Paper I
Question
Immunological effects of TNF
Answer
Tumour Necrosis Factor (TNF-α) is a pro-inflammatory cytokine, produced mainly by activated macrophages (and to a lesser extent T cells, NK cells), that plays a central role in orchestrating both local and systemic inflammatory and immune responses.
Immunological effects:
- Local effects (beneficial in controlled amounts): activates vascular endothelium to upregulate adhesion molecules (E-selectin, ICAM-1), promoting neutrophil/leukocyte adhesion and migration into tissue at a site of infection; increases vascular permeability, allowing plasma proteins (complement, antibody) to reach the site; activates macrophages and neutrophils, enhancing their microbicidal activity; stimulates fibroblasts and promotes tissue repair/granuloma formation (important in containing infections such as tuberculosis).
- Systemic effects (when released in large amounts): acts on the hypothalamus to cause fever (endogenous pyrogen, along with IL-1 and IL-6); induces hepatic acute-phase protein synthesis (CRP, fibrinogen); causes mobilization of metabolic substrates (protein/fat catabolism, contributing to cachexia in chronic disease/malignancy).
- Massive systemic release (as in Gram-negative septicaemia, where TNF is triggered by endotoxin/LPS) causes widespread vascular permeability, hypotension, disseminated intravascular coagulation, and septic shock — a major mediator of the systemic toxicity of endotoxaemia.
- Direct cytotoxic effects — can induce apoptosis in some tumour cells (the origin of its name) and in cells persistently infected by intracellular pathogens.
- Therapeutic relevance: TNF-α is a key target of biologic anti-inflammatory drugs (e.g., infliximab, etanercept) used in autoimmune conditions like rheumatoid arthritis, reflecting its central pathogenic role in chronic inflammation; anti-TNF therapy carries an increased risk of reactivating latent tuberculosis, reflecting TNF’s importance in granuloma maintenance.