REACTIVE OXYGEN SPECIES INDUCES IMMUNO-SUPPRESSION: THERAPEUTIC

STRATEGIES TO IMPROVE IMMUNE STATUS IN AUTOIMMUNITY AND

CHRONIC PATHOPHYSIOLOGICAL STRESS

BY

OYEBAMIJI, DEBORAH BUKOLA [email: bukolaoyebams@yahoo.com]

104/07/2023

OUTLINE INTRODUCTION

SOURCES AND CONSEQUENCES OF INCREASE REACTIVE OXYGEN SPECIES

IMMUNE SYSTEM

ROS AND IMMUNOSUPPRESSION

ROS AND AUTOIMMUNITY

ROS AND CHRONIC PATHOPHYSIOLOGICAL STRESS

THERAPEUTIC STRATEGIES TO IMPROVE IMMUNE STATUS IN

AUTOIMMUNITY AND CHRONIC PATHOPHYSIOLOGICAL STRESS

CONCLUSION204/07/2023

INTRODUCTION• Reactive oxygen species (ROS)

• Antioxidant

• Oxidative stress

• Immunity

• Immunosuppression

• Autoimmunity

• Chronic stress

(Al-Mamun et al., 2007)304/07/2023

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ILLUSTRATIONS

(Holt 2003)

SOURCES AND CONSEQUENCES OF INCREASED ROS GENERATION

• The mitochondrial respiratory chain

• Exogenous factors such as ultraviolet light, ionizing radiations and chemical reactions.

• Respiratory Burst

• Transition metals ions(Trifunovic and Larsson, 2008)

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• Consequences:

lipid peroxidation

DNA damage

Oxidation of protein.

(Devi et al., 2007)

• Oxidative damage to cellular components results in

altered cellular function

compromised tissue and organ function

death (Rahman, 2007)

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THE IMMUNE SYSTEM• The immune system is made up of a vast and highly

complex network of cells, tissues and organs that all work in unison all of the time to protect the body from harm.

• A key element of immunity is the recognition of ‘self’ and of ‘nonself’.

(MRI, 2009)

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CELLS OF THE IMMUNE SYSTEM

Jim Johnson, 2006 804/07/2023

ROS AND IMMUNOSUPPRESSIONImmunosuppression could result from;• Ageing• Diseases• Stress • Malnutrition • UV radiation

904/07/2023

ROS AND IMMUNOSUPPRESSION• Immune cell have high polyunsaturated fatty acids

(PUFA) content.

• Immune cells are at risks of lipid peroxidation by ROS.

• Lipid peroxidation decreases membrane fluidity.

• Loss of membrane fluidity has been related directly to the decreased ability of lymphocytes to respond to challenges to the immune system

(Bendich et al., 1990)1004/07/2023

ROS AND AUTOIMMUNITY• Environmental factor (Stejskal et al., 1999).• Genetic predisposition• Infections via cross-reactivity between foreign and

host antigens. (Dixit et al., 2001) • Inefficient clearance of apoptotic cells (Casiano et

al., 2006).• Exaggerated B cell proliferation• Quantitative or qualitative abnormalities of

regulatory T cells and natural killer (NK) T cells.• Malnutrition (Vit. D deficiency) (Ritterhouse ,2011).

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ROS AND AUTOIMMUNITY• ROS are physiologic activators of transcription

factors(activator protein -1 and nuclear factor-kB) for pro-inflammatory cytokines

• ROS can modulate the expression of a variety of immune and inflammatory molecules leading to inflammatory processes, exacerbating inflammation and can lead to tissue damage

(Sukkar et al., 2004) ) 1204/07/2023

ROS AND CHRONIC PATHOPHYSIOLOGICAL STRESS

Chronic stress could arise from• Disease• Anxiety• Past experience• Psychosocial • Environmental factors• Work pressure• Interpersonal conflict• Bereavement

1304/07/2023

1404/07/2023 Thomas Guilliams and Lena Edwards 2010

ROS AND CHRONIC PATHOPHYSIOLOGICAL STRESS

• Chronic stress is associated with increased ROS production

• The persistent production of large amounts of ROS may induce changes in signal transduction and gene expression determining a chronic stress condition .

(Droge, 2002) 1504/07/2023

Relationship between ROS and Immune system

↑ROS ↑CELL DAMAGE AUTOIMMUNITY ↑CPS IMMUNE SUPRESSION

• Therefore any mechanism that will reduce ROS may serve as a thetaspeutic strategy to improve immune status autoimmunity and chronic pathophysiological stress 1604/07/2023

Antioxidant Protection System

MARK PERCIVAL ,199617

Endogenous Antioxidants• Thiols, e.g glutathione, lipoic acid, N-acetyl cysteine• Enzymes:

Copper/zinc and manganese- dependent superoxide dismutase (SOD)

Iron-dependent catalaseSelenium-dependent gluathione peroxidase

Dietary Antioxidants• Vitamin C• Vitamin E• Beta carotene and other carotenoids e.g. lycopene • Polyphenols e.g flavonoids, flavones,

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THERAPEUTIC STRATEGIES

18

• Vitamin A supports healthy immune function (immunity booster)

• Lycopene and β-carotene possess antioxidant,

anti-infection, anti-proliferative and anticancer activity in humans

(Dahan et al., 2008) 04/07/2023

19

• Vitamin C is a powerful antioxidant acting to alleviate, the deleterious effects caused by ROS.

• It works synergistically with vitamin E to quench free radicals and also regenerates the reduced form of vitamin E

(Arulmozhi et al., 2010)

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20

• Vitamin E α-tocopherols via its interaction with lipids, stabilize membranes, and scavenges ROS and lipid soluble byproducts of oxidative stress

• Vitamin E has been shown to reduce several different markers of inflammation in the body, including inflammatory cytokines

• Vitamin E helps stabilize membranes of lysosomes, or immune cells that contain destructive enzymes used to fight intruders.

(Shao et al., 2008) 04/07/2023

21

• The antioxidant enzymes – metabolize oxidative toxic intermediates and require micronutrient cofactors for optimum catalytic activity.

Glutathione peroxidase – selenium

Catalase – iron

Superoxide dismutase (SOD) - copper, zinc, and manganese

(Corpas et al., 2006)04/07/2023

Antioxidant enzymes

ROS, the primary antioxidant enzymes

and antioxidants. Abbreviations are

indicated in the text. GPx,

glutathione peroxidase; GR, glutathione reductase; GSH,

glutathione; GSSG, glutathione disulphide; MPO, myeloperoxidase;

NADPH oxidase, nicotinamide adenine

dinucleotide phosphate oxidase; Prx,

peroxiredoxin;

SOD, superoxide

dismutase; TR, thioredoxin

reductase; Trx, thioredoxin; Trx-S-S-Trx, thioredoxin

disulfide. The British Journal of Radiology, 80 (2007), S23–S31 2204/07/2023

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• Lipoic acid and its reduced form, dihydrolipoic acid (DHLA), are capable of quenching free radicals in both lipid and aqueous domains and as such has been called a “universal antioxidant.

• Lipoic acid may also exert its antioxidant effect by chelating with pro-oxidant metals.

• Lipoic acid has a sparing effect on other antioxidants as it protect against the symptoms of vitamin E or vitamin C deficiency.

( Packer et al., 1995)04/07/2023

24

• Supplementation with N-acetylcysteine support the body’s antioxidant systems by increasing levels of glutathione, the body’s major antioxidant

• Polyphenols can be classified into phenolic acids, flavonoids, stilbenes and lignans possess antioxidant activity

(Atawodi et al., 2009)

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25

• Vitamin D intervenes in the process of autoimmunity by tilting the properties of T- and B-cells towards "tolerance" of self tissues.

• Vitamin D exerts multiple actions at the cellular level to balance the population of effector cells and regulatory cells

(Bruce 2011)04/07/2023

THERAPEUTIC HERBS• Ginkgo biloba contains flavonoids and terpenoids,

which are antioxidants (Muir 2002).

• Pine bark extract reduce oxidative stress (Stefanescu 2001).

• Curcumin antioxidant, anti-cancer, and anti-inflammatory clinical properties (Kurien 2010).

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27

NEEM ECHINACEA

GINSENGGINKGO BILOBA

PINE BARK

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CURCUMIN

GARLIC BULBONION BULBCAYENNE PEPPER

ROSE MARY

HORSERADISH04/07/2023 28

Others include:• Echinacea• Cayenne pepper• Garlic bulb• Onion bulb• Horse radish• Rosemary• Ginseng• Neem

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30

• Hematopoietic stem cell transplantation (HSCT) (Sykes et al., 2005).

• Monoclonal antibodies (Thanou-Stavraki 2011).

• Immune System Modulators called immunosupressives (Goekoop et al, 2005; Walsh 2007; Shun 2011; Hahn 2011).

• Anti-Inflammatory Drugs Corticosteroids (Ben-Zvi 2011; Chang 2011; Yildirim-Toruner 2011)

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Therapeutic Options For Stress• Regular sleep, relaxation and non-competitive

exercise

• Learning to perceive and respond to stressful situations in ways that do not stimulate the HPA axis

• Mediterranean like balanced diet. (Sofi et al 2008) Supplement with soluble and fermentable fibers Increase phytonutrients (Kurien 2010).

• Supplementing with Dehydroepiandrosterone DHEA (Coates 2010).

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CONCLUSION

• In conclusion, maintaining adequate antioxidant status may provide a useful approach in attenuating ROS mediated cell injury and dysfunction observed in some inflammatory/ autoimmune disorders and chronic Pathophysiological stress

3204/07/2023

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REFERENCES Dixit K, Ali R. Antigen binding characteristics of antibodies induced against nitric

oxide modified plasmid DNA. Biochim Biophys Acta 2001; 1528:1–8. S.G. Sukkar, E. Rossi / Autoimmunity Reviews 3 (2004) 199–206 Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T. Requirement for generation of

H2O2 for platelet-derived growth factor signal transduction.Science 1995; 270:296–9

Tsai KJ, Hung IJ, Chow CK, Stern A, Chao SS, Chin DTY. Impared production of nitric oxide, superoxide and hydrogen peroxide in glucose 6-phosphate dehydrogenase-deficient granulocytes. FEBS Lett 1998; 436:411–4.

Nordberg J, Arne´r ESJ. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free RadicalBiol Med 2001;31:1287 –312.

Droge W. Free radicals in the physiological control of cell function. PhysiolRev 2002;82(1):47 –95.

Dekhuijzen PN. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J. 2004;23(4):629-636

3Bendich. A. 1990. Antioxidant vitamins and their functions in immune responses. Page 33 in Antioxidant Nutrients and Immune Functions. A. Bendich, M. Phillips, and R. P. Tengerdy, ed. Plenum Press, SSNew Yo&, NY.

04/07/2023 34

Sofi, F., Cesari, F. et al. Adherence to Mediterranean diet and health status: meta-analysis. BMJ. 2008; 337:a1344-

Wintergerst ES, Maggini S, Hornig DH: Contribution of selectedvitamins and trace elements to immune function. Ann NutrMetab 2007, 51(4):301-23.

Padayatty, S. J., Doppman, J. L. et al. Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone. Am J Clin Nutr. 2007; 86(1):145-149.

Casiano CA, Pacheco FJ: Cell death and autoimmunity. In Autoantibodies and Autoimmunity Edited by: Pollard KM. Weinheim: Wiley-VCH Verlag; 2006:107-137.

De la Fuente M, Hernanz A, Vallejo MC: The immune system in the oxidative stress conditions of aging and hypertension: favorable effects of antioxidants and physical exercise. Antioxid Redox Signal 2005, 7(9–10):1356-1366.

Roux E, Dumont-Girard F, Starobinski M, Siegrist CA, Helg C, Chapuis B, Roosnek E: Recovery of immune reactivity after Tcell- depleted bone marrow transplantation depends on thymic activity. Blood 2000, 96:2299-2303.

Sykes M, Nikolic B: Treatment of severe autoimmune disease by stem-cell transplantation. Nature 2005, 435:620-627.

04/07/2023 35

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, et al.: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005, 52:3381-3390.

Packer, L. and Witt, E.H., Antioxidant Properties and Clinical Implications of Alpha-Lipoic Acid. in Packer L. and Cadenas E. eds. Biothionls in Health and Disease. New York: Marcel Dekker, Inc, 1995, 479-516.

Kagen, V.E., et al., Dihydrolipoic Acid–a Universal Antioxidant Both in the Membrane and in the Aqueous Phase. Biochem Pharmacol 199244:1637-1649.

Mark Percival Antioxidants; clinical nutrition insights 1996 Advanced Nutrition Publications, Inc.

04/07/2023 36

W ZHAO, PhD, D I DIZ, PhD and M E ROBBINS, PhD Oxidative damage pathways in relation to normal tissue injury The British Journal of Radiology, 80 (2007), S23–S31

Stejskal J, Stejskal VD: The role of metals in autoimmunity and the link to neuroendocrinology. Neuro Endocrinol Lett 1999, 20(6):351-364.].

Jim Johnson Cellular and Physiological Sciences 2006 Ben-Zvi, I., et al., Hydroxychloroquine: From Malaria to Autoimmunity. Clinical

reviews in allergy & immunology, 2011. Bruce D et al. Converging pathways lead to overproduction of IL-17 in the

absence of vitamin D signaling. Int Immunol. 2011 Aug;23(8):519-28. Epub 2011 Jun 22.

Chang, A.Y., et al., Response to Antimalarial Agents in Cutaneous Lupus Erythematosus: A Prospective Analysis. Archives of dermatology, 2011.

Coates, P.M., Encyclopedia of dietary supplements, 2010, Informa Healthcare,: New York. p. 1 online resource (xix, 898 p.).

Haubitz, M., New and emerging treatment approaches to lupus. Biologics : targets & therapy, 2010. 4: p. 263-71.

Hahn, B.H., Targeted therapies in systemic lupus erythematosus: successes, failures and future. Annals of the rheumatic diseases, 2011. 70 Suppl 1: p. i64-i66.

04/07/2023 37

Harbige, L.S., Nutrition and immunity with emphasis on infection and autoimmune disease. Nutrition and health, 1996. 10(4): p. 285-312.

Kurien, B.T., A. D'Souza, and R.H. Scofield, Heat-solubilized curry spice curcumin inhibits antibody-antigen interaction in in vitro studies: a possible therapy to alleviate autoimmune disorders. Molecular nutrition & food research, 2010. 54(8): p. 1202-9.

Ritterhouse, L.L., et al., Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus. Annals of the rheumatic diseases, 2011. 70(9): p. 1569-74.

Shum, K. and A. Askanase, Treatment of lupus nephritis. Current rheumatology reports, 2011. 13(4): p. 283-90.

Singh, U., S. Devaraj, and I. Jialal, Vitamin E, oxidative stress, and inflammation. Annual review of nutrition, 2005. 25: p. 151-74.

Thanou-Stavraki, A. and A.H. Sawalha, An update on belimumab for the treatment of lupus. Biologics : targets & therapy, 2011. 5: p. 33-43.

Walsh, M., et al., Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. Clinical journal of the American Society of Nephrology : CJASN, 2007. 2(5): p. 968-75.

Yildirim-Toruner, C. and B. Diamond, Current and novel therapeutics in the treatment of systemic lupus erythematosus. The Journal of allergy and clinical immunology, 2011. 127(2): p. 303-12; quiz 313-4.

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THANK YOU