NUTRITION, INFECTION & THE IMMUNE SYSTEM

1. NUTRITION, INFECTION & THE IMMUNE SYSTEM Ahmed A Wadee Immunology Division NHLS & School of Pathology University of the Witwatersrand (082 807 2628)

2. AlimentaryTract • 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

3. Multiple Factors Protect Against GI Pathogens • Saliva • Stomach acid & enzymes • Bile • Water and electrolyte secretion • Mucosal products (mucus, defensins) • Epithelial barrier • Peristalsis • Bacterial flora

4. 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

5. Gut Flora Help Prevent Colonisation by Pathogens

6. 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

7. Major components of the innate immune response • Cell mediated • Phagocytic cells • NK cells (natural killer) • Humoral • Complement • Acute phase proteins

8. 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

9. 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

10. Intra-epithelial Lymphocytes • Found between intestinal epithelial cells • CD8+ cells • Cytotoxic • Many are TcRgd+ • Produce IL2 ,IFNg & IL5 • Large granular lymphocytes

11. 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

12. 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

13. Structure of IgA dimer

14. IgA and its transport across epithelial surfaces

15. Location of M Cells Found in: Peyer’s patches Intestinal epithelium Mucosa associated lymphoid aggregates (tonsils)

16. Initiation of Gut Responses

17. Mucosal Lymphoid Tissue

18. The Gut is Challenged by Foreign Antigens Regularly No Response (Tolerance) Response (Immune Activation) mucosal barrier

19. APC migrate to lymph nodes T cells activated in lymph nodes T cells migrate to tissue Inflammation/pathogen eradication Gut Immune Responses

20. Interaction of helper T cells (CD4+) and B cells in Lymphoid Tissues

21. MHC Class I or II restricted Antigen Presentation to T cells

22. Class II MHC – associated presentation of extra-cellular antigen to helper T cells + Class II MHC- associated antigen APC Extracellular Antigen CD4+ Helper T Lymphocyte cytokines

23. + Intracellular Antigen Class I MHC- associated antigen APC CD8+ Cytotoxic T Lymphocyte Lysis of antigen-expressing target cell Class I MHC – associated presentation of intra-cellular antigen to cytotoxic T cells

24. 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)

25. Gut Enterocytes Influence Local Immune Responses

26. 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

27. Nutrient Deficiencies & Immune Responses Malnutrition mainly affects: • Cell-mediated immunity • Phagocyte function • Complement activity • IgA production • Cytokine production • Lymphoid tissue - ‘nutritional thymectomy’

28. 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

29. 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

30. 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)

31. 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

32. Obesity and Immunity Obesity negatively affects:- • Cytotoxicity • NK cell function • Phagocyte function (bacteria & fungi) • Levels of micronutrients, lipids and hormones

33. Malnutrition & Infection Aggravate each other! Affect clinical outcomes of:- • Pneumonia • Diarrhoea • Measles • Tuberculosis HIV

34. 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.

35. Vicious Cycle: HIV & Malnutrition

36. Secondary Immune Deficiencies

37. Oral Tolerance/Vaccination Effects are:- • Systemic (non-mucosal sites) • Dominant (transferable to naïve cells) • Produce local IgA and systemic IgG Ingested antigens may provide tolerance or protection

38. Applications • Polio vaccine • Protein antigens to induce tolerance to food proteins • Possible tolerance in autoimmunity • Mucosal adjuvants/vaccines, eg bacteria-viral combinations

39. VACCINE-PREVENTABLE DISEASES

40. Routine Immunisation Schedule in South Africa