Inflammation and Immune Response

Immunity

• Types of immunity are innate resistance and Adaptive (acquired) immunity

Lines of defence

• The first line of defense is natural barriers: physical, mechanical and biochemical
• The second line of defense consists of inflammation
• The third line of defense is Adaptive (acquired) immunity

First line of defense

• Physical and mechanical barriers include skin and low temp/pH of skin, linings of the gastrointestinal, genitourinary, and respiratory tracts

First line of defense (Cont.)

• Linings of the gastrointestinal, genitourinary, and respiratory tracts have highly interconnected junctions, and use sloughing off of cells, coughing and sneezing, "Washing”, vomiting, urinating, mucus and cilia
• Biochemical barriers involve the synthesis and secretion of substances to trap or destroy microorganisms, such as antibacterial peptides in mucus, perspiration (sweat), saliva, tears, and earwax
• Antimicrobial peptides include cathelicidins, defensins (a defensins in neutrophil granules and β defensins), and collectins (lungs)
• The normal microbiome inhibits colonization by pathogens and releases chemicals that prevent infection
• Lactobacillus is found the vagina, while ammonia, phenols, and indoles are found in the intestine

Second line of defense

• The inflammatory response has causes like Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, and radiation
• The inflammatory response involves cellular and chemical components and is nonspecific and rapidly initiated, with no memory cells
• It takes place in approximately the same way, regardless of exposure to the same stimulus

Second line of defense (Cont.)

• Cardinal signs of the inflammatory response are redness, heat, swelling, pain, and loss of function
• Vascular response of the inflammatory response involves blood vessel dilation, increased vascular permeability and leakage, WBC adherence to the inner walls of the vessels, and migration through the vessels (diapedesis)
• Once cells and chemicals are in the tissues, they prevent and limit infection and further damage and limit and control the inflammatory process
• In the tissues, cells and chemicals interact with components of the adaptive immune system and prepare the area of injury for healing

Plasma Protein Systems

• Protein systems that provide a biochemical barrier against invading pathogens are the complement, clotting, and kinin systems
• These systems all contain inactive enzymes (proenzymes)
• Systems are sequentially activated-cascade, when the first proenzyme is converted to an active enzyme, leading to sequential activation of other components

Plasma Protein Systems(cont)

• the complement system destroys pathogens directly and activates or collaborates with every other component of the inflammatory response
• complement system pathways are classical (antibodies and antigens), Lectin (Mannose-containing bacterial carbohydrates), and Alternative (Gram-negative bacterial and fungal cell wall polysaccharides)
• complement system functions include anaphylatoxic activity resulting in mast cell degranulation; leukocyte chemotaxis; opsonization; cell lysis

Plasma Protein Systems(Cont.)

• The clotting (coagulation) system forms a fibrinous mesh at an injured or inflamed site, and its main substance in fibrinous mesh is insoluble protein is called fibrin
• The clotting system prevents the spread of infection, keeps microorganisms and foreign bodies for removal and forms a clot to stop bleeding
• Extrinsic pathways of the clotting system are activated by tissue factor outside the vascular space
• Intrinsic Pathways of the clotting system are activated in the vascular space when the vessel wall is damaged

Plasma Protein Systems(Cont.)

• The kinin system functions to activate and assist inflammatory cells, and its primary component is bradykinin
• The kinin system causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis
• Kininases degrade kinins

Plasma Protein Systems(Cont.)

• Interactions among the three plasma protein systems are finely regulated to prevent injury to the host tissue and to guarantee activation when needed
• Multiple mechanisms are available to either activate or inactivate (regulate) these plasma protein systems

Plasma Protein Systems(Cont.)

• Interactions among the three plasma protein systems control inflammation and inhibit the three plasma protein systems
• Carboxypeptidase inhibits C3a and C5a, Histiminase and Arylsulfatase inhibit histamine, Kinase inhibits kinins and CI-esterase inhibitor inhibits complement

Cellular Mediators of Inflammation

• Cellular mediators are mast cells, granulocytes (neutrophils, eosinophils, basophils), monocytes and macrophages, natural killer (NK) cells and lymphocytes, and cellular fragments (platelets)
• Biochemical mediators originate from destroyed or damaged cells and modulate the localization and activities of other inflammatory cells
• Tissue regeneration or repair is known as resolution

Cellular Mediators of Inflammation (Cont.)

• Cell surface or cellular receptors are pattern recognition receptors(PRRs), Toll-like receptors(TLRs), Complement receptors, and Scavenger receptors, as well as PAMPS - Damage-associated molecular patterns (DAMPs)
• The inflammatory response is initiated when tissue injury occurs or when PAMPs are recognized by PRRs on cells of the innate immune system

Cellular Mediators of Inflammation (Cont.)

• Cellular products consist of chemokines or cytokines, which regulate innate or adaptive resistance by affecting other neighboring cells
• Chemokines or cytokines can be either proinflammatory or antiinflammatory, and/or synergistic or antagonistic and have pleiotropic actions
• They include interleukins, interferons, and tumor necrosis factor (TNF)

Cytokines

• Interleukins(ILs) are produced primarily by macrophages and lymphocytes in response to microorganisms or stimulation by other products of inflammation and help regulate inflammation
• IL-1 is a proinflammatory cytokine that causes fever, IL-6 is a proinflammatory cytokine that aids in healing, and IL-10 and transforming growth factor-beta (TGF-β) are antiinflammatory cytokines

Cytokines (Cont.)

• Interferons (IFNs) protect against viral infections and are produced and released by virally infected host cells in response to viral double-stranded ribonucleic acid (RNA)
• Interferons do not kill viruses but prevent them from infecting healthy cells
• IFN-a and IFN-B induce the production of antiviral proteins, while IFN-Y increases microbiocidal activity of macrophages

Chemokines

• Chemokines induce WBC chemotaxis and are produced by macrophages, fibroblasts, and endothelial cells
• The vast majority are either CC or CXC chemokines, where CC-chemokines affect mainly monocytes, lymphocytes, and eosinophils and CXC-chemokines generally affect neutrophils

Mast Cells

• Mast cells are cellular bags of granules located in loose connective tissues close to blood vessels, such as the skin, digestive lining, and respiratory tract
• Mast cell activation occurs due to physical injury, chemical agents, immunologic processes, and TLRs
• Chemicals released from mast cells occur by degranulation and by synthesis of lipid-derived chemical mediators

Mast Cell Degranulation

• Mast cell degranulation releases histamine, which causes temporary and rapid constriction of the large blood vessels and dilation of the postcapillary venules
• Histamine also causes endothelial cells that line the capillaries to retract
• H1 receptors are proinflammatory receptors in smooth muscles cells of the bronchi that induce bronchoconstriction.
• H2 receptors are anti-inflammatory receptors found in parietal cells of the stomach mucosa that induce the secretion of gastric acid.

Mast Cell Degranulation (Cont.)

• Neutrophil chemotactic factor attracts neutrophils
• Eosinophil chemotactic factor of anaphylaxis (ECF-A) attracts eosinophils

Mast Cell Synthesis of Mediators

• Leukotrienes are the product of arachidonic acid from mast cell membranes, and have similar effects to histamine, but they occur in the later stages of inflammation
• Prostaglandins have similar effects to leukotrienes and also induce pain
• Platelet-activating factor has similar effects to leukotrienes and also activates platelets

Endothelium

• Endothelium maintains normal blood flow and endothelial cells produce nitric oxide (NO) and prostacyclin (PGI2)
• NO and PG12 maintain blood flow and pressure, while NO maintains vascular tone and inhibits platelet activatio
• During inflammation, the endothelium expresses receptors that help leukocytes leave the circulation and retracts to allow fluid to pass into the tissues
• Damage to endothelium promotes clotting

Platelets

• Platelets are cellular fragments formed from megakaryocytes and are also called thrombocytes
• Activation of platelets stops bleeding and degranulation.
• Platelets contain alpha and dense granules

Phagocytes

• Neutrophils are referred to as polymorphonuclear neutrophils (PMNs), which predominate in early inflammatory responses and ingest bacteria, dead cells, and cellular debris
• Neutrophils are short-lived and become components of the purulent exudate (pus)
• Primary roles of neutrophils include removal of debris in sterile lesions and phagocytosis of bacteria in nonsterile lesions

Phagocytes (Cont.)

• Eosinophils are similar to but not mast cells, are an important source for cytokine IL-4 and are associated with allergies and asthma
• Eosinophils provide defense against parasites and regulate vascular mediators, and help control vascular effects of inflammation
• The role of basophils is uncertain

Phagocytes (Cont.)

• Dendritic cells are phagocytic cells located in peripheral organs and skin providing a link between innate and acquired immune responses
• They can migrate to lymphoid tissue and interact with T lymphocytes to cause acquired immune response, and guide development of T-cells (helper cells)

Phagocytes (Cont.)

• Monocytes are produced in the bone marrow, enter circulation, migrate to the inflammatory site, and develop into macrophages
• Monocytes are precursors to macrophages in tissues, which include Kupffer cells (liver), alveolar macrophages (lungs), and microglia (brain)
• Macrophages are larger and more active as phagocytes than monocytes and are important cellular initiators of inflammation
• In addition, macrophages help in wound healing

Phagocytosis

• Phagocytosis is how a cell ingests and disposes of foreign material and the process of destroying microorganisms and cellular debris
• Phagocytosis involves the production of adhesion molecules, margination (pavementing), where leukocytes adhere to endothelial cells, and diapedesis, where cells emigrate through the endothelial junctions

Phagocytosis (Cont.)

• Steps of phagocytosis are opsonization, engulfment, phagosome formation, fusion with lysosomal granules, and destruction of the target

Phagocytosis (Cont.)

• The respiratory burst and oxygen-dependent killing mechanism are the primary mechanisms for destroying pathogens.
• a1-antitrypsin minimizes the destructive effects of the enzymes released by the dying phagocytes

Phagocytosis (Cont.)

• Natural killer (NK) cells recognize and eliminate cells that are infected with viruses and cancer cells in the blood
• Lymphocytes are the main components of the adaptive immune response

Local Manifestations of Inflammation

• Local manifestations of inflammation result from vascular changes and leakage of components into the tissue which cause heat, redness, swelling, pain, and loss of function

Local Manifestations of Inflammation (Cont.)

• Inflammation functions to dilute toxins, carry plasma proteins and leukocytes to the injury site, and carry bacterial toxins and debris away
• Exudate consists of fluid and cells, such as protein and debris

Exudative Fluids

• Serous exudate is watery and indicates early inflammation
• Fibrinous exudate is thick and clotted, indicating more advanced inflammation
• Purulent (suppurative) exudate is pus, which indicates a bacterial infection, and Hemorrhagic exudate contains blood, which indicates bleeding

Systemic Manifestations of Inflammation

• Systemic manifestations of inflammation include fever, leukocytosis, and increased plasma protein synthesis
• Fever is caused by exogenous and endogenous (IL-1) pyrogens that act directly on the hypothalamus
• Leukocytosis sees increased numbers of circulating leukocytes and left shift/increase in immature cells (bands)
• Increased plasma protein synthesis involves acute-phase reactants such as C-reactive protein, fibrinogen, haptoglobin, amyloid A, and ceruloplasmin

Chronic Inflammation

• Chronic inflammation is inflammation that lasts 2 weeks or longer and is often related to an unsuccessful acute inflammatory response
• Other causes include high lipid and wax content of a microorganism, ability to survive inside the macrophage, toxins, and chemicals/particulate matter/physical irritants

Chronic Inflammation (Cont.)

• Characteristics of include:
  • Dense infiltration of lymphocytes and macrophages
  • Granuloma formation
  • Epithelioid cell formation
  • Giant cell formation

Wound Healing

• Wound healing involves:
  • Regeneration, the most favorable outcome
  • Resolution, returning injured tissue to the original structure and function
  • Repair;replacement of destroyed tissue by scar tissue, and primarily composed of collagen

Wound Healing (Cont.)

• The wound healing process consists of filling in the wound, sealing the wound (epithelialization), and shrinking the wound (contraction)

Wound Healing (Cont.)

• Primary intention wounds heal under conditions of minimal tissue loss, and original tissue structure/function that has been restored
• Secondary Intention wounds require significantly more tissue replacement leading to open wounds and resulting in scar formation

Wound Healing

• Phase I Inflammation involves coagulation and infiltration of Platelets, neutrophils, and Macrophages
• During inflammation, the fibrin mesh of blood clot acts as scaffold, platelets release growth factors
• Neutrophils and macrophages clean the wound via debridement, while blood vessels/ lymph drain away debris and vascular dilation and permeability reverse

Wound Healing (Cont.)

• Phase II Reconstruction sees the wound heals by fibroblast proliferation and collagen synthesis
• Epithelialization allows cells from healthy tissue to grow into the wound via contraction of myofibroblasts and cellular differentiation occurs.

Wound Healing (Cont.)

• Phase III Remodeling and Maturation is the remodeling of the healed wound, which begins several weeks after injury and may last for 2 years
• During this Phase cellular differentiation continues, scar tissue forms, and scar remodeling occurs

Dysfunctional Wound Healing

• Dysfunction during the inflammatory response can involve ischemia, hemorrhage, hypovolemia, fibrous adhesions, excess scar formation, infection, wound sepsis, hypoproteinemia and medications

Dysfunctional Wound Healing (Cont.)

• Dysfunction during the reconstructive phase involves impaired collagen matrix assembly, causing malnutrition, keloid scars or hypertonic scars
• Impaired epithelialization is caused by antiinflammatory steroids, hypoxemia, and nutritional deficiencies and/or cleaning with povidone-iodine and hydrogen peroxide
• Impaired contraction can cause contractures that result from excessive myofibroblast-derived tension

Dysfunctional Wound Healing(Cont.)

• Wound disruption (Dehiscence) is when a wound pulls apart at the suture line, and is caused by excessive strain, wound sepsis, and obesity, and will occurs 5–12 days after suture
• Characteristics:
  • Serous drainage is increased
  • The patient feels like something "gave way"
  • Surgery is required

Pediatrics: Innate Immunity

• Neonates have transiently depressed inflammatory and immune function
• Neonate have neutrophils that are not capable of efficient chemotaxis, a deficient complement system, and are deficient in collectins and collectin-like proteins
• As such, Neonates are susceptible to bacterial infections

Aging: Innate Immunity in the Older Adult

• Impaired or delayed inflammation in older adults is likely a result of chronic illness, such as diabetes mellitus and cardiovascular disease
• Infections are more common in older adults and commonly affect the lungs, urinary tract, and skin
• Older adults have diminished immune function, and decreased expression and function of TLRs

Explore the cardinal signs of inflammation, the role of white blood cells, and activation of the complement system. Learn about opsonization, blood clotting, and the functions of the kinin system, including the role of bradykinin and kininases.