Abstract
The spleen, the largest secondary lymphoid organ in the body, functions both as a blood filter and part of the immune system. Histologically, the spleen is comprised of three main components; the red pulp, the white pulp and the marginal zone. The primary functions of the spleen are largely localized to specific anatomic compartments. The splenic red pulp serves as a blood filter to remove effete erythrocytes and platelets from the blood. Red pulp macrophages also have a role in combating blood-borne infection. The white pulp and marginal zone are the primary sites of innate and adaptive immune responses. The marginal zone is at the interface of red and white pulp, and has a predominance of macrophages, dendritic cells, and B cells that play an important role in innate immunity as well as the capture and presentation of antigens to initiate the adaptive immune response. Abundant lymphocytes in the white pulp are distributed into T cell-rich peri-arteriolar lymphoid sheaths and B cell-rich follicles, which work cooperatively to develop adaptive immune responses. A complex interplay between innate and adaptive immune cells and mediators makes the spleen important in the development of effective immune responses, particularly against circulating pathogens. In performing histological and functional evaluations, it is important to consider the wide range of responses in the spleen as well as differences in responses and background findings that can occur in animals of different species, strains, ages, or physiological states.
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References
Aichele P, Zinke J, Grode L, Schwendener RA, Kaufmann SH, Seiler P (2003) Macrophages of the splenic marginal zone are essential for trapping of blood-borne particulate antigen but dispensable for induction of specific T cell responses. J Immunol 171(3):1148–1155
Altamura M, Caradonna L, Amati L, Pellegrino NM, Urgesi G, Miniello S (2001) Splenectomy and sepsis: the role of the spleen in the immune-mediated bacterial clearance. Immunopharmacol Immunotoxicol 23(2):153–161
Bacha W, Bacha L (2000) Color atlas of veterinary histology. Lippincott, Williams, and Wilkins, Philadelphia
Banks WJ (1993) Applied veterinary histology, 3rd edn. Mosby-Year Book, St. Louis
Blue J, Weiss L (1981) Electron microscopy of the red pulp of the dog spleen including vascular arrangements, periarterial macrophage sheaths (ellipsoids), and the contractile, innervated reticular meshwork. Am J Anat 161(2):189–218, http://www.ncbi.nlm.nih.gov/pubmed/7258115
Borges da Silva H, Fonseca R, Pereira RM, Cassado Ados A, Alvarez JM, D'Imperio Lima MR (2015) Splenic macrophage subsets and their function during blood borne infections. Front Immunol 6:1–9. doi:10.3389/fimmu.2015.00480
Bradley AE (2012) New Zealand white rabbit. In: McInnes EF (ed) Background lesions in laboratory animals: a color atlas. Saunders/Elsevier, Edinburgh, pp 87–92
Brendolan A, Rosado MM, Carsetti R, Selleri L, Dear TN (2007) Development and function of the mammalian spleen. Bioessays 29(2):166–177. doi:10.1002/bies.20528
Brown EM, Dellmann HD (1981) Lymphatic organs. In: Brown EM, Dellmann HD (eds) Textbook of veterinary histology, 2nd edn. Lea and Febiger, Philadelphia, pp 165–186
Cesta MF (2006) Normal structure, function, and histology of the spleen. Toxicol Pathol 34(5):455–465. doi:10.1080/01926230600867743
Chadburn A (2000) The spleen: anatomy and anatomical function. Semin Hematol 37(1 Suppl 1):13–21
Chamanza R, Marxfeld HA, Blanco AI, Naylor SW, Bradley AE (2010) Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fasciularis) used in toxicity studies. Toxicol Pathol 38:642–657
De Jong WH, Van Loveren H (2007) Screening of xenobiotics for direct immunotoxicity in an animal study. Methods 41(1):3–8. doi:10.1016/j.ymeth.2006.09.003
den Haan JMM, Kraal G (2012) Innate immune functions of macrophage subpopulations in the spleen. J Innate Immun 4(5-6):437–445. doi:10.1159/000335216
Descotes J (2006) Methods of evaluating immunotoxicity. Expert Opin Drug Metab Toxicol 2(2):249–259
Dhabhar FS (2009) Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 16(5):300–317
Dhabhar FS, Miller AH, McEwen BS, Spencer RL (1995) Effects of stress on immune cell distribution. Dynamics an hormonal mechansisms. J Immunol 154(10):5511–5527
Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516
Elmore SA (2006) Enhanced histopathology of the spleen. Toxicol Pathol 34:648–655
Everds NE, Snyder PW, Bailey KL, Bolon B, Creasy DM, Foley GL, Rosol TJ, Sellers T (2013) Interpreting stress responses during routine toxicity studies: a review of the biology, impact, and assessment. Toxicol Pathol 41(4):560–614. doi:10.1177/0192623312466452
Frith CH, Ward JM, Chandra M, Losco PE (2000) Non-proliferative lesions of the hematopoietic system in rats. HL-1. In: Guides for toxicologic pathology. STP/ARP/AFIP, Washington, DC. https://www.toxpath.org/ssdnc/HematopoieticNonprolifRat.pdf
Germolec DR, Nyska A, Kashon M, Kuper CF, Portier C, Kommineni C, Johnson KA, Luster MI (2004) Extended histopathology in immunotoxicity testing: interlaboratory validation studies. Toxicol Sci 78(1):107–115
Golub R, Cumano A (2013) Embryonic hematopoiesis. Blood Cells Mol Dis 51(4):226–231. doi:10.1016/j.bcmd.2013.08.004, S1079-9796(13)00201-5 [pii]
Gopinath C (1996) Pathology of toxic effects on the immune system. Inflamm Res 45(Suppl 2):S74–S78
Haley P, Perry R, Ennulat D, Frame S, Johnson C, Lapointe JM, Nyska A, Snyder PW, Walker D, Walter G (2005) STP position paper: best practice guideline for the routine pathology evaluation of the immune system. Toxicol Pathol 33:404–407
Harleman JH (2000) Approaches to the identification and recording of findings in the lymphreticular organs indicative for immunotoxicity in regulatory type toxicity studies. Toxicology 142:213–219
Hobbie K, Elmore SA, Kolenda-Roberts HM (2015) Immune system – Spleen. In: Cesta MF, Herbert RA, Brix A, Malarkey DE, Sills RC (eds) National Toxicology Program Nonneoplastic Lesion Atlas. http://ntp.niehs.nih.gov/nnl/immune/spleen/index.htm
HogenEsch H, Hahn FF (2001) The lymphoid organs: anatomy, development, and age-related changes. Pathobiology of the aging dog, vol 1. pp 127–135. doi: Book chapter
Jones JF (1983) Development of the spleen. Lymphology 16(2):83–89
Kerlin R, Bolon B, Burkhardt J, Francke S, Greaves P, Meador V, Popp J (2016) Scientific and regulatory policy committee: Recommended ("best") practices for determining, communicating, and using adverse effect data from nonclinical studies. Toxicol Pathol 44(2):147–162
Kodama R, Okazaki T, Sato T, Iwashige S, Tanigawa Y, Fujishima J, Moriyama A, Yamashita N, Sasaki Y, Yoshikawa Y, Maeda H (2012) Age difference in morophology and immunohistology in the thymus and spleen in Crl:CD (SD) rats. J Toxicol Pathol 25(1):55–61
Koppel EA, Litjens M, van den Berg VC, van Kooyk Y, Geijtenbeek TBH (2008) Interaction of SIGNR1 expressed by marginal zone macrophages with marginal zone B cells is essential to early IgM responses against Streptococcus pneumoniae. Mol Immunol 45:2881–2887
Korolnek T, Hamza I (2015) Macrophages and iron trafficking at the birth and death of red cells. Blood 125(19):2893–2897. doi:10.1182/blood-2014-12-567776
Kraal G, Mebius RE (2006) New insights into the cell biology of the marginal zone of the spleen. Int Rev Cytol 250:175–215. doi:10.1016/S0074-7696(06)50005-1
Kroese FG, Butcher EC, Stall AM, Herzenberg LA (1989) A major peritoneal reservior of precursors for intestinal IgA plasma cells. Immunol Invest 18:47–58
Kuper CF, Ruehl-Fehlert C, Elmore SA, Parker GA (2013) In: Haschek WM, Rousseaux CG, Wallig MA (eds) Immune system in handbook of toxicologic pathology. Academic Press/Elsevier, Waltham, MA, pp 1795–1859
Kuper CF, Harleman JH, Richter-Reichelm HB, Vos JG (2000) Histopathologic approaches to detect changes indicative of immunotoxicity. Toxicol Pathol 28:454–466
Lockmic Z, Lammermann T, Sixt M, Cardell S, Hallmann R, Sorokin L (2008) The extracellular matrix of the spleen as a potential organizer of immune cell compartments. Semin Immunol 20:4–13. doi:10.1016/j.smim.2007.12.009
Lopes-Carvalho T, Foote J, Kearney JF (2005) Marginal zone B cells in lymphocyte activation and regulation. Curr Opin Immunol 17:244–250
Losco P (1992) Normal development, growth, and aging of the spleen. In: Mohr U, Dungworth DL, Capen CC (eds) Pathobiology of the aging rat, 1st edn. ILSI, Washington, DC, pp 75–94
Luster MI, Portier C, Pait DG, White KLJ, Gennings C, Munson AE, Rosenthal GJ (1992) Risk assessment in immunotoxicology.I. Sensitivity and predictabiligy of immune tests. Fundam Appl Toxicol 18(2):200–210
Mahnke K, Knop J, Enk AH (2003) Induction of tolerogenic DCs: “you are what you eat”. Trends Immunol 24(1):646–651
Matsuno K, Ezaki T, Kotani M (1989) Splenic outer periarterial lymphoid sheath (PALS): An immunoproliferative microenvironment constituted by antigen-laden marginal metallophils and ED2-positive macrophages in the rat. Cell Tissue Res 257(3):459–470, http://www.ncbi.nlm.nih.gov/pubmed/2790931
McInnes EF (2012a) Minipigs. In: McInnes EF (ed) Background lesions in laboratory animals: a color atlas. Saunders/Elsevier, Edinburgh, pp 81–86
McInnes EF (2012b) Wistar and Sprague-Dawley rats. In: McInnes EF (ed) Background lesions in laboratory animals: a color atlas. Saunders/Elsevier, Edinburgh, pp 17–36
Mebius RE, Kraal G (2005) Structure and function of the spleen. Nat Rev Immunol 5(8):606–616, http://dx.doi.org/10.1038/nri1669
Mebius RE, Nolte MA, Kraal G (2004) Development and function of the splenic marginal zone. Crit Rev Immunol 24(6):449–464
Michael B, Yano B, Sellers RS, Perry R, Morton D, Roome N, Johnson JK, Schafer K, Pitsch S (2007) Evaluation of organ weights for rodent and non-rodent toxicity studies: a review of regulatory guidelines and a survey of current practices. Toxicol Pathol 35(5):742–750
Morelli AE, Larregina AT, Shufesky WJ, Zahorchak AF, Logar AJ, Papworth GD, Wang Z, Watkins SC, Falo LDJ, Thomson AW (2003) Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production. Blood 101(2):611–620
Nance DW, Sanders BM (2007) Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav Immun 21(6):736–745
Onkar DP, Govardhan SA (2013) Comparative histology of human and dog spleen. J Morphol Sci 30(1):16–20
Parker GA, Picut CA, Swanson C, Toot JD (2015) Histologic features of postnatal development of immune system organs in the Sprague-Dawley rat. Toxicol Pathol 43(6):794–815
Perryman LE (2004) Molecular pathology of severe combined immunodeficiency in mice, horses, and dogs. Vet Pathol 41(2):95–100, http://dx.doi.org/10.1354/vp.41-2-95
Press CM, Landsverk T (2006) Immune System. In: Eurell JA, Frappier BL (eds) Dellman’s Textbook of veterinary histology, 6th edn. Blackwell, Ames, pp 134–152
Pruett S, Hebert P, Lapointe JM, Reagan W, Lawton M, Kawabata TT (2007) Characterization of the action of drug-induced stress responses on the imune system: evaluation of biomarkers for drug-induced stress in rats. J Immunotoxicol 4(1):25–38
Ram S, Lewis LA, Rice PA (2010) Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev 23(4):740–780
Rosado MM, Gesualdo F, Marcellini V, Di Sabatino A, Corazza GR, Smacchia MP, Nobili B, Baronci C, Russo L, Rossi F, Vito RD, Nicolosi L, Inserra A, Locatelli F, Tozzi AE, Carsetti R (2013) Preserved antibody levels and loss of memory B cells against pneumococcus and tetanus after splenectomy: tailoring better vaccination strategies. Eur J Immunol 43(10):2659–2670
Saint-Mezard P, Chavagnac C, Bosset S, Ionescu M, Peyron E, Kaiserlian D, Nicolas JF, Berard FJ (2003) Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo. J Immunol 171(8):4073–4080
Saito H, Yokoi Y, Watanabe S, Tajima J, Kuroda H, Namihisa T (1988) Reticular meshwork of the spleen in rats studied by electron microscopy. Am J Anat 181(3):235–252, http://www.ncbi.nlm.nih.gov/pubmed/3364383
Sato J, Doi T, Kanno T, Wako Y, Tsuchitani M, Narama I (2012) Histopathology of incidental findings in cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. J Toxicol Pathol 25(1):63–101
Satodate R, Tanaka H, Sasou S, Sakuma T, Kaizuka H (1986) Scanning electron microscopical studies of the arterial terminals in the red pulp of the rat spleen. Anat Rec 215(3):214–216, http://www.ncbi.nlm.nih.gov/pubmed/3740462
Schmidt EE, MacDonald IC, Groom AC (1982) Direct arteriovenous connections and the intermediate circulation in dog spleen, studied by scanning electron microscopy of microcorrosion casts. Cell Tissue Res 225(3):543–555, http://www.ncbi.nlm.nih.gov/pubmed/7127407
Schmidt EE, MacDonald IC, Groom AC (1983) Circulatory pathways in the sinusal spleen of the dog, studied by scanning electron microscopy of microcorrosion casts. J Morphol 178(2):111–123, http://www.ncbi.nlm.nih.gov/pubmed/6655696
Schmidt EE, MacDonald IC, Groom AC (1985) Microcirculation in rat spleen (sinusal), studied by means of corrosion casts, with particular reference to the intermediate pathways. J Morphol 186(1):1–16, http://onlinelibrary.wiley.com/doi/10.1002/jmor.1051860102/abstract
Scudamore C (2012) Beagle Dog. In: McInnes EF (ed) Background lesions in laboratory animals: a color atlas. Saunders/Elsevier, Edinburgh, pp 37–44
Seymour R, Sundberg JP, Hogenesch H (2006) Abnormal lymphoid organ development in immunodeficient mutant mice. Vet Pathol 43(4):401–423. doi:10.1354/vp.43-4-401
Stefanski SA, Elwell MR, Stromberg PC (1990) Spleen, lymph nodes, and thymus. Pathology of the Fischer rat. pp 369-393. doi: Book chapter
Suttie AW (2006) Histopathology of the spleen. Toxicol Pathol 34(5):466–503. doi:10.1080/01926230600867750
Taylor I (2012) Mouse. In: McInnes EF (ed) Background lesions in laboratory animals: a color atlas. Saunders/Elsevier, Edinburgh, pp 45–72
Thomas J, Haseman JK, Goodman JI, Ward JM, Loughran TPJ, Spencer PJ (2007) A review of large granular lymphocytic leukemia in Fischer 344 rats as an initial step toward evaluating the implication fo the endpoint to human cancer risk. Toxicol Sci 99(1):3–19
Ueno H, Banchereau J, Vinuesa CG (2015) Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 16(2):142–152
Van Rees EP, Sminia T, Dijkstra CD (1996) Structure and development of the lymphoid organs. Pathobiology of the aging mouse, vol 1. pp 173–187. doi: Book chapter
Ward JM, Mann PC, Morishima H, Frith CH (1999) Thymus, spleen and lymph nodes. Pathology of the mouse. pp 333–360. doi:Book chapter
Wardemann H, Boehm T, Dear N, Carsetti R (2002) B-1a B cells that link the innate and adaptive immune responses are lacking in the absence of the spleen. J Exp Med 195(6):771–780
White C, Yuan X, Schmidt PJ, Bresciani E, Samuel TK, Campagna D, Hall C, Bishop K, Calicchio ML, Lapierre A, Ward DM, Liu P, Fleming MD, Hamza I (2013) HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 17(2):261–270. doi:10.1016/j.cmet.2013.01.005
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Papenfuss, T.L., Cesta, M.F. (2017). Spleen. In: Parker, G. (eds) Immunopathology in Toxicology and Drug Development. Molecular and Integrative Toxicology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-47385-7_2
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