Write a short note on natural killer cells and tumour necrosis factor alpha.

Natural Killer Cells — Definition

NK cells are large granular lymphocytes of the innate immune system, derived from the common lymphoid progenitor in the bone marrow. They constitute 5–15% of circulating lymphocytes and, unlike T and B lymphocytes, act without prior sensitisation and without antigen-specific receptors or MHC restriction.

Surface markers: CD16 positive, CD56 positive, CD3 negative — the CD3-negative status distinguishes them from T lymphocytes.

Mechanism of Action

• "Missing self" hypothesis: NK cells carry inhibitory killer immunoglobulin-like receptors (KIRs) that recognise MHC class I on normal cells and deliver a switch-off signal. Virus-infected and tumour cells down-regulate MHC class I to escape cytotoxic T cells, thereby removing this inhibition — and are killed by NK cells instead. This complementarity is the central concept to state.
• Killing mechanisms: release of perforin (which polymerises to form pores in the target membrane) and granzymes (which enter and activate caspases, triggering apoptosis); and Fas–FasL interaction.
• Antibody-dependent cellular cytotoxicity (ADCC): the CD16 (FcγRIII) receptor binds the Fc portion of IgG coating a target cell, directing NK-mediated lysis. This is the mechanism underlying the action of rituximab and trastuzumab.
• Cytokine production: NK cells secrete interferon-gamma, activating macrophages and shaping the Th1 response.

Clinical relevance: deficiency predisposes to severe herpesvirus infections; NK cells mediate graft-versus-leukaemia effect after transplantation; NK/T-cell lymphoma is an EBV-associated malignancy; and CAR-NK cells are under development as an "off-the-shelf" alternative to CAR-T.

Tumour Necrosis Factor Alpha — Definition

TNF-α is a pro-inflammatory cytokine produced chiefly by activated macrophages, and also by T cells, NK cells and mast cells, in response to lipopolysaccharide and other microbial products. It was named for its ability to cause haemorrhagic necrosis of tumours.

Actions

• Local: vasodilatation, increased vascular permeability, up-regulation of adhesion molecules and neutrophil recruitment — the cardinal signs of inflammation.
• Systemic: acts on the hypothalamus to cause fever; on the liver to induce acute phase proteins including CRP; on the bone marrow to mobilise leucocytes.
• Metabolic: suppresses appetite and increases catabolism, producing the cachexia of chronic infection and malignancy (TNF's original name was cachectin).
• At high concentration: myocardial depression, systemic vasodilatation, disseminated intravascular coagulation and septic shock.

Role in Disease & Therapeutic Blockade

TNF-α is central to rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, and inflammatory bowel disease. Blocking it is one of the major therapeutic advances in modern medicine.

Anti-TNF agents: infliximab (chimeric monoclonal antibody), adalimumab (fully human antibody), etanercept (soluble receptor fusion protein), golimumab and certolizumab.

Other adverse effects include serious bacterial and fungal infection, reactivation of hepatitis B, demyelinating disease, drug-induced lupus, worsening of heart failure, and a possible increase in lymphoma risk.