Transcript NUTRITION, INFECTION & THE IMMUNE SYSTEM

NUTRITION, INFECTION &
THE IMMUNE SYSTEM
Ahmed A Wadee
Immunology Division
NHLS & School of Pathology
University of the Witwatersrand
(082 807 2628)
Alimentary Tract
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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
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Saliva
Stomach acid & enzymes
Bile
Water and electrolyte secretion
Mucosal products (mucus, defensins)
Epithelial barrier
Peristalsis
Bacterial flora
The Human Gut Flora
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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
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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
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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)
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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
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Found between intestinal epithelial cells
CD8+ cells
Cytotoxic
Many are TcRgd+
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Produce IL2 ,IFNg & IL5
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Large granular lymphocytes
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Lymphocytes in the Lamina
Propria
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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)
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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
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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
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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
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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
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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
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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
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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
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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)