What is the pathology of histiocytosis disorders?

Updated: Sep 16, 2020
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Improved understanding of the pathology of histiocytic disorders requires knowledge of the origins, biology, and physiology of the cells involved. Macrophages and monocytes are members of the mononuclear phagocyte system. Histiocytes are tissue-resident macrophages. Normal histiocytes originate from pluripotent stem cells, which can be found in bone marrow. [13] Under the influence of various cytokines (eg, stem cell factor [SCF], granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-3, IL-4, and others), histiocytes can become committed, differentiating into specific groups of specialized cells. Committed histiocytes can mature into one of two lineages: (1) antigen-processing cells, ie, macrophages and monocytes, or (2) antigen-presenting cells, ie, dendritic cells, interdigitating reticulum cells, and Langerhans cells (with Langerhans cells being dendritic cells located in the epidermis). [14]  Each category of histiocytosis can be traced to reactive or neoplastic proliferation in one of these cell lineages. [14]

The importance of dendritic cells in the capture, uptake, processing, and, ultimately, presentation of antigens to T and B lymphocytes has been increasingly recognized. Dendritic cells appear to develop in several pathways. [15] Immature dendritic cells respond to GM-CSF (not to macrophage colony-stimulating factor [M-CSF]) and become committed to generating dendritic cells, which are “professional” antigen-presenting cells (APCs). [16] These cells can capture antigen and migrate to lymphoid organs, where they present the antigens to naive T cells. [17] Dendritic cells are also efficient stimulators of B-cell lymphocytes. [18]

Effective induction of antigen-specific T-cell responses requires interaction between the dendritic cells and T lymphocytes to prime the latter cells for expansion and subsequent immune responses. [19] The surface of the APC contains 2 peptide-binding proteins (ie, major histocompatability complex [MHC] classes I and II), which can stimulate cytotoxic T (TC) cells, regulatory T (Treg) cells, and helper T (TH) cells. [20, 21] Although circulating T-cell lymphocytes can independently recognize antigens, their number is small. Dendritic cells display a large amount of MHC-peptide complexes at their surface and can increase the expression of costimulatory receptors and migrate to the lymph nodes, spleen, and other lymphoid tissues, where they activate specific T cells.

The first signal may involve interaction between an MHC I–bound and/or MHC II–bound peptide on an APC with the T-cell receptor (TCRs) on the effector lymphocytes. TCRs can recognize fragments of antigen attached to MHC on the surface of an APC. Costimulatory interaction (i.e., second signal) is between CD80(B7.1)/CD86(B7.2) on the dendritic cell, and CD28 on the T cells. [22, 23, 24] A combination of the 2 signals activates the T cell, resulting in upregulation of the expression of CD40L, which, in turn, can interact with the dendritic cell–expressed CD40 receptor. [21] In perforin-deficient mice, abnormally heightened cytokine production by T cells is due to overstimulation by APCs after a viral infection. [22]

This cell-to-cell interaction between dendritic cells and T cells generates an antigen-specific T-cell response. The effective function of antigen presentation by dendritic cells is presumed to reflect that these cells, in addition to MHC molecules, express a high density of other costimulatory factors. Dendritic cells can produce several cytokines, including IL-12, which is critical for the development of TH 1 cells from naive CD4+ T cells. [22, 25, 26, 27, 28]

Ligation of CD40 on dendritic cells triggers the production of large amounts of IL-12, which enhances T-cell stimulatory capacity. This observation suggests that feedback to dendritic cells results in signals that are critical for induction of immune responses. The nature of the latter interaction and requirement for optimal dendritic cell activation is not fully understood. Dendritic cells in culture derived from human blood monocytes exposed to GM-CSF and IL-4 followed by maturation in a monocyte-conditioned medium have heightened antigen-presenting activity. Monocyte-conditioned media contain critical maturation factors that contribute to this process.

Dendritic cells are present in tissues in a resting state and cannot stimulate T cells. Their role is to capture and phagocytize antigens, which, in turn, induce their maturation and mobilization. [29] Immature dendritic cells reside in blood, lungs, spleen, heart, kidneys, and tonsils, among other tissues. Their function is to capture antigen and migrate to the draining lymphoid organs to prime CD4+ and CD8+ T cells. In the process of their function, these cells mature and increase their capacity to express costimulatory receptors and decrease their capacity to process antigen. These cells can phagocytize, forming pinocytic vesicles for sampling and concentrating their surrounding medium, which is called macropinocytosis.

Immature dendritic cells express receptors that mediate endocytosis, including C-type lectin receptors, such as the macrophage mannose receptor and DEC205, FC-gamma, and FC-epsilon receptors. Microbial components, as well as IL-1, GM-CSF, and TNF-alpha, have an important role in cellular response [30, 31] and can stimulate maturation of dendritic cells, whereas IL-10 opposes it. [32]

Mature dendritic cells possess numerous fine processes (veils, dendrites) and have considerable mobility. These cells, rich in MHC classes I and II, have abundant molecules for T-cell binding and co-stimulation, which involves CD40, CD54, CD58, CD80/B7-1, and CD86/B7-1. Mature dendritic cells express high levels of IL-12. High levels of CD83 (a member of the immunoglobulin [Ig] superfamily), and p55 or fascin (an actin-bundling protein) are present in these cells, as opposed to the low levels that are present in the immature cells. [16]

IL-1 enhances dendritic cell function. This effect appears to be indirect and due to activation of TNF receptor–associated factors (TRAFs). Mature dendritic cells also express high levels of the NF-kappaB family of transcriptional control proteins. These proteins regulate the expression of several genes encoding inflammatory and immune proteins. Signaling by means of the TNF-receptor family (eg, TNF-R, CD40, TNF-related activation-induced cytokine [TRANCE], receptor activator of NF-kappaB [RANK]) activates NF-kappaB. Immunologic response of dendritic cells to a given antigen partly involves the triggering of signal-transduction pathways involving the TNF-R family and TRAFs.

Information regarding the fate of dendritic cells after these events is sparse. Dendritic cells disappear from the lymph nodes 1-2 days after antigen presentation, possibly because of apoptosis. [33, 34] CD95 (Fas) is suggested to have a role in the death of the dendritic cell. [35, 36, 37] However, although dendritic cells express CD95, CD95 ligation does not induce apoptosis. [38]

Experiments indicate that immature dendritic cells are partially susceptible to death receptor–mediated apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) may bind to 5 separate receptors. [39] Functional cytoplasmic death domains characterize TRAIL-R1 receptors, TRAIL-R2 receptors, and CD95 receptors. In contrast, TRAIL-R3 is a membrane-anchored truncated receptor, and TRAIL-R4 does not have a functional death domain. Dendritic cells express CD95, TRAIL-R2, and TRAIL-R3 in comparative levels. Similar to the role of CD95L, that of TRAIL-mediated apoptosis of mature dendritic cells has been controversial. Data regarding in vitro TRAIL-mediated apoptosis in these cells have also been reported, although such data remain controversial. Mature dendritic cells are usually resistant to TRAIL- and CD95L-mediated apoptosis.

C-FLIP, which is the caspase-8 inhibitory protein capable of inhibiting death receptor–mediated apoptosis, is highly expressed in mature dendritic cells, whereas only low levels are found in immature cells. [40, 41] Overexpression of C-FLIP inhibits signals of death receptor. [42] C-FLIP expression on dendritic cells is upregulated during maturation. Note that engagement of CD95 on immature dendritic cells by CD95L induces phenotypic and functional maturation of these cells.

In addition, a CD95-activated dendritic cell upregulates the expression of MHC class II and costimulatory receptors, which is essential for the function of these cells. [43] Furthermore, such engagement upregulates the expression of dendritic-cell lysosome-associated membrane protein (DC-LAMP) and causes the secretion of proinflammatory cytokines, including IL-1 beta and TNF-alpha.


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