The gray aspects of white matter disease in multiple sclerosis.

T he major inflammatory disease of the central nervous system is multiple sclerosis (MS). It is often considered a 2-stage disease with an initial inflammatory attack on myelin involving the 2 hallmarks of adaptive immunity: antigen-specific T cells and antibodies directed to protein and lipid components of the myelin sheath (1). This concerted attack involving the adaptive immune system is followed by a ‘‘degenerative’’ course involving the myelin itself, the oligodendrocytes that produce it, and the underlying axons and their neuronal cell bodies themselves in the gray matter. All of this culminates in significant cerebral atrophy as MS progresses (2). Whether or not there is really such a sequential and bifurcated temporal course between ‘‘inflammation’’ in the white matter, followed by neurodegeneration in the gray matter, is actually an open question. In this issue of PNAS, Derfuss et al. (3) identify, via a multifaceted approach including proteomics, one of the first examples of a target recognized by both T cells and antibodies that is located in gray matter. The target is contactin-2, a homologue of transientlyexpressed axonal glycoprotein-1 (TAG-1) expressed on axons and in the juxtaparanodal region of oligodendrocytes producing myelin to insulate these axons (4), and by neurons in gray matter (5, 6). Gray matter involvement may be a much earlier aspect of the pathology in MS than has been appreciated. Similarly, inflammation may be a much greater component of the so-called secondary progressive phase of MS (7). What has been missing in understanding these issues has been identification of targets of adaptive immunity in gray matter. Derfuss et al. (3) provide a stellar example of a molecule that when attacked produces both white and gray matter pathology. Many adaptive immune responses to components of white matter have been identified in MS. These include antibody and T cell responses to constitutive myelin proteins, including myelin basic protein (MBP), proteolipid protein (PPL), and myelin-associated glycoprotein (MAG). Large-scale, custom-made arrays of myelin-related proteins and peptides have been designed to identify peptides and recombinant proteins that bind antibodies found in the cerebrospinal f luid of patients with relapsing remitting MS (RRMS) (8, 9). RRMS patients demonstrated significantly increased autoantibodies against various myelin epitopes, including B crystallin (CRYAB) protein and peptides; J37, a MBP isoform of Golli-MBP; heat shock protein (HSP); and amyloid (Abeta). Immunity to myelin proteins is not the only story in MS. Lipid components