Transcript Non Specific Host Defense Mechanisms

Nonspecific Host Defense
Mechanisms
BY
Prof. DR. Zainalabideen A. Abdulla,
DTM&H., MRCPI, Ph.D., FRCPath. (U.K.)
Learning Objectives
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
First Line of Defense
Skin 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 factors
Intact 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 peptideglycan specially of G+
• Sloughing off of dead skin
cont./…cellular and chemical factors
Mucus 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 Line
Chemical and Cellular
• Transferrin
• Interferon
• Acute phase proteins
• Inflammation
• Fever
• Complement system
• Cytokines
• 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 c
ont
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): Nonspecific (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./… inflammation
Physiological 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