Innate Immunity: Inflammation, Phagocytosis, Interferons, and Complement System

Major Inflammatory Events

Stages of Inflammation

Inflammation is a complex biological response to harmful stimuli such as pathogens, damaged cells, or irritants. It involves a series of coordinated events that help eliminate the initial cause of cell injury, clear out necrotic cells and tissues, and establish tissue repair.

• Injury/Immediate Reactions: Blood vessels constrict (vasoconstriction), blood clots form, and mast cells release chemokines and cytokines into the injured area.

• Vascular Reactions: Nearby blood vessels dilate, increasing blood flow and vascular permeability, which leads to increased leakage of fluid into tissues.

• Edema and Pus Formation: Accumulation of fluid causes edema (swelling); infiltration by neutrophils leads to the formation of pus.

• Resolution/Scar Formation: Macrophages and fibroblasts migrate in, initiating immune response and tissue repair, resulting in scar formation and possible loss of normal tissue function.

Unique Characteristics of Leukocytes

• Diapedesis: Migration of leukocytes out of blood vessels into tissues.

• Chemotaxis: Directed movement of cells toward specific chemicals at the site of injury or infection.

Fever: An Adjunct to Inflammation

Mechanism and Benefits of Fever

Fever is a systemic response to infection and inflammation, initiated by circulating pyrogens.

• Exogenous pyrogens: External substances such as bacterial endotoxins.

• Endogenous pyrogens: Released by monocytes, neutrophils, and macrophages during phagocytosis, including interleukin-1 (IL-1) and tumor necrosis factor (TNF).

Benefits of fever:

• Inhibits multiplication of temperature-sensitive microorganisms.

• Reduces available iron, limiting microbial growth.

• Increases metabolism and stimulates immune reactions.

Second-Line of Defenses: Phagocytosis

General Activities of Phagocytes

Phagocytosis is a crucial process in innate immunity, involving the engulfment and destruction of pathogens and debris.

• Survey and discover microbes, particulate matter, and dead or injured cells.

• Ingest and eliminate these materials.

• Extract immunogenic information from foreign matter for adaptive immune response.

Types of Phagocytes

• Neutrophils: React early to bacteria, foreign materials, and damaged tissue.

• Eosinophils: Attracted to sites of infection and antigen-antibody reactions.

• Macrophages: Scavenge and process foreign substances to prepare them for reactions with B and T lymphocytes.

Development of Monocytes and Macrophages

• Monocytes: Transform into macrophages or dendritic cells.

• Dendritic cells: Concentrated in skin and mucous membrane linings; specialize in antigen presentation.

Phagocytic Recognition

Phagocytes detect foreign molecules using Toll-like receptors (TLRs), which signal the cell to produce chemicals that stimulate an immune response.

Sequential Events in Phagocytosis

1. Chemotaxis, Binding, and Ingestion: Phagocytes migrate to the site of inflammation, bind pathogen-associated molecular patterns (PAMPs) via TLRs, and ingest the pathogen.

2. Phagosome Formation: The pathogen is enclosed in a phagosome.

3. Destruction and Elimination: Lysosomes fuse with the phagosome, digesting the pathogen using toxic oxygen species ($O_2$, $O_2^-$, $HO$), lactic acid, lysozyme, and nitric oxide. Undigestible debris are released by exocytosis.

Interferons

Definition and Types

Interferons are small proteins produced by certain white blood cells (WBCs) and tissue cells. They signal neighboring cells to produce antiviral proteins and are crucial in the defense against viral infections.

• Types: Interferon alpha, interferon beta, and interferon gamma.

Antiviral Activity of Interferon

• Bind to cell surfaces and induce expression of antiviral proteins.

• Inhibit expression of cancer genes.

• Produced in response to viruses, RNA, immune products, and antigens.

Complement System

Definition and Functions

The complement system consists of plasma proteins that destroy bacteria and viruses through a cascade of reactions.

• Membrane Attack Complex (MAC): Directly kills pathogens by forming pores in their membranes.

• Opsonization: Coats pathogens to promote phagocytosis.

• Recruitment of Inflammatory Cells: Stimulates cytokine release and enhances chemotaxis.

Complement Pathways

• Classical Pathway: Activated by the presence of antibody bound to microorganism.

• Lectin Pathway: Nonspecific reaction of a host serum protein that binds mannan.

• Alternative Pathway: Can be triggered spontaneously (Additional info: This pathway is activated directly by pathogen surfaces without antibody involvement).

Stages in the Complement Cascade

• Activation of complement proteins (e.g., C3, C5).

• C3 and C5 have additional inflammatory functions: stimulate mast cell degranulation, enhance chemotaxis, and act as inflammatory mediators.

Summary Table: Key Features of Innate Immune Responses

Component	Main Function	Key Molecules/Cells
Inflammation	Localize and eliminate pathogens, initiate tissue repair	Mast cells, neutrophils, macrophages, cytokines
Phagocytosis	Engulf and destroy pathogens	Neutrophils, macrophages, dendritic cells
Fever	Systemic response to infection, inhibits pathogen growth	Pyrogens (IL-1, TNF), hypothalamus
Interferons	Induce antiviral state, inhibit cancer gene expression	Interferon alpha, beta, gamma
Complement	Direct killing, opsonization, inflammation	C3, C5, MAC

Additional info: The alternative complement pathway is a critical part of innate immunity, providing rapid response to pathogens without the need for antibodies. The complement cascade amplifies the immune response and bridges innate and adaptive immunity.