Local inflammatory responses

Inflammation is the response of vascularized tissues to harmful stimuli such as infectious agents, mechanical damage, and chemical irritants. Inflammation has both local and systemic manifestations and can be either acute or chronic. Local inflammatory response (local inflammation) occurs within the area affected by the harmful stimulus. Acute local inflammation develops within minutes or hours following a harmful stimulus, has a short duration, and primarily involves the innate immune system. The five classic signs of acute local inflammation are redness, swelling, heat, pain, and loss of function. These signs are caused by the sequence of events that is triggered by tissue damage and allows leukocytes to reach the site of damage in order to eliminate the causative factor. This sequence involves changes in local hemodynamics and vessel permeability as well as interaction between leukocytes and endothelium and interstitial tissue, through which leukocytes escape the blood vessels. To sustain the vascular changes and attract more immune cells to the site of inflammation, leukocytes and tissue cells secrete a range of inflammatory mediators, including interleukins and chemokines. Elimination of the causative factor by leukocytes leads to the resolution of acute inflammation and tissue repair with complete regeneration or scarring. Failure to eliminate the causative agent or prolonged exposure to the causative agent leads to chronic inflammation, which confines the causative agent to the site of the initial acute inflammatory response. Chronic inflammation may last months to years and primarily involves the adaptive immune system.

Overview

• Definition: an immediate response to a pathogenic factor (e.g., trauma, necrosis, foreign bodies, infection)
• Characteristics
  • Acute inflammation fulfills the following functions:
    • Elimination of pathogenic factor
    • Removal of necrotic cells resulting from the initial injury
    • Initiation of tissue repair
  • Rapid onset (occurs seconds to minutes after an encounter with a causative factor)
  • Transient and typically short-lasting; (i.e., resolves in minutes to days, provided it is not caused by an immunological condition)
  • Involves the innate immune system (i.e., the response is not as specific as in chronic inflammation)
  • Release of inflammatory mediators leads to the five classic signs of inflammation: see “Classic signs of inflammation” below.
  • Inflammatory reaction itself may be harmful to an individual under the following circumstances:
    • Excessive reaction (e.g., septic shock)
    • Prolonged duration (e.g., persistent tuberculosis)
    • Inappropriate reaction (e.g., multiple sclerosis, rheumatoid arthritis)

Involved components

• Cells of the immune system
  • Neutrophils, eosinophils, basophils
  • Mast cells
  • Macrophages
    • Peak concentration 2–3 days after the onset
    • Predominate in the late stages of acute inflammation (cytokine secretion by macrophages influences the outcome)
• Toll-like receptors
• Inflammasome: cytosolic intracellular multi-protein oligomer of the innate immune system that promotes the initiation of inflammatory responses and induction of pyroptosis (a highly inflammatory form of apoptosis that promotes the maturation, activation, and release of proinflammatory cytokines and pore-forming proteins) ^[1]
  • Recognition of microbial products, crystals (e.g., uric acid crystals), and products of dead cells
  • Activation → cleavage, maturation, and release of proinflammatory cytokines IL-1β and IL-18 → inflammation and pyroptosis ^[2]
• Proteins
  • Complement
  • Antibodies (preexisting)
  • Hageman factor (factor XII)
• Arachidonic acid metabolites

Inflammatory reactions

1. Local hemodynamic changes (vascular response to injury)
   • Initial vasoconstriction is followed by vasodilation → stasis and ↑ blood flow
   • Vasodilation is induced by release of the following inflammatory mediators:
     • Histamine from basophils, platelets, mast cells
     • Serotonin from platelets
     • Prostaglandins (PGE₂, PGD₂, and PGF₂) from leukocytes, platelets, endothelial cells
     • Bradykinin; (an inflammatory mediator that increases vascular permeability and causes vascular dilation and bronchoconstriction ) from plasma
     • Nitric oxide (NO) from endothelial cells
2. Increased vascular permeability
   • Inflammatory mediators (histamine, serotonin, bradykinin, and leukotrienes C₄, D₄, and E₄) rapidly trigger the retraction of endothelial cells → opening of interendothelial spaces and short-lasting paracellular leakage of plasma
   • Endothelial injury → endothelial cell necrosis and detachment → long-lasting leakage until the damaged area is thrombosed or repaired
   • Leakage of plasma content → edema and promotion of migration of immune cells and proteins to the site of injury or infection
3. Cellular effects
   • Leukocyte extravasation: Leukocytes (predominantly neutrophils) exit postcapillary venules, accumulate at the site of infection or injury, and are subsequently activated (see “Chemotaxis and leukocyte extravasation”).
   • Phagocytosis and killing of the phagocytosed pathogen or lysis of the phagocytosed particles (see “Phagocytosis and killing”)

Possible Outcomes

General information

• When tissue is inflamed, leukocytes (mainly neutrophils in early infection) are released from the bone marrow reserve pool into the circulatory system, where they interact with vascular endothelium and leave the blood vessels (predominantly postcapillary venules) to migrate to the site of infection.
• The process of neutrophil extravasation from the blood to the inflamed tissue occurs in 5 steps:
  1. Margination
  2. Rolling
  3. Adhesion
  4. Diapedesis
  5. Migration

Margination

• Definition: a process by which leukocytes are distributed peripherally along the endothelial surface
• Mechanism: The two main mechanisms that allow for margination are rouleaux formation and dilation of post-capillary venules.
  • Rouleaux formation
    • The liver releases increased amounts of fibrinogen in response to cytokines released by macrophages, monocytes, and other cells near the site of inflammation.
    • Increased fibrinogen → rouleaux formation → neutrophils are pushed against endothelium of the venules
  • Dilation of post-capillary venules
    • The release of inflammatory mediators results in vasodilation of the post-capillary venules.
    • As these venules expand, the velocity of blood flow in these areas slows, causing neutrophils to marginate against the endothelium of the venules.
    • The venules are the segment of microvasculature most sensitive to inflammation. Their intercellular endothelial junctions open to allow for the flow of plasma proteins and leukocytes between cells. ^[4]

Rolling

• Definition: a transient weak interaction of leukocytes with endothelial cells that causes them to move slowly along the blood vessel periphery in areas of inflammation in preparation for adhesion
• Mechanism: mediated by adhesion molecules (selectins)
  • On endothelial cells
    • P-selectin
      • Stored in Weibel-Palade bodies
      • Histamine-mediated release within the endothelium in response to inflammation
    • E-selectin: released in response to inflammatory mediators such as TNF and IL-1
    • Other: GlyCAM-1, CD34
  • On leukocytes
    • Neutrophils and other leukocytes express Sialyl-Lewis^X and L-selectin, respectively.
    • These molecules transiently bind to and dissociate from endothelial selectins, allowing leukocytes to roll along the vascular wall.
    • Deficiency of the adhesion molecule Sialyl-Lewis^X causes leukocyte adhesion deficiency type 2.

Leukocyte adhesion

• Definition: the firm binding of leukocytes to endothelium prior to migrating out of the vasculature
• Mechanism: mediated by adhesion molecules
  • On endothelial cells
    • Intercellular adhesion molecule (ICAM, also called CD54)
    • Vascular adhesion molecule (VCAM, also called CD106)
    • Both upregulated by TNF and IL-1
  • On neutrophils and lymphocytes
    • Neutrophils: lymphocyte function-associated antigen-1 (LFA-1)
      • Belongs to β₂-integrin family
      • Composed of CD18 and CD11a
      • Binds to ICAM
    • Lymphocytes and monocytes β₁-integrin (also called VLA-4) binds to VCAM
    • Expression of integrins is activated by leukotriene B4 (LTB₄) and C5a.
    • The deficiency of a CD18 integrin subunit causes leukocyte adhesion deficiency type 1.

Selectins are molecules that allow leukocytes to select the place of their migration (weak binding), while integrins are molecules that integrate (strong binding) the leukocytes with the endothelial cells.

Diapedesis (transmigration)

• Definition: the transmigration of leukocytes across endothelial barriers (can occur paracellularly or transcellularly)
• Mechanism
  • Leukocytes leave the blood vessel by moving between endothelial cells.
  • Neutrophils release type IV collagenase, which dissolves the basement membrane and allows them to exit the interstitial space.
  • Requires expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, also called CD31), an endothelial cell adhesion molecule (ECAM) on neutrophils, endothelial cells, and platelets

Migration

• Definition: the process by which leukocytes travel through the interstitium to the site of inflammation after leaving the blood vessels
• Mechanism: Occurs via chemotaxis, which is mediated by chemoattractants ^[5]
  • Leukotrienes: e.g., LTB₄
  • Platelet-activating factor (PAF)
  • Chemokines: e.g., IL-8
  • Kallikrein: a serine protease enzyme that activates bradykinin and regulates blood pressure
  • Complement fragments, e.g., C5a
  • Bacterial products (e.g., modified peptides called N-formyl peptides)

Overview

• Definition
  • Phagocytosis is the process by which foreign particles, cell debris, or microbes are engulfed and degraded.
  • Cells capable of phagocytosis are phagocytes (e.g., neutrophils, macrophages).
• Mechanism: Phagocytosis involves 3 sequential steps.
  1. Recognition of a target
  2. Engulfment
  3. Degradation or killing of the engulfed particle

Recognition ^[3]

• General
  • Phagocytes have a number of receptors that allow them to recognize and bind surface molecules of target cells or particles.
  • Opsonization facilitates recognition of target particles.
• Phagocyte recognition receptors and their ligands
  • Mannose receptor: mannose, fucose, N-acetylglucosamine
  • Scavenger receptor: low-density lipoprotein
  • Opsonin receptor: Fc fragment of IgG, C3b

Engulfment ^[3]

• Mechanism
  • The phagocyte forms cytoplasmic extensions (pseudopodia) that surround the target cell or particle.
  • The plasma membrane around the engulfed cell or particle separates to form a phagosome.
  • The phagosome fuses with lysosomes, forming a phagolysosome.
  • Lysosomal content is released into the phagolysosome.

Killing and degradation ^[3]

• Oxygen-dependent
  • Involves production of reactive oxygen species (see “Respiratory burst”)
  • There are a number of diseases associated with defective oxygen-dependent killing, including:
    • Chronic granulomatous disease of childhood: deficiency of NADPH oxidase → lack of superoxide ion → recurrent or persistent infections with catalase-positive organisms (e.g., S. aureus)
    • Myeloperoxidase deficiency → recurrent fungal infections
• Oxygen-independent: involves lysosomal enzymes such as acidic hydrolases and lysozyme

Chronic inflammation may be preceded by acute inflammation and can last for months to years. ^[3]

• Etiology
  • Autoimmune diseases
  • Chronic exposure to toxic pathogens and foreign material (e.g., silica)
  • Nondegradable pathogens (e.g., foreign material)
  • Persistent infections (e.g., tuberculosis, syphilis, certain virual and fungal infections) → type IV hypersensitivity reaction
• Cells involved
  • Mononuclear cells
    • Monocytes
    • Macrophages
    • Lymphocytes
    • Plasma cells
  • Fibroblasts
  • T lymphocytes
• Pathophysiology
  • Mononuclear invasion that causes tissue damage on the one hand, but is simultaneously carrying out repair (in form of fibrosis and angiogenesis) on the other
  • Interaction of macrophages and T lymphocytes → chronic inflammation
  • There are two possible ways of activating macrophages:
    • Classical (proinflammatory): mediated by Th1 cells secreting IFN-γ
    • Alternative (repair and anti-inflammatory): mediated by Th2 cells secreting IL-4 and IL-13
• Outcomes
  • Scarring
  • Amyloidosis
  • Neoplasia, such as:
    • Chronic HCV infection → chronic hepatitis → HCC
    • H. pylori infection → chronic gastritis → gastric adenocarcinoma

Overview

• Distinct type of chronic inflammation that is characterized by the formation of granulomas in affected tissues
• May be induced by continuous T-cell response
• When the immune system is unable to completely eliminate a foreign stimulus (e.g., persistent pathogen, foreign body, infections such as TB, immune-mediated diseases), the resulting granulomatous inflammation attempts to wall off the foreign substance within granulomas without completely degrading or eradicating it.
• This results in persistent inflammation that ultimately causes organ damage and fibrosis.

Etiology

• Infections (most common cause)
  • Protozoan infections (e.g., schistosomiasis)
  • Fungal infections (e.g., histoplasmosis)
  • Bacterial infections
    • Mycobacteria (e.g., leprosy, tuberculosis)
    • Bartonella henselae (e.g., cat scratch disease, stellate necrotizing granulomas)
    • Listeria monocytogenes (e.g., granulomatosis infantiseptica)
    • Treponema pallidum (e.g., tertiary syphilis)
• Immune-mediated diseases
  • Sarcoidosis
  • Crohn disease
  • Subacute thyroiditis (de Quervain)
  • Primary biliary cholangitis
• Vasculitis
  • Granulomatosis with polyangiitis
  • Eosinophilic granulomatosis with polyangiitis
  • Giant cell arteritis
  • Takayasu arteritis
• Foreign body exposure
  • Berylliosis
  • Talcosis
  • Hypersensitivity pneumonitis
  • Breast implants
  • Penetrating trauma with glass, wood, etc.
• Others: chronic granulomatous disease

Pathophysiology

• Antigen-presenting cells present antigens to CD4+ Th cells and secrete IL-12 → stimulation of Th cell differentiation into Th₁ cells
• Th₁ cells activate macrophages by secreting IFN-γ → cytokine release from macrophages (e.g., TNF) → formation of epithelioid macrophages and giant cells
• Epithelioid cells secrete TNF-α, which serves to maintain the granuloma.
  • This is the reason why anti-TNF therapy can promote sequestration of granulomas and cause disseminated disease.
  • Therefore, every individual considered for anti-TNF therapy has to be tested for latent TB beforehand.
• Macrophages within the granuloma cause ↑ calcitriol activation due to ↑ 1α-hydroxylase activity → hypercalcemia

Pathology

• Granuloma: a nodular collection of central macrophages, epithelioid cells (a differentiated tissue macrophage characterized by abundant pink cytoplasm), and multinucleated giant cells surrounded by fibroblasts and lymphocytes, which contain the following structures:
  • Schaumann bodies: cellular inclusion bodies consisting of intracytoplasmic calcium and protein with laminar stratification (e.g., sarcoidosis, tuberculosis, Crohn disease, berylliosis)
  • Asteroid bodies: star-shaped, eosinophilic inclusion bodies consisting of various lipids (e.g., from sarcoidosis, foreign body reactions)
• Types of granuloma
  • Caseating granulomas
    • Granulomas with central necrosis
    • Found in infections (e.g., tuberculosis, fungal infections)
  • Noncaseating granulomatous inflammation
    • Granulomas without central necrosis
    • Found in immune-mediated diseases (e.g., sarcoidosis, Crohn disease), vasculitis, and foreign body exposure

TNF-α is important for maintaining the granuloma. It is essential to test patients for latent TB before initiating anti-TNF therapy because the drug causes breakdown of the granuloma and can result in disseminated TB.

References:^[3][5][6]