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Transdermal Histamine in Multiple Sclerosis

Part Two: A Proposed Theoretical Basis for Its Use

George Gillson, MD, PhD, Jonathan V. Wright, MD, Elaine DeLack, RN, and George Ballasiotes, BSc, Pharm

Pathophysiology of MS
The majority of current research supports the view that MS is an autoimmune disorder in which immune cells (T lymphocytes and macrophages) in the blood are "primed" (sensitized), possibly by viral-related antigens, to attack myelinated neurons and glial cells of the central nervous system.^28,29 Candidate viruses include measles,³⁰ herpes,³¹ vaccinia,³² and multiple sclerosis retrovirus.^33,34

The concept of Th1/Th2 balance is central to any discussion of the immunologic aspects of MS. Briefly, many diseases recognized as autoimmune can be classified according to the activity of two T cell subpopulations: Th1 and Th2.³⁵ Differentiation of naive CD4+ T cells to a Th1 phenotype is induced by interleukin-12 (IL-12).³⁶ Th1-polarized cells up-regulate various aspects of cell-mediated immunity by the secretion of cytokine mediators, including IL-1, aIL-1, bIL-2, IL-8, IL-12, tumor necrosis factor alpha (TNFa), and interferon gamma (IFNg). Th1-dominant conditions include infection by intracellular pathogens, rheumatoid arthritis (RA), Crohn's disease, autoimmune thyroiditis, and delayed hypersensitivity reactions.

Differentiation of naive T cells to a Th2 phenotype is primarily promoted by IL-4.³⁶ Th2-polarized cells secrete mediators including IL-4, IL-5, IL-10, and IL-13, which up-regulate humoral immune responses commonly regarded as "allergic," including IgE production and eosinophil function.³⁶ Th2-dominated conditions include parasitic infections, atopic dermatitis, asthma, systemic lupus erythematosus, and progressive systemic sclerosis. Pregnancy is also considered to be a Th2 dominated state.³⁵ Th2 cells may also control the development and activity of Th1 cells.³⁷

Immunochemical factors, including IL-1, granulocyte-macrophage colony stimulating factor (GM-CSF), TNFa and others act to bias naive CD4+ cells toward a Th1 state by stimulating production of IL-12 from antigen-presenting cells, including monocytes and dendritic cells. Other factors, including IL-10, histamine, corticosteroids, vitamin D3, and beta agonists inhibit production of IL-12 from these same cells. Nagelkerken has suggested that hypothalamic-pituitary-adrenal (HPA) axis dysfunction, with deficient corticosteroid production, may lead to Th1 dominant states.³⁷

MS is regarded as a Th1 dominant state, and Beck³⁸ reported increased Th1 cytokine (IL-1, TNFa) secretion prior to relapse. Van Boxel-Dezaire³⁹ demonstrated increased IL-12 mRNA and decreased IL-10 mRNA in MS patients compared to controls, and IL-12 mRNA levels correlated with disease activity. Administration of Copolymer 1 (Copaxone) has been shown to rebalance the immune response in MS by encouraging Th2 responses.^40,41 In contrast, administration of interferon beta (IFNb) actually promotes IFNa production (Th1 response), yet IFNa is beneficial for some MS patients.⁴² Also, evidence of increased activity of Th2 cells in MS is seen in the form of elevated levels of autoantibodies.⁴³ This illustrates that although the Th1/Th2 paradigm is very useful, it is not a complete description of immune dysregulation in MS.

Accepting that "priming" of the immune system occurs, permeability of the blood-brain barrier is an important factor to consider, since no nerve damage occurs unless the primed cells gain access to the central nervous system. Spatial and temporal correlations between breaches in the blood-brain barrier and subsequent development of MS lesions support the central role of changes in permeability of the blood-brain barrier.^44,45 Kwon demonstrated that longstanding plaques exhibit evidence of permanent damage to the blood-brain barrier.⁴⁶

Various factors known to alter the permeability of the blood-brain barrier have been directly or epidemiologically linked to the initiation of MS, or are associated with relapse. Examples include thiamine deficiency,⁴⁷ heavy metal toxicity,⁴⁸ and heat stress.⁴⁹ A good summary of some of the evidence supporting the importance of blood-brain barrier permeability in MS is given by Wallace⁵⁰ along with a discussion of the evidence supporting the use of various supplemental nutrients to improve the integrity of the blood-brain barrier.

The microscopic appearance of MS plaques changes with time, but in both acute and chronic MS there is an inflammatory reaction dominated by T lymphocytes and macrophages. Myelinated fibers are engulfed by macrophages⁵¹ while other cells, such as per-ipheral lymphocytes and plasma cells, are also seen in close contact with myelin.⁵² In fresh lesions, demyelination is accompanied by destruction of other tissue elements, including oligodendrocytes, astrocytes, and axons. This destruction ends within a few weeks in many cases, and remyelination may follow, once the lesion has been repopulated with oligodendrocytes.⁵³

Blakemore⁵⁴ and Franklin⁵⁵ conclude that remyelination depends on migration of oligodendrocyte progenitors, such as those observed by Prineas,⁵⁶ from nearby undamaged tissue into the area of inflammation. Franklin also suggests extensive, recurrent, or longstanding inflammation will deplete surrounding healthy tissue of oligodendrocyte progenitors, ultimately limiting the repopulation of plaques and the remyelination of damaged axons.

Stimuli to remyelination include growth factors, such as platelet-derived growth factor,⁵⁷ triiodothyronine (T3),^58,59 and vitamin B12.^60,61 Elevation of intracellular cAMP has also been shown to play a role in induction of oligodendrocyte progenitor differentiation and myelin synthesis in the rat brain⁶² and in peripheral Schwann cells.^63,64

Thiamine also plays a role in myelination. Demyelination is a hallmark of thiamine deficiency,⁶⁵ although deficiencies of other nutrients such as copper⁶⁶ also cause demyelination. Thiamine, in the form of thiamine pyrophosphate, helps stabilize nerve cell membranes.⁶⁷ Myelin-synthesizing oligodendrocyte cell bodies contain thiamine pyrophosphatase (TPPase),⁶⁸ the enzyme which generates thiamine pyrophosphate. TPPase has been localized to the Golgi complexes of various neuronal cells,⁶⁹ and Trapp found protein zero (P0), the main component of myelin basic protein, in Golgi complex membranes in rat Schwann cells.⁷⁰

The inflammatory cascade leading to demyelination is complex, and current understanding of it is by no means complete. There has been increased awareness lately of the important role of mast cells in central nervous system (CNS) inflammatory processes, including MS.^71,72 Substances released from mast cells can attack myelin, and myelin breakdown products can stimulate further mast cell degranulation.⁷³ Skaper has suggested that down-regulation of mast cell activation could be a therapeutic strategy in neuroinflammatory conditions,⁷⁴ and proxicromil, a mast cell stabilizer, has been employed successfully in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS.⁷⁵

Mast cells are known to release leukotrienes,⁷⁶ inflammatory mediators that affect vascular permeability and exhibit chemoattractant properties. Elevated levels of leukotriene C4 and leukotriene B4 are found in the cerebrospinal fluid (CSF) of MS patients.⁷⁷ Inhibition of 5-lipoxygenase, an enzyme involved in the synthesis of leukotrienes, prevented the development of symptoms in guinea pig EAE and significantly reduced histologic inflammation scores.⁷⁸

Matrix metalloproteinases (MMPs), a family of zinc-containing enzymes which can digest connective tissue and myelin,^72,79 are another important class of inflammatory mediators. They are also known to be disruptive to the blood-brain barrier.⁸⁰ Mast cells contain and release MMPs,^72,79,81 and MMPs are found to be elevated both in the CSF of MS patients⁸² and in EAE mice.⁸³ Blockage of MMPs inhibits or reduces the severity of EAE.^83,84

Earlier, reference was made to "priming" of peripheral immune cells. An example of this is the observation that peripheral monocytes and macrophages contain elevated levels of MMPs.^80,82,83 The release of MMPs by mast cells may feed the inflammatory spiral in several ways. First, by generating myelin fragments such as myelin basic protein, which elicit further mast cell degranulation,^74,79,85 and second, by liberating cytokines such as TNFa from the cell membranes of monocytes⁸⁶ or myelin autoreactive CD4+ T cells.⁸⁴ TNFa levels in the CSF of MS patients have been correlated to disease severity.^87,88 Blockade of TNF by anti-TNF antibodies prevented the development of EAE in one mouse study.⁸⁹

Mast cells also release TNFa directly71,74 and mast cell-derived TNF affects the release of neurotoxic NO radicals (from astrocytes in mast cell/hippocampal co-cultures)⁹⁰ and MMPs.⁹¹ Thus, as mentioned, mast cell degranulation, with release of mediators such as MMPs and TNF, might set up a potential positive feedback loop promoting more mast cell degranulation.

Histamine is the most widely recognized mediator released by mast cells. Release of histamine by brain mast cells may initially accelerate inflammation by increasing the permeability of the blood-brain barrier, an H2 receptor-mediated phenomenon.⁹² Increased blood-brain barrier permeability would then presumably increase the influx of sensitized peripheral immune cells. This process is thought to be central to the pathophysiology of MS. Ongoing mast cell degranulation with histamine release might also create an increased demand for histidine (the direct precursor of histamine), and potentially compromise the supply of histidine at other histamine-synthesizing sites in the brain, such as histaminergic neurons.

Interestingly, the number, location, and histamine content of mast cells in mouse brain have been shown to be inherited traits.^93,94 If this is also true in humans, some individuals might exhibit increased susceptibility to MS and other inflammatory conditions because of this genetic programming.

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