TNF-Alpha Suppressors and Histamines

After the last post, a reader sent me some articles showing the relationship between TNF-Alpha and Histamines. Earlier on this blog, I have discussed the possibility of some CFS patients having histamine sensitivity. It turns out that reducing histamines may increase the inflammatory response :-(. Things are never simple – unfortunately.

“These results suggest that histamine may act as an autocrine regulator of cytokine release by MC and thus modulate inflammatory responses[TNF-Alpha] in allergic asthma.” [1996]

“Histamine injection into human skin engrafted on immunodeficient mice similarly caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules. These results both clarify relationships among TNFR1 populations and reveal a novel anti-inflammatory activity of histamine.” [2003]

Digging a bit deeper we find:

Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy.” [2012] and similar in Cerebral ischemia and brain histamine[2005]

This raises an interesting prospect that histamine levels in CFS may increase in response to the brain trauma which is a typical part of CFS (as seen by SPECT scans). Checking PubMed, we find nothing about histamine levels with Chronic Fatigue Syndrome. On the general internet, there appear to be conjecture and speculation:

  • ” Dr. Cheney has speculated..”  “Tufts University researcher Theorharis Theorharides. For years Theorharides has believed that mast cell activities play a role in a number of chronic illnesses including autism, fibromyalgia, ME/CFS, interstitial cystitus, IBS, migraines, cardiovascular disorders, asthma and multiple sclerosis.” [Phoenix Rising, 2012]

What we find is hypersensitive and not over-production

“What is more, most ME patients are also hypersensitive to biogenic amines (histamine and tyramine) and alcohol.” Prof. K. De Meirleir /  Christine Tobback


Hypersensitive does not mean over-production. “These results demonstrate, that increased reactivity to histamine and airway contraction to allergen induced by passive sensitization, occur through independent mechanisms and that, unlike allergen-sensitivity, histamine hypersensitivity is caused by a serum factor other than IgE.” [1998 this is echo by another study ” In patients with low serum IgE current smoking is associated with increased bronchial responsiveness to histamine in vitro” [2001].

The bottom line is that we do not know the mechanism for hypersensitivity to histamine. 😦 We should be careful not to go down the over production of histamines route because it may result in increase (and permanent) cognitive issues.