Brain, Vol. 123, No. 6, 1073-1074,
June 2000
© 2000 Oxford University Press
Editorial |
P selectin, pioneer cells and the path to inflammation
The Hampers Professor and Chairman, Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire, USA
In this issue of Brain, the report by Carrithers et al. provides the first answer to a question that has long been of interest in neuroimmunology: What adhesion molecules do activated T-lymphocytes utilize to penetrate a normal, non-inflamed endothelium (Carrithers et al., 2000
)? Their study gives some interesting insights into the earliest phases of the process of central nervous system (CNS) inflammation. It appears that P selectin, either expressed constitutively at very low levels or rapidly induced by activated T cells, on CNS endothelia plays a significant role in the early entry of encephalitogenic T cells into the CNS. VCAM-1–VLA-4 interactions, which have been noted previously to play some critical role in the evolution of experimental allergic encephalomyelitis (EAE) (Yednock et al., 1989; Baron et al., 1993; Steffen et al., 1994), do not appear to participate in this early entry. It is of great interest that P selectin has previously been shown to play little, if any, role in the entry of T cells into the CNS later in the pathogenetic process of EAE (Engelhardt et al., 1997).
One of the major aspects of CNS inflammation demonstrated by this study is that the evolution of EAE must be a complex, multiphase process (Hickey, 1999). Obviously, the first step involves the arrival of antigen specific T cells in the target organ. The authors have chosen to examine two types of anti-MBP T cells: one a clone specific for the encephalitogenic peptide in this murine strain but which does not cause disease, the other a T cell line that is encephalitogenic. Also, they have decided to analyse two time points: 2 and 24 hours post-infusion of T cells. These choices determine their results to some extent and also flavour the conclusions that may be derived from them. In other studies of T cells entering the nervous system, it has been noted that the entry seems to be random, and not a true `homing' phenomenon regulated by specific molecules which selectively attract T cells to a specific site (Hickey et al., 1991; Hickey, 1999). Also, in a rodent system, the maximal concentration of T cells in the CNS prior to the onset of overt inflammation occurs between 9 and 12 hours (Hickey et al., 1991), a window of time not examined here. Nevertheless, the marked advantage held by anti-CNS antigen T cells in localizing to the CNS—whether they will produce disease or not—is demonstrated. One key question that must be raised is whether this is a manifestation of `homing', i.e. selective entry, or reflects selective retention of T cells in the site where they encounter their antigen (Hickey, 1999). The data presented do not permit that distinction, and could be compatible with either mechanism. It must be noted that to date there has been no identification of a CNS `addressin', nor a specific cluster of adhesion molecules which determine that a T cell specific for a CNS antigen is preferentially attracted to that site. While such may theoretically exist, it currently appears most likely that the entry of `pioneer' cells into any organ destined to become inflamed is a random process common to all non-inflamed vascular beds. The concept of selective retention of T cells where antigen is encountered would account for the differences noted between CNS and pancreatic cell counts. During later phases of disease, as in the leukocyte recruitment phase, molecules such as VLA-4, VCAM-1, ICAM-1, LFA-1 and others must be playing key roles (Yednock et al., 1989; Archelos et al., 1993; Baron et al., 1993; Steffen et al., 1994; Engelhardt et al., 1997; Romanic et al., 1997; Hickey, 1999). The entire process from arrival of `pioneer' cells to the appearance of overt clinical illness is complex, and not static, with distinct adhesion molecules participating at different phases (Hickey, 1999).
Based on the data the authors have presented, it will now be possible to determine if there exists a specific profile of molecules that selectively attract leukocytes to the CNS. Also, questions arise as to whether Th1 versus Th2 cells, or CD4+ versus CD8+ T cells have an advantage in entering the CNS. The resolution of such issues may shed light on the pathogenesis and potential therapeutic approaches to a number of neuroinflammatory conditions.
In this well-done study there is another point to be noted. P-selectin interactions seem to play only a partial role in the initial penetration of `pioneer' T cells. What other moieties are involved? Certainly, by constructing an experimental system such as the present authors employ, other participants can be identified. It could only be urged that intervening time points between 2 and 24 hours also be examined so as to detect alterations which may have partial, not huge effects on the ability of activated T cells to enter the neural parenchyma. Yet, it seems incontro- vertible that P selectin is critical in the earliest phase of EAE pathogenesis. Further studies of a similar nature should be forthcoming and instructive.
References
Archelos JJ, Jung S, Maurer M, Schmied M, Lassmann H, Tamatani T, et al. Inhibition of experimental autoimmune encephalomyelitis by an antibody to the intercellular adhesion molecule ICAM-1. Ann Neurol 1993; 34: 145–54.[ISI][Medline]
Baron JL, Madri JA, Ruddle NH, Hashim G, Janeway CA Jr. Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med 1993; 177: 57–68.
Carrithers MD, Visintin I, Kang SJ, Janeway CA Jr. Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment. Brain 2000; 123: 1092–101.
Engelhardt B, Vestweber D, Hallmann R, Schulz M. E- and P-selectin are not involved in the recruitment of inflammatory cells across the blood brain barrier in experimental autoimmune encephalomyelitis. Blood 1997; 90: 4459–72.
Hickey WF. Leukocyte traffic in the central nervous system: the participants and their roles. Semin Immunol 1999; 11: 125–37.[ISI][Medline]
Hickey WF, Hsu BL, Kimura H. T-lymphocyte entry into the central nervous system. J Neurosci Res 1991; 28: 254–60.[ISI][Medline]
Romanic AM, Graesser D, Baron JL, Visintin I, Janeway CA Jr, Madri JA. T cell adhesion to endothelial cells and extracellular matrix is modulated upon transendothelial cell migration. Lab Invest 1997; 76: 11–23.[ISI][Medline]
Steffen BJ, Butcher EC, Engelhardt B. Evidence for involvement of ICAM-1 and VCAM-1 in lymphocyte interaction with endothelium in experimental autoimmune encephalomyelitis in the central nervous system in the SJL/J mouse. Am J Pathol 1994; 145: 189–201.[Abstract]
Yednock TA, Cannon C, Fritz LC, Sanchez-Madri F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against 
4ß1 integrin. Nature 1992; 356: 63–6.[Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||