NUTRITION, INFECTION & NUTRITION, INFECTION & THE IMMUNE SYSTEMTHE 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 TcR

Produce IL2 ,IFNIL5

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

No Response(Tolerance)

Response(Immune Activation)

mucosal barrier

The Gut is Challenged by Foreign Antigens Regularly

Gut Immune ResponsesAPC 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 cellsin 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

APCAPC ExtracellularExtracellularAntigenAntigen

CD4CD4++ Helper Helper T T LymphocyteLymphocyte

Class II Class II MHC-MHC-associatedassociatedantigenantigen

++

cytokines

Class I MHC – associated presentation of intra-cellular antigen to cytotoxic T cells

APCAPC

IntracellularIntracellularAntigenAntigen

CD8CD8++ Cytotoxic T Cytotoxic T LymphocyteLymphocyte

Class I MHC-Class I MHC-associatedassociatedantigenantigen

++

Lysis of antigen-expressing target cell

TH1 cells produce IL2 and IFNTH1 cells produce IL2 and IFN

TH2 cells produce IL4, IL5, IL10TH2 cells produce IL4, IL5, IL10

Which in turn determine the type of effector Which in turn determine the type of effector functionfunction

(i.e. macrophage or CTL activation or B cell (i.e. macrophage or CTL activation or B cell stimulation)stimulation)

CD4+ Helper T Lymphocytes secrete Distinct Sets of Cytokines

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

Effects are:- Systemic (non-mucosal sites) Dominant (transferable to naïve cells) Produce local IgA and systemic IgG

Ingested antigens may provide tolerance or protection

Applications

Polio vaccine Protein antigens to induce tolerance to

food proteins Possible tolerance in autoimmunity Mucosal adjuvants/vaccines, eg

bacteria-viral combinations

VACCINE-PREVENTABLE DISEASESDISEASE 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

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)

Routine Immunisation Schedule in South Africa