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Chapter 160 The Spleen and Its Disorders 2317

platelets and leukocytes are not removed by the spleen as they age Expression of all these homeostatic chemokines is reduced when
but adhere to vessel walls and migrate into tissues where they die. signaling through the lymphotoxin receptor or tumor necrosis factor
Pitting refers to the removal of inclusions from within erythrocytes, (TNF)-α receptor 1 is absent, which results in disorganization of the
which are then released back into the circulation. The erythrocyte domains of the white pulp.
membrane is in close apposition to the macrophage membrane so
that aged or damaged glycoproteins, antibody, or complement on the
surface of the cell are easily recognized and activate phagocytosis. Marginal Zone
Particulate matter—Howell-Jolly bodies, Heinz bodies, Pappen-
heimer bodies, and malarial and other parasites—are removed and Similar to the migration of leukocytes across endothelial barriers in
the cell returned to the bloodstream. If membrane-containing inflammation, leukocytes leave the bloodstream and enter the white
adsorbed antibody is present, it is removed and the remainder of the pulp in the marginal zone of the spleen via the function of G
cell is released with changes in shape and volume. Internal vesicles protein–coupled receptors. The marginal zone is an area for cells in
near the erythrocyte membrane appear as if they were on the surface transit as well as home to resident cells with complex interactions.
of the cell and are termed pits or pocks. The spleen also normally Marginal zone metallophilic macrophages form an inner ring close
removes these, with the polished erythrocyte returned to the circula- to the white pulp, marginal zone macrophages form an outer ring,
tion. The lack of this polishing function can be used to assess splenic and dendritic cells and B cells are located between the two sets of
dysfunction as the number of pits or pocks per erythrocyte is increased macrophages. Both trafficking and retention of dendritic cells and B
when the spleen fails to remove them. cells involve complex interactions with integrins and other adhesion
molecules.
Recycling of Iron
Macrophages in the liver and spleen are important for recycling iron Innate Immunity
as erythrocytes are phagocytized and hydrolyzed in the phagolyso- The spleen is important in the recognition of antigens, in the produc-
some. Degradation of hemoglobin releases heme, which is catabolized tion of antibodies, and in the clearance of opsonized and nonopso-
2+
into biliverdin, carbon monoxide, and ferrous iron (Fe ). Iron is then nized particles from the bloodstream (see Table 160.1). The spleen
either released as a low-molecular-weight species for rapid reuse or structure facilitates monitoring of the contents of the blood, with
stored as ferritin. As ferritin accumulates, it aggregates into hemosid- blood flowing through the marginal zone directly along the white
erin. Iron-laden macrophages are a feature of iron overload states in pulp. The white pulp is involved in adaptive immunity, whereas the
both the liver and spleen. Erythrocytes that are destroyed intravascu- marginal zone is involved in both innate and adaptive immunity
larly release hemoglobin that binds to haptoglobin. CD163 on the (Table 160.2).
surface of splenic macrophages mediates endocytosis of circulating Trapping and processing antigens is a major function of the
hemoglobin and haptoglobin-bound hemoglobin. marginal zone. Macrophages are abundant here and the spleen cap-
Iron is released from stores in splenic macrophages in response to tures more than 5% of the cardiac output (greater than 250 mL/
the erythropoietic drive expressed by the bone marrow. The precise min), which allows a large volume of blood to be immunologically
mechanisms are not well understood. Uptake of iron is mediated in scrutinized. Antigens penetrate the germinal center where T lympho-
most cells by a divalent cation transporter, the natural resistance– cytes predominate. Processing of carbohydrate antigens is a special
associated macrophage protein 2 (NRAMP2), in recycling endosomes function of splenic marginal zone lymphocytes. Marginal zone
that express the transferrin receptor. NRAMP2 transports ferritin macrophages express lectin receptors and scavenger molecules.
into the cytoplasm across the endosomal membrane. In addition to Splenic macrophages are more sensitive to small amounts of
the more widely expressed NRAMP2, macrophages and monocytes opsonic antibody or complement present on the surface of particles
express NRAMP1, which was initially described as an iron- than are macrophages in the liver, lung, or bone marrow. In the
transporting protein affecting resistance to intracellular pathogens. A absence of a spleen, individuals may fail to remove bacteria with
third molecule involved in iron metabolism in the spleen is lipocalin-2, limited opsonic coating, and the production of antigen-specific
which is secreted by macrophages and other myeloid cells when immunoglobulin (Ig) M is impaired. An asplenic individual has
activated by exposure to bacterial metabolites. Lipocalin-2 binds to defective recognition of carbohydrate antigens, defective production
bacterial siderophores and sequesters iron from microorganisms. of IgM early during infection, and defective removal of lightly
These and other related molecules tightly link the iron-recycling and opsonized particles—all crucial components of response to an invasive
host-resistance functions of the red pulp of the spleen. infection with encapsulated organisms.
Marginal zone B lymphocytes are sensitive to detection of blood-
Antibody Production borne pathogens and rapidly differentiate into either antigen-present-
After stimulation and differentiating in the follicles of the white pulp, ing cells (APCs) or IgM-producing plasma cells. After activation in
antigen-specific plasmablasts and plasma cells lodge in the red pulp, the marginal zone, some B cells migrate into the white pulp, where
+
where they are closer to macrophages. A similar translocation occurs they function to activate naive CD4 T cells.
in lymph nodes, where plasmablasts migrate to the medullary cords. Similarly, blood-borne dendritic cells activated in the marginal
This translocation occurs after upregulation of expression of CXC- zone migrate into the white pulp. This process appears to be impor-
chemokine receptor 4 (CXCR4), which binds CXC-chemokine tant in control of certain parasitic infections. For example, in
ligand 12 (CXCL12) expressed in red pulp. Leishmania donovani infection, the spread of infection is inversely
proportional to the upregulation or downregulation of CCR7 expres-
sion on activated dendritic cells and migration of APCs into the white
The White Pulp pulp. In human immunodeficiency virus (HIV)–positive patients
with low CD4 T-cell counts (less than 300 cells/µL), there is evidence
The lymphoid region of the spleen incorporates multiple components that IgM memory B-cell depletion might be a risk factor for pneu-
of the immune system that are organized to enhance recognition and/ mococcal disease. Effective antiretroviral therapy appears to reverse
5
or response to pathogens. The white pulp contains lymphoid sheaths this depletion, in turn decreasing the risk for pneumococcal
around branching arterial vessels, similar to the structure of lymph infection.
nodes. Specific chemokines attract B and T cells to their appropriate
domains. The periarteriolar lymphatic sheath contains T cells that Adaptive Immunity
interact with dendritic cells and circulating B cells. T cells and den- Although the white pulp is both anatomically and functionally
dritic cells are attracted to the periarteriolar lymphatic sheath through similar to lymph nodes, all cells enter the white pulp via the marginal
CC-chemokine ligands 19 and 21. Clonal expansion of activated B zone rather than through high endothelial venules and afferent
cells occurs in follicles. B-cell migration to follicles requires CXCL13. lymphatic vessels, exposing them to an environment highly sensitive