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Home , Spleen, Trabecular arteries, Trabecular veins

Functions of in Health and Disease

Bichitra N. Nayak a, Harpal S. Buttar b* a Departments of Human Nutritional Sciences, , Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada, R3T 2N2. b Department of & Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ontario, Canada. K1H 8M5.

ABSTRACT Spleen is a capsulated and compartmentalized lymphoid with a complex vascular and cellular organization. It develops from dorsal mesogastrium. The spleen performs a number of physiological functions namely, phagocytosis of aging erythrocytes and , recycling iron, inducing immune response against antigens, and defending against invading bacteria, fungi, viruses, prions and otherinfective agents. Because thespleen has only the efferent lymphatic vessels, it is therefore, involved in the filtration of blood but not lymph. The splenic functions can be affected by immune suppressant drugs, and biological products, chemo- and radiation-therapy, resulting in and thrombocytopenia (reduced number of platelets). Recently, it has been shown that the splenic play a significant role in the regeneration of tissue following a heart attack.

Keywords: Spleen structure and function, splenic blood circulation, immune functions of spleen, splenomegally splenic plexus pass through the hilus, which is a depressed area in the capsule [1, Introduction 2, 3]. The spleen is an organ which not only The spleen is located in the left effectively uses its own immune cells but hypochondriac region of between also mobilizes the body’s immune cells for the fundus of the and diaphragm. immune surveillance and protecting other In humans, it is about 12 cm long, 7 cm vital organs including heart, and wide, and 3 cm in thickness, and weighs brain [4, 5, 6, 7]. The cells which play an around 150-250 g. The splenic , important role in spleen functions are splenic , efferent lymphatic vessels and , monocytes, natural killer (NK) cells, and B- and T cells. The spleen *Corresponding author: is prone to physical , , and Harpal S. Buttar, D.V.M., Ph.D, various immunological conditions including Department of Pathology & Laboratory . Enlargement of spleen or Medicine, Faculty of Medicine, 451 Smyth splenomegaly may occur due to anaemia, Road, Ottawa, Ontario, Canada K1H 8M5 infections, inflammation, , E-mail: [email protected]. metabolic disorders, and diseases. Telephone: 613-824-1532 Anatomic structural organization of spleen The spleen has four important structures, viz., capsule, (RP), (WP) and (MZ) (Figure 1).

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Each area shows uniquemorphological The follicles not onlycontain B cells but structure and is involved also T cells, which are found adjacent to the inperformingspecific physiological PALS. Significant immunological activities functions. The capsule contains dense and cell trafficking and cross talk between connective tissues, elastic and smooth various immune cells occur. Bordering the muscle fibres, and sympathetic nerve fibres PALS and the follicles is the marginal zone from the splenic nerve plexus. The RP (MZ) which has few but contains numerous sinuses which are filled numerous macrophages and antigen with blood, rich in platelets. Between the presenting cells (APCs). Immunological sinuses, spongy cellular cords (cords of activation of B cells occurs in the MZ as a Billroth), made up of reticular fibres and result of antigenic encounter [9]. Many reticular cells intermingled with a number lymphocytes in MZ migrate into respective of immune cells, such as macrophages, T- and B area. The MZ contains the highest monocytes, , B cells, T cells concentration of blood antigens than any and plasma cells are found. Several RP other area in the spleen because splenic specific functions occur in the spleen arterial blood empties to the MZ. Marginal including blood filtration, antigenic zone B cells show somatic hypermutation, stimulation and proliferation of B and T clonal expansion [10] and positive cells and production of of selection [11]. B cell clonal expansion also different specifications. RP constitutes occurs in the germinal centre of the B cell about 70 % of the total splenic volume in follicle following antigenic stimulation. adult. The WP is a rich area which contains periarterial lymphatic Blood supply and lymphatic organization sheath (PALS) around the arterial vessels Figure 1 illustrates the spleen’s anatomical particularly around the central artery and features. An important feature of spleen's central , follicles and loose central artery and arterioles is that these lymphatic tissues. The PALS is a sheath of vessels show periarterial lymphatic sheath lymphocytes mostly CD4 + T cells that envelope the central arterial vessels [8].

Fig. 1. Illustration of the anatomical structures of spleen (PALS) which contains predominantly plasma cells, interdigitating dendritic cells CD4 +T cells, some CD8 + cells, APCs, and fibroblastic reticular cells. The splenic

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microcirculation and lymphatic marginal sinus at the junction of the white organization is presented in Table 1. Spleen pulp and the marginal zone, others gets its blood supply through splenic artery terminate within the marginal zone, and a and removes blood through splenic vein few extend beyond the white pulp and lymph via efferent lymphatic vessels. toterminate in the red pulp [13, 14, 15]. As Lymph carries APCs, T cells, B cells, the central arterioles continue, the white cytokines, chemokines, growth factors and pulp wanes and they become the penicillar peptide hormones.Following the filtration surrounded by red pulp. Blood from of RBCs, the mature B- and T-cells and the red pulp collects in the venous sinuses plasma are transported via splenic vein to which enter the trabeculae and merge into the general circulation. the trabecular . The differentiated B cells, differentiated then converge at the hilus to form the T cells, RBCs, platelets, and blood antigens splenic vein which drains into the hepatic enter thespleen through splenic artery. portal system [1, 3]. Blood from terminal Venous blood from sinusoids is emptied (arterioles) directly enter to through the trabecular vein, then to the venous sinus (closed circulation) or enter to splenic vein, and eventually to the inferior the splenic cords, then to sinus (open vena cava. The splenic artery divides into circulation). In humans open venous located within the circulation in spleen is favoured [1, 16]. trabeculae entering the splenic parenchyma. The trabecular artery gives off central Antigenic exposure and B cell clonal artery. The central artery branches out as expansion central arterioles. These arterioles provide Bone marrow derived naïve B cells enter blood to the WP (Table 1). Central through the central artery to the PALS, MZ arterioles are surrounded by sheaths of and to the GC of the follicle. The naive B lymphoid tissues (PALS) at different point cells under the influence of antigen become [12]. Some of these terminate in the activated and undergo clonal expansion.

Table 1. Splenic Blood Circulation Branches of splenic Supply to Characteristic PALS artery Mostly to red pulp, and A very narrow sheath of Trabecular artery also to white pulp lymphocytes Red pulp, white pulp, Heavily sheathed with Central artery/ germinal centre, mantle lymphocytes; (PALS) zone Penicillar Red pulp Very few lymphocytes artery/arteriole

Heavy sheathing with Sheathed arteriole lymphocytes, platelets, (Ellipsoids) Red pulp macrophages Lymphocytes, Terminal capillaries Red pulp and MZ macrophages, plasma cells, RBCs These B cells may undergo somatic and immunoglobulin (Ig) locus. They can hypermutation at the B cell receptor (BCR) also undergo class switchfrom IgM to IgG.

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Some B cells with complementary receptor affinity plasma cells which produce to antigenic epitope transform intoplasma antibodies of certain specificities. Some of cells while others may become memory B theGC-derivedB cells tend to become cells. The long-term survival, growth and memory B cells and not plasma cells [18, differentiation of selected B cell clones are 19]. These cells are capable of becoming thought to be dependent on stimulation by plasma cells only on subsequent exposure antigens and stromal cells. B cells that to antigens. These processes require the encounter blood antigens complementary to participation of stromal cells as well as their receptors develop into CD4 + T cells. Activated T-helper cells (on plasma cells and plasma cells produce exposure to antigens and also B cells) antigen specific antibody. CD4 +T cells secrete a number of cytokinessuch as IL1, actas supporting cells for growth and IL4, IL5, and IL6. These cytokines promote differentiation of B cells. CD4 +T cells and B cell proliferation and differentiation. In CD8 + T cells are found in various parts of addition to the B cells, T cells, NK cells, the spleen [8]. Majority of T cells in spleen spleen shows compartment and function are CD4 + T cells. Most of CD4 +cells are specific macrophages particularly those found in PALS, splenic cords, marginal found in the marginal zone [5]. The splenic zone, and marginal sinuses and in the monocytes are also actively involved in periphery of follicles. B cells are found in processes associated with tissue thefollicles, marginal zone, and splenic regeneration such as angiogenesis and cords. The B cells found in MZ are tissue vasculogenesis, either by producing pro- specific and are non-migratory (non- angiogenic factors or even by evolving to circulatory). However, some published data structural components of the vascular wall show that human MZ B cells are circulatory [5]. The spleen contains heterogeneous [17]. population of macrophages varying in morphological structures, biochemical and Role of immune cells in splenic functions immunological properties [5]. Some of The spleen not only produces and brings these cells perform phagocytic functions, together the function of various immune while others act as antigen presenting cells cells, but also helps the body to maintain (APCs) and participate in generating the normalquality of blood, consequently immune response. Those which act as protecting from adverse effects of blood APCs carry MHC II molecules on their cell borne antigens and infective agents that receptors. may cause harm to the other organs. Following antigenic stimulation, T helper Spleen-related immune response cells secrete cytokines which regulate the Antigens enter to the MZ through marginal differentiation of T helper cells to T 1 and T 2 sinus. The MZ lies between red pulp and helper cells. The naive B cells from the white pulp, and containshigh concentrations bone marrow enter germinal centre (GC), of blood antigensas the central arterioles and under the influence of IL-21 GC- empty blood to the MZ. The MZ has a derived B cells transform into plasmoblasts, unique group of B cells. The marginal zone and then become mature B cells. Germinal B cells are non-circulatory (in centres are the central core of follicles both rodents)/circulatory (in humans) and need in the primary and secondary follicles. In Notch 2 and other signalling molecules for GC, B cells following antigenic exposure proliferation. Antigens enter germinal undergo B cell maturation, Beta Cell centres through the marginal sinus. The Receptor (BCR) organization and genetic fenestrated nature of the marginal sinus recombination. Mature B cells become high facilitates the entry of blood-borne antigens

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into the MZ. A selection process for B cells such as Gaucher’s disease, liver disease, occurs in the MZ that have high affinity for and sickle cell anaemia. antigens in question.A activity of APCs, CD4 + T cells and B cellsto the antigen triggers an immune response. Some MZ-derived B cells can act as APCs after getting signals from B cell receptor but most of the APCs are macrophages or dendritic cells.

Pathophysiology of spleen:

Fig. 3. Heavy cellular infiltration of lymphocytes in the (MZ) of spleen due to lymphoma of splenic MZ. Source: Google One of the most common causes of splenomegaly is portal hypertension with hepatic . Splenic infarcts may occur as a consequence of patients with endocarditis. Congenital absence of spleen, Fig. 2. Histology of normal human or surgical removal of spleen predisposes spleen. Source: Google an individual to infections, particularly with

capsulated bacterial organism such as As discussed earlier, one important function pneumococcus. In the fetal life, the spleen of the spleen is to maintain the normal functions temporarily as a hematopoietic quality of blood. Spleen plays a major role organ, whereas in post-natal life it acts as in the prevention of certain diseases such as lymphoid organ and graveyard for red , sickle cell , , blood cells. There are some differences in pernicious anemia, Hodgkin’s disease, the cellular composition of spleen between mononucleosis, Epstein-Barr virus young compared to adults. B cells in the and . The spleen may show spleen of lack CD 21; IgD – and IgM pathological changes [20] due to a variety + compared with adult marginal zone B of causes, wheresplenomegaly becomes a cells. In rare cases (< 10 %), an accessory major clinical diagnosis concern. spleen may be found without any apparent Enlargement of spleen may occur due to a pathological implications. wide variety of causes such as: bacterial,

viral and malarial infections, Effects of immunosuppressants on mononucleosis, toxoplasmosis, splenic function endocarditis, leukemia and lymphoma of Certain immunosuppressant drugs (e.g. spleen, Hodgkin’slymphoma, follicular glucocorticoids), vaccines and biological lymphoma of spleen, chronic myelogenous agents, administration of antibodies and leukemia, chronic lymphocytic leukemia, antibiotics as well as chemo- and radiation- , splenic MZ lymphoma, therapy may cause either splenomegaly certain inflammatory diseases, such as and/or thrombocytopenia (reduced number rheumatoid arthritis, lysosomal diseases

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of platelets) which may lead to bleeding [7] S.M. Hamza, and S. Kaufman. Role of problems. spleen in integrated control of splanchnic vascular tone: physiology Conclusion and pathophysiology. Can J Physiol. The spleen has a very complex lymphatic and Pharmacol. 87(1), (2009), 1-7 and vascular organization. It is an organ [8] B.N. Nayak, J.K. Friel, C.B. Rempel, with multiple functions. Although its and P.J. Jones. Energy-restricted diets primary functions are to filter blood and result in higher numbers of CD4 +, CD8 protect body from invading pathogens and +, immunoglobulin (A, M, G), and antigens, it also plays a significant role in CD45 RA cells in spleen, and CD4 +, maintaining the immunologic homeostasis immunoglobulin A, and CD45RA cells and tissue regeneration processes.When in colonic lamina propia. Nutrition Res. spleen is surgically removed due to the 29 (7)(2009), (2012), 487-493 pathological conditions, Kupffer cells from [9] A.Cerutti. M.Cols, and I. Puga. the liver may act as phagocytic cells to Marginal zone B cells: virtues of innate remove aging RBCs from the circulation like antibodyproducing lymphocytes. with limited capacity. Nat. Rev. Immunol. 13 (2), (2013), 118-132 Conflict of interest [10] A.Tierens, J. Delabie, L. Michiels et The authors have no conflict of interest, al. Marginal zone B cells in the human financial or personal. and spleen show somatic hypermutations and display clonal References expansion. Blood 93(1), (1999), 226- [1] Gray’s : The Anatomical 234 Basis of Clinical Practice. Editor- in - [11] L.Wen, J. Brill-Dashoff, Chief S. Standring, 2008. Churchill S.A.Shinton, M.Asano, R.R. Hardy, K. Livingstone, Elsevier, pp.1192-5 Hayakawa. Evidence of marginal zone [2] Fawcett, D.W. & Jensh R.P. (2002). B cells-positive selection in spleen. Bloom & Fawcett’s Concise Histology, Immunity 23, (2005), 297-3008. nd 2 edition,Arnold, New York. pp. 159- [12] R. Satodate, H.Tanaka, S.Sasou, 61 T.Sakuma and H. Kaizuka. Scanning [3] Guyton A.C. and Hall J.E. (2006). Text electron microscopical studies of the book of Medical Physiology. Elsevier arterial terminals in the red pulp of the Saunders.pp. 180, 440 rat spleen. Anat Rec 215(3), (1986), [4] R.E.Mebius and G.Kraal. Structure and 214–6. function of the spleen. Nat. Rev. [13] J.C.Weill., S.Weller, and Immunol. 5(8),(2005), 606–16. C.A.Reynaud. Human marginal zone B [5] J.M. den Haan and G. Kraal. Innate cells. Annu Rev Immunol. 27 (2009), immune functions of 267–285. subpopulations in the spleen. J of [14] C.D. Dijkstra, A.J.P.Veerman. In Innate Immunity 4(5-6), (2012), 437- Monogrphs on Pathology of Laboratory 445 Animals:Hemopoietic System, Normal [6] X. Zhao, N. Wu, and L. Huang. Anatomy, Histology, Ultrastructure, Endothelial progenitor cells and spleen: Rat, eds. Jones T,Ward J.M., Mohr U, New insights in regeneration medicine. and Hunt RD. Springer- Verlag, Berlin, Cytotherapy, 12(1), (2010), 7-16 (1990) pp. 185-193.

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[15] M.F. Cesta. Normal structure, [18] Seifert M., and R.Kuppers. Functions, and Histology of Spleen. Molecular footprints of a germinal Toxicologic Pathology 34(5), (2006), center derivation of human IgM+ 455-465. (IgD+) CD27+ B cells and the [16] B.Steiniger, M. Bette, and H. dynamics of generation. Schwarzbach. The open J Exp Med. 206(12), (2009), 2659– microcirculation in human : a 2669. three dimentional approach. J [19] S.G.Tangye, K.L.Good. Human Histochem Cytochem. 59(6), (2011), IgM+CD27+ B cells: memory B cells 639-648 or “memory” B cells J Immunol. [17] S. Weller, M.C. Braun, B.K.Tan, A. 179(1), (2007), 13–19. Rosenwald, C. Cordier, M.E. Conleyet [20] B. Baron, &J.M.Baron. Disorders of al. Human blood IgM “memory” B spleen: Pathophysiology & cells are circulating splenic marginal Management. JAMA 263(3), (1990), zone B cells harbouring aprediversified 462 immunoglobulin repertoire. Blood. 104(12), (2004), 3647–3654.

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