Transcript immune system

IMMUNE PATHOLOGY
IMMUNE SYSTEM
– genetically encoded elements
– developmental programs
– continuous generation and death of cells
– continuous contact with the environment
• Decreased, inhibited immunity
– One or more functions are
missing, down regulated
• Enhanced, dysregulated immunity
– One or more functions are
upregulated
Genetically determined
Acquired
– Loss of function mutation
– Environmental factors
– Altered gene expression
– Deviated reactions
– Genetic predisposition
– Spectral diseases
Disturbed cell differentiation – B, T, NK or other collaborating cells
Disturbed cellular function – activation, cell death, signaling, communication
Levels of dysregulation – DNA, RNA, protein, post-translational, secretory
THE IMMUNE RESPONSE TO PATHOGENS
PATHOGENS
Bacteria, Viruses, Fungi
Parasites
Unicellular protozoa
Multicellular worms
REQUIRES HIGH INITIAL DOSE
ESCAPE MECHANISMS TO AVOID DEFENSE MECHANISMS
HUMAN BODY
RESOURCE RICH ENVIRONMENT FOR PATHOGENS
DEFENSE MECHANISMS
Physical barriers
Innate immunity
Adaptive immunity
Diseases – Medical practice
Innate immunity fails to terminate infection
Pathogen spreading into lymphoid tissues and activation of
adaptive immunity
MECHANISMS OF TISSUE DEMAGE INDUCED BY
PATHOGENS
DIRECT
EXOTOXIN
ENDOTOXIN
CYTOPHATHIC
Streptococcus pyogenes
Staphylococcus aureus
Corynebacterium diphteriae
Clostridium tetani
Vibrio cholerae
Escherichia coli
Haemophylus influenzae
Salmonella typhi
Shigella
Pseudomonas aeruginosa
Yersinia pestis
Variola
Varicella zoster
Hepatitis B virus
Polio virus
Measles virus
Influenza virus
Herpes simplex virus
DISEASE
Tonsilitis
Scarlet fever
Toxic shock syndrome
Food poisoning
Diphteria
Tetanus
Cholera
Gram (-) sepsis
Meningitis
Pneumonia
Typhoid fever
Baccillary dysentery
Wound infection
Plague
Small pox
Chicken pox, shingles
Hepatitis
Polyiomyelitis
Measles
Subacute sclerosing
panencephalitis
Influenza, cold sores
INFLAMMATORY RESPONSES TO INFECTIOUS AGENTS
CYTOPATHIC – CYTOPROLIFERATIVE INFLAMMATION
Acute and chronic inflammation
Death of individual cells
No or weak host – mediated inflammation
Virus inclusion bodies – CMV, adenovirus
Fused multinucleated cells
Modification and proliferation of epithelial cells
Epithelial and lymphoid dysplasia – tumorigenic viruses
NECROTIZING INFLAMMATION
Toxin – mediated lesions
Clostridium, HBV-infected hepatocytes, HHV neurons
CHRONIC INFLAMMATION
HBV cirrhosis in liver
Schistosoma – fibrosis in liver
MECHANISMS OF TISSUE DEMAGE INDUCED BY
PATHOGENS
INDIRECT
IMMUNE COMPLEX
Hepatitis B virus
Malaria
Strreptococcus pyogenes
Treponema pallidum
Most acute infections
ANTI-HOST ANTIBODY
CELL-MEDIATED IMMUNITY
Streptococcus pyogenes
Mycoplasma pneumoniae
Mycobacterium tuberculosis
Mycobacterium leprae
Lymphocytic choriomeningitis virus
Borrelia burgdorferi
Schistosoma mansoni
Herpes simplex virus
DISEASE
Kidney disease
Vascular deposits
Glomerulonephritis
Kidney demage
in secondary syphilis
Transient renal deposits
Rheumatic fever
Hemolytic anaemia
Tuberculosis
Tuberculoid leprosy
Aseptic meningitis
Lyme arthritis
Schistosomiasis
Herpes stromal keratitis
INFLAMMATORY RESPONSES TO INFECTIOUS AGENTS
Diversity in pathogens and inflamatory mediators
Common features of histology and morphologic patters
POLYMORPHONUCLEAR
MONONUCLEAR
INFILTRATION
INFILTRATION
Acute tissue demage
Effector cell infiltration

Increase vascular permeability

Plasma cells (Syphilis lesions)

Neutrophilic exudation (pus)

T cell infiltration
 Pyogenic bacteria
 virus infection – acute
 Chemoattractant f-Met peptides
 intracellular bacteria – acute
 Chemoattractant C5a
 Helminths, spirochetes – chronic
 LPS-mediated macrophage
activation
 Granulamotous inflammation
M. tuberculosis, Schistosoma

Spectral diseases M. leprae, Leishmania
Strong response, many lymphocytes
Few pathogens and macrophages
Weak response, few lymphocytes
Many pathogens and macrophages
ACUTE INFLAMMATION
The cardinal signs of inflammation are rubor (redness), calor (heat), tumor
(swelling), dolor (pain), and loss of function. Seen here is skin with erythema.
Seen here is vasodilation with exudation that has led to an outpouring of fluid with fibrin into the
alveolar spaces, along with PMN's. The series of events in the process of inflammation are:
1.Vasodilation: leads to greater blood flow to the area of inflammation, resulting in redness and heat.
2.Vascular permeability: endothelial cells become "leaky" from either direct endothelial cell injury or
via chemical mediators.
3.Exudation: fluid, proteins, red blood cells, and white blood cells escape from the intravascular space
as a result of increased osmotic pressure extravascularly and increased hydrostatic pressure
intravascularly
4.Vascular stasis: slowing of the blood in the bloodstream with vasodilation and fluid exudation to
allow chemical mediators and inflammatory cells to collect and respond to the stimulus.
The arm at the bottom is swollen
(edematous) and reddened (erythematous)
compared to the arm at the top.
As in the preceding diagram, here PMN's that are
marginated along the dilated venule wall (arrow) are
squeezing through the basement membrane (the
process of diapedesis) and spilling out into
extravascular space.
Acute inflammation is marked by an increase in
inflammatory cells. Perhaps the simplest indicator of
acute inflammation is an increase in the white blood cell
count in the peripheal blood, here marked by an
increase in segmented neutrophils (PMN's).
SITE OF REPLICATION
EXTRACELLULAR
Interstitial spaces
Blood, lymph
Bronchial,
gastrointestinal lumen
Viruses
Bacteria
Protozoa
Fungi
Worms
INTRACELLULAR
Epithelial surfaces
Neisseria gonorrhoeae
Worms
Mycoplasma
Streptococcus
pneumoniae
Vibrio cholerae
Escherichia coli
Candida albicans
Helicobacter pylori
Cytoplasmic
Viruses
Chlamydia ssp.
Richettsia ssp.
Listeria monocytogenes
Protozoa
Vesicular
Mycobacteria
Salmonella typhimurium
Seishmania spp.
Listeria ssp.
Trypanosoma spp.
Legionella pneumophila
Cryptococcus neoformans
Histoplasma
Yersinia pestis
PROTECTIVE IMMUNITY
Antibodies
Complement
Phagocytosis
Neutralization
IgA type Antibodies
Anti-microbial peptides
Cytotoxic T cells
NK cells
T cell and NK celldependent
macrophage activation
THE SITE OF PATHOGEN DEGRADATION DETERMINES THE TYPE
OF IMMUNRE RESPONSES
PATHOGEN TYPE
PROCESSING
RESPONSE
Extracellular
ANTIBODY PRODUCTION
Acidic vesicles
MHCII
Neutralization
Complement activation
Phagocytosis
MHC II binding
CD4+ T cells
B-se jt
Intravesicular
KILLING BACTERIA OF
PARASITE IN VESICLES
Acidic vesicles
MHCII
MHC II binding
Intracellular killing
CD4+ T cells
Th1
Cytosolic
MHCI
Cytoplasm
MHC I binding
MHC II binding
CD8+ T cells
CD4+ T cells
MHCII
NK
KILLING OF INFECTED CELL
Extracellular killing
ANTIBODY PRODUCTION
Acute bronchopneumonia of the lung
This tissue gram stain of an acute pneumonia
demonstrates gram positive cocci that have
been eaten by the numerous PMN's exuded
into the alveolar space. Opsonins such as IgG
and C3b facilitate the attachment of PMN's to
offending agents such as bacteria so that the
PMN's can phagocytose them.
Neutrophilic alveolar exudate with PMN
The patient had a "productive" cough because
of large amounts of purulent sputum.
Numerous neutrophils fill the alveoli in this case of
acute bronchopneumonia in a patient with a high
fever. Pseudomonas aeruginosa was cultured from
sputum. Dilated capillaries in the alveolar walls from
vasodilation with the acute inflammatory process.
Fibrin mesh in fluid with PMN's at the area
of acute inflammation. It is this fluid
collection that produces the "tumor" or
swelling aspect of acute inflammation.
The vasculitis shown here demonstrates the
destruction that can accompany the acute
inflammatory process and the interplay with the
coagulation mechanism. The arterial wall is
undergoing necrosis, and there is thrombus
formation in the lumen.
Edema with inflammation is not trivial at all: Marked
laryngeal edema such that the airway is narrowed.
This is life-threatening. Thus, fluid collections can be
serious depending upon their location.
A purulent exudate is seen beneath the
meninges in the brain of this patient with acute
meningitis from Streptococcus pneumoniae
infection. The exudate obscures the sulci.
Environment
Immune system
Tolerance
SELF
NON-SELF
Destructive
SELF
Immune
response
THE IMMUNE RESPONSE TO BACTERIA
Streptococci in the lung
CONTEST OF B CELLS AND BACTERIA
B Lymphocyte
Bacterium
12 hrs
6x1010 Bacteria
Toxin
THE IMMUNE RESPONSE TO
EXTRACELLULAR BACTERIA
Polysaccharide capsule
Exotoxins – secreted by bacteria
- Cytotoxicity of various mechanisms
- Inhibition of various cellular functions
- Induction of cytokines
pathology, septic shock
Endotoxins – released by phagocytic cells
- Cell wall – Gram (-) rods LPS
Gram (+) cocci glycane
THE IMMUNE RESPONSE TO BACTERIA COLONIZING
THE EPITHELIUM
Mucosa
INNATE IMMUNITY
Dendritic cells
Cytotoxic CD8+ T cells
Activated macrophage
Langerhans cells
DRAINING LYMPH
NODE
Activation of B and T
cells
ESCAPE OF BACTERIA
TO OTHER SITES
MECHANISMS OF PROTECTION
INNATE IMMUNITY
Complement activation
Gram (+)
Gram (-)
peptidoglycane 
LPS

Mannose + MBL 
alternative pathway
alternative pathway
lectin pathway
Phagocytosis
Antibody and complement mediated opsonization
Inflammation
LPS

Peptidoglycane 
TLR macrophage activation
TLR macrophage activation
ACQUIRED IMMUNITY
Humoral immune response
Targets: cell wall antigens and toxins
T-independent
T-dependent
 cell wall polysaccharide
 bacterial protein
 isotype switch
 inflammation
 macrophage activation
ESCAPE MECHANISMS - overcome complement activation
THE IMMUNE RESPONSE AGAINST EXTRACELLULAR
BACTERIA
Complement-mediated lysis
T-INDEPENDENT
IgM/IgG antibody + Complement
plasma
B
CR1
CR3macrophage
FcR
Plasma level
LPS
TNF-α
IC
IL-1β
IL-6
1
2
3
4
5
INNATE IMMUNITY
hours
Helper T-cell activation
IgM  IgG switch
ANTIBODY MEDIATED EFFECTOR FUNCTIONS
SPECIFIC ANTIBODY
Bacterial toxin
Bacteria in interstitium
Bacteria in plasma
Toxin
receptor
Neutralization
Opsonization
Complement activation
COMPLEMENT
Neutralization
Phagocytosis
Phagocytosis and lysis
Environment
Immune system
Tolerance
SELF
NON-SELF
Destructive
SELF
Immune
response
Evasion of immune mechanisms by extracellular bacteria
Antigenic variation/shedding
Nesseria gonorrhoeae (pilin)
E. coli
Inhibition of complement mediated lysis
Sialic acid containing capsule inhibits complement (alternative pathway)
Scavenging of reactive oxigen intermediates
Catalase-positive staphylococci
Carbohydrate capsule inhibits phagocytosis
Streptococcus pneumonae
Nesseria meningitis
Haemophilus
Secretion of proteases to degrade antibodies
Nesseria, Haemophilus, Streptococcus
Staphylococcus protein A binds Fc region of antibody
SUBVERSION OF THE IMMUNE SYSTEM BY
EXTRACELLULAR BACTERIA
Superantigens of staphylococci – staphylococcal enterotoxins (SE)
– toxic shock syndrom toxin-1 (TSST-1)
PROFESSIONAL APC
2
2
Simultaneous binding to MHC class II and TCR chain irrespective of peptide binding specificity
Mimic specific antigen
1
1
induce T cell activation and proliferation
2 – 20% of CD4+ T cells, which share V


Over production of cytokines
Systemic toxicity
Suppression of adaptive immunity by
T cell
apoptosis