SIRPα/CD172a and FHOD1 Are Unique Markers of Littoral Cells, a Recently Evolved Major Cell Population of Red Pulp of Human Spleen This information is current as of September 28, 2021. Javier Gordon Ogembo, Danny A. Milner, Jr., Keith G. Mansfield, Scott J. Rodig, George F. Murphy, Jeffery L. Kutok, Geraldine S. Pinkus and Joyce D. Fingeroth J Immunol 2012; 188:4496-4505; Prepublished online 4 April 2012; Downloaded from doi: 10.4049/jimmunol.1103086 http://www.jimmunol.org/content/188/9/4496 http://www.jimmunol.org/ References This article cites 95 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/188/9/4496.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology SIRPa/CD172a and FHOD1 Are Unique Markers of Littoral Cells, a Recently Evolved Major Cell Population of Red Pulp of Human Spleen Javier Gordon Ogembo,*,†,1 Danny A. Milner, Jr.,†,‡,1 Keith G. Mansfield,†,x Scott J. Rodig,†,‡ George F. Murphy,†,‡ Jeffery L. Kutok,‡ Geraldine S. Pinkus,†,‡ and Joyce D. Fingeroth*,† Asplenic individuals are compromised not only in their ability to destroy infectious agents, but are at increased risk for death from autoimmune disease, certain tumors, and ischemic heart disease. Enhanced mortality is attributed to lack of phagocytes sequestered in spleen that efficiently engulf and destroy appropriate targets, although related cells are found elsewhere. To determine whether a unique population regulates RBC-pathogen clearance and filtration of altered self, we reviewed the anatomic literature and an- alyzed in situ by immunohistochemistry and immunofluorescence the expression patterns of a little-characterized cell that dom- Downloaded from inates the splenic red pulp of humans and closely related primates: the venous sinus-lining or littoral cell (LC). High expression of the formin homology domain protein 1 outlines the LC population. Although LCs are endothelial-like in distribution, they express several macrophage-directed proteins, the RBC Duffy Ag receptor for chemokines and T cell coreceptor CD8a/a, yet they lack lineage-associated markers CD34 and CD45. Strikingly, SIRPa (CD172a) expression in human spleen concentrates on LCs, consistent with recent demonstration of a key role in RBC turnover and elimination versus release of infected or altered self. + + + 2 2 Our results indicate human LCs (SIRPa , formin homology domain protein 1 , CD8a/a , CD34 , CD45 ) comprise a highly http://www.jimmunol.org/ plastic barrier cell population that emerged late in primate evolution coordinate with CD8 expression. Unique to Hominidae, LCs may be the ultimate determinant of which cells recirculate after passage through human spleen. The Journal of Immunology, 2012, 188: 4496–4505. ndividuals who are asplenic or functionally asplenic (hypo- a filter that mediates the ultimate retention and destruction of splenic) are unable to eliminate many bacterial and parasite senescent and modified cells (5, 6). pathogens (1). They also display an increased risk for auto- Opsonization with Ab and/or complement enhances clearance of I by guest on September 28, 2021 immune disease (1), some cancers (2), and ischemic cardiac dis- foreign Ags, cell debris, and altered self by phagocytes (1, 7). In ease (2, 3). Perhaps this is not surprising because the spleen is the humans, inflammatory particles that are opsonized and immobi- largest secondary immune system organ in mammals. However, lized by complement fragments are regularly transported through although the overall organization of splenic white pulp is similar the circulation tethered by complement receptor type 1 (CD35) on to that of lymph nodes, the spleen is not connected to the lym- the RBC membrane for efficient phagocytosis at distant locations phatic system (4). Rather, soluble and particulate Ags, pathogens, (4, 8, 9). This process, a sophisticated mechanism known as im- RBCs, and altered, apoptotic, necrotic, and tumor cells are all mune adherence clearance, evolved with mammals to remove delivered to and leave the spleen via the circulation. In contrast inflammation-inducing particles from blood (10). However, utili- with white pulp, the red pulp of mammalian spleen serves as zation of RBCs for immune adherence clearance is a recent de- velopment in the evolution of the immune system restricted to humans and closely related primates, because nonprimates, in- *Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA 02215; †Harvard Medical School, Boston, MA 02115; ‡Department of Pathology, cluding rodents, primarily rely on platelet-based transport mech- Brigham and Women’s Hospital, Boston, MA 02115; and xDivision of Primate Med- anisms (11, 12). Much evidence indicates liver and spleen are icine, New England Primate Research Center, Southborough, MA 01772 where CD35-bound immune complexes (ICs) are delivered (9), 1 J.G.O. and D.A.M. contributed equally to this work. although precisely how ICs are removed at each location is not Received for publication October 26, 2011. Accepted for publication February 29, well understood. 2012. RBCs themselves (residual IC loaded, infected, and aging) are This work was supported by National Institutes of Health Grants R01AI063571 (to sequestered, variably internalized, and removed as they course J.D.F.) and K23AI072033 (to D.A.M.), an American Heart Association Grant-in-Aid (to J.D.F.), and a fellowship from the Cancer Research Institute (to J.G.O.). through the red pulp of the spleen (13). Precisely where and how J.D.F., J.G.O., and D.A.M. designed and analyzed all experiments, reviewed the RBCs and other altered cell types delivered by the circulation are literature, and wrote the manuscript. J.G.O. and D.A.M. performed most experiments. destroyed or filtered is unknown. The stroma of human red pulp is K.G.M., S.J.R., G.S.P., G.F.M., and J.L.K. provided expertise and additional samples composed of the cords of Billroth and the sinusoids (14). In for analysis. contrast with human, the mouse has an asinusal spleen, and thus it Address correspondence and reprint requests to Dr. Joyce D. Fingeroth, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, is architecturally and functionally distinct (4, 15–21). Human red CLS-445, Boston, MA 02215. E-mail address: jfi[email protected] pulp has a high content of diverse phagocytes; however, to return Abbreviations used in this article: DARC, Duffy Ag receptor for chemokines; to the venous circulation, most splenic constituents must pass FHOD1, formin homology domain protein 1; IC, immune complex; IHC, immuno- between or through the sinus-lining cell or littoral cell (LC). Al- histochemistry; LC, littoral cell; LCA, LC angioma. though the morphologic appearance of the LC suggests it may be Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 a key mediator of particle clearance and cellular filtration (13), www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103086 The Journal of Immunology 4497 direct demonstration of function is lacking. In fact, little is known CD47 into the venous circulation may ultimately be determined by about these cells. the LC, a hypothesis examined in this study. Littoral literally means “shoreline” or “tidal,” which accurately describes the polarized cells that line the venous sinusoids of Materials and Methods human spleen with cytoplasmic fronds protruding into the sinus. Tissue LCs comprise ∼30% of the red pulp, and thus are a major con- Normal discarded and unidentified human spleen consented for research stituent of human spleen (22). Morphologically, LCs are elongate was obtained from the Pathology Departments of Beth Israel Deaconess and contain prominent cytoplasmic filaments (stress fibers) (23). Medical Center, Brigham and Women’s Hospital, and New England Organ Their abundant cytoplasm is filled with many pinocytic vesicles, Bank. The tissues were obtained in accordance with the policies of the lysosomes, and dense deposits that surround the nucleus. Phago- Institutional Review Board at each of the respective sites. Splenic tissues were processed immediately to optimize conservation of cell morphology cytosed RBCs, leukocytes, hemosiderin, and other debris can be and composition. LCA slides were provided by the Brigham and Women’s visualized within these cells (24–26), even more so in the setting Hospital Pathology Department (to S.J.R., generously provided by Dr. of certain diseases (27, 28). RBCs can also be seen coursing be- Christopher D.M. Fletcher). Archived formalin-fixed, paraffin-embedded, tween adjacent LCs (10, 13). nonhuman primate spleens were obtained from a repository at the New Based on their