EFFECTS OF ALCOHOLISM ON IMMUNE RESPONSE

PATHOGEN & MOLECULAR REGULATION

• Whenever the human body encounters a foreign particle, the immunological response is triggered in the following manner,

Firstly, the antigen binds to the cell surface receptor.

The receptor then conveys a signal to the cell’s interior & then to the nucleus.

Then the cellular DNA directs the synthesis of proteins specific to the antigen.

ALCOHOLISM vs MOLECULAR REGULATION

• Alcohol alters the molecular mechanisms that control cellular responses to normal stimuli.

• There are no specific receptors for alcohol.• Alcohol disturbs the normal molecular regulation in

two ways,Modifies the structure of the receptors

harbored in the cell.By frequently fluctuating the ionic

concentration (K⁺, Ca⁺⁺) in the cell.

• Both potassium and calcium ion concentrations change rapidly in the cell’s interior during various types of cell activation events.

• They act as indirect indicators of changes within the cell.

IONIC BALANCE

IONIC FLUCTUATIONS

• After short-term alcohol exposure, potassium conductance increases(potassium channels in the cell membrane are opened) in T-cells.

• Intracellular calcium concentrations are shifted in neutrophils and in Kupffer cells.

EFFECT OF ALCOHOLISM – A CASE OF kappa B (NFκB).

• One of the cytoplasmic elements involved in the activation of cellular responses is a transcription factor called nuclear factor kappa B (NFκB).

• This molecular complex is activated by signaling events.

• It is then transported to the nucleus, where it binds to DNA and initiates the synthesis of mRNA.

• The study of human cells reported that alcohol disturbs the NFκB complex in such a way that the signal to the nucleus is inhibitory rather than stimulatory.

EFFECTS AT MACRO LEVEL

• Alcohol has a great array of effects at the cellular and organ levels.

• The primerily targeted organ is Liver.• Alcohols greatly increase the level of undesired

immunoglobulins in blood.• The major classes of these antibodies are

immunoglobulins A, G, and M ( IgA, IgG, and IgM), each of which has a specialized role in the immune response.

ELEVATION OF ANTIBODIES

• Typically, IgA is elevated in the blood of alcoholics both with and without alcoholic liver disease.

• IgG is elevated in those with liver disease. • IgM is also elevated only in patients with active liver

disease, such as alcoholic hepatitis. • IgA also may be found as tissue deposits in the skin,

liver and kidney of alcoholics.

AUTOIMMUNITY

• These higher antibody levels may be due to abnormal regulation in the production of antibodies, or they might be a manifestation of autoimmunity.

• Most of the antibody produced attack the self-cells.(Autoimmune in nature)

• Alcohol-triggered autoimmunity.

ALCOHOLISM

• Alcoholics without liver disease typically have normal number of lymphocytes in their peripheral blood, while those with liver disease have a wide range of abnormalities.

• In patients with alcoholic hepatitis (an earlier stage of alcoholic liver disease), there is a mild reduction in lymphocyte numbers, with a return to normal levels after several weeks of recovery.

• Patients with alcoholic cirrhosis (a later stage of alcoholic liver disease) may have lymphopenia, a severe reduction in lymphocyte numbers.

• Abnormalities of immune function can be accompanied by changes in the percentages of different types or subsets of lymphocytes.

• Changes in cell surface markers might also occur.

NUTROPHILS

• In alcoholic hepatitis, there is an increase in the number of neutrophils in the blood.

• Since these cells typically release powerful enzymes that damage tissue, an abnormal number of neutrophils in the liver of alcoholics is one possible mechanism for liver damage.

T-CELLS & B-CELLS

• In patients with alcoholic liver disease, the ratio of helper T-cells (designated CD4) to cytotoxic and suppressor T-cells (designated CD8) is abnormal.

• In patients with alcoholic liver disease, B-cells are often decreased in number.

• Cytokine balance is disrupted in alcoholic liver disease.

• The monocytes in the bloodstream and the macrophages such as the Kupffer cells in the liver produce an excess of the proinflammatory cytokines IL-1, IL-6, and TNF in response to alcohol.

MONOCYTE AND MACROPHAGE-DERIVED SUBSTANCES POTENTIALLY AFFECTED BY

ALCOHOL

• These same cells are sensitive to stimulation by a lipopolysaccharide, known as LPS or endotoxin, a toxic substance produced in the cell walls of bacteria that commonly reside in the intestine.

• LPS is a powerful activator of many immune system cells.

• It can potentiate the effects of alcohol in activating macrophages, particularly the Kupffer cells.

ROS

• Cells of the innate immune system produce reactive oxygen species (ROS), toxic substances that kill bacteria and causes inflammation.

• Studies of liver injury find that alcohol-fed animals have higher levels of ROS resulting from increased NO(nitric oxide) production.

ACETALDEHYDE-PROTEIN ADDUCTS

• Acetaldehyde, the first product of alcohol metabolism is reactive and combines chemically with proteins in the cells or blood of the person consuming the alcohol.

• These chemical combinations are called adducts. • The development of autoimmunity after alcohol

exposure may be a result of the formation of these acetaldehyde-protein adducts.

• Alcoholics show increased susceptibility to,Pneumonia (MacGregor and

Louria1997)Tuberculosis(Centers for Disease

Control and Prevention[CDC] 1996)HIV - AIDS (MacGregor and

Louria1997)Cancer(Centers for Disease Control

and Prevention[CDC] 1996)

REFERENCES

• Zhang, P.; Nelson, S.; Summer, W.R.; and Spitzer, J.A. Acute ethanol intoxication suppresses the pulmonary inflammatory response in rats challenged with intrapulmonary endotoxin. Alcohol Clin Exp Res 21(5):773–778, 1997b.

• Zeldin, G.; Yang, S.Q.; Yin, M.; Lin, H.Z.;Rai, R.; and Diehl, A.M. Alcohol and cytokineinducible transcription factors [Review]. Alcohol Clin Exp Res 20(9):1639–1645, 1996.

• Viitala, K.; Israel, Y.; Blake, J.E.; and Niemela, O. Serum IgA, IgG, and IgM antibodies directed against acetaldehyde-derived epitopes: Relationship to liver disease severity and alcohol consumption. Hepatology 25(6):1418–1424, 1997.

• LE Dı´az, A Montero, M Gonza´lez-Gross, AI Vallejo, J Romeo and A Marcos Influence of alcohol consumption on immunological status: a review European Journal of Clinical Nutrition (2002) 56, Suppl 3, S50–S53 2002 Nature Publishing Group

Spread awareness about the ill-effectsof ALCOHOLISM, NOT THE HABIT

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