IMMUNE PATHOLOGY

• Decreased, inhibited immunity– One or more functions are missing

and/or down-regulated

• Enhanced and/or dysregulated immunity– One or more functions are up-regulated

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 modification, secretory function etc.

IMMUNE SYSTEM – genetically encoded elements– developmental programs– continuous generation and death of cells – continuous contact with the environment

Genetically determined

– Loss of function mutation

– Altered gene expression

– Genetic predisposition

Acquired

– Environmental factors

– Deviated reactions

– Spectral diseases

THE IMMUNE RESPONSE TO PATHOGENS

PATHOGENSBacteria, Viruses, Fungi

ParasitesUnicellular protozoaMulticellular worms

REQUIRES HIGH INITIAL DOSE FOR INFECTIONESCAPE MECHANISMS TO AVOID DEFENSE MECHANISMS

HUMAN BODY

VAST RESOURCE RICH ENVIRONMENT FOR PATHOGENSDEFENSE MECHANISMS

Physical barriers/Innate immunity – STOP MOST INFECTIONS WITHOUT CALLING Adaptive immunity

Diseases – Medical practice

DISEASEDISEASE Innate immunity fails to terminate infection

Pathogen spreading into lymphoid tissues and activation of adaptive immunity

Successful evasion and subversion of the immune Successful evasion and subversion of the immune system by pathogenssystem by pathogens

Environment

SELF

NON-SELF

Destructive SELF

Immune system

Tolerance

Immune response

MagnitudeMagnitude

QualityQuality

DIRECT

EXOTOXIN ENDOTOXIN CYTOPHATHIC

Streptococcus pyogenesStaphylococcus aureus

Corynebacterium diphteriaeClostridium tetani

Vibrio cholerae

Escherichia coliHaemophylus influenzae

Salmonella typhiShigella

Pseudomonas aeruginosaYersinia pestis

VariolaVaricella zosterHepatitis B virus

Polio virusMeasles virusInfluenza virus

Herpes simplex virus

TonsilitisScarlet fever

Toxic shock syndromeFood poisoning

DiphteriaTetanusCholera

Gram (-) sepsisMeningitisPneumonia

Typhoid feverBaccillary dysentery

Wound infectionPlague

Small poxChicken pox, shingles

HepatitisPolyiomyelitis

MeaslesSubacute sclerosing

panencephalitisInfluenza, cold sores

MECHANISMS OF TISSUE DEMAGE INDUCED BY PATHOGENS

DISEASE

CYTOPATHIC – CYTO-PROLIFERATIVE INFLAMMATIONAcute and chronic inflammation

Death of individual cells

No or weak host – mediated inflammation

Virus inclusion bodies – CMV, adenovirus, Ebola

Fused multinucleated cells

Modification and proliferation of epithelial cells

Epithelial and lymphoid dysplasia – tumorigenic viruses

INFLAMMATORY RESPONSES TO INFECTIOUS AGENTS

NECROTIZING INFLAMMATION Toxin – mediated lesions

Clostridium, HBV-infected hepatocytes, HHV neurons

CHRONIC INFLAMMATION HBV cirrhosis in liver Schistosoma – fibrosis in liver

INCLUSION BODIES IN THE LIVER AFTER EBOLA VIRUS INCLUSION BODIES IN THE LIVER AFTER EBOLA VIRUS INFECTIONINFECTION

MULTINUCLEATED CELL IN HIV INFECTIONMULTINUCLEATED CELL IN HIV INFECTION

INDIRECT

IMMUNE COMPLEX ANTI-HOST ANTIBODY CELL-MEDIATED IMMUNITY

Hepatitis B virusMalaria

Strreptococcus pyogenesTreponema pallidumMost acute infections

Streptococcus pyogenesMycoplasma pneumoniae

Mycobacterium tuberculosisMycobacterium lepraeLymphocytic chorio-

meningitis virusBorrelia burgdorferi

Schistosoma mansoniHerpes simplex virus

Kidney diseaseVascular deposits

GlomerulonephritisKidney demage

in secondary syphilisTransient renal deposits

Rheumatic feverHemolytic anaemia

TuberculosisTuberculoid leprosyAseptic meningitis

Lyme arthritisSchistosomiasis

Herpes stromal keratitis

MECHANISMS OF TISSUE DEMAGE INDUCED BY PATHOGENS

DISEASE

INFLAMMATORY RESPONSES TO INFECTIOUS AGENTS

Diversity in pathogens and inflamatory mediators

Common features of histology and morphologic patters

POLYMORPHONUCLEAR

INFILTRATION

Acute tissue demage Increase vascular permeability

Neutrophilic exudation (pus)

Pyogenic bacteria

Chemoattractant f-Met peptides

Chemoattractant C5a

LPS-mediated macrophage activation

MONONUCLEAR

INFILTRATION

Effector cell infiltration Plasma cells (Syphilis lesions)

T cell infiltration

virus infection – acute

intracellular bacteria – acute

Helminths, spirochetes – chronic

Granulamotous inflammation

M. tuberculosis, Schistosoma

Spectral diseases M. leprae, Leishmania

Strong response, many lymphocytesFew pathogens and macrophages

Weak response, few lymphocytesMany pathogens and macrophages

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 intravascularly4.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 cardinal signs of inflammation are rubor (redness), calor (heat), tumor (swelling), dolor (pain), and loss of function. Seen here is skin with erythema.

ACUTE INFLAMMATION

The arm at the bottom is swollen (edematous) and reddened (erythematous) compared to the arm at the top.

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).

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.