Clin. exp. Immunol. (1992) 89, 327-329
EDITORIAL REVIEW
The spleen? Who needs it anyway? M. HAZLEWOOD & D. S. KUMARARATNE* Department of Immunology, The Medical School, and *Dudley Road Hospital, Birmingham, UK
(Acceptedfor publication 9 July 1992)
That the spleen is not essential to life has been known for a long time. Nevertheless, in a seminal review of experimental splenectomy appearing in 1919, Morris & Bullock [1] concluded that splenectomy may result in an increased susceptibility to infection and that a splenectomized individual may not 'weather a critical illness' caused by bacterial sepsis. With the general decline in the incidence of bacterial sepsis in developed countries the subject has become of practical importance in the last decade of the present century, as evidenced by several major reviews on the subject recently published [2-4] and studies on the immunological consequences of splenectomy [5,6] including one [7] appearing in this issue of Clinical and Experimental Immunology. Asplenic individuals are at risk of developing fulminant sepsis caused most often by encapsulated bacteria. Streptococcus pneumoniae is the organism responsible for over half the cases of post-splenectomy sepsis, with mortality rates exceeding 50%. Haemophilus influenzae type b is the next commonest (67% of cases of sepsis) with case fatalities of 30% [2,8]. Infections caused by meningococci and Gram-negative bacteria have been reported, but the small number of cases makes it difficult to assess if there is a real increase in incidence
macrophages which remove parasitized erythrocytes from the circulation. To understand the consequences of splenectomy it is helpful to review the physiological role of the spleen. The spleen comprises two main compartments (i.e. the red pulp and the white pulp) and has three primary functions: (i) contribution to the specific immune responses (especially to antibody responses to polysaccharide antigens); (ii) filtration of effete blood corpuscles and circulating microbes; (iii) acting as a site of extramedullary haematopoiesis which is only important in fetal life and when medullary haematopoiesis is deficient. On entering the splenic hilum, the splenic artery branches repeatedly and the terminal arborizations are called the central arterioles of the white pulp. The splenic lymphoid tissue is concentrated around three central arterioles to form the socalled white pulp or malpighian corpuscles (see Fig. 1). The inner region of this lymphoid tissue is termed the periarteriolar lymphatic sheath (PALS) and is densely populated by small T lymphocytes. Also present are MHC class II antigen-rich, interdigitating reticulum cells (IRC). These IRCs can act as accessory cells for the initiation of T cell responses [15]. Aggregates of small recirculating, surface IgM, IgD, CD119, CD20, CD21 and CD23 positive B cells, filling the interstices of a network of follicular dendritic cells (FDC), are arranged at intervals at the periphery of the PALS, like sessile berries on the branches of a tree [16]. These so-called primary follicles also contain small numbers of CD4+ T cells and a minority population of surface IgM +, IgD- non-recirculating B cells [16]. Following exposure to T cell-dependent antigens (TD), B lymphoblasts enter the central region of these primary follicles which are rich in follicular dendritic cells with antigen-antibody complexes trapped on their surface. This displaces the nonparticipating B cells into the lymphocytic corona (or follicular mantle). The physiology of the germinal centre reaction has been reviewed elsewhere [16]; it serves to produce memory B cells and to select for high-affinity antigen-specific B cell clones. In humans, B cell follicles are surrounded by the marginal zone (MZ), which contains approximately one third of the splenic B cells [17]. MZ B cells have several distinctive features which differentiate them from follicular B cells. They are larger cells with less condensed nuclear chromatin ('vesicular nuclei') and more abundant pyroninophilic (RNA-rich) cytoplasm. They are surface (s) IgM+~, IgD- and express CD 19, CD2O, CD4O, CD25 and are uniformly negative for CD23 [18]. Before 2 years of age, human MZ B cells are CD2 1 (C3d, Epstein-Barr virus (EBV) receptor) negative [19]. Adult phenotype MZ cells
[2]. Healthy adults have the lowest risk of post-splenectomy sepsis ( < 1% per year) [9]. Infection rates are much higher in infants and children, with annual rates of up to 3%. Splenectomy in the presence of underlying diseases such as spherocytosis, thalassaemia, autoimmune cytopenias or Hodgkin's disease dramatically increases the risk of sepsis [2,8,10,11]. Splenic reticuloendothelial dysfunction occurring in sickle cell disease also results in increased risk of encapsulated bacterial sepsis, with rates in young children approaching 5% per year [12]. Infections are commonest in the first 2 years after splenectomy, but over a third occur more than 5 years later and cases have been recorded over 20 years after surgery [2,13]. Bacterial capsules inhibit phagocytosis. These anti-phagocytic effects can be overcome by opsonization with anti-capsular antibody and complement, following which the microbes can be engulfed and destroyed by circulating phagocytes or macrophages of the reticuloendothelial system. The absence of a spleen prejudices the control of parasitaemia in human and experimental malaria and babesiosis [14]. This is likely to be primarily due to the loss of splenic red pulp
Correspondence: D. S. Kumararatne, Dept. of Immunology, Dudley Road Hospital, Dudley Road, Birmingham B18 7QH, UK.
327
M. Hazlewood & D. S. Kumararatne
328
/R/
PF.
PAL
G_ \.: . -
\"'LC V / M MZ .
/ /
Fig. 1. The histological compartments of the splenic white pulp of man. CA, Central arteriole; PALS, periarteriolar lymphocytic sheath; PF, primary follicle; GC, germinal centre; LC, lymphocytic corona; MZ, marginal zone; RP, red pulp. (CD21 +, sIgM+, sIgD-) appear after this age. Thus there appears to be a coincidence between the slow ontogeny of antibody responses to polysaccharide antigens and the maturation of MZ B cells in human infants [19]. The MZ contains memory B cells generated during follicular B cell responses to protein (TD) antigens as well as B cells derived from bone marrow precursors that have not undergone antigen-driven expansion (virgin B cells) [18]. MZ cells do not recirculate [20] but can be induced to migrate into the outer PALS and the follicles following antigenic stimulation or injection with endotoxin [18]. The MZ cells are bathed in blood from a rich sinusoidal network which is fed directly by branches of the central arterioles. Antigens (and lymphoid cells) first enter the spleen via the MZ and the antigen-induced migration of B cells appears to be important for transport of antigen and human complexes to the interdigitating cells (IDC) and the FDC within the white pulp [18]. In mammals most mature T and B lymphocytes recirculate continuously between the blood, secondary lymphoid organs and the lymph. In the adult rat approximately 25% of the total recirculating lymphocyte pool resides in the spleen and only 5% is found in the blood [21]. In the rat within a few minutes after intravenous injection, labelled T and B cells localize in the splenic MZs from where T cells migrate into the PALS and B lymphocytes sweep through this area and enter the follicles. T lymphocytes leave the spleen after about 4-5 h, migrate into the red pulp and leave via the splenic vein. The transit time of B lymphocytes through the spleen is much longer (24 h). The magnitude of lymphocyte recirculation through the spleen exceeds that of all other lymphoid tissues together. The kinetics of lymphocyte migration through the human spleen are very similar and about half of all lymphocytes trafficking through the blood per day migrate through the spleen [22]. Therefore, it is not surprising that splenectomy increases mean transit time of blood lymphocytes and the number of B cells in the blood are increased [23]. Surprisingly, there may be a reduction in the total number of peripheral blood T cells (CD3 +,
^~
CD2+ cells) [3]. Since the blood only contains < 5% of the total lymphocyte pool, redistribution of lymphocytes which would otherwise traffic through the spleen is likely to cause profound changes in blood lymphocytes without significantly affecting in \vivo immunological competence. Thus in vitro studies using blood lymphocytes [7,24,25] are unlikely to provide particularly significant information. B cells resident within the MZ are able to respond to thymusindependent type 2 (TI-2) antigens, like bacterial capsular polysaccharides, unlike follicular or newly produced (virgin) B cells [16,18]. Hence removing this large reservoir of polysaccharide-responsive B cells by splenectomy may compromise antibody responses to bacterial capsular polysaccharides. Small numbers of B cells of the MZ phenotype are found in other lymphoid organs and these may increase with time, following splenectomy [26]. In animal models, splenectomy promotes TI-2 antibody responses in the MZ-equivalent areas of other lymphoid organs [27]. Nitrogen mustard and related cytotoxic agents like cyclophosphamide cause prolonged depletion of MZ B cells [28]. This may explain why chemotherapy for Hodgkin's disease causes prolonged depression of anti-polysaccharide antibody responses (see below). Splenic MZs also contain dendritic macrophages which can take up and retain neutral polysaccharides for long periods and they may provide a means of maintaining antibody reponses against these antigens which as a class (i.e. TI-2 antigens) do not induce germinal-centre reactions or B-memory cell generation. However, MZ macrophages do not take up acidic polysaccharides and their selective depletion does not eliminate TI-2 antibody responses [29]. The spleen is particularly important for clearing bacteria opsonized with complement alone, in the absence of high levels of antibody, while other reticuloendothelial organs like the liver can remove microbes opsonized by high concentrations of antibody and complement [30]. Most, though not all, asplenic adults who have no other associated illness have intact antibody responses to polysaccharide vaccines [31,32]. Antibody responses are more variable in children and are particularly reduced in patients with lymphoma who receive chemotherapy, especially together with radiotherapy [33]. The decline in pneumococcal antibodies following immunization may be significantly accelerated in asplenic individuals and re-vaccination may be required in 3-5 years [34]. While it is generally recommended that immunization with polysaccharide vaccines should precede elective splenectomy, immunization after splenectomy did not especially reduce antibody responses, except in those receiving chemotherapy. Monitoring antibody levels in splenectomized individuals at 6 monthly intervals would appear to be useful. Immunization does not provide complete protection from severe bacterial sepsis. A few cases of fulminant sepsis caused by pneumococcal serotypes included in the 23-valent vaccine have been reported in asplenic individuals despite prior vaccination [35]. Up to 15% of serious pneumococcal infections may be caused by serotypes not contained in the vaccine formulation [33]. Vaccine-induced antibody responses may not completely compensate for the lack of the splenic macrophage filter-bed. Hence oral penicillin (alternatively, Co-trimoxazole or Erythromycin, in penicillin-sensitive patients) should ideally be recoinmended in asplenic patients. Due to the large number of patients and the long term follow up required, a randomized controlled trial comparing vaccination and antibiotic prophylaxis with
The spleen? Who needs it? antibiotic prophylaxis alone or vaccination alone is unlikely to be carried out in the foreseeable future. Since compliance with routine long term antibiotic prophylaxis may be unreliable, patients should carry a letter detailing their susceptibility to infection and be instructed to seek prompt medical attention for febrile illnesses. They may also be given a supply of Amoxycillin or Co-trimoxazole to commence therapy while awaiting medical attention. Ideally asplenic patients should avoid travel to areas with drug-resistant Falciparum malaria and should pay scrupulous attention to anti-malarial prophylaxis when travelling to endemic areas. Clearly, the lack of a spleen, especially in the absence of underlying disease states like thalassaemia, is compatible with long periods of good health. However, these patients are at increased risk of developing, without warning, life threatening disease caused by encapsulated bacteria or blood-borne parasites. That the occurrence of such infections is sporadic is a testament to the efficiency of compensatory immune mechanisms and possibly also to infrequent exposure. The situation is analogous to the occasional occurrence of meningococcal disease in individuals with homozygous deficiency of a complement component. With the above considerations in mind, surgeons are well aware of the value of splenic salvage following traumatic rupture [36]. Where splenectomy cannot be avoided, the other precautionary measures detailed above are to be strongly recommended, arguably throughout life. In conclusion, the answer to the question in the title must be in the affirmative. REFERENCES 1 Morris DH, Bullock FD. The importance of the spleen in resistance to infection. Ann Surg 1919; 70:513-21. 2 Holdsworth RJ, Irving AD, Cuschieri A. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Surg 1991; 78:1031-8. 3 Kreuzfelder E, Obertacke U, Erhard J et al. Alterations of the immune system following splenectomy in childhood. J Trauma 1991; 31:358-64. 4 Styrt B. Infections associated with asplenia: risks, mechanisms and prevention. Am J Med 1990; 88:33N-42N. 5 Zimmerli W, Schaffner A, Scheidegger C, Scherz K, Spath PJ. Humoral immune response to pneumococcal antigen 23F in an asplenic patient with recurrent fulminant pneumococcaemia. J Infect 1991;22:59-69. 6 McElroy PJ, Henderson F, Brown DL. Immune status and response to Immunisation with polysaccharide vaccines of a healthy congenitally asplenic woman. Clin Exp Immunol 1989; 78:402-5. 7 Foster PM, Trejdosiewicz LK. Impaired proliferative responses of peripheral blood B cells from splenectomized subjects to phorbol ester and ionophore. Clin Exp Immunol 1992; 89:369-73. 8 Singer D. Postsplenectomy sepsis. Perspectives. Paediatr Pathol 1973; 1:285-311. 9 Robinette CD, Fraumeni JF Jr. Splenectomy and subsequent mortality in veterans in the 1939-45 war. Lancet 1977; fi:127-9. 10 Constantoulakis M, Economopoulos P. Constantopoulos A. infections after splenectomy. Ann Int Med 1973; 78:780-1. 11 Notter DT, Crossman PL, Rosenburg SA, Remongton JS. Infections in patients with Hodgkin's Disease. Rev Infect Dis 1980; 2:761800. 12 Powars D. Overturf G, Turner E. Is there an increased risk of Haemophilus influenzae septicaemia in children with Sickle cell anaemia? Paediatrics 1983; 71:927-31. 13 White BP, Aanning HL. Overwhelming postsplenectomy sepsis twenty two years after operation: risks, managment and prevention. SDJ med 1991; 44:317-20.
329
14 Shute PG. Splenectomy and susceptibility to malaria and babesia infection. Br Med J 1975; 1:516. 15 Fossum S, Rolstead N, Ford WL. Thymus dependance, kinetics and phagocytic ability of interdigitating cells. Immunobiology 1984; 168:403. 16 MacLennan ICM, Liu YJ, Oldfield S, Zhang J, Lane PJL. The evolution of B cell clones. Curr Top Microbiol Immunol 1990; 159:37-63. 17 Kumararatne DS, Bazin H, MacLennan ICM. Marginal zones: the major B cell compartment in rat spleens. Eur J Immunol 1981; 11:858. 18 MacLennan ICM, Liu Y-J. Marginal zone B cells respond to both polysaccharide antigens and protein antigens. Res Immunol 1991; 142:346-51. 19 Timens W, Boes A, Rozeboom-Uiterwijk T, Poppema S. Immaturity of human splenic marginal zone in infancy. J Immunol 1989; 143:3200-6. 20 Kumararatne DS, MacLennan ICM. Cells of the marginal zone of the spleen are derived from recirculating precursors. Eur J Immunol 1981; 11:865-9. 21 Ford WL. Lymphocyte migration and immune responses. Prog allergy 1975; 19:1-21. 22 Pabst R. The spleen in lymphocyte migration. Immunol Today 1988; 9:43-5. 23 Durig M, Landmann RMA, Harder F. Lymphocyte subsets in human peripheral blood after splenectomy and autotransplantation of splenic tissue. J Lab Clin Med 1984; 104:110-5. 24 Drew PA, Kiroff GK, Ferranti A, Cohen RC. Alterations in immunoglobulin synthesis by peripheral blood mononuclear cells from splenectomised patients with and without splenic regrowth. J Immunol 1984; 132:191-6. 25 DiPadova F, Durig M, Harder F, DiPadova C. Zanuussi C. Impaired antipneumococcal antibody production in patients without spleens. Br Med J 1985; 290:14-16. 26 Gray D, Chassoux D, MacLennan 1CM, Bazin H. Selective depression of thymus independent anti-DNP antibody responses induced by adult but not neonatal splenectomy. Clin Exp Immunol 1985; 60:78. 27 Liu Y-J, Oldfield S, MacLennan ICM. Thymus independent type 2 responses in lymph nodes. Adv Exp Biol Med 1989; 237:113. 28 Kumararatne DS, Gagnon RF, Smart Y. Selective loss of large lymphocytes from the marginal zones of the white pulp in rat spleens following a single dose of cyclophosphamide-a study using quantitative histological methods. Immunology 1980; 40:123. 29 Kraal G, Ter Hart H, Meelhuizen C et al. Marginal zone macrophages and their role in immune response against T-independant type 2 antigens: modulation of cells with specific antibody. Eur J Immunol 1989; 19:675-80. 30 Hosea SW, Brown EJ, Hamburger M, Frank MM. Opsonic requirements for intravascular clearance after splenectomy. New Eng J Med, 1981; 304:245-50. 31 Sullivan JL, Ochs HD, Schiffmann G et al. Immune response after splenectomy. Lancet 1978; i:178-81. 32 Hosea SW, Burch CG, Brown EJ, Berg RA, Frank MM. Impaired immuneresponse of splenectomised patients to polyvalent pneumococcal vaccine. Lancet 1981; 1:804-7. 33 Siber GR, Gorham C, Marten P, Corkery J, Schiffmann G. Antibody response to pre-treatment immunisation and post-treatment boosting with bacterial polysaccharide vaccines in patients with Hodgkin's disease. Ann Int Med 1980; 104:467-75. 34 Konradson HB, Pederson FK, Henrichsen J. Pneumococcal revaccination of splenectomised children. Paediatr Infect Dis J 1990; 9:258-63. 35 Sumaya CV, Harbison RW, Bretton HA. Pneumococcal vaccination failures. Ann J Dis Child 1981; 135:155-8. 36 Hansen VA, Johnson MB, Rappaport WD. Splenic salvage vs splenectomy. Care of the trauma patient. AORN-J 1991; 53:1519-
2.8.
EDITORIAL REVIEW
The spleen? Who needs it anyway? M. HAZLEWOOD & D. S. KUMARARATNE* Department of Immunology, The Medical School, and *Dudley Road Hospital, Birmingham, UK
(Acceptedfor publication 9 July 1992)
That the spleen is not essential to life has been known for a long time. Nevertheless, in a seminal review of experimental splenectomy appearing in 1919, Morris & Bullock [1] concluded that splenectomy may result in an increased susceptibility to infection and that a splenectomized individual may not 'weather a critical illness' caused by bacterial sepsis. With the general decline in the incidence of bacterial sepsis in developed countries the subject has become of practical importance in the last decade of the present century, as evidenced by several major reviews on the subject recently published [2-4] and studies on the immunological consequences of splenectomy [5,6] including one [7] appearing in this issue of Clinical and Experimental Immunology. Asplenic individuals are at risk of developing fulminant sepsis caused most often by encapsulated bacteria. Streptococcus pneumoniae is the organism responsible for over half the cases of post-splenectomy sepsis, with mortality rates exceeding 50%. Haemophilus influenzae type b is the next commonest (67% of cases of sepsis) with case fatalities of 30% [2,8]. Infections caused by meningococci and Gram-negative bacteria have been reported, but the small number of cases makes it difficult to assess if there is a real increase in incidence
macrophages which remove parasitized erythrocytes from the circulation. To understand the consequences of splenectomy it is helpful to review the physiological role of the spleen. The spleen comprises two main compartments (i.e. the red pulp and the white pulp) and has three primary functions: (i) contribution to the specific immune responses (especially to antibody responses to polysaccharide antigens); (ii) filtration of effete blood corpuscles and circulating microbes; (iii) acting as a site of extramedullary haematopoiesis which is only important in fetal life and when medullary haematopoiesis is deficient. On entering the splenic hilum, the splenic artery branches repeatedly and the terminal arborizations are called the central arterioles of the white pulp. The splenic lymphoid tissue is concentrated around three central arterioles to form the socalled white pulp or malpighian corpuscles (see Fig. 1). The inner region of this lymphoid tissue is termed the periarteriolar lymphatic sheath (PALS) and is densely populated by small T lymphocytes. Also present are MHC class II antigen-rich, interdigitating reticulum cells (IRC). These IRCs can act as accessory cells for the initiation of T cell responses [15]. Aggregates of small recirculating, surface IgM, IgD, CD119, CD20, CD21 and CD23 positive B cells, filling the interstices of a network of follicular dendritic cells (FDC), are arranged at intervals at the periphery of the PALS, like sessile berries on the branches of a tree [16]. These so-called primary follicles also contain small numbers of CD4+ T cells and a minority population of surface IgM +, IgD- non-recirculating B cells [16]. Following exposure to T cell-dependent antigens (TD), B lymphoblasts enter the central region of these primary follicles which are rich in follicular dendritic cells with antigen-antibody complexes trapped on their surface. This displaces the nonparticipating B cells into the lymphocytic corona (or follicular mantle). The physiology of the germinal centre reaction has been reviewed elsewhere [16]; it serves to produce memory B cells and to select for high-affinity antigen-specific B cell clones. In humans, B cell follicles are surrounded by the marginal zone (MZ), which contains approximately one third of the splenic B cells [17]. MZ B cells have several distinctive features which differentiate them from follicular B cells. They are larger cells with less condensed nuclear chromatin ('vesicular nuclei') and more abundant pyroninophilic (RNA-rich) cytoplasm. They are surface (s) IgM+~, IgD- and express CD 19, CD2O, CD4O, CD25 and are uniformly negative for CD23 [18]. Before 2 years of age, human MZ B cells are CD2 1 (C3d, Epstein-Barr virus (EBV) receptor) negative [19]. Adult phenotype MZ cells
[2]. Healthy adults have the lowest risk of post-splenectomy sepsis ( < 1% per year) [9]. Infection rates are much higher in infants and children, with annual rates of up to 3%. Splenectomy in the presence of underlying diseases such as spherocytosis, thalassaemia, autoimmune cytopenias or Hodgkin's disease dramatically increases the risk of sepsis [2,8,10,11]. Splenic reticuloendothelial dysfunction occurring in sickle cell disease also results in increased risk of encapsulated bacterial sepsis, with rates in young children approaching 5% per year [12]. Infections are commonest in the first 2 years after splenectomy, but over a third occur more than 5 years later and cases have been recorded over 20 years after surgery [2,13]. Bacterial capsules inhibit phagocytosis. These anti-phagocytic effects can be overcome by opsonization with anti-capsular antibody and complement, following which the microbes can be engulfed and destroyed by circulating phagocytes or macrophages of the reticuloendothelial system. The absence of a spleen prejudices the control of parasitaemia in human and experimental malaria and babesiosis [14]. This is likely to be primarily due to the loss of splenic red pulp
Correspondence: D. S. Kumararatne, Dept. of Immunology, Dudley Road Hospital, Dudley Road, Birmingham B18 7QH, UK.
327
M. Hazlewood & D. S. Kumararatne
328
/R/
PF.
PAL
G_ \.: . -
\"'LC V / M MZ .
/ /
Fig. 1. The histological compartments of the splenic white pulp of man. CA, Central arteriole; PALS, periarteriolar lymphocytic sheath; PF, primary follicle; GC, germinal centre; LC, lymphocytic corona; MZ, marginal zone; RP, red pulp. (CD21 +, sIgM+, sIgD-) appear after this age. Thus there appears to be a coincidence between the slow ontogeny of antibody responses to polysaccharide antigens and the maturation of MZ B cells in human infants [19]. The MZ contains memory B cells generated during follicular B cell responses to protein (TD) antigens as well as B cells derived from bone marrow precursors that have not undergone antigen-driven expansion (virgin B cells) [18]. MZ cells do not recirculate [20] but can be induced to migrate into the outer PALS and the follicles following antigenic stimulation or injection with endotoxin [18]. The MZ cells are bathed in blood from a rich sinusoidal network which is fed directly by branches of the central arterioles. Antigens (and lymphoid cells) first enter the spleen via the MZ and the antigen-induced migration of B cells appears to be important for transport of antigen and human complexes to the interdigitating cells (IDC) and the FDC within the white pulp [18]. In mammals most mature T and B lymphocytes recirculate continuously between the blood, secondary lymphoid organs and the lymph. In the adult rat approximately 25% of the total recirculating lymphocyte pool resides in the spleen and only 5% is found in the blood [21]. In the rat within a few minutes after intravenous injection, labelled T and B cells localize in the splenic MZs from where T cells migrate into the PALS and B lymphocytes sweep through this area and enter the follicles. T lymphocytes leave the spleen after about 4-5 h, migrate into the red pulp and leave via the splenic vein. The transit time of B lymphocytes through the spleen is much longer (24 h). The magnitude of lymphocyte recirculation through the spleen exceeds that of all other lymphoid tissues together. The kinetics of lymphocyte migration through the human spleen are very similar and about half of all lymphocytes trafficking through the blood per day migrate through the spleen [22]. Therefore, it is not surprising that splenectomy increases mean transit time of blood lymphocytes and the number of B cells in the blood are increased [23]. Surprisingly, there may be a reduction in the total number of peripheral blood T cells (CD3 +,
^~
CD2+ cells) [3]. Since the blood only contains < 5% of the total lymphocyte pool, redistribution of lymphocytes which would otherwise traffic through the spleen is likely to cause profound changes in blood lymphocytes without significantly affecting in \vivo immunological competence. Thus in vitro studies using blood lymphocytes [7,24,25] are unlikely to provide particularly significant information. B cells resident within the MZ are able to respond to thymusindependent type 2 (TI-2) antigens, like bacterial capsular polysaccharides, unlike follicular or newly produced (virgin) B cells [16,18]. Hence removing this large reservoir of polysaccharide-responsive B cells by splenectomy may compromise antibody responses to bacterial capsular polysaccharides. Small numbers of B cells of the MZ phenotype are found in other lymphoid organs and these may increase with time, following splenectomy [26]. In animal models, splenectomy promotes TI-2 antibody responses in the MZ-equivalent areas of other lymphoid organs [27]. Nitrogen mustard and related cytotoxic agents like cyclophosphamide cause prolonged depletion of MZ B cells [28]. This may explain why chemotherapy for Hodgkin's disease causes prolonged depression of anti-polysaccharide antibody responses (see below). Splenic MZs also contain dendritic macrophages which can take up and retain neutral polysaccharides for long periods and they may provide a means of maintaining antibody reponses against these antigens which as a class (i.e. TI-2 antigens) do not induce germinal-centre reactions or B-memory cell generation. However, MZ macrophages do not take up acidic polysaccharides and their selective depletion does not eliminate TI-2 antibody responses [29]. The spleen is particularly important for clearing bacteria opsonized with complement alone, in the absence of high levels of antibody, while other reticuloendothelial organs like the liver can remove microbes opsonized by high concentrations of antibody and complement [30]. Most, though not all, asplenic adults who have no other associated illness have intact antibody responses to polysaccharide vaccines [31,32]. Antibody responses are more variable in children and are particularly reduced in patients with lymphoma who receive chemotherapy, especially together with radiotherapy [33]. The decline in pneumococcal antibodies following immunization may be significantly accelerated in asplenic individuals and re-vaccination may be required in 3-5 years [34]. While it is generally recommended that immunization with polysaccharide vaccines should precede elective splenectomy, immunization after splenectomy did not especially reduce antibody responses, except in those receiving chemotherapy. Monitoring antibody levels in splenectomized individuals at 6 monthly intervals would appear to be useful. Immunization does not provide complete protection from severe bacterial sepsis. A few cases of fulminant sepsis caused by pneumococcal serotypes included in the 23-valent vaccine have been reported in asplenic individuals despite prior vaccination [35]. Up to 15% of serious pneumococcal infections may be caused by serotypes not contained in the vaccine formulation [33]. Vaccine-induced antibody responses may not completely compensate for the lack of the splenic macrophage filter-bed. Hence oral penicillin (alternatively, Co-trimoxazole or Erythromycin, in penicillin-sensitive patients) should ideally be recoinmended in asplenic patients. Due to the large number of patients and the long term follow up required, a randomized controlled trial comparing vaccination and antibiotic prophylaxis with
The spleen? Who needs it? antibiotic prophylaxis alone or vaccination alone is unlikely to be carried out in the foreseeable future. Since compliance with routine long term antibiotic prophylaxis may be unreliable, patients should carry a letter detailing their susceptibility to infection and be instructed to seek prompt medical attention for febrile illnesses. They may also be given a supply of Amoxycillin or Co-trimoxazole to commence therapy while awaiting medical attention. Ideally asplenic patients should avoid travel to areas with drug-resistant Falciparum malaria and should pay scrupulous attention to anti-malarial prophylaxis when travelling to endemic areas. Clearly, the lack of a spleen, especially in the absence of underlying disease states like thalassaemia, is compatible with long periods of good health. However, these patients are at increased risk of developing, without warning, life threatening disease caused by encapsulated bacteria or blood-borne parasites. That the occurrence of such infections is sporadic is a testament to the efficiency of compensatory immune mechanisms and possibly also to infrequent exposure. The situation is analogous to the occasional occurrence of meningococcal disease in individuals with homozygous deficiency of a complement component. With the above considerations in mind, surgeons are well aware of the value of splenic salvage following traumatic rupture [36]. Where splenectomy cannot be avoided, the other precautionary measures detailed above are to be strongly recommended, arguably throughout life. In conclusion, the answer to the question in the title must be in the affirmative. REFERENCES 1 Morris DH, Bullock FD. The importance of the spleen in resistance to infection. Ann Surg 1919; 70:513-21. 2 Holdsworth RJ, Irving AD, Cuschieri A. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Surg 1991; 78:1031-8. 3 Kreuzfelder E, Obertacke U, Erhard J et al. Alterations of the immune system following splenectomy in childhood. J Trauma 1991; 31:358-64. 4 Styrt B. Infections associated with asplenia: risks, mechanisms and prevention. Am J Med 1990; 88:33N-42N. 5 Zimmerli W, Schaffner A, Scheidegger C, Scherz K, Spath PJ. Humoral immune response to pneumococcal antigen 23F in an asplenic patient with recurrent fulminant pneumococcaemia. J Infect 1991;22:59-69. 6 McElroy PJ, Henderson F, Brown DL. Immune status and response to Immunisation with polysaccharide vaccines of a healthy congenitally asplenic woman. Clin Exp Immunol 1989; 78:402-5. 7 Foster PM, Trejdosiewicz LK. Impaired proliferative responses of peripheral blood B cells from splenectomized subjects to phorbol ester and ionophore. Clin Exp Immunol 1992; 89:369-73. 8 Singer D. Postsplenectomy sepsis. Perspectives. Paediatr Pathol 1973; 1:285-311. 9 Robinette CD, Fraumeni JF Jr. Splenectomy and subsequent mortality in veterans in the 1939-45 war. Lancet 1977; fi:127-9. 10 Constantoulakis M, Economopoulos P. Constantopoulos A. infections after splenectomy. Ann Int Med 1973; 78:780-1. 11 Notter DT, Crossman PL, Rosenburg SA, Remongton JS. Infections in patients with Hodgkin's Disease. Rev Infect Dis 1980; 2:761800. 12 Powars D. Overturf G, Turner E. Is there an increased risk of Haemophilus influenzae septicaemia in children with Sickle cell anaemia? Paediatrics 1983; 71:927-31. 13 White BP, Aanning HL. Overwhelming postsplenectomy sepsis twenty two years after operation: risks, managment and prevention. SDJ med 1991; 44:317-20.
329
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