Deficient NF-kB inhibitor (CARD8) in Alzheimer’s and rheumatoid arthritis
The two studies briefly summarized below are consistent with the theory that excess inflammation often results from the body’s inability to shut down NF-kB – the Master Switch of inflammation.
Turning on NF-kB results in inflammation. If NF-kB cannot be turned off, chronic inflammation results.
One of many ways the body turns off NF-kB is with a protein messenger known as “CARD8.” Normally, CARD8 is made when NF-kB is activated. The negative feedback loop (the result of turning on NF-kB is a product that feeds back and turns off NF-kB) is one reason inflammation does not normally get out of hand.
A genetic defect has been identified that results in less effective CARD8. Less effective CARD8 means the normal, negative feedback loop that helps keep inflammation in check is missing – so inflammation continues.
This defect in CARD8 has been identified as a contributor to Alzheimer’s and rheumatoid arthritis. Some studies have suggested that defective CARD8 might also be associated with Crohn’s disease.
What seems clear is that CARD8 is only one of many ways the body keeps inflammation in control. To the extent that this and other defects result in deficient NF-kB inhibitors, supplementing NF-kB inhibitors, as suggested on this site, might be helpful.
In the first study below, defective CARD8 was found to increase the risk of developing Alzheimer’s 2.4x in women.
In the second study below, defective CARD8 was found to predict the severity of rheumatoid arthritis.
The first publication:
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Dement Geriatr Cogn Disord. 2008;26(3):247-50. Epub 2008 Oct 8.
Deficiency of CARD8 is associated with increased Alzheimer’s disease risk in women.
Fontalba A, Gutiérrez O, Llorca J, Mateo I, Berciano J, Fernández-Luna JL, Combarros O.
Unidad de Genética Molecular, Marqués de Valdecilla University Hospital, Santander, Spain.
Summary of the abstract
NF-kB, a major transcription factor controlling inflammation, is activated in Alzheimer’s disease (AD) brains.
CARD8 protein has been implicated in the suppression of NF-kB activity, but a slight genetic alteration makes CARD8 non-functional and results in more active NF-kB and an amplification of the inflammatory process.
The major genetic risk factor of AD, is associated with hyperactivation of NF-kB and enhanced brain inflammation.
In a case-control study in 300 AD patients and 300 healthy controls, we examined whether the slight genetic alteration leading to non-functional CARD8 might predispose to AD. Women, but not men, had a 2.39-fold higher risk of developing AD than subjects without the alteration.
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The second publication:
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J Immunol. 2007 Oct 1;179(7):4867-73.
Deficiency of the NF-kappaB inhibitor caspase activating and recruitment domain 8 in patients with rheumatoid arthritis is associated with disease severity.
Fontalba A, Martinez-Taboada V, Gutierrez O, Pipaon C, Benito N, Balsa A, Blanco R, Fernandez-Luna JL.
Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Santander, Spain.
Summary of the abstract
CARD8 potently inhibits NF-kappaB signaling, which plays a key role in inflammation, and may contribute to avoid a pathologic activation of NF-kB; however, the transcriptional mechanisms regulating CARD8 expression and the relevance of this protein in inflammatory diseases are poorly understood.
To study the relevance of CARD8 in chronic inflammatory disorders, we functionally characterized a deleterious polymorphism (p.C10X) and studied its association with rheumatoid arthritis (RA).
Deficiency of CARD8 was found to predict the severity of rheumatoid arthritis.
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