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Host defense mechanisms Non-Specific Defense: 1. First line of defense - Intact skin & mm 2. Second line of defense - Inflammation & phagocytosis Specific Defense: 3. Third line of defense - The immune system
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Nonspecific Host Defense Mechanisms
BY
Prof. DR. Zainalabideen A. Abdulla,DTM&H., MRCPI, Ph.D., FRCPath. (U.K.)
Learning Objectives
Host defense mechanismsNon-Specific Defense:
1 .First line of defense - Intact skin & mm
2 .Second line of defense - Inflammation & phagocytosis
Specific Defense : 3 .Third line of defense
- The immune system
First Line of DefenseSkin and Mucous Membranes
• Physical/mechanical barriers e.g. Bacteria can not penetrate intact skin,
or intact mm/sticky mucus produced (by goblet cells) entraps invaders
• Certain helminthes able to penetrate skin,
e.g. Hookworm, Schistosomiasis
Cellular and chemical factorsIntact skin
• Skin dryness: Inhibits pathogens • Acidity (pH ̴ 5.0)
• Temperature (< 37Celsius) • Oily Sebum (sebaceous glands)- Fatty acids
toxic to pathogens • Perspiration- Flushing organisms
- Lysozyme degrades peptide- glycan specially of G+
• Sloughing off of dead skin cont …/.
cont./…cellular and chemical factorsMucus membranes
•Substances kill or inhibit bacteria: Lysozyme (saliva, tears, nasal secretions)
Lactoferrin (Binds iron required by pathogens) Lactoperoxidase (toxic superoxide radicals)
•Rapidly dividing cells/ expelled with microbes •Respiratory tract: Hair, mm, nose, cilia
•GIT: Digestive enzymes, acidity of the stomach) pH ̴ 1.5 ,(alkalinity of intestines
•GUT: Urination, low vaginal pH
Microbial Antagonism • Nonspecific host defense/ Factors mentioned
• Superinfection: When microbiota reduced
Second LineChemical and Cellular
• Transferrin • Fever • Interferon • Complement system
• Acute phase proteins • Cytokines • Inflammation • Phagocytosis
Transferrin • Glycoprotein; synthesized by the Liver
• Store/deliver iron to host • Sequestered: Deprive pathogens from iron
• Increased: In systemic bacterial infections
Fever • Normal = 36.2 – 37.5 (mean: 37) Celsius
• Fever = > 37.8 • Substance: Pyrogens (pyrogenic)
e.g. Endotoxin, IL-1 (endogenous pyrogen) cont…/.
Fever augmentation of host defenses • Stimulate WBC
• Reducing plasma iron levels • Production of IL-1: Stimulate lymphocytes
Fever development during infectious disease • Gram negative sepsis
• Endotoxin • Phagocytes ingest endotoxin IL-1
• Prostaglandins Up hypothalamic thermostat
•Vasoconstriction; temp decreases when IL-1
Interferons • Small anti-viral proteins
• Produced by virally infected cells“ • Interfere” with viral replication
• Types: Alpha, beta, gamma • Stimulants: Viruses, tumors, bacteria, cells“F.
• Alpha: B-cells, monocytes, macrophages Beta: Fibroblasts, other virus-infected cells
Gamma: T-cells, NK cells • Save surrounding cells; spread inhibited
• Not specific, but species (animal) specific cont
cont./… interferons • Genetically produced by bacteria in which
human genes inserted
• Use: Warts, H. simplex, Hepatitis B & C, and Cancer (leukemia, lymphoma, Kaposi
sarcoma in AIDS(
• Activate NK cells
• Cause: Flulike (malaise, myalgia, chills, fever)
The complement system “C” • 30 different proteins (C1 – C9 & others)
“ • Complementary” to immune system • Complement cascade (stepwise)
• Consequences of “C” activation: 1 .Initiation/amplification of inflammation
2 .Attraction of phagocytes to site 3 .Activation of leukocytes
4 .Lysis of bacteria/ foreign cells (target) 5 .Opsonization (increased phagocytosis)
Opsonization • Opsonins: Antibodies, C3b
• Opsonins attach to surface of target cells • Phagocytes have receptors to opsonins
• The process facilitate phagocytosis of certain particles such as encapsulated bacteria.
Complement pathways: 1 .Classical (C1-C9): Specific immunity
2 .Alternative “ Properdin” (C3-C9): Non- specific (innate) immunity
Acute phase protein • Increased: Infections, inflammation, tissue
injury
• Function: - Enhance resistance to infections - Promote tissue repair
• Examples: C-reactive protein (inflammation marker), serum amyloid A protein, protease
inhibitors, coagulation proteins
Cytokines •For cells’ communication (chemical messages)
•Cells “sense” cytokines by surface receptors
•Roles/examples : - Chemo-attractants (e.g. phagocytes)
- Role in host defense
Inflammation (inflammatory response) • Vasodilatation
• Increased vascular permeability; plasma escape
•Leukocytes escape • Purpose: - Localize infection
- Prevent spread of invaders - Neutralize toxins
- Aid in repair of tissue damage • Cardinal (main) 4 signs: redness, heat, pain,
swelling (edema); + Pus, Function loss cont…/.
cont./… inflammationPhysiological events
• Vasodilatation (histamine & PG)- endothelial cells stretches/separate > Blood
Redness, Heat, Plasma escape Edema
• Influx of phagocytes (chemotactic agents)
• Pain/tenderness (nerve damage: Injury, PG, Toxins, pressure by edema(
cont…/.
cont./… inflammation •Inflammatory exudate: Fluid + cellular debris
•Purulent exudate: Thick greenish yellow exudate + live/dead leukocytes (PUS)
e.g. Staphylococci, Streptococci •Pseudomonas aeruginosa Green pus
) due to bluish pigment of m.o.: Pyocyanin( •Lymphatic system: - Draining circulating fluid
- Transport fat from GI - Filter: T, B, macrophages
- Antibodies/others sub .
Phagocytosis • Engulf (phagocytosis)
• Professional phagocytes ( M & N) • Phagocytic granulocytes (N & E; 1st >> 2nd)
• Monocytes Macrophages - Wandering macrophages
- Fixed macrophages: Histiocytes in C.T,. Liver: Kupffer cells, Brain: microglia
• Phagocytosis steps : Chemotaxis, Attachment, Ingestion, Digestion
Chemotaxis • Chemotaxis (to site): Chemotactic Agent
) Chemokines(
• Produced during complement activation
• Move along concentration gradient
• Attract: N, Mo, E
Attachment • Attachment to objects (microbes) by receptors
• Role of opsonization (Ab & C)
Ingestion • Surround objects by pseudopodia & FUSE
) Phagosome “membrane bound vesicle (”
Digestion • Phagosome + Lysosome Phagolysosome
• Lysosomes: Membrane-bound vesicles with digestive enzymes:
- Lysozyme, Beta-lysin, Lipase, Protease, Peptidase, DNAses, RNases Degrade
CHO, lipids, proteins, and nucleic acids • Neutrophils :
- NADPH oxidase reduces Oxygen Superoxide Anions, Hydroxyl Radicles ,
Hydrogen Peroxide, and Singlet Oxygen/cont
cont./… digestion
• Myeloperoxidase (from lysosomes) in the presence of hydrogen peroxide & chloride
ion Hypochlorous acid (potent microbicidal agents(
• Example: Phagocytosis of Giardia lamblia by neutrophils
Pathogens escape destruction • Capsule: Anti-Phagocytic
• Leukocidin by m.o.: Kills phagocytes
• Wax protects: Mycobacterium tuberculosis
• Survival inside phagocytes: Transported e.g. Salmonella spp., Brucella abortus,
Toxoplasma gondii, Leishmania spp .
Disorders affecting phagocytic and inflammatory processes
Leukopenia •Low WBC numbers; Neutropenia (low N No.)
•Bone marrow injury: Radiation, drugs, nutritional deficiencies, congenital stem cell defects
Disorders of Leukocyte Mobility/Chemotaxis • Defect in actin production (for mobility)
• Corticosteroids
• Chediak-Higashi syndrome: N chemotaxis affected, PMN abnormal lysosomes (not fuse
to phagosomes) resulting in decreased bactericidal activity + albinism, CNS
abnormalities, recurrent bacterial infections
Disorders of intracellular killing • Deficiency of myeloperoxidase (MP)
• Inability to generate: Superoxide anion , hydrogen peroxide (HP), Hypochlorite
• Chronic Granulomatous Disease (CGD): - Fatal genetic disorder
- Repeated bacterial infections - PMNs can ingest bacteria, but can not kill - Forms: Unable to produce HP or lack MP
Additional Factors: See Table