Immunity to Infection: Inflammation, Sepsis & Immune Response

Immunity to Infection II : 2025

• Outline
• Fever and Inflammation will be discussed
• Chemical mediators in inflammation will be discussed
• Acute and chronic inflammation will be discussed
• Sepsis will be discussed
• Effects of the immune response will be discussed
• Immune evasion will be discussed

Adaptive Immune Response

• Adaptive immune responses for extracellular pathogens is reviewed

• This involves:

  • Neutralization of bacteria, viruses, and toxins
  • Opsonization and Fc receptor-mediated phagocytosis
  • Phagocytosis of C3b-coated bacteria
  • Inflammation via C5a
  • Lysis of microbe
  • Macrophage activation, phagocytosis, and bacterial killing

• Cell-mediated immunity against intracellular pathogens is reviewed

• Phagocytes ingest microbes and microbial antigens in vesicles

• CD4+ T cells make phagocytes better killers of microbes

• Cytokine secretion is involved

• This leads to macrophage activation, killing of ingested microbes, and inflammation

• Infected cells with microbes exist in the cytoplasm

• CD8+ T cells eliminate the reservoir of infection through killing of infected cells

Immune Response and Bacterial infection

• The effects of the immune response against bacterial infection is inflammation and repair
• Mast cells release mediators like histamine
• Polymorphonuclear leukocytes, lymphocytes, and monocytes participate in VESSEL responses
• Platelets are involved in the immune response
• Mediators, clotting factors and kininogens contribute to inflammation

Bacterial Pattern Recognition

• Bacterial pattern recognition review
• Gram-negative bacteria release LPS, which binds to LBP and interacts with CD14 and TLR4
• Gram-positive bacteria release LTA, which interacts with TLR2
• This leads to mediators of inflammation

Cytokines in Acute Inflammation

• TNF

  • Principal sources: macrophages, mast cells, and T lymphocytes
  • Principal roles include leukocyte activation, endothelial activation, and systemic acute phase response

• IL-1

  • Principal sources: macrophages, endothelial cells, and some epithelial cells
  • Principal roles include systemic acute phase response and a greater role in fever

• IL-6

  • Principal sources: macrophages and possibly others
  • Principal role is the systemic acute phase response

Acute inflammation Events

• Vascular Events*
• Cellular Events
• Arterial and Venular changes
• Neutrophilic Influx in Vessels
• Vasodilation and Increased Venular Permeability
• Margination, Rolling, and Adhesion for Immune cells
• Hyperemia (Redness) and Swelling (Edema) Occur
• Transmigration (Diapedesis) Occurs

Cell-Derived Inflammatory Mediators

• Platelets: Release serotonin

• Leukocytes: Produce ROS and chemokines

• Mast cells: Release histamine, prostaglandins, leukotrienes, and platelet-activating factor

• Endothelium and macrophages: Produce cytokines (IL-1, TNF) and nitric oxide and chemokines

• Mediators cause

  • Vasodilation and increased vascular permeability in addition to chemotaxis
  • Microbial killing and tissue damage
  • Multiple local and systemic effects

Fever and Pyrogens

• Fever is a result of pyrogens from the breakdown of pathogens

• Immune response mediators such as IL-1, IL-2, TNF, and IFN are invovled

• Leukocytes, endothelium, glial cells and mesenchymal cells are invovled

• Pyrogenic cytokines IL-1, TNF, and IFN can activate gp130 receptor ligands

• Hypothalamic endothelium produces PGE2 which acts as a neurotransmitter

• This elevates the set-point, activating vasomotor center neurons and peripheral vasoconstriction for heat production

• Paracetamol reduces fever but doesn't kill bacteria because it inhibits prostaglandin production

Fever and Chills

• The presence of bacteremia, viremia, or parasitemia may cause fever with chills
• Shivering results from pyrogens from bacteria, which may include exotoxins, endotoxins, or LPS from the cell wall
• These substances are released in large quantities, stimulating the production of inflammatory cytokines such as TNF-α, IL-1, and IFN-γ

Macrophage Activation and Clinical Signs

• Macrophages are activated by PAMPS and DAMPS
• PRRs bind to activators
• Clinical signs include
  • Vasodilation and vascular leakage
  • Fever and hyperalgesia
  • Leukocyte recruitment to the site of inflammation
  • Release of acute-phase proteins

Systemic Inflammatory Response Syndrome (SIRS)

• SIRS is characterized by two or more of the following:
  • Body temperature greater than 38°C or less than 36°C
  • Heart rate greater than 90/min
  • Respiratory rate greater than 20/min or PaCO2 less than 32 mmHg
  • WBC count greater than 12,000/mm³ or less than 4,000/mm³ with young forms greater than 10%

Sepsis Definition

• Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection

• The process of sepsis

  • Sources of infection lead to bacteria entering the blood
  • Leaking blood vessels decrease plasma volume
  • Resulting organ dysfunction can cause death

• Sepsis worsens shock, impacting the bowel, CNS, autonomic functions, heart, liver, pancreas, inflammatory systems, hemostatic systems, endothelial systems, lungs, and kidneys

Sepsis Cascade

• LPS from lysed bacterial cells binds to LPS-binding protein to form a complex

• Macrophages expressing CD14, CD11/CD18, TLR-2/TLR-4 LPS-Receptors, binding causes

• Adult Respiratory Distress Syndrome (ARDS)

• Disseminated Intravascular Coagulation (DIC)

• Multiple Organ System Failure

• Increase TNF, IL-1, IL-12, IL-6, IFNgamma

• Cascade of Activation of coagulation Prostaglandins leukotrienes complement

• Endothelial cell damage reduces gas transfer and Increases vascular permeability

Sepsis Procoagulant and Anticoagulant Pathways

• Sepsis has both procoagulant and anticoagulant influences

• Tissue factor initiates procoagulant pathways

• Sepsis downregulates protein C which inhibits clotting.

• Thrombin leads to fibrin formation

• Enhanced formation of fibrin blood clots

• Increased fibrogen

• Impaired tissue perfusion

ARDS Pathogenesis

• Normal alveolus are injured during the acute phase
• The result is high levels of protein, cellular debris and migration of damaging immune components lead to:
• Denuded Basement Membrane
• Hyaline Membrane from damaged tissue
• Widening of interstitial space from fluid

Septic Shock Complications

• ARDS occurs in 18% of septic shock cases
• ARF (acute renal failure) occurs in 51% of septic shock cases
• DIC occurs in 38% of septic shock cases

Sepsis Bedside Criteria

• Quick Sepsis-Related Organ Failure Assessment (qSOFA) Criteria:
  • Respiratory rate ≥ 22
  • Altered cognition
  • Systolic blood pressure ≤ 100 mmHg

Shock Definition

• Shock is defined as poor tissue perfusion and inadequate tissue perfusion
• A mean arterial pressure (MAP) of <65 mmHg defines shock
  • BP< 90/60
• MAP = Pd+(Ps-Pd)/3
  • Pd = diastolic blood pressure
  • Ps = systolic blood pressure

Poor Tissue Perfusion

• Signs of poor tissue perfusion and shock include
  • Low urine output
  • Altered mentation or loss of conciousness
  • Metabolic acidosis

Physiology of Shock

• Peripheral Chemoreceptor Pathways are activated in response to shoc
• Carotid and Aortic bodies control sensory signals that can control heart muscle contractions
• Low BP causes increase in sympathetic tone

Reflex Tachycardia

• Tachycardia is a common response to shock
• This is often caused by low cardiac output and hypoxemia in cases of shock
• Baroreceptors in the carotid sinus activate
• Reflex happens by control of heart and blood vessels in the brain stem
• Sympathetic activity and Contraction increases HR and can cause fever

Clinical Monitoring of Sepsis

• Clinical monitoring can include measuring fluid output and clinical measurement of BP and HR

Outcomes of Acute inflammation

• Resolution
• Suppuration
• Repair and organization
• Chronic inflammation

Acute vs Chronic Inflammation

• Acute Inflammation

  • Short duration (few minutes to days)
  • Protein exudate
  • Neutrophils predominate

• Chronic Inflammation

  • Days to years
  • Mainly macrophages and lymphocytes
  • Proliferation of blood vessels, fibrosis and tissue necrosis
  • Fewer neutrophils

Sites of infection compared

• Extracellular sites of infections

  • Interstitial spaces and blood in lymph systems: Viruses, Bacteria, Protozoa, Fungi, Worms. Uses Antibodies and Complement activation

• Intracellular sites of infections

  • Cytoplasmic infections: Viruses, Chlamydia Species uses Ctotoxic T cells and Macrophages
  • Vesicular infections: Mycobacteria and Trypanosoma. Use Activates Macrophages

• Epithelial surfaces: Neisseria gonorrhoeae, Candida albicans Worms.

Immune Evasion By Bacteria

• Bacteria utilize immune evasion strategies:

  • Avoiding antibody detection from immune system
  • Change protein surface, and genetic variation to avoid anitbodies
  • Produce protese to destory antibodies (IgA protease)

• Avoid being destroyed by phagocytosis using

  • Capsule protect macrophage (S. pneumoniae...)
  • Inhibit phagolysosome by inhbibition of reactive oxigen species and Nitrous Oxide
  • Inhibiting Complements

Streptococcus Pneumoniae capsule formation and resistance

• Streptococcus pneumoniae have a gram and formation of capsules
• capsule ms prevent upsonization

Immune Evasion by Viruses

• Viruses can evade the immune and the body via several different mechanisms:
  • Inhibition of humoral immunity by multiple mechanisms like: -mutation or Antigenic variation (influenza virus, HIV.)
• A genetic drift over time
  • Causing the immune system to be blind with replication in cells

Latency in Herpes Simplex

• Establishment of latency: (HSV, HIV...)
• A latent peroid where infection is in nerves Ganglion
• so immue system mn cant be detet