Barbara Cannella

The expression of the adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and their respective receptors on leukocytes, very late activation antigen-4 (VLA-4) and lymphocyte function-associated antigen-1 (LFA-1), together with a selection of proinflammatory and immunomodulatory cytokines (interleukin [IL]-1, IL-2, IL-4, IL-10, tumor necrosis factor-alpha [TNF-alpha], transforming growth factor-beta [TGF-beta], and interferon-gamma [IFN-gamma] was examined by immunocytochemistry in multiple sclerosis (MS) lesions of different ages and compared with central nervous system (CNS) tissue from other neurological diseases, both inflammatory and noninflammatory, and normal CNS tissue. These molecules play key roles in lymphocytic infiltration and interactions during tissue inflammation and are in large part normally not expressed by CNS cells. High levels of expression of all the molecules tested were found in MS, particularly in chronic active lesions. Positivity for all molecules was also seen in other neurological diseases, even in noninflammatory conditions. There was some suggestion that the VCAM-1/VLA-4 adhesion pathway was expressed at higher levels in chronic MS lesions, while ICAM-1/LEA-1 was used more uniformly in lesions of all ages. Of the cytokines examined, there was increased expression of TNF-alpha and IL-4 in MS; this was found to be statistically significant when compared with noninflammatory neurological diseases. The expression of most adhesion molecules and some cytokines was negligible in normal CNS tissue although low-level reactivity for ICAM-1 TGF-beta, IL-4, TNF-alpha, and IL-10 was detected, perhaps indicative of immunoregulatory mechanisms. Microglial cells and astrocytes were the major CNS cell types expressing cytokines. The results indicate a potential in the CNS for widespread induced expression of molecules involved in the inflammatory cascade. No adhesion or cytokine molecule or pattern of expression unusual for MS was apparent.

Encounters with antigen can stimulate T cells to become activated and proliferate, become nonresponsive to antigen, or to die. T cell death was shown to be a physiological response to interleukin-2-stimulated cell cycling and T cell receptor reengagement at high antigen doses. This feedback regulatory mechanism attenuates the immune response by deleting a portion of newly dividing, antigen-reactive T cells. This mechanism deleted autoreactive T cells and abrogated the clinical and pathological signs of autoimmune encephalomyelitis in mice after repetitive administration of myelin basic protein.

Magnetic resonance imaging is a highly sensitive method for the detection of the lesions of multiple sclerosis and renders possible the study and the evolution of early lesions. Previous reports on magnetic resonance imaging following gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) injection demonstrated that new lesions can be recognized by contrast enhancement. The pathological basis of these observations is uncertain. We have had the opportunity to study at autopsy the brain of a patient with chronic progressive multiple sclerosis who suffered acute worsening leading to death. Magnetic resonance imaging performed 10 days and 4 weeks prior to death showed new Gd-DTPA-enhanced lesions in the posterior hemispheric white matter adjacent to the lateral ventricles. Light microscopic examination of these areas demonstrated them to be fresh lesions comprising intense inflammatory activity and dense perivascular cuffs within an edematous lesion center and a striking parenchymal mononuclear cell infiltration at the margins of the lesions. Lesions that were demonstrated by increased signal on T2-weighted images, but were not enhanced following administration of Gd-DTPA, were all of the chronic type, either inactive or active. None of these showed the intense inflammatory activity of the acute lesions and most displayed fibrous astrogliosis.