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DEFINITIONS C3
The macrophage:
A macrophage is the phagocytic, tissue phase of the hematopoietic monocyte (3,4). It is a common, reacting cell in inflammatory processes, including infectious processes. During periods of increased demand, monocytes
are produced in the bone marrow; they then enter the circulation. They are attracted to, and aggregate in, sites of cell-mediated immune reactions. Under the influence of an antigenic stimulus, they undergo
transformation to activated macrophages (phagocytes). In its tissue phase, the macrophage is also classified as a histiocyte, but the latter term does not clearly define a single line of cells.
The degree, and the success, of the response of macrophages to an antigenic stimulus is determined by the immune status of the host, and the nature of the offending agent. In cell-mediated immune reactions,
sensitized T-lymphocytes, either locally, or in regional lymph nodes, undergo blastic transformation. They undergo modulations to generate a clone of effector T lymphocytes (6,7). The latter cells, in contact with
antigen, secrete lymphokines, one of which inhibits the migration of macrophages (migration inhibitory factor) (8). Monocytes move from the circulation into the sites of a reaction between T-lymphocytes and antigen.
Their movement out of blood vessels is influenced by inflammation, the effects of which include altered vascular permeability.
Activated histiocytes produce part of the tissue damage that histologically characterizes a cell-mediated immune reaction. The domain of T-lymphocytes in the skin is the adventitial dermis (the papillary dermis, the perifollicular connective tissue sheath, and the vascular adventitia). From these sites, T-lymphocytes easily move into zones in which antigens, or immune complexes, are sequestered.
Conceptually, the component cells of the reticuloendothelial system are closely related to fixed macrophages (resident cells), and to monocytes (4). As defined by Aschoff and Kiyono, intra- and extra-vascular cells
are included. The histiocytes of the sinusioids of the lymph nodes, the red pulp of the spleen, the sinusoids of the liver, the pulmonary alveoli, and the mesothelial (and synovial ?) membranes conceptually qualify
as a dispersed system of resident histiocytes. Cells of the reticuloendothelial system of the spleen, liver, and lymph nodes may function as phagocytes, but are relatively fixed in sinusoids. They are associated
with either blood vascular, or lymphatic channels. Immune responses are compromised by “blockade”of this system.
Actually, phagocytosis is part of a broader concept, namely endocytosis. Endocytosis is the common denominator of cells belonging to the R-E system. It encompasses phagocytosis and pinocytosis. Phagocytosis is the
engulfment of particles that would be visible, if examined with the light microscope. Pincytosis denotes the ingestion of sub-light microscopic particles, colloidal solutions, and fluid droplets. Following
endocytosis, the endocytotic vesicles move away from the plasma membrane and fuse with lysosomes containing various enzymes. In the resulting phagosomes and pinosomes, the engulfed material is enzymatically
degraded.
Although there is general agreement that it is important to conceptualize a system of cells, whose prime function is endocytosis, there is disagreement as to what cells should belong to this system and what the
system should be named. Furth, et al, have introduced the term "mononuclear phagocyte system" to include all avidly phagocytic, mononuclear cells and their precursors. This system is made up of monocytes
and their derivatives, including microglia, alveolar macrophages, Langerhans cells, and osteoclasts.
The macrophage (as an example of an inhibited monocyte) is a secretory cell (10). The secretory products of macrophages include enzymes, complement components, fibronectins, nucleosides, reactive metabolites of
oxygen, some prostaglandins, chemotactic factors for neutrophils, factors promoting replication of erythroid, myeloid, and lymphoid cells, and factors inhibiting replication of tumor cells and viruses. Some of its
enzymes are released into the tissue, but much of its activity is sequestered in specialized cytoplasmic organelles, the phagosomes. Attached particles may remain on the surface, or may be endocytosed. Phagocytosis
may be seen in a variety of cells and patterns, but the ingestion of particles greater than 0.1 mm characterizes the response of macrophages.
The process of phagocytosis may be a mechanical enclosure of particles attached to the surface, or may require metabolic activity (ATP). If the enclosed particle is a facultative, intra-cellular organism, such as
mycobacterium, and the organism is viable, lysosomes do not fuse with the phagosome. Fusion of lysosomes with phagosomes (secondary lysosomes) occurs after death of the bacterium; it results in digestion of the dead
organism.
The reticular cell:
In this category, the cells are mesenchymal derivatives which are concerned primarily with the maintenance of the supporting reticulum of parenchymatous organs (16). The reticular cell is distinguished by cytoplasmic prolongations, some of which form adherences with prolongations from neighboring cells and some of which encircle delicate fibers (reticular fibers). Reticulum is composed of reticular fibers and the supporting reticular cells. It supports parenchymatous cells and may also be a locus for proliferation of stem cells. Lennert has defined four types of reticulum cells. The phagocytic “reticulum cell” is represented by the tingible body cells of germinal centers; it is a dendritic histiocyte. The main function of the fibroblastic reticulum cell is the production of reticulin fibers. The other two variants are the dendritic reticulum cells, and the interdigitating reticulum cells. Reticular cells are weakly phagocytic and have metallophilic properties
The dendritic reticular cells:
These cells are dendritic histiocytes of the lymphoid B cell domain with an important role in the fixation of antigens (16). The dendritic cells of lymph nodes may influence the development of germinal centers (i.e., the recruitement of lymphoid cells). The neoplastic nodules of nodular B-cell lymphomas contain dendritic cells.
In the T cell domain (paracortical areas) of lymph nodes, a distinctive reticular cell, the interdigitating reticular cell, is associated with T lymphocytes. In aggregates, it is the characteristic reacting cell in
dermatopathic lymphadenitis (16). It is functionally related to the Langerhans cell of the skin and is rich in ATP-ase.
"Histiocytic" transformed B lymphocytes:
In the older neoplastic systems of lymphomas, the modulations of the transformed B lymphocyte included a large cell with a cleaved nucleus. This large cell was classified as a histiocyte by Rappaport, but has the surface markers of a B lymphocyte (17). It is properly excluded from the category of histiocytes and the term histiocytic lymphoma in the context of a B cell lymphoma has been discarded. On the other hand, a distinctive “lymphocytic” lymphoma is characterized by infiltrates of lymphoid cells whose cytologic features have been characterized as “monocytoid.” Monocytoid lymphocytes are closely related to cells of the marginal zones of germinal centers; in neoplastic processes, monocytoid B cell lymphomas have much in common with MALT-type lymphomas.
The neutrophil: This cell shares enzymatic properties with a macrophage. It is attracted by chemotaxins and is phagocytic. It is the first line of defense for many bacterial infections. If neutrophils are
incapable of digesting the bacteria, due either to distinctive qualities of the bacteria (i.e. non-antigenic mycolates of mycobacteria), or to defects in phagocytic functions (i.e. the peroxidase deficiency of
granulomatous disease of childhood), the macrophage forms the second line of defense.
Granuloma:
For the histologic definition of a granuloma, an inflammatory infiltration is composed of compact aggregates of epithelioid macrophages (1, 2). The criteria for a clinical diagnosis of granuloma do not define a process with specific histologic features. The character of a granuloma is influenced by the nature and properties of the offending agent. If the offending antigen, or the complex has special characteristics (high lipid content or poor solubility), macrophages may adapt with the expression of epithelioid qualities. In epithelioid aggregates, macrophages show a marked reduction in phagocytic activity.
Epithelioid histiocytes express a metabolic state in which lytic functions are directed extracellularly. The epithelioid histiocyte is poorly phagocytic. It may ingest particles by micropinocytosis, but it is
primarily a secretory cell (11). An epithelioid granuloma may be relatively stable with little recruitment of monocytes from the circulation (low turnover), or may be unstable with rapid recruitment of circulating
monocytes (high turnover). In the presence of insoluble antigen-antibody complexes (antibody excess?), the tissue response may be granulomatous.
Pure granuloma:
In pure granulomas, epithelioid cells form spherical, compact aggregates, with little or no evidence of necrosis; they do so to the relative exclusion of lymphocytes. This pattern in part reflects the insolubility of the irritant, or antigen and, in part, can reflect a high level of immunity. The compactly aggregated macrophages of a granuloma displace, or lyse, the pre-existing fibrous matrix. The cells have rounded nuclei and moderate amounts of acidophilic cytoplasm which may be finely vacuolated. The close attachment between neighboring macrophages denies inflammatory cells, other than occasional T-lymphocytes, access to the interstitium of the granuloma. Often, the cell membranes of macrophages are indistinct, but occasionally are prominent. Macrophages have the capacity to fuse with neighboring cells to form multinucleated giant cells (3). The multinucleated giant cell is an adaptation by which degenerating macrophages and newly recruited macrophages are fused into a functioning unit. The usefulness of the cytoplasmic factories of the degenerating cells is thereby extended. In addition, the contents of the phagosomes are retained intra-cellularly, thus limiting tissue damage and the possible spread of infectious agents. A relatively pure form of granulomatous inflammation has been qualified as the
naked tubercle; this characterization gives recognition to a relative lack of non-specific inflammation at the periphery of an area of granulomatous inflammation.
A tubercle is a rounded collection of epithelioid cells. Its name derives from aggregates of epithelioid cells induced by the tubercle bacillus, but it has acquired histologic specificity that lacks etiologic
connotations. In one or more tubercles, there may be small, focal areas of necrosis but, to qualify as a pure granuloma, the necrosis should be a minimal component and should not be in contact with extensions of
hyperplastic squamous epithelium. Areas of contact between a zone of necrosis in a granuloma and hyperplastic epidermis may represent transepidermal elimination (18). The latter pattern is more characteristic
of infectious granulomas in which the cellular response is mixed, rather than pure. The pure granuloma may be in part perivascular (hematogenous) in distribution, but usually extends into the reticular dermis. In
the latter location, the granuloma displaces and digests dermal collagen.
Pure granulomas may be seen in the following processes:
1. sarcoidosis
2. sarcoid-like reactions in infectious processes (e.g. histoplasmosis)
3. tuberculoid leprosy
4. necrobiosis lipoidica
5. tuberculosis (lupus vulgaris)
6. some foreign body reactions
The concept of a pure granuloma, as an expression of cell mediated immunity, has been extended to define a spectrum of tissue responses. The pure granuloma is the prototype of one extreme of a spectrum; sarcoidosis
provides the model (19) for a disease in which pure granulomas are fully expressed. It is an error to assume that all sarcoidal reactions are antigen-specific immune responses of a single type. The concept of a
spectrum of tissue reactions should not becloud the need for a clear definition of sarcoidosis as a clinicopathologic syndrome.
In a pure granuloma, the spherical aggregates are initially well outlined and often perivascular. With extension of the process, adjacent tubercles fuse to produce nodular aggregates. In the skin, they are usually
confined to the reticular dermis, but may extend to, and press upon, the epidermis. Occasionally, they extend into the subcutis. Some of large aggregates of epithelioid cells may show a central area of fibrinoid
necrosis. The perivascular infiltrates may contain lymphocytes and plasma cells. A pure granuloma may regress and leave a hyalinized fibrous matrix as a marker. In some examples, involution is marked by active
fibroplasia, atrophy of skin appendages, and the formation of a dense scar.
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