewpoint of the clinician, perhaps the mostimportant finding about ascorbic acid ac-tivity is its competition with glucose withinthe body. In 1975. Mann proposed that.because of their structural similarity, ascor-bic acid and glucose might utilize the samemembrane transport.' This extremely im-portant concept was eventually confirmedexperimentally'" '̂ and ultimately led to anunderstanding of how glucose and ascor-bic acid compete for transport by insulinand entry into cells.'''

Independent of the mechanisms bywhich ascorbic acid performs its essentialbiochemical roles, the facts of this interre-lationship between glucose and ascorbicacid should be widely disseminatedthroughout the medical and nutrition com-munities. For one, it explains why some

studies have shown little or no benefit fromoral administration of ascorbic acid; theydid not control for dietary provision of glu-cose, which would successfully competewith ascorbic acid and prevent its utiliza-tion. And two, it underscores the need fordietary carbohydrate restriction if ascorbicacid supplementation is to be of benefit ina healthful nutrition program.

Ascorbic Acid's Role in ImmunityNumerous reports in the older scien-

tific literature describing the antibacterialactivity of ascorbic acid in vivo and invitro"'-^^ suggested a role for ascorbic acidin immunity. Other studies demonstratedthat the ascorbic acid content of leukocytes,which are responsible for host defence, wasup to 80 times greater than that in theplasma.""'' Such a large difference betweenintra- and extracellular concentrationscould only be effected by an active trans-port system. The fact that ascorbic acid isactively transported into leukocytes againsta plasma concentration gradient is testi-mony to the importance of ascorbic acid forimmune function. Studies such as thesewere accompanied by many others andeventually led to elucidation of the role ofascorbic acid in immune function.-"''

Figure f (p. 181) presents a simplifiedoverview of the relationship of ascorbic acidto the immune system. Starting at the upperleft-hand comer of the diagram, it shows thatinsulin carries both glucose and ascorbic acidto all cells of the body, including the phago-cytic cells that seek, attack, and remove bac-teria, viruses, tumor cells, and assorted mi-croscopic cellular debris from the blood. Thiscommon transport system describes thecompetition between glucose and ascorbicacid and explains why. in order to exert a ben-eficial efFect. large doses of ascorbic acid arenecessary to overcome inhibition by glucose.Glucose not only inhibits the transport ofascorbic acid to all cells of the body but alsoinhibits stimulation of the hexose monophos-phate (HMP) shunt by ascorbic acid."

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Ascorbic Acid and the Immune System

Figure 1. The relationship of ascorbic acid to the immune system.

AntioxidantDestructionor Hxcess(Toxic)

He.xoseMonopbusphatc

ShuntA scries OT

biochemical reactionsUsed to:

1 Reducu iiiai;mcoenzN'nie NADPto hADPH

2. > Produc:e 5-carbon(ribiise) sugars

5-Carbon Sugars

I'.xcessReactiveOxygenSpecies

Used lomake R]s'Aand DKAfor immunecell prolif-eration

Embdcn-MeyerhoffPathway

(Glycoiysis) PhagocyticImmune Cells

NADPH Used toMake

Reactive OxygenSpecies

/ Krebs \\ Cyele ,;

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The HMP shunt is a detour betweenthe first and second steps of the Hmbden-Meyerhoff glycolytic pathway. As shown inFigure 1, the first step in glycolysis, inpreparation for conversion of glucose toCO2. H,iO. and energy in the Krebs cycle, isphosphorylation to glucose-6-P. The sec-ond step iu glycolysis is rearrangement ofglucose-6-P to fructose-6-P Again in Fig-ure 1, ascorbic acid stimulates the diver-sion of glucose-6-P from glycolysis to theHMP shunt.

Two of the functions of the HMP shuntare important for the immune system. Oneis conversion of glucose (six carbons) to tbefive-carbon sugars, ribose and deoxyribose,wbicb are essential for synthesis of tbe ge-netic components RNA and DNA. respec-tively Tbe second is reduction of tbe niacincoenzyme NADP to NADPH, wbicb is neededfor participation in a variety of oxidation re-actions. Tbe components of tbe sbunt tbatare leftover after tbe needs for five-carbonsugars and NADPH are met are returned toglycolysis at tbe fructose-6 P step.

Tbe five carbon sugars are needed bytbe immune system to support elevatedmitotic activity for proliferation of immunesystem cells. Tbe first line in bost defenceagainst patbogens is rapid deployment oflarge numbers of pbagocytic leukocytes. Assbown in Figure 1, tbe five-carbon sugarspermit syntbesis of tbe DNA and RNA re-quired for tbis proliferation of pbagocyticcells. Tbe NADPH generated by tbe HMPsbunt is used by pbagocytes to producesuperoxide and a series of bigbly reactiveoxygen species, wbicb are used, in turn, tokill tbe invading patbogens.''-'

Finally, pbagocyte-derived bigbly reac-tive oxidants tbat are in excess of what areused by pbagocytes for tbeir killer activityleak out of tbeir cells into extracellular space.Tbese oxidant biocbemicals are toxic lo bostcells and must be destroyed before tbey dodamage to tbe bost. Ascorbic acid comesinto play bere and, serving as an antioxidant.destroys tbese excess toxins.-'

ConclusionTbere exists in tbe scientific literature

a wealtb of data tbat explains tbe role ofascorbic acid in immune system functionand documents its requirement for greatertban micronutrient quantities to figbt in-fections. Tbe inbibitory effect by glucoseof tbe actions of ascorbic acid could wellexplain tbe lack of beneficial effect of ascor-bic administration in many studies re-ported in tbe literature because few, if any,sucb studies controlled for dietary carbo-bydrates. In ligbt of tbe current dietarysugar excesses and concomitant obesityepidemic, clinicians sbould be reminded oftbe great importance of tbe long recognizedbut largely unappreciated inbibitory actionof glucose against ascorbic acid. In sum-mary, ascorbic acid is essential for effec-tive immune system function and, furtber,it can be a potent immune systemstimulator wben bigb glycemic dietary car-bobydrates are restricted.

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