Central Concepts of Pathophysiology: Innate Immunity (Inflammation)
Physiologic Mechanisms of Defense
- First Line
- Physical, mechanical, and biochemical barriers along with the normal microbiome.
- Second Line
- Innate immunity, also known as inflammation or the inflammatory response to injury or infection.
- Third Line
- Adaptive immunity, also known as the immune response.
First Line of Defense – Natural Barriers
- Mechanical
- Skin
- Epithelial layers
- Gastrointestinal peristalsis
- Bronchopulmonary cilia
- Biochemical
- Tears
- Sweat
- Saliva
- Nasal secretions
Human Microbiome
- Normal flora of bacteria and fungi coexist on skin and within various body sites.
- Normal flora do not normally produce disease but can produce opportunistic infections with immune compromise.
Second Line of Defense – Inflammation
- Inflammation is the body’s most immediate response to injury, infection, or allergy.
- Its purpose is to destroy or decrease the effects of invading pathogenic microorganisms.
- Purposes of inflammation include:
- To limit the extent of tissue damage
- To protect against infection
- To initiate repair of damaged tissue
Inflammation versus Immunity
- Inflammation and immunity are sometimes confused but they are not the same entity.
- Inflammation follows a predictable stepwise physiological response.
- Inflammation is activated before the body’s total immune response, also known as adaptive immunity.
Third Line of Defense Adaptive (Acquired) Immunity
- Immune responses involved humoral and cell-mediated actions.
- Adaptive Immunity develops in active and passive manner.
- Topic to be described in a following module.
The Inflammatory Response
- Initiated by either cellular injury or pathogenic invasion.
- Initial response involves mast cell degeneration, activation of the complement system, clotting, and kinin systems, and the release of end - products from damaged cells.
- The body further responds with actions directed at the inflammatory site and widely accepted as visible signs of inflammation:
- Vasodilation (redness, heat)
- Increased vascular permeability (edema or swelling)
- Thrombosis (clotting)
- Stimulation of nerve endings (pain)
- Cellular infiltration (pus)
Exudate
- Serous – watery fluid that contains proteins and a few white blood cells, such as in a blister.
- Fibrous – thick and clotted fluid with white blood cells, such as from the lungs.
- Purulent – known as pus that contains a large or ongoing deposit of white blood cells at the injury site.
- Hemorrhagic – containing blood – red blood cells.
Inflammatory Response
- Etiologies of cellular damage
- Infection
- Mechanical damage
- Ischemia
- Nutrient deprivation
- Temperature extremes
- Radiation exposure
- Inflammation occurs in vascularized tissue.
- Classic or cardinal localized signs and symptoms
- Redness (rubor)
- Heat (calor)
- Swelling (tumor)
- Pain (dolor).
Inflammatory Response – Vascular and Cellular
- Tissue Injury
- Local vasodilation
- Increased vascular permeability
- Diapedesis
- White blood cells adhere to vessel wall and migrate through vessels to site of injury
Plasma Protein Systems
- Complement System
- Contains different plasma proteins (10%) of circulating proteins.
- Directly destroys pathogens.
- Activates and integrates with all other immune components.
- These pathways converge to activate the complement system
- Classical pathway
- Acquired immunity – Antigen/Antibody complex
- Lectin pathway – Bacterial carbohydrates
- Alternative pathways – Gram negative bacteria and fungal wall polysaccharides
Plasma Protein Systems
- Clotting System
- Plasma proteins form a fibrinous mesh at site of tissue injury:
- Prevents the spread of infection to adjacent tissues.
- Traps microorganisms and foreign bodies at the inflammatory site so they can be removed by infiltrating cells.
- Forms a clot that stops any bleeding, and
- Provides a framework for tissue repair and healing.
- Intrinsic and extrinsic clotting pathways converge.
- Result is a fibrin mesh of insoluble protein as the end-product of the clotting cascade.
Plasma Protein Systems
- Kinin System – Bradykinin production augments inflammation
- Dilation of blood vessels (redness, heat)
- Acting with prostaglandin to stimulate nerve endings and produce pain (pain)
- Contraction of smooth muscle cells
- Increased vascular permeability (swelling)
- Increased leukocyte chemotaxis.
- Biologic process by which certain cells direct their movement according to chemicals in their environment.
- Bradykinin directs the leukocytes to the area of injury.
Cellular Response
- Two major cellular components involved
- Granulocytes
- Neutrophils
- Eosinophils
- Basophils
- Monocytes
- Plasma protein system
- Chemical mediators released by cell destruction
- Cells are recruited and activated by:
- Cellular receptors
- Mast cells
- Phagocytosis
- Neutrophils
- Monocytes and macrophages
- Basophils
- Natural killer cells
- Thrombocytes (platelets)
- Each cell has receptors on the cell surface that bind to soluble substances that are produced during tissue damage or infection
- Receptors on cell surface bind soluble substances produced during inflammation
- Receptor binding activates intracellular signaling pathways - Triggers inflammatory response
- Activation:
- Physical injury
- Chemical injury
- Immune response (anaphylactic reaction)
- Toll-like receptors (bacteria and fungi)
- Action:
- Chemical mediators released by these processes:
- Degranulation (Histamine, neutrophils, and eosinophils
- Mediated synthesis (Leukotrienes, prostaglandins, platelet activating factor
- Activated mast cells stimulate production of chemical mediators obtained from lipids in cell membranes with clinically significant effects.
- Leukotrienes – produced from arachidonic acid released from cell membranes have effects similar to histamine although they are released later and have longer effects than histamine.
- Airway constriction
- Increased vascular permeability
- Prostaglandins – also produced from arachidonic acid and with different groups
- Platelet activating factor –produced by mast cells, neutrophils, monocytes, endothelial cells, and platelets (thrombocytes).
- Effects are considered identical to leukotrienes
- Process when an immune system cell engulfs or ingests cellular debris or foreign material.
- Most phagocytes are circulating in the blood, so they must leave the blood stream and advanced to the injured site.
- Once at the site of injury they engulf the undesired material, then fuse with lysosome granules to help destroy the material.
- When the phagocytic cell fulfills its purpose, it begins to break apart.
- When liberated from the now dead phagocytic cell, enzymes contribute to increase inflammation and the cycle begins again.
- Neutrophils
- Phagocytosis begins 6-12 hours after injury
- Sensitive to acidic environment
- Lifespan peak of about 24 hours
- Become a component of purulent exudate
- Monocytes & Macrophages
- Larger cells than neutrophils with slower and longer onset of action
- Activity usually begins about 3-7 days after tissue injury
- These cells divide and replicate
- Basophils
- Similar to mast cells
- Elevated with asthma and allergic reactions
- Natural Killer Cells
- Recognize and eliminate viral-infected cells
- Site of action is mostly in the circulation, not tissues
- Can differentiate infected or tumor cells from normal cells
- Thrombocytes
Cellular Products
- Soluble factors that contribute to the inflammatory response.
- Are either pro-inflammatory or anti-inflammatory.
- Cytokines
- Interleukins
- Interferons
- Tumor necrosis factor - α
- Chemokines
Inflammation – Local Manifestations
- What are the classic or cardinal signs/symptoms of acute inflammation?
- You should be able to explain the rationale for these findings.
Inflammation – Systemic Manifestations
- Acute Inflammation
- Fever
- Leukocytosis
- Increased plasma proteins
- Interleukin -1
- Interleukin-4
- Fibrinogen
- C-reactive protein
- Chronic Inflammation
- Occurs when acute inflammation unresolved.
- Macrophages, lymphocytes, and fibrous tissue build up in sites of chronic inflammation