Body defense of respiratory infection and common preventive strategies

Assoc.Prof. Wanlop Kaewkes MD., M.Sc.(microbiology) ,Dip Thai Board (Family Medicine)

Objective
Pulmonary defense mechanism -Innate immunity -Adaptive immunity Pulmonary host defenses in acute pneumonia Impairment of pulmonary defense

Pulmonary defense mechanism and normal flora

Pulmonary defense mechanism 1.Innate immunity-Structural defense antimicrobial molecule alveolar macrophage -Phagocytic defense PMN 2.Adaptive immunity-B cells,T cells ,APC (dendritic cells) stimulate T cells ,secrete Cytokines,B cells produce antibody

Innate immune defense

Mechanical host defense Mucociliary clearance-particle>5micron -particle<5 micron destroyed by antimicrobial molecules -Lysozyme -Complement -ImmunoglobulinA and G -Fibronectin -Defensins

 Respiratory epithelium
Functions-Barrier against bacterial invasion -Mucociliary clearance -Chemokine production

Alveolar macrophages
phagocytosis -inflammatory immune response
- bacterial product secrete proinflammatory cytokines IL-8,TNF-alpha ,TNF1 beta

 toxic Neutrophil- phagocytosis

intracellular molecule superoxide anion,hydroxyl radical,nitric oxide neutrophil chemotactic chemkine macrophage ,lung epithelium ,endothelial cell,lymphocyte Dendritic cells
-antigen capture -antigen processing

 Toll-like receptor(TLR) Signaling receptor

TLR-dendritic cell ,alveolar macrophage ,airway epithelial cell TLR recognize molecular pattern TLR2 epithelial cell pili Pseudomonas

aeruginosa

Signaling myeloid differentiation factor88(MyD88) NF-KB cytokine,chemkine

Adaptive immune defense

CD4+ T-helper(Th) cell

Th1-cytokines-IL2,IFN gamma,lymphotoxin -alpha -Cell-mediated immunity,inflammation Th2- cytokines-IL-4,IL-5,IL-9,IL-10,IL-13

- Humoral immunity -stimulate antibody production, especially IgE, and stimulate eosinophil activity.

Antimicrobial functions of Antibodies

COMPLEMENT ACTIVATION augment the action of antibodies by facilitating phagocytosis, attracting leukocytes, and directly lysing microbes OPSONIZATION Neutrophils, monocytes, and macrophages as phagocytes Phagocytes also have receptors for the Fc end of IgG molecules (FcR) and for the C3b fragment of complement, . Facilitation of phagocytosis is called opsonization, and IgG and C3b, in this role, are called opsonins.

ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY (ADCC) -carried out by monocyte-macrophages, NK cells, and neutrophils. -ADCC allows these effector cells to kill targets, such tumo cells, that are too large to be ingested. Perforins, granzymes, and in some case reactive oxygen intermediates are involved in this microbicidal activity

NEUTRALIZATION Viruses and exotoxins bind to specific receptors before entering the cell. Antibodies can prevent the binding of viruses, toxins e.g.,Diphtheria toxin

Pulmonary host defenses in acute pneumonia

Location Upper Airways Nasopharynx Host Defense Mechanism
Nasal hair Turbinates Anatomy of upper airways Mucociliary apparatus IgA secretion Saliva Sloughing of epithelial cells cough Bacterial interference Complement production

Oropharynx

Conducting Airways Trachea, bronchi Cough, epiglottic reflexes Sharp-angled branching of airways Mucociliary apparatus Airway surface liquid (lysozyme, lactoferrin, secretory leukocyte proteinase inhibitor) Dendritic cells Bronchus-associated lymphoid tissue (BALT)} -Antigen processing and presentation -stimulation of memory and effector T cells and cells Immunoglobulin production (IgG,IgM,IgA)

Lower Respiratory Tract

Terminal airways, alveoli Alveolar lining fluid (surfactant, fibronectin, immunoglobulin, complement, free fatty acid, iron-binding proteins) Alveolar macrophages Neutrophil recruitment (pattern recognition receptorstranscription factor stimulationproinflammatory and anti-inflammatory cytokine and chemokine production) Dendritic cells Bronchus-associated lymphoid tissue (BALT)} - Antigen processing and presentation -stimulation of memory and effector T cells and B cells

PULMONARY DEFENSE SYSTEMS The pulmonary defense system involves both innate and adaptive immunity, including anatomic and mechanical barriers, humoral immunity, cell-mediated immunity, and phagocyte activity The upper airways, including the nasopharynx, oropharynx,and larynx, are the sites first exposed to inhaled microorganisms. The nasal mucosa contains ciliated epithelium and mucus-producing cells.

. Airway surface liquid contains lysozyme, lactoferrin, and secretory leukocyte proteinase inhibitor, all of which possess microbicidal activity . Respiratory epithelial cells produce other potent antimicrobial peptides including cathelicidins and defensins. These peptides possess individual antimicrobia activity

. Most bacteria are 0.5 to 2 micron in size. This size particle may reach the terminal airways and alveoli. No mucociliary apparatus exists at this level, humoral and cell-mediated host defenses function here The alveolar-lining fluid contains surfactant, fibronectin, IgG, and complement, all of which are effective opsonins.

 Four distinct populations of macrophages exist in the lung and vary in

their location and function.

The alveolar macrophage It serves as the

resident phagocytic cell in the lower airway and is the first phagocyte encountered by potential pathogens entering the lung via inspired air. -Alveolar macrophages play several critical roles. As phagocytic cells, they can eliminate certain organisms.

 If the numbers of organisms increase beyond the macrophages capability to handle them or if the organisms involved are particularly virulent (e.g., Pseudomonas aeruginosa), the macrophage becomes a mediator of an inflammatory response by producing cytokines that recruit neutrophils into the lung. Interstitial macrophages are located in the lung connective tissue and serve both as phagocytic cells and antigen-processing cells.

 Dendritic cells derive from monocytes and

are located within the epithelium of the trachea, conducting airways, terminal airways, alveolar septa, pulmonary vasculature, and visceral pleura. These cells are therefore positioned to interact with antigens in inhaled air.

 Dendritic cells possess an enhanced capacity to capture, process. They can migrate to lymphoid tissue, where they can stimulate T-cell immune responses. Dendritic cells can also produce a variety of cytokines and chemokines, including interleukin (IL)-12,which serves to stimulate B-cell immune function.

The intravascular macrophage is located

in the capillary endothelial cells. These cells are actively phagocytic and remove foreign or damaged material entering the lungs via the bloodstream.

Lymphocytes in the lung have three major

roles: (1)antibody production (2) cytotoxic activity (3)inflammatory mediator production

IMPAIRMENT OF PULMONARY DEFENSES

. Alterations in the level of consciousness from any cause (stroke, seizures, drug intoxication, anesthesia, alcohol abuse) Cigarette smoking disrupts both mucociliary function and macrophage activity.

Alcohol impairs the cough and epiglottic

reflexes, increased colonization of the oropharynx with aerobic gram-negative bacilli, decreased mobilization of neutrophils,

Infections with Mycoplasma pneumoniae or Haemophilus influenzae

may interfere with normal ciliary function Viruses may actually destroy respiratory epithelium and may disrupt normal ciliary activity, neutrophil function, including chemotaxis, phagocytosis.

Iatrogenic manipulation that bypass the usual

host defenses of the upper airways (endotracheal tubes, nasogastric tubes, and respiratory therapy machinery)

Other factors that impair pulmonary host

defenses include hypoxemia, acidosis, toxic inhalations, pulmonary edema, uremia, malnutrition, immunosuppressive agents

Older adults are at increased risk for the

development of pneumonia