Nonspecific Host Defense Mechanisms BY Prof. DR. Zainalabideen A. Abdulla, DTM&H., MRCPI, Ph.D., FRCPath. (U.K.)

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