NF-κB: Nuclear factor-κB Pathway defects

What is NF-κB Pathway

Nuclear factor-κB (NF-κB) represents a family of inducible transcription factors, regulating multiple genes involved in immune and inflammatory responses. Includes 5 members:

• NF-κB1 (p50)
• NF-κB2 (p52)
• RelA (p65)
• RelB
• c-Rel

Normally, these proteins are sequestered by inhibitory proteins (IκB family, e.g., IκBα). Upon activation (signal), inhibitors are degraded, freeing NF-κB to enter the nucleus of the cell and activate certain gene elements, these gene elements will produce proteins, which will result in pro-inflammatory cytokines.

Canonical Pathway

The canonical NF-κB pathway is a major signaling pathway responsible for regulating the immune and inflammatory responses. The canonical pathway is triggered by various stimuli that bind to surface receptors like Toll-like receptors (TLRs), tumor necrosis factor receptors (TNFRs), and interleukin-1 receptor (IL-1R). IKK Complex Activation: Upon activation of these receptors, a signal is transmitted to a protein complex known as the IKK complex. This complex consists of IKKα, IKKβ, and NEMO / IKK g (regulator). IKKβ, in particular, plays a key role in the canonical pathway by phosphorylating inhibitor proteins (IκB).

Degradation of IκB: In its resting state, NF-κB dimers (composed of p65 and p50) are bound to an inhibitor protein called IκB. This prevents NF-κB from entering the nucleus. Once the IKK complex is activated, it phosphorylates IκB, marking it for degradation by ubiquitination. As IκB is degraded, the NF-κB dimer (p65/p50) is freed. NF-κB Translocation to the Nucleus: Freed NF-κB (p65/p50) translocates into the nucleus. 

Gene Activation: In the nucleus, NF-κB binds to specific DNA sequences (promoters) and activates the transcription of target genes involved in immune responses, inflammation, and cell survival. These genes lead to the production of cytokines, chemokines, and other factors that amplify the immune response

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Non-Canonical Pathway

NIKs (NF-κB Inducing Kinases) activate NF-κB through a different pathway.

Mutations in NF-κB: Normally: NF-κB Pathway is involved in Inflammation, immune response to viral and Bacterial infections, Tolerance Induction (Involves B cells and Treg cells). Mutations lead to dysregulation, resulting in:

1. Unregulated inflammation.
2. Decreased Immune response (recurrent infections).
3. Autoimmunity.

Types of NF-κB Pathway Defects

Treatment

• Immunoglobulin Replacement (IVIG).
• Infection Prevention through prophylaxis.
• HSCT is last resort therapy.

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Important Points to Remember

• PIRD - Primary Immune Regulatory Disorders, Also called as IEIs - Inborn Errors of Immunity
• They are a type of Primary Immunodeficiencies (PIDs) that are characterized by hyperinflammation, autoimmunity, endocrinopathy, enteropathy, & non-malignant lymphoproliferation.
• The canonical pathway is triggered by various stimuli that bind to surface receptors like Toll-like receptors (TLRs), tumor necrosis factor receptors (TNFRs), and interleukin-1 receptor (IL-1R).
• NF-κB Translocation to the Nucleus: Freed NF-κB (p65/p50) translocates into the nucleus.
• NIKs (NF-κB Inducing Kinases) activate NF-κB through a different pathway.

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