Bacterial Endotoxins: Mechanisms and Effects

• Microbes damage host cells via three mechanisms; direct damage to host cells, inflammation and bacterial toxins.

Mechanism of Endotoxin

• Endotoxins, especially lipid A, activate macrophages, complement and Hageman factor to cause various effects in the host.
• Activated macrophages release IL-1 and TNF and nitric oxide to subsequently cause fever, fever + hypotension and hypotension, respectively.
• Activated complement releases C3a and C5a, leading to hypotension, edema, neutrophil chemotaxis and inflammation.
• Activated Hageman factor results in disseminated intravascular coagulation.
• The tumor necrosis factor (TNF) is a cytokine that can cause cell death and is among the proteins formed by the cleavage of complement component 3, thus playing a role in the immune response.
• Coagulation factor XII known as Hageman factor, plays a crucial role in the coagulation cascade.

Clinical Effects of Endotoxin

• Fever is mediated by the endotoxin, Interleukin-1.
• Hypotension, aka shock, is mediated by bradykinin and nitric oxide.
• Inflammation is mediated by the alternative pathway of complement as well as C3a and C5a.
• Disseminated intravascular coagulation (DIC) is mediated by the activation of Hageman factor.
• The activation of macrophages and many clones of B lymphocytes leads to increased antibody production; endotoxin is a polyclonal activator of B cells, but not T cells.

Endotoxins and Pyrogenic Response

• Cytokines induce the hypothalamus to release lipids called prostaglandins, which reset the thermostat in the hypothalamus, thus resulting in a higher-than-normal temperature. -Interleukins are a group of cytokines (secreted proteins and signal molecules) first seen to be expressed by white blood cells.
• A macrophage ingests a gram-negative bacterium, which is then degraded within a vacuole, thus releasing endotoxins, then induces macrophages to produce interleukin-1 (IL-1).
• IL-1 is released and travels through the bloodstream to the hypothalamus of the brain.
• Finally, IL-1 induces the hypothalamus to produce prostaglandins to reset the body's thermostat to a higher temperature and produce a fever.
• Macrophages are important immune system cells and are formed in response to infections or accumulating damaged and dead cells.
• Macrophages are large, specialized cells that engulf, recognize and destroy target cells.

Exotoxins vs Endotoxins: Comparison of Properties

• Source: Exotoxins come from certain species of both gram-positive and gram-negative bacteria, while endotoxins come from the cell wall of gram-negative bacteria.
• Secretion: Exotoxins are secreted by the cell, but endotoxins are not.
• Chemistry: Exotoxins are polypeptide, but endotoxins are lipopolysaccharide.
• Location of genes: Exotoxins are found on the plasmid or bacteriophage, while endotoxins are located on the bacterial chromosome.
• Toxicity: Exotoxins are highly toxic, but endotoxins are considered low.
• Clinical effects: Exotoxins lead to various effects, while endotoxins present as fever, shock.
• Mode of action: Exotoxins have various methods of action, while endotoxins include TNF and interleukin-1.
• Antigenicity: Exotoxins induce high-titer antibodies called antitoxins, but endotoxins are poorly antigenic.
• Vaccines: Toxoids are used as vaccines against exotoxins; no toxoids form, and no vaccine is available for endotoxins.
• Heat stability: Exotoxins are destroyed rapidly at 60°C (except staphylococcal enterotoxin), but endotoxins are stable at 100°C for 1 hour.

Diseases Caused by Long-Term Endotoxin-Induced Inflammation

• Endotoxins can cause long-term diseases in the circulatory, nervous and respiratory systems and can also cause general pain.
• Circulatory: vasculitis, lymphangitis, atherosclerosis, SIRS, sepsis, endotoxemia.
• Nervous system: Parkinson's disease, polyneuritis, Alzheimer's disease, multiple sclerosis and stroke.
• Respiratory tract: toxic pneumonitis, asthma and airway inflammation.
• Pain: arthritis, fibromyalgia, neuralgia, headaches and migraines.

Immunopathogenesis

• It is the process through which a disease develops that involves an immune response or elements of it.
• Examples: endotoxins and the pyrogenic (acidic) reaction, Type 1 diabetes, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, inflammatory bowel, ulcerative colitis, thyroid diseases, immune vasculitis and celiac disease.