Immunity to bacteria

AAnnttiimmiiccrroobbiiaall DDeeffeennsseess ffoorr IInnffeeccttiioouuss AAggeennttss Bacteria Intracellular

bacteria Viruses Fungi Parasites

Neutrophils Macrophages Complement NK cells CD4 TH1-DTH CD8-CTL Antibody

++ + + - - - ++

- ++ - - ++ - +

- + - + ++ ++ +

- + - - - - +

- - - - - -

++(IgE)

Barrier defenses of human body

Antibacterial Responses

“Protection is initiated on activation of innate responses on a local basis and progress to acute-phase and antigen specific

responses on a systemic scale”

major events in acute inflamation

1. Expansion of capilaries to increase blood flow (seen as blushing or a rash)

2. Increase in the permeability of the microvasculature structure to allow escape of fluid, plasma proteins, and leukocytes from the circulationedema

3. Exit of leukocytes from the capillaries and their accumulation at the site of injury

Bacterial components that activate Protective Responses I

• Direct activation– LPS– Lipoteichoic acid– Lipoarabinomannan– Glycolipids and glycopeptides– Polyanions– N-Formyl peptides

Bacterial components that activate Protective Responses II

• Chemotactic– Peptidoglycan fragments– Cell surface activation of alternative pathways

of complement (C3a, C5a)

Complement in antibacterial response

• Alternative and Lectin pathways activated by bacterial surfaces

• Classic pathway activated later by antibody-antigen complexes

• Production of chemotactic and anaphylotoxic proteins (C3a, C5a)

• Opsonization of bacteria (C3b)• Promotion of killing of gram-negative bacteria• Activation of B cells (C3d)

Complement cascade

Neutrophil diapedesis in response to inflamatory signals

Phagocytes & Phagocytosis• PMNs, monocytes, and eosinophils are

the first cells to appear in response to acute inflammation; they are followed later by macrophages

Neutrophils• major antibacterial response

• an increased number of neutrophils in the blood, body fluids or tissue indicates:

“bacterial infection”

• “left shift”

Steps in Phagocytosis

• Attachment–bacterial carbohydrates (lectins)– receptor for opsonins– fibronectin receptors–Fc receptors

• Internalization (phagocytic vacuole)

• Digestion (phagosome)

Antibacterial compounds of the phagolysosome I

• Oxygen-dependent compounds– Hydrogen peroxide: NADPH oxidase

and NADH

– Superoxide

– Hydroxil radicals (OH)

– Activated halides (Cl_, I

_, Br

_):

myeloperoxidase

– Nitrous oxide

Antibacterial compounds of the phagolysosome II

• Oxygen-independent compounds– Acids

– Lysosome (degrades bacterial peptidoglycan)

– Lactoferrin (chelates iron)

– Defensin and other cationic proteins (damage membranes)

– Proteases, elastase, cathepsin G

Phagocytosis & killing of bacteria

Macrophages in antibacterial response

• Important antibacterial phagocytic cells– Killing by oxygen-dependent and oxygen-

independent mechanisms– Production of IL-1, IL-6, and IL-12; TNF- and

TNF-, and interferon-– Activation of acute-phase and inflammatory

responses– Presentation of antigen to CD4 T cell

Antibacterial responses

Acute-Phase Reactants 1-antitrypsin

1-glycoprotein

• Amyloid A & P

• Antithrombin • C-reactive protein

• C1 esterase inhibitor

• C3 complement

• Ceruloplasmin

• Fibrinogen

• Haptoglobulin

• Orosomucoid

• Plasminogen

• Transferrin

• Lypopolysaccharide-binding proteins

Specific Immune Responses to Bacteria I

• Macrophages move to lymph nodes and interact with CD4 T cells after ingestion of bacteria

• initially: Macroph(APC). CD4 TH0 cells

antigenic peptides + class MHC

TCR + CD4, on TH0

Specific Immune Responses to Bacteria II

• costimulatory signals from the interaction of CD28 (T cells) B7 molecule

(macrophage)

+

IL-1, IL-12

• TH0 produce IL-2, IFN- and IL-4

• B cells produce IgM

• LPS and cell wall polysaccharides activate B cells

Specific Immune Responses to Bacteria III

• TH0 TH1 (IL-12 & IFN-)– activation of Macrophages, T cells, B cells– important for intracellular infections

• CD4 TH2 T-cell response– occur later– initiated by the B cell presentation of antigen– presentation to TH2 cell

(Ag + class II MHC)

– TH2 IL-4, IL-5, IL-6, IL-10 IgG , Plasma-cells, memory cells

T cells in antibacterial response• TH1 CD4 responses important for

intracellular bacterial infections

• TH2 CD4 response important for all bacterial infections

• CD8 cytolytic T cells not very important

Antibody in antibacterial response

• primary protection against extracellular bacteria and reinfection

• Binding to surface structures of bacteria (fimbriae,lipoteichoic acid, capsule)– Blocking attachment

– Opsonization of bacteria for phagocytosis

– Promotion of complement action

– Promotion of clearence of bacteria

– Neutralization of toxins and toxic enzymes

Bacterial Immunopathogenesis“tissue and systemic damage”

• IL-1, IL-6 and TNF-life-threatening in systemic infection

• endotoxin macrph. TNF- in the blood symptomes of sepsis

• antibodies which share determinants with human proteins post-streptococcal glomerulonephritis and rheumatic fever

• superantigens STSS

Bacterial Evasion of Protective Responses

1. the inhibition of phagocytosis and intracellular killing in the phagocyte

2. inactivation of complement function

3. cleavage of IgA

4. intracellular growth (avoidance of antibody)

5. change in bacterial antigenic appearence