PREFACE

Gives thanks to God, because only by His blessing, author can finish this paper with great ease. Without the help of Him, author probably will not be able to complete the paper properly. I also want to express my great appreciation to dr.Suweino,Sp.Bkm as my supervisor, who has given me a lot of input and advises when I made this paper. I want to express my gratitude to my parents and my friends for all of the support, interests, and partnership, so I could finish this paper. This paper is structured so readers can know the effect of free radicals to general immune system. Nowadays free radicals have been proven as the reason which involves destroying human body cells in many people. So it is important to us to know more about this issue. Hopefully this paper can provide the broader insight to the reader. I am going to be very pleasant if reader can give some inputs, so that I can make better writing for the next papers.

Jakarta, July 2010 Elizabeth Joan Salim 030.07.080

TABLE OF CONTENT

PREFACE 1 TABLE OF CONTENTS. 2 ABSTRACT. 3 CHAPTER I : INTRODUCTION... 4 A. Issue Background. 4 B. The History of Free Radical Theory. 5 C. Free Radical.. 6 D. Major Type of Free Radical.. 8 E. Biological Effect of Free Radical. 9 F. Limitation of Problems.11 CHAPTER II : THE EFFECT OF FREE RADICAL TO IMMUNE SYSTEM12 CONCLUSION15 REFERENCES.16

ABSTRACT

One of the most widely accepted theories proposed to explain ageing is the free radical theory, according to which oxygen derived free radicals cause age-related impairment through oxidative damage to bio molecules, with mitochondria being the main target of free radical attack. Some of free radical compounds called reactive oxygen species (ROS), reactive oxygen intermediates (ROI), reactive nitrogen species (RNS), and reactive nitrogen intermediates (RNI) are produced by nearly all cells in the human body. Free radicals are normal by products of metabolic processes. Relating to the immune system specifically, free radicals damage immune cells and wipe out cytokine (communication) pathways.

CHAPTER I
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INTRODUCTION
A. ISSUE BACKGROUND Free radicals are highly reactive atoms or group of atoms with an unpaired electron. This is what makes them to become dangerous as they can react with important cellular components such as DNA, or the cell membrane in our body. The cells in our body may be damaged and die by such chemical reactions. They can cause all sorts of deadly diseases such as cancer, leukemia, diabetes, kidney problems, liver problems, skin problems, etc.. Needless to say, free radicals also speed up the aging process. We're living in a free radical environment; ionizing radiation from industry, lead, radiations, automobile pollutions, etc. Our body is always bombarded by free radicals in the environment. Upon breathing, oxygen induces a process called oxidation. And it is where free radicals form. This process is likened to the oxidation of metals. Once oxidized, aluminum turns to be white, iron becomes rusty, and copper transforms into green. In the same logic that oxidation damages metals; free radicals are also harmful to our body. Of course, free radicals are not only come from the environment, they can also be produced by our body's metabolism as a result of our diets. Therefore, living a healthy lifestyle and eating well-balanced diets can also help to curb free radicals. As you can see, we need to take proactive actions to protect our body from free radicals. The solution to this problem is antioxidants as they are our body's defense system. Antioxidants can neutralize and prevent free radical damage to the body.

B. THE HISTORY OF FREE RADICAL THEORY In 1956, Denham Harman suggested that free radicals produced during aerobic respiration cause cumulative oxidative damage, resulting in aging and death. He noted parallels between the effects of aging and of ionizing radiation, including mutagenesis, cancer, and gross cellular damage. At the time, it had recently been discovered that radiolysis of water generates hydroxyl radical (OH), and early experiments using paramagnetic resonance spectroscopy had identified the presence of OH in living matter. Harman therefore hypothesized that endogenous oxygen radical generation occurs in vivo, as a by-product of enzymatic redox chemistry. He ventured that the enzymes involved would be those "involved in the direct utilization of molecular oxygen, particularly those containing iron." Finally, he hypothesized that traces of iron and other metals would catalyze oxidative reactions in vivo and that peroxidative chain reactions were possible, by analogy to the principles of in vitro polymer chemistry. All of these predictions have been confirmed during the past 40 years. The theory gained credibility with the identification in 1969 of the enzyme superoxide dismutase (SOD), which provided the first compelling evidence of in vivo generation of superoxide anion (O2-), and from the subsequent elucidation of elaborate antioxidant defenses. The use of SOD as a tool to locate subcellular sites of O2generation led to a realization that buttressed the free radical theory, namely, that mitochondria are a principal source of endogenous oxidants. Gerontologists had long observed that species with higher metabolic rates have shorter maximum life span potential (MLSP); they age faster. The realization that energy consumption by mitochondria may result in O2- production linked the free radical theory and the rate of

living theory irrevocably: a faster rate of respiration, associated with a greater generation of oxygen radicals, hastens aging. By now, the two concepts have essentially merged. C. FREE RADICAL The human body is composed of many different types of cells. Cells are composed of many different types of molecules. Molecules consist of one or more atoms of one or more elements joined by chemical bonds. Atoms consist of a nucleus, neutrons, protons and electrons. The number of protons (positively charged particles) in the atoms nucleus determines the number of electrons (negatively charged particles) surrounding the atom. Electrons are involved in chemical reactions and are the substance that bonds atoms together to form molecules. Electrons surround, or "orbit" an atom in one or more shells. The innermost shell is full when it has two electrons. When the first shell is full, electrons begin to fill the second shell. When the second shell has eight electrons, it is full, and so on. The most important structural feature of an atom for determining its chemical behavior is the number of electrons in its outer shell. A substance that has a full outer shell tends not to enter in chemical reactions (an inert substance). Because atoms seek to reach a state of maximum stability, an atom will try to fill its outer shell by:

Gaining or losing electrons to either fill or empty its outer shell Sharing its electrons by bonding together with other atoms in order to complete its outer shell Atoms often complete their outer shells by sharing electrons with other atoms. By

sharing electrons, the atoms are bound together and satisfy the conditions of maximum stability for the molecule. 6

Normally, bonds dont split in a way that leaves a molecule with an odd, unpaired electron. But when weak bonds split, free radicals are formed. Free radicals are very unstable and react quickly with other compounds, trying to capture the needed electron to gain stability. Generally, free radicals attack the nearest stable molecule, "stealing" its electron. When the "attacked" molecule loses its electron, it becomes a free radical itself, beginning a chain reaction. Once the process is started, it can cascade, finally resulting in the disruption of a living cell. Some free radicals arise normally during metabolism. Sometimes the bodys immune systems cells purposefully create them to neutralize viruses and bacteria. However, environmental factors such as pollution, radiation, cigarette smoke and herbicides can also spawn free radicals. Normally, the body can handle free radicals, but if antioxidants are unavailable, or if the free-radical production becomes excessive, damage can occur. Of particular importance is that free radical damage accumulates with age.

D. MAJOR TYPES OF FREE RADICALS Reactive Oxygen Species There are many types of radicals, but those of most concern in biological systems are derived from oxygen, and known collectively as reactive oxygen species (ROS). Oxygen has two unpaired electrons in separate orbitals in its outer shell. This electronic structure makes oxygen especially susceptible to radical formation. Sequential reduction of molecular oxygen (equivalent to sequential addition of electrons) leads to formation of a group of reactive oxygen species: o superoxide anion o peroxide (hydrogen peroxide) o hydroxyl radical The structure of these radicals is shown in the figure below, along with the notation used to denote them. Note the difference between hydroxyl radical and hydroxyl ion, which is not a radical.

Reactive Nitrogen Species The NO radical (NO) is produced in higher organisms by the oxidation of one of the terminal guanido-nitrogen atoms of L-arginine. This process is catalyzed by the enzyme NOS. Depending on the microenvironment, NO can be converted to various other reactive nitrogen species (RNS) such as nitrosonium cation (NO +), nitroxyl anion (NO ) or peroxynitrite (ONOO ). Some of the physiological effects may be mediated through the intermediate formation of S-nitroso-cysteine or S-nitrosoglutathione.

Reactions Involving Free Radicals Free radicals are highly unstable molecules that attempt to achieve a more stable state by reacting with other atoms or molecules in the cell. The four primary types of chemical reactions that free radicals undergo are: Hydrogen abstraction, in which a radical interacts with another molecule that has a free hydrogen atom (i.e., a hydrogen donor). As a result, the radical binds to the hydrogen atom and becomes stable, whereas the hydrogen donor is converted to a free radical. Addition, in which the radical binds to another, originally stable molecule, converting the combined molecule into a radical. Termination, in which two radicals react with each other to form a stable compound. Disproportionation, in which two identical radicals react with each other, with one of the radicals donating an electron to the other so that two different molecules are formed, each of which is stable. E. BIOLOGICAL EFFECTS OF FREE RADICALS

It is best not to think of oxygen radicals as "bad". They are generated in a number of reactions essential to life and, as mentioned above, phagocytic cells generate radicals to kill invading pathogens. There is also a large body evidence indicating that oxygen radicals are involved in intercellular and intracellular signaling. For example, addition of superoxide or hydrogen peroxide to a variety of cultured cells leads to an increased rate of DNA replication and cell proliferation - in other words, these radicals function as mitogens. Despite their beneficial activities, reactive oxygen species clearly can be toxic to cells. By definition, radicals possess an unpaired electron, which makes them highly reactive and thereby able to damage all macromolecules, including lipids, proteins and nucleic acids. One of the best known toxic effects of oxygen radicals is damage to cellular membranes (plasma, mitochondrial and endomembrane systems), which is initiated by a process known as lipid peroxidation. A common target for peroxidation is unsaturated fatty acids present in membrane phospholipids. A peroxidation reaction involving a fatty acid is depicted in the figure below:

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Reactions involving radicals occur in chain reactions. Note in the figure above that a hydrogen is abstracted from the fatty acid by hydroxyl radical, leaving a carbon-centered radical as part of the fatty acid. That radical then reacts with oxygen to yield the peroxy radical, which can then react with other fatty acids or proteins. Peroxidation of membrane lipids can have numerous effects, including: increased membrane rigidity decreased activity of membrane-bound enzymes (e.g. sodium pumps) altered activity of membrane receptors altered permeability

In addition to effects on phospholipids, radicals can also directly attack membrane proteins and induce lipid-lipid, lipid-protein and protein-protein cross-linking, all of which obviously have effects on membrane function. F. LIMITATION OF PROBLEMS To clarify the scope of discussion, the issues discussed is limited to The Effect of Free Radical to General Immune Systems. Author makes this limitation because there are many effect of free radical to our body, and this paper will discuss too many things if all of the effect is explain. If that happens, I am afraid this paper will losses its focus and discusses something less important.

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CHAPTER II THE EFFECT OF FREE RADICAL TO GENERAL IMMUNE SYSTEM

The immune cell functions such as those involved in the cytotoxic activity and particularly in phagocytes as regards their microbicidal activity, are specially linked to reactive oxygen species (ROS) generation. However, as mentioned above, excessive amounts of ROS which are not counteracted by the antioxidant defenses of the cell, can become a source of tissue damage, since free radicals can attack cellular components and lead to death because of the molecular damage resulting from oxidative stress. Thus, the immune cell functions are strongly influenced by the antioxidant / oxidant balance and, therefore, the antioxidant levels in these cells play a pivotal role in maintaining immune cells in a reduced environment and in protecting them from oxidative stress and preserving their adequate function. More specifically, antioxidants maintain the integrity and function of membrane lipids, cellular proteins, and nucleic acids and the control of signal transduction of gene expression in immune cells. For this reason the immune cells are particularly sensitive to changes in their antioxidant status. Moreover, since the immune system cells have a high percentage of polyunsatured fatty acids in their plasma membrane, it is not surprising that these cells usually contain higher concentrations of antioxidants than do other cells. Indeed, since the early years of the twentieth century the history of the relationship between antioxidants and immunology began with an appreciation that antioxidant nutrient deficiencies may cause disease, and that antioxidants have an immuno-stimulating action. Although recent results throw doubt on this concept, since a total neutralization of ROS could block their functional role and higher 12

levels of antioxidants can produce oxidant effects, the administration of antioxidants has been shown to improve several immune functions.

The first part of the immune system - the Complement System - is made up of proteins that meet invaders such as bacteria. These proteins flow freely in the blood. They quickly reach the site of invasion where they trigger inflammation, attract "eater" cells to the area, or coat the intruders so eater cells can devour and kill the pathogens. Phagocytes are a group of immune cells that specialize in finding and "eating" bacteria, viruses, and dead or injured body cells. There main types of phagocytes include: granulocytes. They take the first stand during an attack or infection. They attack invaders in large amounts and "eat" until they die. The "pus" in an infected wound consists chiefly of dead granulocytes. macrophages or "big eaters". They are slower to respond to invaders than granulocytes, but they are larger, live longer, and have far greater capacities. 13

They produce free radicals (ROS) and (RNS) which they use to kill bacteria. For decades, researchers believed free radicals killed bacteria by destroying their DNA. New studies show that macrophages dump free radicals on extracellular bacterial targets in order to destroy the microbes. Macrophages also play a key part in alerting the rest of the immune system members. dendritic cells or "eater" cells devour intruders and help activate the immune system. They filter body fluids to clean them of foreign organisms and particles. neutrophils are white blood cells that kill bacteria or pathogens with superoxide radical (O2-) and hydrogen peroxide (H2O2). Neutrophils and macrophages kill bacteria through respiratory or oxidative burst - the rapid release of superoxide radical and hydrogen peroxide when the cells come into contact with pathogens. There are many ways the free radicals thwart humans immune system: 1. The immune cells themselves (T-cells, natural killer cells, etc) are damaged. 2. They knock out the cytokine pathways 3. And last, but not least, it upsets the delicate balance of free radicals that macrophages use to work. Macrophages actually release their own free radical, nitrous oxide, to destroy bacteria, parasites and viruses. If the free radical/antioxidant balance is out, the nitrous oxide ends up destroying the macrophage also.

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CHAPTER III CONCLUSION

Free radicals are atoms or groups of atoms with an odd (unpaired) number of electrons and can be formed when oxygen interacts with certain molecules. Once formed these highly reactive radicals can start a chain reaction, like dominoes. Their chief danger comes from the damage they can do when they react with important cellular components such as DNA, or the cell membrane. Cells may function poorly or die if this occurs. To prevent free radical damage the body has a defense system of antioxidants. There are many ways the free radicals thwart humans immune system: 1. The immune cells themselves (T-cells, natural killer cells, etc) are damaged. 2. They knock out the cytokine pathways 3. It upsets the delicate balance of free radicals that macrophages use to work.

REFERENCES
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1. De la Fuente M & Victor VM (2000) Antioxidants as modulators of immune function. Immunol.Cell Biol. 78, 49 54. 2. Harman D (1956): Aging: a theory based on free radicals and radiation chemistry. J. Gerontol. 11, 298 300. 3. Knight JA (2000): Review: free radicals, antioxidants and immune system. Ann. Clin. Lab. Sci. 30, 145 158 4. Acworth, I.N., and B. Bailey. Reactive Oxygen Species. In: The handbook of oxidative metabolism. Massachusetts: ESA Inc., 1997, p. 1-1 to 4-4. 5. Halliwell, B., and J.M.C. Gutteridge. The chemistry of oxygen radicals and other oxygen-derived species. In: Free Radicals in Biology and Medicine. New York: Oxford University Press, 1985, p. 20-64. 6. R.J. Mehlhorn, in Physiological Basis of Aging and Geriatrics, edited by Paola S. Timiras (CRC Press, Ann Arbor, 1994), pp. 61-72. 7. Takayuki Ozawa in Understanding the Process of Aging, edited by Enrique Cadenas and Lester Packer (Marcel Dekker, New York, 1999), pp. 265-292. 8. Nathan C et al. "Nitric Oxide and Macrophage Function" Ann Rev of Immunol 1997 April;15:323-350 9. Harman D (1986): Free radical theory of aging: role of free radicals in the origination and evolution of life, aging and disease processes. In: Free Radicals, Aging and Degenerative Diseases ed. JE Johnson Jr, R Walford, D Harman, J Miquel, pp 3 49. New York: Liss. 10. Karlsson, J. Introduction to Nutraology and Radical Formation. In: Antioxidants and Exercise. Illinois: Human Kinetics Press, 1997, p. 1-143.

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