Innate Immune Response and Superantigens

Innate Immune Response

• The innate immune system is activated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPS).
• PAMPs are derived from microbes or microbial toxins and elicit an innate immune response.
• DAMPS are danger signal molecules derived from necrotic cells that elicit a response similar to PAMPS.

Superantigens

• Superantigens are bacterial proteins, usually toxins, that cause polyclonal T-cell activation resulting in massive cytokine release.
• Examples of superantigens include Staphylococcus aureus (toxic shock syndrome) and Streptococcus pyogenes (group A strep, streptococcal toxic shock).

PAMPs and DAMPS

• PAMPs and DAMPS bind with Toll-like receptors (TLRs) or other receptors.
• This binding results in the intranuclear translocation of nuclear factor kappa B (NF-kB), leading to the release of multiple cytokines, complement activation, and cell proliferation stimulation.
• These processes contribute to alterations in cell and organ function, potentially leading to multiorgan dysfunction and shock.
• Concomitant or subsequent activation of immunosuppressive systems also occurs.

Sepsis and SIRS

• Early recognition of sepsis is crucial for improving outcomes.
• Due to heterogeneous presentations, early, accurate recognition of sepsis is difficult.
• Aggressive treatment of non-septic conditions can be harmful.
• Sepsis-3 replaces SIRS and severe sepsis in the Sepsis-3 lexicon..

Sepsis-3

• Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.
• Septic shock is characterized by the need for treatment to maintain systolic blood pressure and address lactic acidosis.

Sequential Organ Failure Assessment (SOFA)

• SOFA is used to predict the risk of mortality in sepsis.
• SOFA involves multiple tests to determine organ dysfunction/failure in the ICU setting.
• qSOFA is a simplified version used outside the ICU, measuring respiratory rate, mental status, and blood pressure, but its use for screening is not currently recommended.

Sepsis-Induced Coagulopathy (SIC)

• SIC is sepsis-induced activation of coagulation that may progress to disseminated intravascular coagulation (DIC).
• DIC/SIC is characterized by systemic activation of the coagulation system with widespread thrombosis, fibrinolysis, and consumption of coagulation factors, ultimately resulting in bleeding.
• Damage to endothelium, production of pro-coagulation factors, and likely NETs contribute to this complex process.
• DIC/SIC can also cause fibrin thrombi within capillary blood vessels, leading to tissue ischemia, necrosis, and multiorgan failure.

Microangiopathic Hemolytic Anemia

• Fibrin microvascular thrombi can traumatize erythrocytes as they pass through small blood vessels, leading to microangiopathic hemolytic anemia.
• Schistocytes, torn erythrocytes, are a characteristic finding in this condition.

Sepsis and the Liver

• The liver plays a crucial role in lactate conversion to glucose (gluconeogenesis) and acetyl-CoA for oxidative metabolism.

Diffuse Alveolar Damage (DAD)

• DAD is neutrophil and cytokine-induced damage to pulmonary endothelium and epithelium, leading to clinical respiratory failure.
• DAD is characterized by decreased PaO2/FiO2 and pulmonary infiltrates.
• Pathology includes:
  • Early: Increased vascular permeability leading to marked pulmonary edema.
  • Intermediate: Hyaline membranes and type two pneumocyte hyperplasia.
  • Late (if patient survives): Fibrosis.

COVID-19 and DAD

• COVID-19 often exhibits a hypercoagulative state skewed toward thrombosis.
• Multiple thrombi within small pulmonary arteries, systemic deep venous thromboses, pulmonary emboli, and consumption of coagulation factors (leading to low platelet count and less frequent bleeding) are common complications.
• Very high D-dimers are characteristic in COVID-19.

Sepsis and Cardiac Dysfunction

• Sepsis can cause cardiac dysfunction through cytokine-induced damage, hypoperfusion, mitochondrial dysfunction, and myocardial cell adaptation.
• Cardiac cells may shut down to conserve energy, leading to decreased cardiac contractility and peripheral vasodilation, further exacerbating hypoperfusion and ischemia.
• Severe sepsis can lead to myocardial ischemia, necrosis, and infarction, similar to atherosclerotic myocardial infarction.
• Nitric oxide, known for its antimicrobial and anti-inflammatory properties, can also act as a potent vasodilator and may play a role in the development of septic shock.

This quiz explores the principles of the innate immune response, including the roles of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPS). Additionally, it covers the function of superantigens and their impact on T-cell activation. Test your understanding of these essential immunological concepts.