IMMUNITY TO INFECTION

dr. Arthur E. Mongan, M.Sc., Sp.PK

SEMESTER-7 BLOK-VI
MODUL-3 PENYAKIT INFEKSI TROPIS
FK UNSRAT
2011
 Overview:
Immunity to Microbes
 IMMUNITY TO MICROBES
(A BRIEF OVERVIEW)

• The key events during infection :

– entry of the microbe,
– invasion
– colonization of host tissues
– evasion of host immunity
– tissue injury or functional impairment
 General Features of Immune
Responses to Microbes
• Mediated by the effector mechanisms of innate and adaptive
immunity

• The immune system responds in distinct and specialized ways to

different types of microbes

• The survival and pathogenicity of microbes in a host are critically

influenced by the ability of the microbes to evade or resist the
effector mechanisms of immunity

• In many infections, tissue injury and disease may be caused by the

host response to the microbe and its products rather than by the
microbe itself
main features microbes:
– extracellular bacteria √
– intracellular bacteria √
– fungi
– viruses
– protozoan
– multicellular parasites
Extracellular bacteria
 Extracellular bacteria

• capable of replicating outside host cells

– the circulation
– in connective tissues
– tissue spaces (lumens of the airways & gastrointestinal tract)

• disease is caused by 2 principal mechanisms:

1. Induce inflammation → tissue destruction at the site of infection
2. Produce toxins → diverse pathologic effects
• Endotoxins: components of bacterial cell walls
• Exotoxins: actively secreted by the bacteria
INNATE IMMUNITY to
Extracellular Bacteria

The principal mechanisms:

• Complement activation
• Phagocytosis
• Inflammatory response
 ADAPTIVE IMMUNITY to
Extracellular Bacteria
• Humoral immunity is the principal protective
immune response against extracellular bacteria

• Functions:
– block infection
– eliminate the microbes
– neutralize their toxins
ADAPTIVE Immune Response to Extracellular Bacteria
(antibody and T-helper response)
Extracellular bacteria Examples of human diseases
Staphylococcus aureus Skin and soft tissue infections,
lung abscess;
systemic: toxic shock syndrome,
food poisoning
Streptococcus Pharyngitis, Skin infection
pyogenes (group A) (impetigo, erysipelas, cellulitis),
Systemic (scarlet fever)
Streptococcus pyogenes Pneumonia, Meningitis
(pneumococcus)
Escherichia coli Urinary tract infections,
gastroenteritis, septic shock
Mechanisms of pathogenicity
Skin infection; acute inflammation
induced by toxins (cell death by
pore-forming toxins)
Systemic: enterotoxin
‘superantigen’ - induced cytokine
production by T cells causing skin
necrosis, shock, diarrhea
Acute Inflammation
Acute Inflammation
Toxins act on intestinal epithelium
and cause increased chloride and
water secretion; endotoxin (LPS)
stimulates cytokine secretion by
macrophages
Extracellular bacteria Examples of human diseases Mechanisms of pathogenicity

Vibrio cholerae Diarrhea (cholera) Cholera toxin ADP ribosylates G

protein subunit, which leads to
increased cyclic AMP in intestinal
epithelial cells and results in
chloride secretion and water loss

Clostridium tetani Tetanus Tetanus toxin binds to the motor

endplate at neuromuscular
junctions and causes irreversible
muscle contraction

Neisseria meningitidis Meningitis Acute inflammation and systemic

(meningococcus) disease caused by potent endotoxin

Corynebacterium Diphtheria Diphtheria toxin ADP ribosylates

Diphtheriae elongation factor-2 and inhibits
protein synthesis
Intracellular bacteria
 Immunity to
Intracellular Bacteria
 INNATE IMMUNITY to
Intracellular Bacteria

• Initially
neutrophils and later macrophages
→ ingest and attempt to destroy these microbes

• mainly mediated by phagocytes and natural

killer (NK) cells
 ADAPTIVE IMMUNITY to
Intracellular Bacteria

• The major protective immune response

against intracellular bacteria is T cell
mediated immunity
 Cooperation of CD4+ and CD8+ T cells
in defense against intracellular bacteria
 Patterns of T cell responses to intracellular microbes
are important determinants of disease progression and
clinical outcome
IMMUNITY TO SPECIFIC
(Mycobacterium tbc)
INFECTION
 INTRODUCTION

Mycobacterium tuberculosis infection

 One-third of the world population
.. Indonesia?
 But only 5-10% → a lifetime risk of
developing active tuberculosis, either within 1 or
2 years after infection (PRIMARY TBC) or thereafter (POSTPRIMARY TBC)
ACTIVE TUBERCULOSIS
Variation in:
 Localization
 Severity
 Outcome
 ACTIVE TUBERCULOSIS
Variation in:
 Localization → any where in the
body (usually pulmonary infection, ranging from
mild infiltration to chronic, cavitary, and severely
destructive disease)

 Severity (milliary tbc / the most serious disease

manifestation to tuberculous pleuritis / self limiting)
 Outcome (the quality of host defense determines
outcome)
 THE PATHOGENESIS OF
TUBERCULOSIS
STAGES (Lurie’s fundamental studies in rabbit) :
 1. Inhalation of tubercle bacilli (die or
escape)
 2. the blood monocyte and other
inflammatory cells are attracted to the lungs
 3. symbiotic stage
 4. chronicity
Phagocytosis and immune recognition of M. tuberculosis
INFLAMMATORY RESPONSE of phagocytic
cells upon activation with M. tuberculosis
M. tbc chronicity
ADAPTIVE → Cellular Mediated Immunity
(antigen presentation, costimulation, cytokine
production)
COSTIMULATION

→ COSTIMULATORY MOLECULES for T stimulation

(B7.1 or CD80 and B7.2 or CD86 on macrohages or dendritic

cells respectively bind to CD28 and CTLA-4 on T cells)

Without proper COSTIMULATION

→ Antigen presentation leads to apoptosis of T cells

 CONCLUDING REMARK

IMMUNITY to M. tbc infection:

INNATE → the role of MACROPHAGES,

DENDRITIC CELLS

ADAPTIVE → CMI (antigen presentation,

costimulation, cytokine production)
Masih ingatkah anda ..
pada kuliah ‘demam’
(immunity of fever)
dulu…. ?
 IMMUNITY

 NATURAL (INNATE, NON-SPECIFIC)

 ACQUIRED (ADAPTIVE, SPECIFIC)
NATURAL AND ACQUIRED
IMMUNE DEFENSE
 NATURAL and ACQUIRED
(immune defenses against bacterial agents)
 NATURAL
 BARRIERS TO INFECTION
 CELLS
 SERUM PROTEINS and THE
COMPLEMENT SYSTEM
NATURAL IMMUNITY
→ BARRIERS TO INFECTION
NATURAL IMMUNITY
→ CELLS
○ PHAGOCYTES
(PMN, MN phagocyte
system: monocytes,
macrophages)
○ NATURAL KILLER
CELLS (NK cells)
○ DEGRANULATING
CELLS (Mast cells,
Basophils)
NATURAL IMMUNITY
→ SERUM PROTEINS
○ inflammatory cytokines
(IL-1, IL-6, TNF)
○ acute phase proteins
(C-reactive protein, Serum
amyloid A, complement
components, fibrinogen, a1-
antitrypsin, ceruloplasmin,
haptoglobulin)
NATURAL and ACQUIRED
(inflammatory response)
NATURAL – phagocytosis by macrophages
 NATURAL and ACQUIRED
antibody-dependent cell-mediated
cytotoxicity (ADCC)
NATURAL – complement cascade
 ACQUIRED
 HUMORAL IMMUNITY (B
cells and antibody production)
 CELL-MEDIATED IMMUNITY
(CTL)
ACQUIRED IMMUNITY
→ HUMORAL (Ab class)
○ COMPLEMENT ACTIVATION
○ ADCC
○ NEUTRALIZATION (of bacterial
toxins and viruses)
○ MUCOSAL IMMUNITY (Ig A-
mediated)
ACQUIRED IMMUNITY
→ CELL MEDIATED (mainly T-cells)
○ Cytotoxic T lymphocytes (CTL)
Purpose to eliminate of:
- intracellular pathogens and infected
cells
- tumour cells
- foreign grafts
ACQUIRED – development T
helper cell phenotypes
ACQUIRED – CTL (effector response)
ACQUIRED – DTH response
(mycobacterial infections)
 INFECTIONS
TYPE OF INFECTIOUS AGENTS:
 BACTERIAL
 MYCOBACTERIAL
 VIRAL
 PARASITIC (PROTOZOAL,
HELMINTHS)
 FUNGAL
MAJOR IMMUNE DEFENSE MECHANISMS
AGAINST PATHOGENS
 BACTERIAL : Antibody,
immunocomplex, and cytotoxicity
 MYCOBACTERIAL : DTH and
granulomatous reactions
 VIRAL : Antibody
(neutralization), CTL, and TDTH
 PROTOZOAL : DTH and antibody
 PARASITIC WORMS : Antibody (atopic,
ADCC) and granulomatous reactions
 FUNGAL : DTH and
granulomatous reactions
 YOU LEARN ! ..

 Antibody, immunocomplex, ADCC

(adaptive immunity)
 DTH, granulomatous reactions
(adaptive immunity)
 NEUTRALIZATION Ab, CTL, and
TDTH (adaptive immunity)
MECHANISMS OF INFECTIOUS
ORGANISMS TO AVOID IMMUNE
DEFENSES
1. Inhibit chemotaxis
2. Secrete toxins
3. Block complement-mediated pathways
4. Have outer capsules to block attachment,
phagocytosis
5. Inhibit lysosomal fusion
6. Have outer coat resistant to degradative
enzymes
7. Escape from phagosome
8. Turn off cytokine activation
9. Activate cytokine inappropriately
 YOU LEARN ! ..
 CHEMOTAXIS (innate immunity)
 BACTERIAL TOXINS
 COMPLEMENT PATHWAYS (innate
immunity)
 PHAGOCYTOSIS (innate immunity)
 DEGRADATIVE ENZYMES (innate
immunity)
 CYTOKINES (innate immunity)
 REFERENCES:
1. Actor JK. Immunology and Microbiology.
1st ed., Mosby Elsevier. Philadelphia USA,
2007.
2. Van Crevel R, Ottenhoff T.H.M, van der
Meer J.W.M. Innate immunity to
Mycobacterium Tuberculosis. Clinical
Microbiology Reviews. 2002, vol. 15 no.2,
pp.294-309
3. Immunology Textbook, Abdul Abbas, ed.
6th. 2010