Sympathetic skin responses are decreased and lymphocyte beta‐adrenergic receptors are increased in progressive multiple sclerosis

Abstract

Immune abnormalities, including deficient CD8 lymphocyte-mediated suppression, have been implicated in the progression of multiple sclerosis (MS). The peripheral sympathetic branch of the autonomic nervous system innervates the lymphoid organs and affects immune function. Animals with an ablated sympathetic nervous system develop more severe experimental allergic encephalomyelitis than control animals and exhibit an increased density of beta-adrenergic receptors on their lymphocytes. Experimental allergic encephalomyelitis shares many features with MS. Accordingly, we investigated the psychogalvanic skin reflex in patients with rapidly progressive MS and found that 13 patients (57%) lacked this sympathetic-mediated response. The density of beta-adrenergic receptors on lymphocyte subsets was increased in progressive MS, most notably on the CD8 suppressor/cytotoxic subset. B lymphocytes had the greatest number of receptors with 12.1 +/- 1.8 fmol/10(6) cells in control subjects and 18.7 +/- 2.6 fmol/10(6) cells in patients with MS. CD8 lymphocytes possessed an intermediate number of receptors with 3.4 +/- 0.4 fmol/10(6) cells in control subjects and 9.1 +/- 1.6 fmol/10(6) cells in patients with MS. CD4 lymphocytes demonstrated the fewest receptors with 1.2 +/- 0.1 fmol/10(6) cells in control subjects and 1.8 +/- 0.4 fmol/10(6) cells in patients with MS. No differences in the affinity or function (cyclic adenosine monophosphate levels in response to 10(-5) M (-)isoproterenol) of the adrenergic receptor were found when patients with progressive MS and control subjects were compared. Autonomic abnormalities in progressive MS and the increased beta-adrenergic receptor density found on CD8 lymphocytes may be related.

G protein-coupled receptors as therapeutic targets for multiple sclerosis

“…Similarly, in the MRL-lpr/lpr mouse, a genetic model of the human autoimmune disease systemic lupus erythematosus, noradrenergic innervation and noradrenaline content were reduced in the spleen prior to the onset of observed splenomegaly and remained reduced at all ages examined [49]. In MS patients, increased β-adrenergic receptor density on PBMCs, including lymphocytes, has been well documented [50][51][52][53][54][55]. This increase in β-adrenoreceptor density has been shown to be correlated with the expression of high affinity IL-2 receptors (IL-2R) on PBMCs and disease activity of RRMS.…”

Sympathetic modulation of immunity: Relevance to disease

“…In progressive MS, sympathetic skin responses decrease and lymphocyte β-AR expression increase [346]. While the density of β-AR on monocytes, B cells, and CD41 cells remain unchanged, receptor numbers on CD8+ T cells increase 2-to 3-fold, compared with age-matched controls [338,346,347].…”

“…In progressive MS, sympathetic skin responses decrease and lymphocyte β-AR expression increase [346]. While the density of β-AR on monocytes, B cells, and CD41 cells remain unchanged, receptor numbers on CD8+ T cells increase 2-to 3-fold, compared with age-matched controls [338,346,347]. Increased β-AR may result from a compensatory response to reduced concentration of NE in secondary lymphoid tissues in EAE [348], and suggests an adaptive response to lower NE availability in the spleen observed in MS [338].…”

Cytokine Dysregulation, Inflammation and Well-Being

“…Whether this abnormality is primary or secondary has not been established [112] . Several lines of evidence indicate that the sympathetic-immune interface might also be defective in MS and RA [114][115][116][117][118] . Interestingly, patients with long-term RA have a highly signifi cant reduction in sympathetic nerve fi bers in synovial tissues with preponderance of about 10: 1 for primary sensory, SP-positive fi bers as compared with sympathetic fi bers [119] .…”