Table of Contents
Active resistance (also called the innate or nonspecific active immune response) consists of defense reactions that the body itself actively performs as soon as pathogens have overcome external barriers. Unlike passive resistance (which relies mainly on pre‑existing, structural, or chemically “always on” protections), active resistance involves cells and soluble factors that recognize danger and respond dynamically.
In this chapter, the focus is on how this cellular and humoral (soluble) nonspecific defense works and how it is triggered and coordinated.
Components of Active Nonspecific Resistance
Active resistance includes:
- Cellular components (innate immune cells)
- Soluble components in blood and tissue fluids
- Local inflammatory reactions
- General reactions of the whole organism (systemic responses)
All of these act without needing prior contact with a particular pathogen and therefore do not show the specificity and memory characteristic of the adaptive (specific) immune system.
Important Cell Types
Several types of white blood cells (leukocytes) are crucial for active resistance. They differ in origin, appearance, and function, but they work together closely.
Neutrophil Granulocytes
- Make up the majority of circulating leukocytes in humans.
- Short‑lived cells (hours to a few days) that are rapidly recruited to infection sites.
- Specialized in phagocytosis (cellular “eating”) of bacteria and fungi.
- Contain granules with digestive enzymes and antimicrobial substances.
- After ingesting pathogens, they often die, forming part of the pus in infected tissues.
Neutrophils are typically the first cellular responders in acute bacterial infections.
Monocytes and Macrophages
- Monocytes circulate in the blood; after entering tissues, they differentiate into macrophages.
- Longer lived than neutrophils and less numerous in the blood.
- Highly efficient phagocytes; they remove:
- Bacteria and other microbes
- Dead cells and cell debris
- Foreign particles (e.g., dust in the lungs)
Macrophages also link innate and adaptive immunity by:
- Releasing messenger substances (cytokines)
- Presenting pieces of pathogens (antigens) to cells of the specific immune system (covered in the chapter on Specific Immune Response).
Dendritic Cells (Innate Sentinel Cells)
- Found in many tissues that contact the external environment (skin, mucous membranes).
- Constantly sample their surroundings by taking up material from pathogens.
- Act as key “sentinels”: when activated, they migrate to lymphoid organs and help initiate specific immune responses.
- In active nonspecific resistance, they function mainly as early detectors and cytokine producers.
Eosinophil Granulocytes
- Particularly important in defense against:
- Multicellular parasites (e.g., helminths)
- Some allergic reactions
- Release toxic granule substances onto the surface of large parasites that cannot be phagocytosed easily.
- Modulate inflammatory and allergic reactions by producing or degrading mediators.
Basophils and Mast Cells
- Basophils circulate in the blood; mast cells reside in tissues (especially in skin, lung, and gut).
- Contain granules rich in histamine and other inflammatory mediators.
- Play central roles in:
- Immediate allergic reactions (e.g., hay fever, anaphylaxis)
- Defense reactions against parasites
- On activation, they rapidly degranulate, increasing blood flow and vascular permeability at the site.
Natural Killer (NK) Cells
- A subtype of lymphocytes belonging to the innate immune system.
- Recognize and kill:
- Virus‑infected cells
- Tumor cells showing abnormal or reduced expression of certain surface molecules
- Do not require prior sensitization to a specific antigen.
- Kill target cells by:
- Releasing perforins and granzymes that trigger programmed cell death (apoptosis).
Soluble Factors in Active Resistance
Besides cells, a variety of soluble molecules participate in nonspecific active defense.
Complement System (Overview in the Context of Active Resistance)
- A group of blood proteins that circulate in an inactive form.
- When activated by pathogens or antibody–pathogen complexes, they:
- Punch holes in microbial membranes (membrane attack complex)
- “Tag” pathogens for phagocytosis (opsonization)
- Attract immune cells to infection sites (chemotaxis)
- Promote local inflammation (e.g., by increasing vascular permeability)
In active resistance, early complement activation can occur even without antibodies, through alternative and lectin pathways.
Cytokines and Chemokines
- Cytokines are small signaling proteins released by immune and other cells.
- Examples: interleukins, interferons, tumor necrosis factor (TNF).
- Chemokines are a subgroup that primarily guide cell migration.
Functions in active resistance:
- Coordinate communication between immune cells.
- Induce inflammation (pro‑inflammatory cytokines).
- Attract specific cell types to the infection site.
- Influence body temperature and systemic responses (e.g., fever).
Acute‑Phase Proteins
- Proteins whose concentration in the blood increases or decreases markedly during inflammation.
- Produced mainly by the liver in response to cytokines (especially IL‑6).
- Examples:
- C‑reactive protein (CRP): binds to bacterial components and activates complement.
- Fibrinogen: involved in clotting and can facilitate barrier formation.
- Serve as early systemic markers of inflammation (also relevant clinically).
Recognition of Pathogens in Active Resistance
To respond rapidly yet broadly, cells of the innate immune system use pattern recognition receptors (PRRs). These receptors detect structures that are typical for groups of pathogens but not for host cells.
Pathogen‑Associated Molecular Patterns (PAMPs)
- Conserved molecular structures on pathogens:
- Bacterial lipopolysaccharides (LPS) in Gram‑negative bacteria
- Peptidoglycan in bacterial cell walls
- Flagellin of bacterial flagella
- Double‑stranded RNA or unmethylated CpG DNA motifs in viruses and bacteria
- These PAMPs are recognized as “danger signals” by PRRs.
Pattern Recognition Receptors (PRRs)
- Include several receptor families; a central group are the Toll‑like receptors (TLRs).
- Located on:
- Cell surfaces (for detecting extracellular pathogens and their products)
- Endosomal membranes (for detecting internalized microbial nucleic acids)
- In the cytoplasm (for detecting viral RNA or bacterial components inside the cell)
Upon binding PAMPs, PRRs:
- Trigger intracellular signaling cascades.
- Induce the production of cytokines, chemokines, and antimicrobial molecules.
- Activate the cell’s functional program: phagocytosis, killing of microbes, or presentation of pathogen fragments.
Phagocytosis and Killing of Pathogens
Phagocytosis is a central process in active resistance, performed mainly by neutrophils and macrophages.
Steps of Phagocytosis
- Chemotaxis
- Phagocytes migrate toward higher concentrations of chemotactic signals (chemokines, complement fragments, bacterial products).
- Recognition and Attachment
- Pathogens bind to receptors on phagocytes.
- Opsonins (e.g., complement components, certain acute‑phase proteins) coat microbes and facilitate binding.
- Engulfment
- The cell membrane extends around the pathogen and encloses it in a membrane‑bound vesicle (phagosome).
- Phagolysosome Formation
- The phagosome fuses with lysosomes containing digestive enzymes, forming a phagolysosome.
- Killing and Digestion
- Enzymes and antimicrobial substances degrade the pathogen.
- Reactive oxygen and nitrogen species contribute to microbial killing.
- Exocytosis or Antigen Presentation
- Indigestible residual material may be expelled.
- Portions of degraded pathogens can be presented on the cell surface to cells of the specific immune system.
Oxidative Burst
- During phagocytosis, phagocytes can generate large amounts of reactive oxygen species (ROS).
- This rapid increase in oxygen consumption is called the respiratory burst or oxidative burst.
- ROS (e.g., superoxide radical, hydrogen peroxide) are highly reactive and lethal to many microbes.
- Some pathogens have evolved mechanisms to resist or neutralize ROS, highlighting an evolutionary “arms race” between host and microbe.
Inflammation as a Local Defense Reaction
Active resistance commonly manifests as inflammation at sites of tissue damage or infection. Inflammation is a complex, coordinated response that aims to:
- Eliminate the initial cause of cell injury (e.g., pathogens).
- Remove damaged tissue components.
- Initiate tissue repair.
Cardinal Signs of Acute Inflammation
Historically, inflammation is characterized by:
- Redness ($\text{rubor}$)
- Heat ($\text{calor}$)
- Swelling ($\text{tumor}$)
- Pain ($\text{dolor}$)
- Loss of Function ($\text{functio\ laesa}$; later addition)
These signs result from underlying physiological changes at the inflamed site.
Vascular and Cellular Events
- Vasodilation
- Local blood vessels widen due to mediators such as histamine and nitric oxide.
- Leads to increased blood flow → redness and warmth.
- Increased Vascular Permeability
- Vessel walls become more permeable.
- Plasma proteins and fluid leak into the tissue → swelling (edema).
- Leukocyte Recruitment
- Circulating leukocytes slow down and adhere to the vessel wall (margination, rolling, adhesion).
- They then migrate through the vessel wall into the tissue (diapedesis).
- Accumulation and Activation of Immune Cells
- Neutrophils are usually first, followed later by monocytes/macrophages and lymphocytes.
- These cells phagocytose pathogens, release mediators, and shape the course of the inflammation.
- Resolution or Progression
- If the pathogen is eliminated and damage is limited, anti‑inflammatory mediators promote resolution and tissue repair.
- Persistent stimuli can lead to chronic inflammation (covered in pathogen‑specific or disease chapters).
Mediators of Inflammation
Several locally acting substances (mediators) orchestrate the inflammatory process:
- Histamine from mast cells and basophils:
- Causes vasodilation and increased vascular permeability.
- Prostaglandins and leukotrienes:
- Modulate vasodilation, vascular permeability, and pain sensation.
- Bradykinin:
- Strong pain mediator and vasodilator.
- Cytokines (e.g., TNF‑α, IL‑1):
- Activate endothelium, increase adhesion molecule expression, and act systemically (fever, acute‑phase reaction).
These mediators act in concert and in tightly regulated cascades.
Systemic Reactions: Fever and Acute‑Phase Response
When active resistance is strongly triggered locally, systemic (whole‑body) reactions appear.
Fever
- Elevated body temperature above the normal range, regulated by the hypothalamus.
- Triggered by endogenous pyrogens (e.g., IL‑1, IL‑6, TNF‑α) released by immune cells, or by exogenous pyrogens such as bacterial toxins.
- Functions:
- Many pathogens grow less efficiently at higher temperatures.
- Some immune reactions (e.g., phagocytosis, cytokine production) are enhanced.
- Excessively high or prolonged fever, however, can be harmful.
Acute‑Phase Reaction
- Liver cells increase synthesis of acute‑phase proteins in response to cytokines.
- Effects:
- Support pathogen elimination (e.g., opsonization, complement activation).
- Influence coagulation and tissue protection.
- Clinically, concentrations of certain acute‑phase proteins (e.g., CRP) serve as markers to assess the presence and intensity of inflammation.
Coordination With the Specific Immune System
Although active nonspecific resistance functions independently of prior antigen contact, it strongly shapes the subsequent specific immune response.
Key aspects:
- Antigen Presentation
Macrophages and dendritic cells present processed pathogen components to lymphocytes, helping to set off adaptive immunity. - Cytokine Environment
Cytokines produced early by innate cells determine: - The magnitude of the adaptive response.
- The type of response (e.g., more effective against intracellular vs extracellular pathogens).
- Efficient Pathogen Clearance
Rapid, robust innate responses can sometimes clear an infection before a pronounced specific immune response is needed.
Thus, active nonspecific resistance not only defends immediately but also prepares and guides the later, highly specific and memory‑forming immune responses.