Innate Immunity and Inflammation

Innate Immunity

• Innate immunity is a natural defense system involving epithelial barriers and inflammation for resistance and protection.
• Physical barriers include epithelial cells and membranes in the gastrointestinal (GI), genitourinary (GU), and respiratory tracts.
• Epithelial structures like goblet cells and cilia have high cell turnover to eliminate infections.
• The skin's low temperature and the stomach's low pH inhibit microbial growth.
• Biochemical barriers involve epithelial surfaces synthesizing and secreting substances to trap or destroy pathogens.
• Mucus and sebaceous glands provide antibacterial and antifungal properties.
• Sweat, saliva, and tears contain lysozyme, which attacks gram-positive bacteria.
• Antimicrobial peptides at high concentrations are toxic to bacteria, fungi, and viruses.
• Organisms in the normal biome can cause infection through skin defects or compromised immune/inflammatory responses.

Inflammation

• Inflammation is a response to cellular or tissue damage and activates rapidly in vascularized tissues.
• Inflammation relies on cellular and chemical components, including plasma proteins and is nonspecific
• Systemic inflammation can manifest as fever, leukocytosis (LEFT shift in neutrophil ratios), and changes in plasma protein synthesis (acute-phase reactants).
• Plasma protein synthesis can be pro- or anti-inflammatory and occurs primarily in the liver
• Chronic inflammation lasts over 2 weeks, potentially following an unsuccessful acute response or a distinct initial response

Exudate Accumulation

• Swelling and pain result from exudate accumulation, a watery fluid with few plasma proteins, indicative of early or mild inflammation.
• Fibrinous exudate is thick and clotted, characterizing severe or advanced inflammation.
• Purulent exudate accompanies persistent bacterial infection and contains a large number of leukocytes.
• Hemorrhagic exudate is exudate mixed with red blood cells.

Vascular Response

• Vascular responses include erythema, heat, edema, and pain.
• Arterioles constrict briefly, then vasodilate
• Microcirculation changes occur- vasodilation (decreased blood velocity, increased blood flow), increased permeability, and Diapedesis.
• Diapedesis- WBCs migrate through endothelial cell junctions into surrounding tissues

Benefits of Inflammation

• Inflammation dilutes toxins, prevents further infection and damage, and helps plasma proteins destroy bacteria.
• Neutrophils and macrophages remove cellular debris and infectious agents.
• Interaction with the adaptive immune system leads to more specific responses against pathogens.
• Inflammation helps prepare tissues for healing

Plasma Protein Systems

• Plasma protein systems are crucial for an effective inflammatory response and trigger a cascade of components which provide protection for the individual

Complement System

• Complement system activation produces an immune response, especially against bacterial infections with anaphylactic activity
• Activation can lead to anaphylactic activity in mast cell degranulation, leukocyte chemotaxis, opsonization, and cell lysis.
• The classic pathway is activated by adaptive immune system proteins like antigen-antibody complexes.
• The lectin pathway is antibody-dependent and activated by mannose-containing bacterial carbohydrates.
• The alternative pathway is activated by Gram-negative bacteria and fungal cell wall polysaccharides.

Mast Cells and Degranulation

• Mast cell degranulation releases histamine, causing vasodilation and increased capillary permeability.

Chemotaxis and Opsonins

• A chemotactic factor is a biochemical substance attracting leukocytes to inflammation sites.
• Opsonins (C3b) 'tag' microorganisms for destruction by neutrophils and macrophages.

Clotting System and Intrinsic Pathway

• The clotting system is a group of plasma proteins that form blood clots, creating a fibrin meshwork.
• Platelets trap other cells at injury sites.
• The intrinsic pathway activates when damaged vessel walls expose negatively charged subendothelial substances to Hageman Factor (XII).

Kinin System & Hageman Factor

• The Kinin System, activated by Hageman Factor, produces bradykinin, causing blood vessel dilation and smooth muscle contraction.
• Prostaglandins stimulate nerve endings, induce pain, and may increase leukocyte chemotaxis.
• Hageman Factor impacts all 3 plasma protein systems by activating clotting, controlling clotting via plasmin, activating the Kinin system, and activating the complement cascade.
• Biochemical mediators must be confined to injured tissues to prevent damage to healthy tissues.

Leukocytes

• Leukocytes include granulocytes, monocytes (precursors to macrophages), and lymphocytes (Natural Killer cells and B & T cells).

Cytokines and Chemokines

• Cytokines are intercellular-signaling molecules that bind to specific receptors and regulate innate and adaptive immunity.
• They can be pro- or anti-inflammatory, inducing synthesis of additional cellular products in target cells.
• Chemokines are chemotactic cytokines that attract leukocytes to inflammation sites and are produced by macrophages, fibroblasts, and endothelial cells.
• Cytokines and chemokines are pleiotropic, exhibiting diverse biological activities

Interleukins & Interferons

• Interleukins are biochemical messengers produced by macrophages and lymphocytes to stimulate pattern recognition receptors or other cytokines.
• Interleukin 6 is produced by macrophages & lymphocytes.
• Interferons are low molecular weight (LMW) proteins that primarily protect against viral infections and modulate inflammatory response.
• Type 1 interferons do not directly kill viruses but are secreted by virally infected cells to protect neighboring cells.

Mast Cells & Basophils

• Mast cells are important cellular activators of inflammatory responses, located close to blood vessels.
• Mast cells are activated by physical injury, chemical agents, immunologic means (IgE), bacteria, and viruses.
• They initiate other mediators like leukotrienes, prostaglandins, and platelet activating factor.
• Basophils are found in the blood and function similarly to mast cells.

Degranulation & Histamine

• Degranulation in mast cells releases histamine, chemotactic factors, and cytokines within seconds, with immediate effects.
• Histamine, a vasoactive amine, impacts many cells, particularly circulation.
• The H1 receptor is proinflammatory and present on smooth muscle cells of the bronchi.
• The H2 receptor is anti-inflammatory, suppressing leukocyte function and abundant on parietal cells of the stomach.

Chemotaxis & Leukotrienes

• Chemotaxis is the directional movement of cells along a chemical gradient formed by a chemotactic factor.
• Leukotrienes are products of arachidonic acid that affect membrane phospholipids, smooth muscle contraction, and increase vascular permeability.

Prostaglandins & Endothelial Cells

• Prostaglandins are long-chain unsaturated fatty acids made from arachidonic acid by cyclooxygenase (COX).
• Endothelial cells regulate normal blood flow by preventing clotting.

Nitric Oxide, Prostacyclin, & Platelets

• Nitric Oxide (NO) is produced from arginine, while prostacyclin (PGI2) is derived from arachidonic acid.
• Both relax vascular smooth muscle, suppress cytokine effects, and maintain vascular tone.
• Platelets circulate until vascular injury occurs, leading to activation.
• Activation causes a coagulation cascade to stop bleeding, releases serotonin, and synthesizes TXA2.

TXA2 & Phagocytosis

• TXA2 is a potent vasoconstrictor and inducer of platelet aggregation, suppressible by low-dose aspirin.
• Phagocytosis involves a cell ingesting and disposing of damaged cells, foreign material, and microorganisms.
• Opsonization prepares the target
• Engulfment forms a phagosome
• The phagosome fuses with lysosomal granules to form a phagolysosome
• Destruction of the target occurs

Neutrophils, Eosinophils, & Basophils

• Neutrophils are the predominant phagocytes in early inflammation, arriving within 6-12 hours, activated by mediators.
• Eosinophils are mildly phagocytic defense against parasites and regulate vascular mediators released from mast cells.
• Basophils are similar to mast cells.

Dendritic Cells, Monocytes, & Granuloma

• Dendritic cells link the innate and adaptive immune responses, located in peripheral organs/skin, migrating to lymphoid tissue to interact with T lymphocytes.
• Monocytes are the largest normal blood cells that are produced in the bone marrow,migrate to the site of inflammation and develop into macrophages
• Monocyte-derived macrophages appear at the site in circulation within 24 hours but typically 3 to 7 days later.
• Granuloma is a walled-off area of infection that macrophages cannot limit.

Wound Healing

• Wound healing involves filling in, sealing, and shrinking.
• The inflammatory phase includes fibrin mesh and scaffolding with platelets, neutrophils, and macrophages.
• The proliferative phase begins 3-4 days post-injury, lasting up to 2 weeks, involving macrophage invasion, fibroblast recruitment/proliferation, collagen synthesis, epithelialization, contraction, and cellular differentiation.
• Wound Contraction is the final process, necessary for all wounds but especially those undergoing secondary intention.
• Tissue remodeling and maturation begins weeks after injury, completing normally within 2 years.
• The reconstructive phase involves assembly and remodeling of the collagen matrix, epithelialization, and contraction.

Collagen Synthesis

• Dysfunctional collagen synthesis leads to hypertrophic scars or keloids.

Adaptive Immunity

• Adaptive immunity is the third line of defense which augments defenses, provides security against reinfection, is slower than inflammation, is inducible and specific, and has memory.
• Central Lymphoid Organs include the Thymus and bone marrow
• Peripheral Organs include Peyer's patches in the Ilieum, Adenoids, Tonsils, lymph nodes and Spleen

Clonal Diversity

• Clonal Diversity occurs in fetus, which involves recognizing almost any foreign antigen.
• Lymphoid stem cells migrate to lymphoid organs from the bone marrow.
• Differentiation results in immunocompetent cells that migrate to secondary organs and take up residence

Clonal Selection

• Clonal Selection begins at birth, and continues as new antigens are encountered, memory B cells produce more antibodies upon second challenge with the antigen.
• Begins in lymphoid organs and the appendix.

Humoral Immunity

• Humoral Immunity protects against viruses and bacteria and defends against extracellular microbes and microbial toxins.

Types of Immunity

• Active Immunity is acquired and produced after natural exposure to an antigen or after immunization
• Passive Immunity occurs through the passage of maternal antibodies across the placenta or artificially through immunotherapy (temporary).

Antigens

• Antigens can react with binding sites on antibodies or receptors on B & T cells.
• The most important feature is to be foreign to the host
• Has to be an appropriate size, chemical complexity, and present in sufficient quantity

Antibodies

• Antibodies: serum proteins produced by plasma cells in response to an immunogen.
• Its chief function is to protect against infection via neutralization, agglutination and precipitation.
• IgG: most abundant, proactive against infection.
• IgA1 is found in blood, IgA2 is found in body secretions.
• IgM is the largest, is produced during the first initial response.
• IgE is normally low, is a mediator in allergic response.

B & T Cell Maturation

• B Cells reside in bone marrow where they are exposed to hormones and cytokines that influence proliferation and differentiation.
• T Cell maturation is similar to B cells but found in the Thymus
• B cell Clonal Selection- Immunocompetent cells encounter antigens for the first time, memory cells become factories for anitbodies.

Titer & Immunity

• Titer is a measure of the amount of antibodies
• Secondary Immune response: a faster production, due to memory cells.
• Vaccines may produce long-lived protection but most require boosters at specific intervals