THE IMMUNE RESPONSES TO PATHOGENS

Viruses, Bacteria, Fungi Parasites PATHOGENS Viruses, Bacteria, Fungi Parasites Unicellular protozoa Multicellular worms REQUIRES HIGH INITIAL DOSE FOR INFECTION ESCAPE MECHANISMS TO AVOID DEFENSE MECHANISMS HUMAN BODY VAST RESOURCE RICH ENVIRONMENT FOR PATHOGENS DEFENSE MECHANISMS Physical barriers/Innate immunity – STOP MOST INFECTIONS WITHOUT CALLING Adaptive immunity Diseases – Medical practice DISEASE Innate immunity fails to terminate infection Pathogen spreading into lymphoid tissues and activation of adaptive immunity Successful evasion and subversion of the immune system by pathogens

MECHANISMS OF TISSUE DEMAGE INDUCED BY PATHOGENS 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 Poliomyelitis Measles Subacute sclerosing panencephalitis Influenza, cold sores

MECHANISMS OF TISSUE DEMAGE INDUCED BY PATHOGENS 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

PROTECTIVE IMMUNITY Viruses Bacteria Protozoa Fungi Worms Neisseria gonorrhoeae Worms Mycoplasma Streptococcus pneumoniae Vibrio cholerae Escherichia coli Candida albicans Helicobacter pylori Viruses Chlamydia ssp. Richettsia ssp. Listeria monocytogenes Protozoa 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 cell- dependent macrophage activation

KILLING BACTERIA IN VESICLES THE SITE OF PATHOGEN DEGRADATION DETERMINES THE TYPE OF IMMUNE RESPONSES PATHOGEN TYPE PROCESSING RESPONSE Extracellular Intravesicular Cytosolic Acidic vesicles MHC II binding CD4+ T cells ANTIBODY PRODUCTION Neutralization Complement activation Phagocytosis Acidic vesicles MHC II binding CD4+ T cells KILLING BACTERIA IN VESICLES Intracellular killing Th1 NK Cytoplasm MHC I binding MHC II binding CD8+ T cells CD4+ T cells KILLING OF INFECTED CELL Extracellular killing ANTIBODY PRODUCTION

EVASION OF THE IMMUNE RESPONSE TO STREPTOCOCCI B Lymphocyte 12 hrs Bacterium 6x1010 Bacteria Toxin S. pneumoniae in the lung

CONSEQUENCES OF SKIN DAMAGE INFLAMMATION IN CONNECTIVE TISSUE

Fibrin mesh in fluid with PMN's at the area of acute inflammation 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 IMMUNE RESPONSE AGAINST EXTRACELLULAR BACTERIA Complement-mediated lysis T-INDEPENDENT IC IgM antibody + Complement Bacterial killing CR1 CR3 plasma B macrophage Helper T-cell activation IgM  IgG switch FcR Plasma level hours LPS TNF-α IL-1β IL-6 INNATE IMMUNITY

MECHANISMS OF PROTECTION INNATE IMMUNITY Complement activation Gram (+) peptidoglycan  alternative pathway Gram (-) LPS  alternative pathway Mannose + MBL  lectin pathway Phagocytosis Antibody and complement mediated opsonization Inflammation LPS  TLR macrophage activation Peptidoglycan  TLR macrophage activation ACQUIRED IMMUNITY Humoral immune response Targets: cell wall antigens and toxins T-independent  cell wall polysaccharide T-dependent  bacterial protein  isotype switch  inflammation  macrophage activation

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

GENERAL SUPPRESSION OF THE IMMUNE RESPONSE

SUBVERSION OF THE IMMUNE SYSTEM BY EXTRACELLULAR BACTERIA Superantigens of staphylococci – staphylococcal enterotoxins (SE) – toxic shock syndrom toxin-1 (TSST-1) PROFESSIONAL APC 1 1 2 2 Simultaneous binding to MHC class II and TCR -chain irrespective of peptide binding specificity Mimic specific antigen Induce massive but ineffective T-cell activation and proliferation in the absence of specific peptide 2 – 20% of CD4+ T-cells, which are not specific for the bacteria but share V get activated and develop to effector T-lymphocytes Over production of cytokines – IL-1, IL-2, TNF-α Systemic toxicity – sepsis/septicemia Suppression of adaptive immunity by apoptosis T cell  

Sepsis/Septicemia TNF-α→platelet activating factor by endothelial cells→clotting, blockage restricts plasma leakage & spread of infection Infection of blood – Sepsis Systemic edema, decreased blood volume, collapse of vessels Disseminated intravascular coagulation, multiple organ failure

High carbohydrate variability ESCAPE High carbohydrate variability Competition of strains ~90 serotypes Serotype-specific Ab response Opsonization

EVASION MECHANISMS OF EXTRACELLULAR BACTERIA Proteins to increase adhesion Bordetella pertussis Inhibition of phagocytosis S.aureus, Str. pneumoniae, Antigenic variants Neisseria gonorrhoeae (pilin) Inhibition of complement-dependent cell lysis Str. pyogenes M-protein Sialic acid rich capsule inhibits activation of the alternative complement pathway Elimination of reactive oxygen species Catalase positive staphylococci Degradation of IgA antibodies Neisseria, H. influenzae