Table of Contents
Overview of the Nonspecific Immune Response
The nonspecific (innate) immune response is the body’s built‑in, always‑ready defense system. It reacts quickly and in the same basic way to many different pathogens and harmful stimuli, without needing prior contact or “learning.” It forms the first and second lines of defense that act before the specific (adaptive) immune response is fully activated.
Key features:
- Present from birth
- Responds rapidly (minutes to hours)
- No specificity for particular antigens in the fine molecular sense
- No immune memory (same response on first and later contacts)
- Works closely with physical barriers and, later, with the specific immune system
In this chapter, the focus is on the components and typical reactions of the nonspecific immune response. The more detailed subdivision into “Passive Resistance: General Defense” and “Active Resistance” is treated in the corresponding subchapters.
Components of the Nonspecific Immune System
The nonspecific immune response relies on both structural features of the body and specialized cells and substances in blood and tissues.
Physical and Chemical Barriers
These are often called the body’s “first line of defense.” They prevent pathogens from entering or make conditions unfavorable for them.
Typical examples:
- Skin
- Tight cell layers and keratin form a mechanical barrier.
- Slightly acidic pH and secreted fatty acids inhibit many microbes.
- Normal skin microbiota compete with potential pathogens.
- Mucous membranes
- Line the respiratory, digestive, and urogenital tracts.
- Produce mucus that traps dust, bacteria, and viruses.
- Some areas (e.g., respiratory tract) have cilia that transport trapped material outwards (mucociliary escalator).
- Chemical defenses in secretions
- Lysozyme in tears, saliva, and mucus splits bacterial cell walls.
- Acidic pH in the stomach and vagina kills or inhibits many pathogens.
- Antimicrobial peptides (e.g., defensins) attack microbial membranes.
- Mechanical processes
- Flushing by urine, saliva, and tears removes microbes from surfaces.
- Peristalsis in the gut moves contents along, preventing prolonged colonization.
These barriers act continuously; they do not “recognize” specific pathogens but protect broadly against invasion.
Cellular Components
Once pathogens breach barriers and enter tissues or blood, a set of innate immune cells reacts. They are mainly derived from white blood cells (leukocytes).
Phagocytes
Phagocytes (“eating cells”) engulf and destroy pathogens and debris.
- Neutrophil granulocytes
- Most abundant phagocytes in blood.
- Rapidly recruited to infection sites.
- Engulf bacteria and fungi, then kill them with toxic enzymes and reactive oxygen species inside granules.
- Macrophages
- Develop from monocytes that leave the bloodstream and enter tissues.
- Long‑lived, resident in many organs (e.g., liver, lungs, spleen).
- Functions:
- Phagocytosis of microbes and dead cells
- Release of signaling molecules (cytokines)
- Bridge to the specific immune system by presenting antigens (details in specific immunity).
Dendritic Cells (Innate Role)
Dendritic cells are important “sentinels” in tissues.
- Sense and phagocytose microbes at entry sites (skin, mucosae).
- Produce cytokines that trigger local inflammation.
- Transport ingested microbial material to lymphoid organs, where they play a central role in activating the adaptive immune system (covered elsewhere).
Natural Killer (NK) Cells
NK cells recognize and kill certain virus‑infected cells and some tumor cells without prior sensitization.
- Detect cells with abnormal or reduced expression of “self” markers (especially MHC I molecules).
- Induce apoptosis (programmed cell death) in target cells by releasing cytotoxic molecules (e.g., perforin and granzymes).
- Important early defense before specific cytotoxic T cells are active.
Soluble Factors in Blood and Tissue Fluid
Several nonspecific proteins and small molecules circulate in the blood or are present in tissue fluids.
Complement System
The complement system is a group of plasma proteins that can be activated in a cascade.
Basic nonspecific functions:
- Opsonization: Complement fragments coat microbes, making them easier for phagocytes to recognize and ingest.
- Chemotaxis: Some fragments attract immune cells to the infection site.
- Cell lysis: The “membrane attack complex” (MAC) can form pores in microbial membranes, leading to their destruction.
Although complement can be activated by antibodies (link to specific immunity), it also has innate activation pathways that detect broad patterns on pathogen surfaces.
Cytokines and Chemokines
Cytokines are signaling proteins released by immune and non‑immune cells.
In the nonspecific response, important cytokines include:
- Pro‑inflammatory cytokines
- e.g., interleukin‑1 (IL‑1), tumor necrosis factor‑α (TNF‑α), interleukin‑6 (IL‑6)
- Trigger fever, increase blood vessel permeability, and stimulate production of acute‑phase proteins in the liver.
- Chemokines
- Direct migration of leukocytes to infection or injury sites (chemotaxis).
- Interferons (especially type I interferons, IFN‑α and IFN‑β)
- Produced by virus‑infected cells.
- Induce an antiviral state in neighboring cells (e.g., inhibit viral replication).
- Activate NK cells and increase antigen presentation.
Acute‑Phase Proteins
The liver produces acute‑phase proteins in response to inflammatory cytokines.
Examples (innate functions):
- C‑reactive protein (CRP): Binds to microbial surfaces and damaged cells; can activate complement.
- Mannose‑binding lectin (MBL): Recognizes certain sugar patterns on microbes and activates complement.
These factors enhance recognition and removal of pathogens and tissue debris.
Recognition of Pathogens in the Nonspecific Immune Response
Unlike antibodies or T‑cell receptors, innate immune receptors recognize general patterns that are typical of many pathogens but absent (or differently arranged) in the body’s own cells.
Pattern Recognition Receptors (PRRs)
Innate immune cells express pattern recognition receptors that detect:
- Pathogen‑associated molecular patterns (PAMPs)
- Conserved structures on microbes, e.g.:
- Lipopolysaccharide (LPS) on Gram‑negative bacteria
- Peptidoglycan and teichoic acids on Gram‑positive bacteria
- Double‑stranded RNA of some viruses
- Certain fungal cell wall components
- Damage‑associated molecular patterns (DAMPs)
- Molecules released from damaged or dying body cells, e.g.:
- Nuclear or mitochondrial DNA in the wrong location
- ATP or uric acid crystals in extracellular spaces
Important classes of PRRs:
- Toll‑like receptors (TLRs) on cell surfaces or inside endosomes
- NOD‑like receptors (NLRs) in the cytoplasm
- Other cytosolic sensors for viral RNA or DNA
Activation of these receptors leads to:
- Production of cytokines and chemokines
- Upregulation of antimicrobial mechanisms inside cells
- Initiation of inflammation
This allows a rapid, standardized response to many different but structurally similar threats.
Inflammation as a Typical Nonspecific Reaction
Inflammation is a local, nonspecific reaction of tissues to infection or injury. It aims to:
- Eliminate or isolate the damaging factor.
- Remove damaged tissue.
- Initiate repair processes.
Classical Signs of Inflammation
The typical local signs (in Latin) are:
- Rubor – redness
- Calor – warmth
- Tumor – swelling
- Dolor – pain
- Functio laesa – impaired function
These symptoms arise from underlying vascular and cellular processes.
Vascular and Cellular Changes
Main events during acute inflammation:
- Vasodilation
- Local blood vessels widen.
- Leads to increased blood flow (redness, heat).
- Increased vascular permeability
- Gaps between endothelial cells widen.
- Plasma proteins and fluid leave the vessels (edema → swelling).
- Complement proteins and antibodies can reach the tissue.
- Leukocyte recruitment
- Endothelial cells express adhesion molecules.
- Neutrophils and later monocytes/macrophages bind to vessel walls and migrate into the tissue (diapedesis).
- Chemokines guide them to the focus of damage.
- Phagocytosis and killing
- Infiltrating phagocytes ingest pathogens and debris.
- They release microbicidal substances inside phagosomes.
- Some substances can spill into the tissue and contribute to collateral damage if the reaction is strong or prolonged.
Typically, if the cause is removed, inflammation subsides and tissue regeneration occurs. If the cause persists, a chronic inflammatory state may develop, with different cell compositions and potential tissue remodeling.
Systemic Nonspecific Reactions
If the inflammatory response is strong or widespread, systemic (whole‑body) reactions can occur.
Fever
Fever is a controlled rise in body temperature above the normal range, coordinated by the thermoregulatory center in the hypothalamus.
- Certain cytokines (e.g., IL‑1, TNF‑α, IL‑6) act as endogenous pyrogens.
- The hypothalamic “set‑point” temperature is raised.
- The body produces and retains more heat (shivering, vasoconstriction in the skin) until the new set point is reached.
Possible advantages of fever in innate defense:
- Some pathogens grow more poorly at elevated temperatures.
- Certain immune processes (e.g., phagocyte activity) may function more efficiently.
Leukocytosis and Acute‑Phase Response
- Leukocytosis: Increase in circulating white blood cells due to stimulation of bone marrow.
- Acute‑phase response: Increased production of acute‑phase proteins in the liver, enhancing opsonization and complement activation.
These systemic responses support local immune reactions but can become harmful if uncontrolled or extreme (e.g., in severe sepsis).
Interplay with the Specific Immune Response
Although the nonspecific immune system acts independently of prior exposure, it is tightly connected to the specific (adaptive) immune system.
Key points of interaction:
- Antigen presentation
- Macrophages and dendritic cells process ingested pathogens and display fragments on their surface.
- This is essential for the later activation of specific T cells.
- Cytokine milieu
- Cytokines produced by innate cells influence the type and strength of the adaptive response (e.g., which T‑cell subsets become dominant).
- Complement and antibodies
- Complement proteins can be activated in a nonspecific way, but also by antibody–antigen complexes.
- Opsonization by complement and antibodies together greatly enhances phagocytosis.
Thus, the nonspecific immune response not only provides immediate protection but also prepares and shapes the subsequent specific immune response.
Summary of the Nonspecific Immune Response
- Acts as a rapid, general defense against a wide variety of pathogens and damaging influences.
- Relies on:
- Physical and chemical barriers.
- Innate immune cells (phagocytes, NK cells, dendritic cells in sentinel role).
- Soluble factors (complement, cytokines, interferons, acute‑phase proteins).
- Recognizes broad patterns on pathogens and damage signals via pattern recognition receptors.
- Typical local manifestation is inflammation; systemic manifestations include fever and acute‑phase responses.
- Provides crucial early protection and forms the functional foundation on which the specific immune response builds.