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Introduction:
Pathologists have struggled with the characterization of mononuclear, non-lymphoid cells of inflammatory infiltrates. In the beginning, and for years thereafter, they were handicapped
by the adynamic quality of their preparations. It was difficult to make distinctions between cells that are native to the site and those that are immigrants from the circulation. In attempting to refine their
characterizations, they have related function to morphology, but not always appropriately. It serves little purpose to review either the history of the problems, or the compromises in the classification of the
non-lymphoid, mononuclear cells of inflammation.
The reticulo-endothelial system is basically a conceptual adaptation of morphology to function. It embraces a group of fixed phagocytic cells in the liver, lymph nodes, spleen, and
bone marrow. A definition of the R-E system that is based on a set number of viscera is compromised. Conceptually, fixed phagocytic cells of mesothelial surfaces, and the pulmonary alveoli are members of the
reticulo-endothelial system. The reticulo-endothelial system remains a morphologically ill-defined, functional component. Much of the current confusion in the classification of histiocytic disorders is an outgrowth
of attempts to relate function to phenotype. In practice, the generic term, histiocyte, embraces a variety of cells, expressed in different phenotypes.
Morphologically, the monocyte-macrophage system is easily defined. The representative of the tissue phase is the macrophage; it is comnmonly characterized as a histiocyte.
Mononuclear mesenchymal cells of local, rather than hematopoietic origin, have also been classified as histiocytes. “Reticulum cells,” including dendritic cells of the germinal centers and interdigitating cells in
the paracortical zones of lymph nodes, are commonly included in a general category of histiocytes. Some lesions of mesenchyme are composed of "fibro-histiocytic" cells, but some of the latter lesions have
little, or no relationship, to the monocyte-macrophage system. The mesenchymal fibroblast is a mesenchymal cell which interacts intimately with immigrating histiocytes; lesions, in which the relationships are
manifested, often are classified as fibro-histiocytic disorders.
It is improper to assume from an evaluation of histologic findings that a cell with "histiocytic" qualities is a derivative of a single line of cells. The evidence indicates
that qualities of a histiocyte may be manifested as functional adaptations in a variety of cell lines. Schwann cells and mesenchymal cells may function as facultative histiocytes. The histiocytic functions of
Schwann cells are manifested in leprosy (5).
In discussing histiocytic disorders, emphasis will be placed on common morphologic criteria, rather than on inferences related to observations of functional characteristics. In the
category of the granulomatous, histiocytic disorders, the reacting cell is clearly an activated cell of the monocytic-macrophage system. Similarly, lymphohistiocytic granulomas are acceptable as reactions in the
latter system. For some other disorders included in this SECTION, it would be incorrect, or premature, to assume that the component cells are derived from the monocytic-macrophage system.
Historically, a granuloma is a tumor-like proliferation of “granulation tissue.” In the histologic definition of a granuloma, an inflammatory infiltrate is composed of compact
aggregates of epithelioid macrophages (1,2). It is productive rather than exudative; in its growth, it pushes preexisting tissue aside. If mesenchymal elements become entrapped, they are digested, and thus
eliminated. The criteria for a clinical diagnosis of granuloma do not define a process with specific histologic features. The diverse histologic and clinical implications of the term granuloma are illustrated by a
comparison of pathogenetically unrelated processes such as granuloma inguinale, granuloma annulare, granuloma fungoides, granuloma pyogenicum, granuloma faciale, and granuloma multiforme.
Lymphocytes, although morphologically monotonous, are phenotypically heterogeneous. In the embryo, lymphocytic precursors develop in the hematopoietic tissue of the yolk sac, and
migrate from there to the thymus, the liver, and the bone marrow. Those, which select and, initially, develop in the thymus, become T-lymphocytes. From the thymic resevoir, they migrate to lymphoproliferative organs
to undergo further maturation. They are the mediators of the phenomena of cell mediated immunity. Cellular immunity is involved in the rejection of grafts, delayed hypersensitivity reactions, and in granulomatous
inflammation, wherein lymphokines from the activated T-cells attract histiocytes (macrophages).
A second functional and morphologic line of lymphocytes is comprised of B-lymphocytes. The latter are involved in humoral immunity in which reactions are mediated by secretory
products, the immunoglobulins. The secretory products of B-lymphocytes are involved in immediate hypersensitivity reactions and are important in the control of some infectious agents. Reactions between the secretory
products of B-lymphocytes and antigens result in the formation of immune complexes, the nature of which influences the subsequent character of the immune response. Occasionally, the immune complexes themselves
are pathogenic, rather than beneficial.
Functional B- and T-lymphocytes reside in lymphoid resevoirs such as lymph nodes, and the white pulp of the spleen. The precursors of B-immunocytes reside, and undergo modulations, in
the germinal centers. Immunocytes (B-lymphocytes showing terminal differentiation) migrate through the paracortical zones. They then concentrate in the medullary cords and in the lymphoid tissue that abuts upon the
peripheral sinus. In the germinal centers, dendritic histiocytes are concerned with antigen presentation and, in turn, with the modulations of the resident B-lymphocytes.
T-lymphocytes reside, and undergo modulations, in the paracortical regions of lymph nodes. They are associated with a distinctive plexus of post-capillary venules. T-lymphocytes, from
the circulation, gain access to the paracortical regions through the post-capillary venules. Distinctive interdigitating reticulum cells (histiocytes) in the paracortical zones are functionally related to the
modulations of T-lymphocytes in the paracortical zones. They are the characteristic, pale histiocytes which are prominently displayed in dermatopathic lymphadenitis.
Characteristics of B- and T-lymphocytes: Multiple interactions between B- and T-lymphocytes are required for the generation of the immune response. Subsets of T-lymphocytes,
including "helper-inducer" and "suppressor-cytoxic" cells have been identified. Mature B- and T-lymphocytes are morphologically indistinguishable. In vitro, T-cells can be identified by their
ability to form rosettes with sheep erythrocytes. They undergo blastic transformation when exposed to phytohemagglutinin. B-lymphocytes are characterized by surface bound inmmunoglobulins that can be tagged with a
variety of reagents to facilitate identification. The availability of monoclonal antibodies, and advances in both immunofluorescence and immunoperoxidase techniques have facilitated the identification of T-cells
(and their subsets), B-cells, and macrophages in appropriatedly processed tissue sections.
T-lymphocytes have distinctive protein antigens on their surfaces. Some of the antigens are shared by all T-cells and others are specific for certain subsets. They can be identified by
commerically available monoclonal antibodies. CD3 and CD45RO are "pan" T-cell reagents; thus, they are present on all circulating T-cells. CD2, also a pan T-cell reagent, recognizes the erythrocyte rosette
receptor present on all T-cells. The helper T-cell subset can be recognized with monoclonal antibody CD4. Suppressor-cytotoxic T-cell subset reacts with CD8. Monoclonal antibodies which are specific for
B-lymphocytes are also available. Surface immunoblobulin-positive B-cells can be recognized with immunoperoxidase techniques by using antibodies to specific immunoglobulins and kappa and lambda light chains. B-cell
infiltrations which are positive for only one light chain type, either kappa or lambda, (i.e., monoclonal) often are accepted as lymphomatous. Polyclonal infiltrations are positive for both lambda and kappa light
chains and, in the appropriate settings, are likely to be characterized as reactive. "Null cells" are lymphoid cells without identifiable surface markers.
Morphology and cell markers: Histiocytes have an open, round to oval, nucleus; the nucleus of some of the cells are grooved or reniform. The nucleus is usually eccentric in pale,
acidophilic cytoplasm. Histiocytes are rich in acid phosphatase and nonspecific esterases. Using the immunoperoxidase technique, histiocytes have been shown to contain muramidase, alpha 1-antichymotrypsin, alpha
1-antitrypsin, and ferritin. CD68 (KP-1) recognizes an antigen expressed on all peripheral macrophages.
A macrophage (histiocyte) may process, and directly fix, antigens to its surface. It has surface receptors for the Fc portion of IgG and for the C3 component of complement.
An activated macrophage shows marked surface irregularities, and contains primary lysosomes. It may attach antigen-antibody complexes to its surface
receptors (9). A coated surface may play an important role in the attachment of particles. Surface antigens which are attached to macrophages are exposed to T-lymphocytes. In turn, the lymphocytes become sensitized.
The antigenic receptors on T-lymphocytes are limited. Some antigens may be altered by macrophages (RNA-complexes) to meet the requirements of receptor sites on the surface of T-lymphocytes. Many of the functions of
activated macrophages are nonspecific, and are not antigenically directed. Antigenic recall by lymphocytes, however, is specific.
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