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NUTRITION, INFECTION & THE IMMUNE SYSTEM Ahmed A Wadee Immunology Division NHLS & School of Pathology University of the Witwatersrand (082 807 2628) Alimentary Tract General defense mechanisms • Mucous secretions • Integrity of mucosal epithelium • Peristaltic motions of the gut propel contents downward • Secretory IgA and phagocytic cells Stomach • Generally sterile due to low pH Small Intestine • Upper portion contains few bacteria • As distal end of ilieum is reached flora increases Colon • Enormous numbers of microorganisms • 50-60% of fecal dry weight is bacteria Multiple Factors Protect Against GI Pathogens Saliva Stomach acid & enzymes Bile Water and electrolyte secretion Mucosal products (mucus, defensins) Epithelial barrier Peristalsis Bacterial flora The Human Gut Flora Rapidly colonises gut after birth Comprises more than 1014 organisms More than 400 species Symbiotic relationship with host (commensals) Weighs 1-2 kg Gut Flora Help Prevent Colonisation by Pathogens The Immune System of The Gut The gut is the major site of contact in the body for foreign antigens Gastrointestinal diseases kill more than 2 million people every year Non-specific (innate) immunity Specific immunity Major components of the innate immune response Cell mediated • Phagocytic cells • NK cells (natural killer) Humoral • Complement • Acute phase proteins Immune Cells and Innate Immunity Phagocytes • Neutrophils • Monocyte/macrophage • Eosinophils (to a lesser extent) NK cells (large granular lymphocytes) • Antibody-dependent cell-mediated cytotoxicity (ADCC) • Have two major functions •Lysis of target cells •Production of cytokines (IFN-γ and TNF-a) • Act against intracellular pathogens •Herpesviruses, Leishmania, Listeria monocytogenes • Act against protozoa •Toxoplasma, Trypanasoma Organisation of the Mucosal Immune system (specific) Gut Associated Lymphoid Tissue (GALT) / Mucosa Associated Lymphoid Tissue (MALT) • Tonsils • Adenoids • Peyer’s patches • Appendix Intra-epithelial lymphocytes (IEL’s) Lamina propria lymphocytes Intra-epithelial Lymphocytes Found between intestinal epithelial cells CD8+ cells Cytotoxic Many are TcRgd+ Produce IL2 ,IFNg & IL5 Large granular lymphocytes Lymphocytes in the Lamina Propria Found in the epithelium & connective tissue of Lamina Propria Mostly activated CD4+ (T helper cells) • TH1 cells: cell mediated responses (intracellular pathogens) • TH2 cells: antibody mediated responses (allergens, parasites, helminths) • Activated B cells; plasma cells IgA Immunoglobulin A (IgA) The major immunoglobin in the body-GUT The GI tract is major source Synthesised by plasma cells (B cells) in lamina propria Transported via epithelium Protects against infectious agents Prevents attachment of bacteria or toxins to epithelia Structure of IgA dimer IgA and its transport across epithelial surfaces Location of M Cells Found in: Peyer’s patches Intestinal epithelium Mucosa associated lymphoid aggregates (tonsils) Initiation of Gut Responses Mucosal Lymphoid Tissue The Gut is Challenged by Foreign Antigens Regularly No Response (Tolerance) Response (Immune Activation) mucosal barrier Gut Immune Responses APC migrate to lymph nodes T cells activated in lymph nodes T cells migrate to tissue Inflammation/pathogen eradication Interaction of helper T cells (CD4+) and B cells in Lymphoid Tissues MHC Class I or II restricted Antigen Presentation to T cells Class II MHC – associated presentation of extra-cellular antigen to helper T cells + APC Extracellular Antigen Class II MHCassociated antigen CD4+ Helper T Lymphocyte cytokines Class I MHC – associated presentation of intra-cellular antigen to cytotoxic T cells + Intracellular Antigen APC Class I MHCassociated antigen CD8+ Cytotoxic T Lymphocyte Lysis of antigen-expressing target cell CD4+ Helper T Lymphocytes secrete Distinct Sets of Cytokines TH1 cells produce IL2 and IFNg TH2 cells produce IL4, IL5, IL10 Which in turn determine the type of effector function (i.e. macrophage or CTL activation or B cell stimulation) Gut Enterocytes Influence Local Immune Responses Local Immunity in the Small Intestine Enterocytes secrete TGF-β, IL1, IL6 etc Panath cells produce microbicidal proteins Enterocytes promote migration and activity of lymphocyte populations in the villi Nutrient Deficiencies & Immune Responses Malnutrition mainly affects: Cell-mediated immunity Phagocyte function Complement activity IgA production Cytokine production Lymphoid tissue - ‘nutritional thymectomy’ Malnutrition and Immunity Loss of fat cells results in low leptin (adipose tissue-derived hormone) levels: • signals nutritional status to the hypothalamus • modifies pro-inflammatory immune responses • provides a key link between nutritional deficiency and immune dysfunction Protein-energy Malnutrition Associated with reduced Numbers of CD4 helper T cells CD4/CD8 ratios Macrophage activation Levels of C3,C5 and Factor B opsonisation phagocytosis Intracellular killing of bacteria by phagocytes Lysosyme levels TNF &IL2 Wound healing Magnesium, Iron and Zinc Deficiency Impairs CMI (TH1) & phagocyte function Reduced CD4/CD8 ratios Post-operative patients, athletes, elderly Chronic deficiency seems to be associated with acute lymphoblastic leukemia and malignant lymphoma (Mg & Zn) Altered NK and macrophage cytotoxicity (may affect tumor surveillance) Vitamin Deficiency Vitamin A deficiency Alters epithelial structure metaplasia & increased bacterial binding Reduced T cell numbers and CMI Vitamin B6 and folate deficiencies Reduced CMI Reduced antibody production Obesity and Immunity Obesity negatively affects: Cytotoxicity NK cell function Phagocyte function (bacteria & fungi) Levels of micronutrients, lipids and hormones Malnutrition & Infection Aggravate each other! Affect clinical outcomes of: Pneumonia Diarrhoea Measles Tuberculosis HIV HIV/AIDS HIV/AIDS has a negative impact on nutritional status and may lead to malnutrition Malnutrition weakens the immune system and increases vulnerability to opportunistic infections Opportunistic infections cause symptoms such as anorexia and fever that reduce food intake and nutrient utilisation and increase nutrient requirements. Reduced food intake and poor nutrient absorption weaken the immune system and hasten disease progression. Vicious Cycle: HIV & Malnutrition Secondary Immune Deficiencies Cause Mechanism of Defect Human Immunodeficiency Virus Depletion of CD4+ T cells Protein – Calorie Malnutrition Metabolic Derangements inhibit lymphocyte maturation and function Cancer metastases to Bone Marrow Reduced site of leukocyte development Removal of Spleen Decreased phagocytosis of microbes Oral Tolerance/Vaccination Ingested antigens may provide tolerance or protection Effects are: Systemic (non-mucosal sites) Dominant (transferable to naïve cells) Produce local IgA and systemic IgG Applications Polio vaccine Protein antigens to induce tolerance to food proteins Possible tolerance in autoimmunity Mucosal adjuvants/vaccines, eg bacteria-viral combinations VACCINE-PREVENTABLE DISEASES DISEASE POTENTIAL COMPLICATIONS Chicken pox Encephalitis, meningitis, death Diphtheria Upper airway obstruction, toxic myocarditis, death Haemophilus influenzae meningitis Seizures, brain damage, death Hepatitis A and B Fulminant hepatitis with liver failure, death Influenza (flu) Pneumonia, death Measles Encephalitis, pneumonia, death Mumps Sterility (in men), myocarditis, encephalitis, hearing loss Pertussis (whooping cough) Apnea (respiratory arrest), pneumonia, seizures, brain damage Pneumococcal disease Meningitis, serious invasive infections, brain damage Poliomyelitis (polio) Aseptic meningitis, paralysis, death Rubella (German measles) Congenital rubella syndrome (birth defects), miscarriage or foetal death Tetanus Lockjaw, death Routine Immunisation Schedule in South Africa At birth BCG (bacillus Calmette Guerin against TB meningitis in infants) OPV (oral polio vaccine) 6 weeks OPV; DTP (diphtheria, tetanus, pertussis (whooping cough)) HBV (hepatitis B); Hib (Haemophilus influenzae group b) 10 weeks OPV; DTP; HBV; Hib 14 weeks OPV; DTP; HBV ; Hib 9 months Measles 18 months OPV; DTP; Measles 5 years OPV; DT (diphtheria, tetanus)