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Monocytes and Histiocytes
Histiocytes come in many guises. In the blood, the progenitor of common histiocytes is the monocyte (a non-activated histiocyte). The monocyte emerges from the blood, and enters tissue in sites of injury as a
migratory histiocyte. This migratory form, little altered in morphology from the monocyte of the blood, may be found in most inflammatory infiltrates. These distinctive forms, that appear in tissue as naked, thin,
wavy nuclei, are migratory forms; they differ morphologically from activated histiocytes, but are difficult to distinguish from dendritic histiocytes (if emphasis is to be placed on the results of
immunohistochemistry). They are particularly common in inflammatory reactions involving the "reactive superficial unit" of the skin. Pityriasic disorders with prominent lichenoid qualities are
distinguished by a high component of migratory histiocytes in the epidermal infiltrates. A high component of migratory histiocytes is a prominent feature of the dermal and epidermal infiltrates of secondary lues.
In most lymphoid reactions, histiocytes have a role; they usually are prominently represented. The designation, histiocyte, in the absence of other specific qualifications, does not convey the remarkable diversity of
function of the cells included in the generic category. The basic cell type is the migratory phagocyte (a thin elongated cell with an elongated, wavy nucleus). Histiocytes are the tissue phase of monocytes. In the
context of a histiocyte-rich inflammatory infiltrate, most of the "histiocytes" are cells that are immunoreactive for Kp-1 (CD-68). This basic reacting cell is complemented in extracutaneous sites by
"fixed" phagocytic histiocytes of the reticuloendothelial system (the latter concept retains utility, particularly in regard to the role of "blockade" of the R-E system in the initiation of
certain reactions, such as the Schwartzman reaction, or in the failure of organs in hemochromatosis).
Monocytes are common in those disorders in which lymphocytes and "histiocytes" first collect near the dermal-epidermal interface and then migrate into the epidermis. The migratory "histiocytic"
cells in such lesions, particularly in some lichenoid reactions, are elongated with scanty, pale cytoplasm, and have characteristic, thin, elongated, wavy nuclei with delicate nuclear chromatin. Their morphology
expresses the ideal for migrating cells; these thin, elongated cells easily adapt to the limited space of the mucinous avenues of the epidermal interstitium.
In response to some inflammatory reactions of tissue, the migratory monocyte becomes activated. In the act, it acquires more cytoplasm, and an enlarged nucleus that is either rounded or indented. Nuclear chromatin is
delicate. Cytoplasm is pale and faintly acidophilic. Nucleoli of activated histiocytes are more prominent than those of migratory histiocytes. The activated histiocyte acquires more cytoplasm, and tends to
cluster with other similar cells. In some forms of inflammation, activated histiocytes closely aggregate; they displace the connective tissue framework of the native tissue. The resulting patterns are spoken of as
granulomatous (in this context, an “epithelioid” quality), and the component cells are "epithelioid" histiocytes. The activated histiocyte is phagocytic. It functions as a scavenger in damaged tissue.
Morphologically, dendritic histiocytes are difficult to distinguish from common migratory histiocytes. Both appear as elongated, wavy nuclei; the cytoplasm is inconspicuous. In some histiocytic tumors, the tumor
cells may be immunoreactive for CD68, S100-protein, and factor XIIIa and, in some others, for CD68 and either S-100 protein or factor XIIIa. These immunoreactions have been used to define certain histiocytes as
phenotypically distinct from the basic line of common histiocytes. The factor XIIIa + histiocytes seems to be peculiarly related in a functional capacity to the cells of connective tissue. In the skin, they seem to
have a role in maintaining certain qualities of the fibrous matrix of the dermis, particularly the mucinous component. The S-100+ histiocyte has a relationship with the mucinous matrix of the epidermis (and perhaps
the fibrous matrix of the papillary dermis and tumor stroma). CD1a also has a role in the characterization of some dendritic histiocytes (the respective antibodies generally reacting with the some of the histiocytes
that are reactive for S-100 protein). In the epidermis, S-100+ dendritic histiocytes have more cytoplasm and a darker nucleus than migratory histiocytes. There are pitfalls in placing great reliance on
immunohistochemical panels; results that are emphasized in the literature are not chiselled in stone; as reagents are “improved” (made more sensitive for use with formalin-fixed tissue), or antigens made more
accessible, accepted panels for the definition of a disease may be invalidated.
HISTIOCYTES AND GRANULOMAS
Histiocytes are prominent in intraepidermal spongiotic vesicles. In some epidermal vesicles, histiocytes are numerous and closely spaced. Certain patterns, as expressions of a cellular immune reaction in the dermis,
are composed preponderantly of activated histiocytes in closely clustered patterns: the close clustering of activated histiocytes is a "granulomatous" quality. There are experimental models of cell
mediated immunity that are expressed in similar patterns. The relationships of cells and antigens in the initiation of granulomatous reactions in experimental pathology can be offered as a model for the
interpretation of granulomatous patterns in human disease, including certain forms of connective tissue disease. It has been proposed that certain patients have a proclivity for the formation of granulomas; in this
manner, they then define sarcoidosis. The granulomas as seen in a positive Kviem skin test are prototypic of a specific form of cellular immunity. In many reactions, activated histiocytes tend to form tight clusters
that displace and push aside connective tissue fibers (they form tubercle-like aggregates). These compact aggregates are “tubercle-like” granulomas; they are epithelioid granulomas, and the component cells are
epithelioid histiocytes.
Histiocytes are the reactive cells in a variety of foreign body reactions. The response of the body to foreign bodies is often characterized by infiltrates of histiocytes in granulomatous patterns. "Foreign
body" giant cells are usually represented in these reactions. The foreign bodies may be endogenous, and as diverse as keratinized debris, extruded hair, or metabolic products that have crystallized in tissue.
They may be exogenous, including vegetable fibers, metallic pigments, insoluble injectables, and suture materials.
HISTIOCYTES AND INFECTIONS
Histiocytes are also important in the tissue response to infectious agents. Some bacteria, by their nature, are unlikely to elicit a preponderant neutrophilic response. In the infectious disorders, organisms, that
are resistant to the effects of neutrophils, are likely to be phagocytized by histiocytes. Organisms which regularly elicit a histiocytic response include forms that have lipid-rich cell walls, or capsules.
Organisms, which tend to induce a histiocytic response, are likely to be phagocytyzed by histiocytes. The organisms become sequestered in cytoplasmic organelles, the phagosomes. Reactions in which intracellular
organisms are prominent include: mycobacterial infections, fungal infections, klebsiella infections, granuloma inguinale, disseminated histoplasmosis, cryptococcosis, malakoplakia, Whipple's disease, leishmaniasis,
and granulomatous disease of childhood. In many of these disorders, the pattern of inflammation is granulomatous. Even having been phagocytyzed, mycobacterial organisms may prove to be relatively resistant to
enzymatic digestion. In mycobacterial infections, the reactions are either purely granulomatous, or suppurative and granulomatous. For the deep fungus infections, the response is likely to be both neutrophilic and
histiocytic (i.e., a suppurative granuloma).
For some infectious diseases, histiocytes may cluster without forming tubercle-like aggregates. The infiltrates in granuloma inguinale are rich in histiocytes, but the histiocytes do not form compact, epithelioid
aggregates. The infiltrates of malakoplakia, a cellular disorder as a manifestation of an abnormal response to phagocytized bacteria, are histiocytic but are not truly granulomatous. They are associated with
microscopic, intracytoplasmic concretions, the concentrically laminated Michealis-Gutman bodies.
In the face of alterations in immune competence, the primacy of neutrophils, as the characteristic reacting cells that are encountered in most bacterial infections, may be lost. Disseminated histoplasmosis and
cryptococcosis are diseases of immune incompetence. Lepromatous leprosy is an additional example. Granulomatous disease of childhood might be cited as an example in which infections, that normally elicit a
neutrophilic response, induce instead a granulomatous response. In these infections, the tissue response is likely to be preponderantly histiocytic, and often is granulomatous. The bacteria of cat-scratch disease
induce a suppurative granuloma; in the presence of altered immunity (HIV infection), the response to the bacteria of cat-scratch disease is a granulation tissue-like with prominent colonies of bacteria adjacent to
some of the newly formed vessels (bacillary angiomatosis). A variety of infectious disorders are common in the setting of HIV infection. Mycobacteria avium infection can present as a complication of HIV infection;
the organisms are both acid-fast and PAS positive. In such a lesion, the infiltrates of histiocytes are in the pattern of solid sheets. The altered tissue response of Crohn's disease may be manifested as
granulomatous skin lesions, including vasculitis.
ALLERGIC GRANULOMAS
The allergic granuloma is distinguished by collections of epithelioid histiocytes, central zones of brightly eosinophilic necrosis, and rich infiltrates of eosinophils. It may be a reaction to foreign material such
as a parasite, or a manifestation of an altered immune response, as manifested in allergic granulomatosis. The so-called flame figure of eosinophilic collagenosis (cellulitis) is usually emphasized as a feature of
Well's syndrome, but may be encountered in other forms of hypereosinophilia, including familial disorders. Flame figures have variable features and, in some examples, the small zones of eosinophilic necrosis are
associated with local accummulations of both eosinophils and histiocytes. In these histiocyte-rich variations, a small flame figure incorporates the basic features of an allergic granuloma.
VACUOLATED (LIPID-RICH) HISTIOCYTES
Activated histiocytes are rich in organelles, including lysosomes and phagosomes. In some reactions, histiocytes are lipid-rich; they have vacuolated cytoplasm. In certain inflammatory disorders, particularly in
examples in which the infiltrates extend into adipose tissue, lipid-rich, vacuolated histiocytes may be a common component of inflammatory infiltrates. Some of the histiocytes in inflammatory infiltrates may have
multi-vacuolated cytoplasm, and other have uniformly clear cytoplasm. Vacuolated histiocytes may also be encountered in the setting of metabolic disorders such as hyperlipidemias, and in some familial disorders,
independent of hyperlipidemias. Foamy histiocytes are characteristic of the reaction to leprae bacilli, particularly in the range of reactions near the lepromatous pole. At the tuberculoid pole, the reaction is a
pure granuloma.
DENDRITIC HISTIOCYTES
Dendritic histiocytes, identified primarily by location and anatomic associations, are distinguished by immunohistochemical markers. Some of the cells of the dendritic system function in part as targets for the
fixation of antigens; once fixed, antigens are presented to functionally related cells of the lymphoid system in the expressions of cell-mediated immunity. Migratory histiocytes morphologically are somewhat similar
to epidermal, dendritic histiocytes (S-100 +). The other dendritic cell of the skin, a dermal histiocyte, that is immunoreactive for factor XIIIa, is found in the papillary dermis, the vascular adventitia, and in
the reticular dermis among collagen bundles. It too is morphologically similar to the non-activated monocyte in the blood, or in tissue in early reactions to injury. It seems to have a role in the activation of
connective tissue.
HUMORAL IMMUNE REACTIONS
In an entirely different setting of immune reactions, histiocytes are attracted to antigen-antibody complexes in the evolution of humoral immune reactions. In humoral processes, particularly in the setting of
circulating immune complexes, both histiocytes and neutrophils may be prominently represented in sites in which the immune complexes have found their way into tissue.
VESSELS AND INFLAMMATION
Some "lymphocytic" angiitides are rich in histiocytes. In these "vasculitides," histiocytes react in the same manner as do neutrophils in neutrophilic leukocytoclastic vasculitides; they migrate
out of the perivenular infiltrates into the reticular dermis among collagen bundles. In the latter location, they undergo lysis and fragmentation. The connective tissue disintegrates, and a basophilic matrix,
containing nuclear debris, is the result. Leukocytoclastic vasculitides, in which infiltrates are rich in histiocytes, may be an expression of a response to relatively insoluble immune complexes. Close inspection of
the character of the infiltrating inflammatory cells is required for the recognition of this variant of leukocytoclastic vasculitis. In some examples of neutrophilic collagenosis (including neutrophilic dermatitis
or Sweet's syndrome), histiocytes numerically are as prominent as neutrophils in the interstitial infiltrates.
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