Infection and immunity
Prof. Kijeong Kim
May 10, 2013
학습목표
1.
2.
3.
4.
바이러스에 대한 면역반응을 설명한다.
세포외 기생세균에 대한 면역반응을 설명한다
세포내 기생세균에 대한 면역 반응을 설명한다
감염 후 면역반응에 의한 합병증을 열거한다.
√
Three basic lines of protection against
invasion of infectious agents
1. Natural barriers: restrict entry of the agent
(e.g., skin, mucus, ciliated epithelium, gastric acid,
bile).
2. Innate, antigen-nonspecific immune defenses
– provide rapid, local responses to challenge by an
invader
(e.g., lysozyme, lactoferrin, interferon, complement,
neutrophils, macrophages, natural killer [NK] cells).
3. Antigen-specific immune responses: specifically
target, attack, and eliminate the invaders that succeed in
passing the first two defenses (e.g., antibody, T cells).
√
Antimicrobial
defense
mechanisms
• Bacterial infections: Phagocytic cells, complement
(alternative path), antibody
• Intracellular bacteria (i.e., mycobacteria): TH1, DTH
• Viral infections
– Interferon, NK, T cell
– Antibody: restricts the spread of virus (viremia)
• Fungal infection: TH1-DTH responses are especially
important.
• Parasitic infections: Activated macrophage, T-cell,
eosinophil, IgE-mast cell
√ Table 1. Antimicrobial Defenses for Infectious Agents
(Extracellular)
Bacteria
Neutrophils
Intracellular
bacteria
Viruses
Fungi
Parasites
++++
-
-
+
+
Interferon
-
-
++++
-
-
Macrophages
+
+++
++
++
+
Complement
+
-
-
-
-
NK cells
-
+
+++
-
-
CD4 Th1-DTH
-
++
+++
+
+
CD8-CTL
-
+
++++
-
-
Antibody
++
-
+
+
++(IgE)
Immunity to bacteria
Immunity to bacteria
Pathogenesis of extracellular and intracellular
bacteria
•Extracellular bacteria
– Two mechanisms
• Inflammatory damage of infected tissues by bacterial
growth and metabolism, cytolytic enzymes (e.g., pyogenic
inflammation by S. aureus infection)
• Toxin production (endotoxin, exotoxin)
– Endotoxin: LPS,
» very strong activator of macrophages
» induces macrophages to release cytokines
– Exotoxin: causes cytotoxicity
•Intracellular bacteria
– Intracellular pathogens (e.g., M. tuberculosis) are not easily
killed by phagocytic cells.
– Bacteria can survive in the cells  antibodies can not access
into the cells
– Resolution of the disease relies on the cell-mediated immunity
√ Extracellular bacteria
• Innate immunity:
– Nonspecific humoral defense
• Lysozyme (degrades bacteria peptidoglycan layer),
lactoferrin (chelates iron)
– Neutrophils
– Complement
– Macrophages
– Inflammation
√ Extracellular bacteria
• Innate immunity:
– Neutrophils
• A major antibacterial phagocytic cell
• are attracted to the site of infection
• phagocytose and kill the internalized bacteria
– Complement
• Very early and important antibacterial defense
• Alternative and Lectin pathways activated by bacterial surfaces
and components (LPS, polysaccharides)
• Production of chemotactic and anaphylatoxic proteins (C3a, C5a)
• Opsonization of bacteria (C3b)
• Direct killing of gram-negative bacteria
• Activation of B cells (C3d)
– Macrophages
• Activated by bacterial components teichoic acid, peptidoglycan
fragments, LPS
Extracellular bacteria
• Innate immunity:
– Inflammation
• early defense mechanism
• contain an infection
• prevent its spread from the initial focus
• signal subsequent specific immune responses
Extracellular bacteria
• Acquired immunity
– Major defense: Humoral immunity (Antibody)
• Binding to surface structures of bacteria (fimbriae,
lipoteichoic acid, capsule)
– Blocking of attachment
– Opsonization of bacteria for phagocytosis
– Promotion of complement action
– Promotion of clearance of bacteria
– Neutralization of toxins and toxic enzymes
– CD4 TH2 T-cell responses are important
√ Intracellular bacteria
• Innate immunity; incomplete
– Macrophages produce IL-12  NK cell activation
– NK cells produce IFN-  Macrophage activation
• Acquired immunity: cell-mediated immunity
– CD4 TH1 T cells (IFN-)  activate macrophages  killing
of intracellular bacteria
– CD8 cytotoxic cells kill the infected cells
CD4 TH1 T cells
• promote and reinforce inflammatory responses (e.g., IFN-
activation of macrophage)
• usually occurs first as a local response.
• promote growth of T and B cells (IL-2) to expand the immune
response
• promote B cells to produce complement-binding antibodies (IgM,
IgG)
• essential for combating intracellular infections (mycobacteria)
– IFN- activates macrophage and DTH to kill the infected cell.
CD4 TH2 T-cell responses
• often initiated by the B-cell presentation of antigen.
– Binding of antigen (to B cell surface Ab.) activates the B
cells, promotes uptake, processing of the antigen, and
presentation of antigenic peptides on class II MHC molecules
to CD4 TH2 cell.
• produces IL-4, IL-5, IL-6, and IL-10, which enhance IgG
production and, depending on other factors, production of IgE
or IgA.
• promotes terminal differentiation of B cells to plasma-cell
antibody factories or production of memory B cells.
Bacterial immunopathogenesis (Complication)
•
Extracellular bacterial infection
– Inflammation (tissue damage)
– Septic shock (life threatening)
• Activation of macrophages in the liver and spleen by
endotoxin can promote release of TNF- into the blood,
causing many of the symptoms of sepsis, including circulatory
collapse, disseminated intravascular coagulation (DIC) and
death.
– Complications of humoral immunity
• √ After recovery of Streptococcus pyogenes infection
– Rheumatic fever: Antibodies produced against bacterial
antigens that share determinants with cardiac muscle
proteins can initiate tissue destruction (myositis) 
Rheumatic fever
– Post-streptococcal glomerulonephritis: caused by immune
complex deposition of bacterial antigens and antibody
Bacterial immunopathogenesis (Complication)
• Intracellular bacterial infection
– Persistent survival of bacteria in the macrophages  chronic
antigenic stimulation  formation of granulomas 
tissue necrosis and fibrosis, dysfunction
– Results from protective immunity and immunopathologic
hypersensitive reaction
• E.g., mycobacteria infection, Hansen disease
• Bacteria
– Cellular organisms
– Mostly capable of fully independent life
• Bacterial infection has been controlled by chemotherapy.
• Because of the recent rise in antibiotic-resistant strains of
bacteria, there is renewed interest in developing new or
improved vaccines against :
– Tuberculosis
– Meningitis
– Food-poisoning
• Usual destiny of unsuccessful bacteria is death by phagocytosis
– Bacterial survival entails avoidance of this fate
• The main ways avoiding phagocytosis
– Capsule …………(affects attachment)
– Cell wall ………..(affects digestion)
– Exotoxins ………(damage phagocytic and other cells)
– Most cell wall components and toxins are strongly antigenic
• antibody overcomes many of their effects
• the basis of the majority of antibacterial vaccines
• Capsule
– A virulence factor
– Protects bacteria from contact with phagocytes
– Most are large branched polysaccharide molecules
– Some are protein
– Many of capsular polysaccharides are T-independent antigens
– Examples of capsulated bacteria:
• Pneumococcus, meningococcus, Haemophilus
• Exotoxins
– The proteins secreted often by gram-positive bacteria
– Destructive effects on phagocytes, local tissues, CNS, etc.
– Frequent cause of death
– Aggressins; proteins collectively known
• Help the bacteria to spread by dissolving host tissue
• Sepsis
– Uncontrolled systemic responses to bacterial infection
– Can lead to rapid life-threatening disease
– An important cause of death after major surgery
– Overproduction of TNF-, especially by macrophages, plays
a major role in these reactions
Immunity to viruses
Immunity to viruses
• Virus characteristics
– Much smaller than all other infectious organisms
– Lack cell walls
– Lack independent metabolic activity
• Are unable to replicate outside the cells of their host
• Key process in virus infection is intracellular
replication
– May or may not lead to cell death
Protection from viral infection
• √ Prevention of infection
– Interferon (,)
• Provides the rapid protection
– Induces “antiviral state” in neighboring normal cells
– Blocks local viral replication by inhibition of protein synthesis
• Plays the same ‘natural antibiotic’ role as lysozyme in bacterial
infection
• Activates NK cells
• Increases expression of MHC antigens II and I
– Promotes APC’s antigen presentation to T cells
– Makes infected cells a better target for cytotoxic T cells
– Antibody
• Prevents entry and blood-borne spread of viruses (extracellular)
– Blocks viral attachment proteins (Neutralization)
– Opsonizes virus for phagocytosis (Opsonization)
• Dose not prevent cell to cell viral spread
Protection from viral infection
• √ Control of infection
– Natural Killer (NK) Cells
• Are activated by interferon-, IL-12
• Kill virus-infected cells
– Can destroy some virus-infected cells but are not MHC
restricted
– Come into action more rapidly than TC cells.
• Activate macophages (interferon-)
– T cells
• Cytotoxic T cell (TC cell) system
– Recognizes altered ‘self’ MHC class I antigens by viral
peptides
– CD4 TH1 cells activate TC cells (CD8)
• Prevention of virus cell to cell spread by:
– Cytotoxic T cell (TC cell) system
– NK cells
• Macrophages
– Filter viral particles from blood
– Phagocytose (opsonized) virus particles
• Tissue damage result from:
– Virus itself
– Host immune response to the virus
• Receptors
– All viruses need to interact with specific receptors on the cell
surface
• E.g.
– Epstein-Barr virus (EBV) – CR2 on cells
– Rabies – acetylcholine receptor on neurones
– Measles – CD46 on cells
•
•
•
Interferon
– A group of proteins produced in response to virus infection (and
also bacterial LPS, etc.)
– Stimulates cells to make proteins that block viral transcription and
protects from infection.
c
T , NK, CMI
– Tc cells ‘learn’ to recognize class I MHC antigens, and then
respond to these in association with virus antigens on the cell
surface
– NK cells can destroy some virus-infected cells but are not MHC
restricted
– The role of DTH in viral infection, via macrophage activation,
remains controversial
Antibody
– Specific antibody can bind to virus and thus block its ability to bind
to its specific receptor and hence infect cells
= Neutralization
– Neutralizing antibody is probably an important part of protection
against many viruses (e.g. influenza)