American Journal of Pathology, Vol. 139, No. 6, December 1991 Copyright X) American Association of Pathologists

Central Nervous System Endothelial Cell-Polymorphonuclear Cell Interactions During Autoimmune Demyelination Anne H. Cross*t and Cedric S. Raine*tt From the Departments of Neurology,* Pathology (Division of Neuropathology), t and Neuroscience,* and the Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine,

Bronx, New York

The homing and adhesion of circulating cells to target tissue vasculature precedes their subsequent invasion of inflamed tissue. Polymorphonuclear cells (PMNs), key players in most inflammatory events, are among the first cells to arrive. The present work, performed on CNS lesionsfrom mice with experimental autoimmune encephalomyelitis, provides morphologic evidence for interactions between PMNs and unique, frondlike extensions from endothelial cells (EC) during early attachment Platelets also were seen attached to these endothelial fronds. The structures projected into vessel lumina from the vicinity of tightjunctions and were often branched and complex, the latter characteristics suggesting a possible role in cellular 'trapping.' Polymorphonuclear cells appeared to traverse the CNS vasculature between EC where the blood-brain barrier was severely compromised with junctional complexes reduced to simple contact points. The cells from which the fronds derived were often plump and possessed cytoplasm rich in organelles; perhaps indicative of activation The present report contrasts with previous observations on lymphocytes in the same system where lymphocytic pseudopodia formed intimate contacts before their burrowing directly through the endothelium and where EC fronds were not involved. (AmJPathol 1991, 139:1401-1409)

The homing to and the adhesion of circulating leukocytes to vascular endothelium is fundamental to tissue inflammation. Polymorphonuclear cells (PMNs), a subset of leukocytes responding in an antigen-nonspecific fashion to chemotactic factors released at sites of inflammation, are generally among the first cells to arrive.1 Although exten-

sive work has been performed on the phenomena of PMN adhesion and transmigration of blood vessels, it has only recently been recognized that the vascular endothelium plays more than a passive role in such phenomena.2 The concept of a passive role was traditionally supported by morphologic studies of systemic inflammation that demonstrated no evidence for an active role by endothelial cells (EC). With the aid of cultures of EC, an increasingly important role is now being attributed to the endothelium in PMN adhesion.34 Further work has demonstrated the induction, by exposure to cytokines, of changes in cultured EC leading to leukocyte adhe-

sion.5 8 In contrast to the above work in vitro, the present report provides morphologic support for a direct role for EC in the adhesion of neutrophils during inflammation in vivo. This study, an offshoot of a series on lymphocyte homing,9'10 derives from the repeated observation of unique morphologic changes between central nervous system (CNS) EC and PMNs. The EC/PMN relationships were observed in CNS lesions of several different strains of mouse, usually during the initial hours of clinical onset of experimental autoimmune encephalomyelitis (EAE), and involved parajunctional fronds emanating from reactive EC with an enriched cytoplasm. The EC/PMN interactions were morphologically distinct from those observed between EC and lymphocytes.10 To our knowledge, these PMN/EC associations have not been described previously.

Materials and Methods Animals Female mice, 4 to 12 weeks of age, of the SJUJ (H-2s), A.CA (H-2f) and SWR/J (H-2q) strains (Jackson Labs, Bar Supported by Grants JF 2042-A-2 and RG 1001-G-7 from the National Multiple Sclerosis Society; and NS 1 1920 and NS 08952 from the USPHS. Accepted for publication July 19, 1991. Address reprint requests to Anne H. Cross, MD, Albert Einstein College of Medicine, K-436, 1300 Morris Park Ave., Bronx, NY 10461.

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Harbor, ME), were maintained in an NIH-approved animal facility.

Induction of Experimental Autoimmune Encephalomyelitis The method of induction of EAE was similar to that published previously.911 Guinea pig myelin basic protein (MBP), prepared according to the procedure of Deibler et al.,12 was used to immunize naive donor mice at four sites over the flanks. Ten days later, draining lymph nodes were aseptically removed and single-cell suspensions were prepared by pressing the whole nodes through sterile wire mesh. The cells were cultured for 3 days at 37°C in 7% C02 at 4 x 106/ml in RPMI-1640 supplemented with 10% fetal calf serum (GIBCO, Grand Island, NY), penicillin G (100 units/ml, Sigma, St. Louis, MO), streptomycin (100 230-S,g/ml, GIBCO), glutamine (2 mmol/l [millimolar], Sigma) and 50 230-,ug MBP/ml. For adoptive transfer, lymph node cells were washed twice and injected in a volume of 0.2 to 0.3 ml through a tail vein into naive, syngeneic recipients. Recipient mice were evaluated every 2 days and graded clinically according to a 0 to 5 scale, where 1 = floppy tail; 2 = mild weakness of hindlimbs; 3 = moderate weakness of hindlimbs or forelimbs; 4 = plegia of two limbs; 5 = moribund.13 Recipient SJL mice first showed signs of EAE 6 to 8 days after transfer (dpt). Initial signs occurred between days 7 and 10 in the SWR and A-CA strains.

Pathology Mice were sampled for study within the first 48 hours of clinical onset or a relapse. Two normal, unsensitized SJL females served as controls. Mice were anesthetized by ether inhalation and perfused through the left cardiac ventricle with 40 ml cold, phosphate-buffered 2.5% glutaraldehyde. The CNS was removed, and thin slices of brain, spinal cord, spinal roots and, in some instances, peripheral lymph nodes, were postfixed in cold 1% osmium tetroxide for 60 minutes, after which the tissue was dehydrated through a graded series of ethanol, cleared in propylene oxide, and embedded in Epon 812 (E. Fullam, Latham, NY).11 One-micron epoxy sections stained with toluidine blue were examined by light microscopy. For ultrastructural study, thin sections of areas of interest identified by light microscopy were made and placed on uncoated grids, stained with uranium and lead salts, carbon-coated, and scanned in a Siemens 101 or a Hitachi HS 600.

Immunocytochemistry One-micron epoxy sections on glass slides from active lesions of a grade 2 mouse perfused at 12 dpt with 0.1% buffered glutaraldehyde (un-osmicated) and from a grade 2, 6 dpt mouse perfused with 2.5% glutaraldehyde were etched with saturated sodium ethoxide for 30 minutes, washed sequentially in distilled water and phosphate-buffered saline, quenched in 0.03% H202, and stained with the avidin-biotin-peroxidase complex (ABC) technique using an ABC kit (Vector Laboratories, Burlingame, CA). 3',3-Diamino-benzidine was used as the chromogen. A monoclonal antibody to the endothelial leukocyte adhesion molecule-1 (ELAM-1), provided as ascites fluid by Dr. M.P. Bevilacqua, Boston, Massachusetts,1415 was applied at a 1:100 dilution. Frozen sections were not used because of the lack of ability to resolve detailed structures on microvasculature.

Results Four mice from each of the SJL, A.CA, and SWR strains, perfused during the initial acute episode of adoptively transferred EAE (days 6 to 10 after transfer), and one each SJL and A.CA mouse sampled during a relapse were examined. All levels of the CNS were analyzed. For control purposes, two normal, age-matched female SJL mice were examined. In all cases where active inflammatory cell invasion was apparent, long thin fingerlike fronds could be observed emanating from the luminal surface of involved vessels (Figure 1 a-c). These EC projections were often branched, clustered, and complex and were observed on up to 50% of EC in venules of early, acute lesions (< 24 to 48 hours clinical signs). The fronds appeared to arise at junctions between cells, a finding confirmed by ultrastructural studies (vide infra), and the endothelium beneath them often appeared compromised (Figure 1 c). Because the CNS tissue under study was perfused fresh in situ, inflammatory cells were still adhered to vessel surfaces, and nonadherent cells (eg, erythrocytes) were not apparent. This observation was supported by serial sections through apparently freefloating cells (Figures 2a-c, 3a-c), which demonstrated them to be attached at some level. The above-described EC fronds contacted adherent PMNs (Figures 1c, 2, 3) and not infrequently were also associated with attached platelets (Figures 3c, 4). Conversely mononuclear cells with the morphology of small lymphocytes were rarely observed in association with EC fronds. Rather such cells appeared to attach to CNS endothelium by pseudopodia extending from the mononuclear cell itselflO (Figure 1a, loc. cit.,1 Figure 16, loc. cit.). For immunocytochemistry, 1 -,u sections were exam-

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Figure 1. SJL/J mouse with adoptively transferred EAE, 6 days post-transfer (DPT). Sections from two different levels of spinal cord (a) and (b), show blood vessels containing endothelial cells (EC) from which cytoplasmic fronds emanate (arrows). Inflammatory cells are few; (c) A.CA mouse, adoptively transferred EAE, 3 months post-transfer, sampled during a relapse. A venule at the margin of the dorsal horn in the cervical spinal cord displays a region of attenuated endothelium from which two fronds extend into the lumen and beneath which a cavity is apparent The frond to the left contacts an adherent PMN One micron epoxy sections, toluidine blue stain, a, b, and C, X875. Figure 2. SJL mouse, 6 DPT. In these serial sections from a developing perivascular cuff, note the several infiltrating cells (mostly PMNs) attached to the luminal aspect of the venule. Some of the cells are associated with ECfronds, and some attached cells (e.g., arrows), appear asffree-floating elements in later sections. a, b, and c, x875.

ined from several levels of lumbar spinal cord from two SJL mice with acute EAE with extensive inflammatory cell involvement, one of which was perfused with 0.1% glutaraldehyde, and from a nonsensitized, age-matched SJL control. Tissue from the EAE animals appeared to show periodic ELAM-1 staining on the luminal surface of blood vessels and on CNS cells located within both gray and white matter. In no section, however, was intense reactivity seen. A similar pattern of ELAM-1 immunoreactivity, but less intense in degree, was noted in CNS tissue from the control mouse. Ultrastructurally, cytoplasmic fronds emanating in the

vicinity of complex tight junctional arrays between adjacent EC were readily observed (Figure 4). The structures were unusually rich in microfilaments and lacked organelles. On many occasions, the fronds were branched and were associated with trapped or adherent hematogenous elements. Groups of adherent PMNs and platelets (Figure 5) were frequently observed to contact the EC fronds. Adherent PMNs frequently overlaid apparently leaky tight junctions where the junctional complex was reduced in cross section to a simple point of contact and the adjacent parenchymal space was filled with fibrin. This suggested that these weakened junctions may rep-

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Figure 3. SJL mouse, 6 DPT A series of sections to show ECfronds (arrows) arnsingfrom different cells, some of which in adjacent sections make contact with the same cell (upper right). A platelet, bottom arrow in (c), is also in contact with an ECfrond, x875.

resent a likely route of entry for PMNs into the tissue. Mononuclear cells did not appear to associate with EC fronds, confirming the light microscope impression. On rare occasions, red blood cells were seen enmeshed by fronds (Figure 6). In one of two control mice, a single white matter vessel (out of approximately 50 studied) possessed small fingerlike EC projections. These were in no way as extensive as those encountered in experimental animals. The EC of many involved vessels were unusually plump and possessed a thickened cytoplasm filled with mitochondria and rough endoplasmic reticulum (Figure

7). Although precise quantitation of organelles was not performed, the general impression was obtained that involved blood vessels contained an increased number of organelles and a thicker endothelial lining than CNS endothelium in noninflamed areas and in control mice.

Discussion The present short report highlights an unusual association between collections of cytoplasmic extensions from EC and hematogenous elements, particularly PMNs and

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Figure 4. SJL mouse, sampled during a relapse after 125 DPT. An electron micrograph of the luminalswface of a small vein displays several

separated by crypts at the bases of which (*) tight junctional complexes are present. A platelet (p) lies below, x 16,000. ECffronds Figure 5. Same animal as Figure 5. Two PMNs are attached to the surface of a blood vessel in association with a group of ECfronds. Two

platelets (p) are also present. Note how the tight junction beneath the PMN to the right is represented by a small point of contact on&. The endothelial cytoplasm (below) is unusually rich in organelles, x 12,000. Figure 6. Same animal as Figure 5. A red blood cell appears trapped between ECfronds emanating fiom the surface of a vessel. Note the associated tight junctions, x 10,500.

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Figure 7. SJL mouse, 10 DPT. A superficial small vein at the surface of the spinal cord displays endothelial cells, two of which are plump (arrows) and others of which are rich in organelles (lower left). The developing perivascular cuff contains PMNs and mononuclear cells. Myelinated CNSfibers lie to the upper left. The area at the asterisk is shown in the inset, above. Inset: A tight]unction (arrow) is present between the two EC, X 15,000 and x87,500.

platelets. These were only seen during active stages of CNS inflammation in animals with EAE, and mononuclear cells were not involved. The adhesion of inflammatory cells to vascular endothelium, a process identified and termed 'pavementing' by Cohnheim in the late 1800S,16 is

an essential initial step in the invasion of tissue by infiltrating cells. Polymorphonuclear cells, a subset of white blood cells, are among the first cells to arrive at sites of inflammation. With regard to the attachment of PMNs, it is now known that they selectively adhere to injured endot-

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helium in a cation-dependent manner.17 Endothelial cells have been shown to synthesize platelet-activating factor and leukotriene B4,18 both potent chemoattractants and activators of PMNs1 2'19-phenomena perhaps related to the present structural associations. Furthermore, activated PMNs elaborate a number of agents (lysozyme, collagenase, elastase, fibrinolysins, cationic proteins) that are capable of damaging vasculature on adhesion and activation at the endothelial barrier,2'" and this may account for the attenuation and weakening of EC tight junctions in association with the above-described relationships. It is also known that PMNs are capable of migrating across vessels even when blood flow has ceased, implying that hydrostatic pressure is not necessary for their movement, and that PMNs can migrate actively.20'21 An active role for the EC itself in inflammatory cell adhesion and invasion has not previously been stressed. For example, the elegant ultrastructural studies of Marchesi, on a model of inflammation induced in the rat mesentery by mechanical trauma, demonstrated that PMNs, eosinophils, and monocytes emigrated through the extension of cell pseudopodia into and through EC junctions, apparently with no participation by EC.22 In recent years, the availability of tissue culture preparations of EC has allowed studies on adhesion in vitro and it has been shown that the cytokines, interleukin-1, and tumor necrosis factor (IL-1 and TNF) can act directly to increase formation of complexes between PMN surface molecules and their ligands on EC.56 In some instances, this association appeared to involve CD11/18 (integrin) molecules on PMNs interacting with intercellular adhesion molecules 1 or 2 (ICAM-1 or ICAM-2) on EC.23 Bevilacqua and colleagues14,15 have identified yet another adhesion molecule, ELAM-1, which they have claimed to be more specific for PMNs. This molecule can be induced on cultured EC by cytokines (eg, IL-1, TNF, and lymphotoxin), but its expression is more transient than that of ICAM-1 and it appears to be operative in PMN-EC interactions occurring specifically in the early phases of inflammation,141524 although more recently, ELAM-1 has been implicated in the adhesion of T cells to endothelium in other tissues.2526 Thus, a role for the murine homolog of ELAM-1 in the initial PMN adhesion and influx observed in early EAE lesions might be anticipated. In the present study, however, expression of ELAM-1 could not convincingly be shown. It therefore remains speculative whether this or any other adhesion molecule might be involved in the phenomena outlined herein. Studies on a role for cytokine-induced molecules on EC during PMN adhesion suggest a crucial role for EC, but have only been performed on large-vessel endothelium in vitro.27 The presence or significance of surface molecules on EC in the generation of inflammation of the microvasculature in vivo (as is the case in EAE), remains

to be demonstrated. The present study provides new morphologic evidence for the induction of unique structural alterations on EC intimately involved in PMN (and platelet) adhesion to CNS microvasculature, however, a pattern different from that described during the passage of lymphocytes into the CNS.'1 With regard to the plump endothelium noted in the present study, similar cells are known to develop in chronically inflamed tissue in other putative autoimmune disorders, such as rheumatoid arthritis, autoimmune thyroiditis, and Crohn's disease,28 30 as well as EAE.9 '0 Plump or cuboidal EC expressing specific surface molecules are normally present at sites where lymphocytes pass from the bloodstream into lymphoid tissue and have been termed 'high endothelial venules' (HEV2932). The cuboidal morphology of HEV appears to depend on the presence of lymph-borne cells or their factors, because when afferent lymph flow is blocked, HEV return to a flat morphology.3', The HEV-like endothelium observed in EAE, unlike normal CNS vasculature, have been shown to express lymph node HEV molecular markers,'1035 and together with the present demonstration of an enriched cytoplasm, might support the interpretation that the EC were activated. The present findings also serve to underscore differences in the manner by which PMNs and lymphocytes actually attached to blood vessels. Lymphocyte adhesion has been observed to occur by a morphologically distinct mechanism whereby pseudopodia are extended and burrow into the endothelium.10 There is also evidence that lymphocytes migrate across endothelium near, but not directly through, intact tight junctions.10'36'37 Such appearances suggest active, directed invasion on the part of the lymphocyte. Endothelial cell fronds in contact with lymphocytes have not been observed, a difference that might be due to the different adhesion molecules expressed by lymphocytes. In contrast, the association of PMNs with EC fronds suggested a 'trapping' mechanism that might implicate less specific migration. Furthermore, early ultrastructural work by Marchesi22 on rat mesentery, and Beesley et all on EC cultures, demonstrated PMNs to migrate directly through tight junctions. Although not observed in transit through CNS endothelium in the present work (a finding perhaps suggestive of the rapidity of the process in the CNS), PMNs were noted to adhere over leaky tight junctions (Figure 6), perhaps indicative of impending passage. In summary, the present study has shown novel morphologic changes on blood vessels involved in early inflammation during EAE, an autoimmune disorder of the CNS. These took the form of frondlike luminal projections from reactive EC arising adjacent to tight junctions and were intimately involved in PMN, and occasionally platelet, adhesion, or perhaps trapping. We suggest that this

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attachment preceded migration of PMNs through the tight junction. The present study has focused on CNS vessels, and it remains to be determined whether similar changes occur in inflamed vessels of other tissues. Our observations may represent the structural counterparts of molecular interactions between activated EC and PMNs documented elsewhere in vitro57 and may underscore an important role for activated endothelium in the development and perpetuation of inflammation.

Acknowledgments The authors thank Drs. Barbara Cannella, Celia Brosnan, and Dennis Dickson for advice and discussion; Dr. Michael Bevilacqua (Brigham and Women's Hospital, Boston, MA) for antibody to ELAM-1; Tom O'Mara, Howard Finch, Miriam Pakingan, and Earl Swanson for excellent technical assistance; and Michele Briggs for careful preparation of the manuscript.

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65:513-525. 3. Hoover RL, Briggs RT, Karnovsky MJ: The adhesive interaction between polymorphonuclear leukocytes and endothelial cells in vitro. Cell 1978, 14:423-428 4. Pearson JD, Carleton JS, Beesley JE, Hutchings A, Gordon JL: Granulocyte adhesion to endothelium in culture. J Cell Sci 1979, 38:225-235 5. Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone MA: Interleukin-1 acts on cultured human vascular endothelium to increase adhesion of polymorphonuclear leukocytes, monocytes and related cell lines. J Clin Invest 1985, 76:2003-2011 6. Gamble JR, Harlan JM, Klebanoff SJ, Vadas MA: Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci (USA) 1985, 82:8667-8671 7. Schleimer RP, Rutledge BK: Cultured human vascular endothelial cells acquire adhesiveness for neutrophils after stimulation with interleukin 1, endotoxin and tumorpromoting phorbol diesters. J Immunol 1986, 136:649-654 8. Mantovani A, Dejana E: Cytokines as communication signals between leukocytes and endothelial cells. Immunol Today 1989, 10:370-375 9. Cross AH, Cannella B, Brosnan CF, Raine CS: Homing to central nervous system vasculature by antigen-specific lymphocytes: I. Localization of 14C-labeled cells during acute, chronic, and relapsing experimental allergic encephalomyelitis. Lab Invest 1990, 63:162-170 10. Raine CS, Cannella B, Duijvestijn AM, Cross AH: Homing to

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25. Picker W, Kishimoto TK, Smith CW, Warnock RA, Butcher EC: ELAM-1 is an adhesion molecule for skin-homing T cells. Nature 1991, 349:796-799 26. Shimizu Y, Shaw S, Graber N, Gopal lV, Horgan KJ, Van Seventer GA, Newman W: Activation-indpendent binding of human memory T cells to adhesion molecule ELAM-1. Nature 1991, 349:799-802 27. Pober JS, Gimbrone MA, Lapierre LA, Mendrick DA, Fiers WA, Rothlein R, Springer T: Overlapping patterns of activation of human endothelial cells by interleukin-1 tumor necrosis factor and immune interferon. J Immunol 1986, 137:1893-1896 28. Freemont AJ, Jones CP, Bromley M, Andrews P: Changes in vascular endothelium related to lymphocyte collections in diseased synovia. Arthritis Rheum, 1983, 26:1427-1430 29. Duijvestijn AM, Horst E, Pals ST, Rouse BN, Steere AC, Picker W, Meijer CJIM, Butcher EC: High endothelial differentiation in human lymphoid and inflammatory tissues defined by monoclonal antibody HECA-452. Am J Pathol 1988, 130:147-155 30. Kabel PJ, Voorbij HAM, de Haan-Meullman M, Pals ST, Drexhage HA: High endothelial venules present in lymphoid cell accumulations in thyroids affected by autoimmune disease: A study in men and BB rats of functional activity and development. J Clin Endocrinol Metab 1989, 68:744-751 31. Gowans JL, Knight EJ: The route of recirculation of lymphocytes in the rat. Proc R Soc Lond (Biol) 1964, 159:257-282 32. Duijvestijn A, Schreiber AB, Butcher EC: Interferon-gamma

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Central nervous system endothelial cell-polymorphonuclear cell interactions during autoimmune demyelination.

The homing and adhesion of circulating cells to target tissue vasculature precedes their subsequent invasion of inflamed tissue. Polymorphonuclear cel...
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