Despite the large variation of clinical and pathological features of canine histiocytic diseases, the majority represent proliferations of cells of dendritic lineage. Histiocytes differentiate from CD34+ committed stem cell precursors into macrophages and a several dendritic cell (DC) lineages which include epithelial DC or Langerhans cells (LC), interstitial DC in many organs (eg dermal DC), and interdigitating DC of T cell domains in peripheral lymphoid organs (see diagrams). Cytokines influencing DC development include GM-CSF and TNF-a. Macrophage development from CD34+ precursors is influenced by GM-CSF and M-CSF. Blood monocytes can differentiate into either macrophages under influence of M-CSF, or into DC under influence of GM-CSF and IL-4. Recently a new human dendritic lineage of myeloid origin was identified. These DC differentiate under the influence of GM-CSF and IL-3 and are the major source of non-activated resident DC in T cell domains of peripheral lymphoid organs. They are supplemented by migration of activated DC from skin and interstitial tissues, which arrive in lymph nodes as veiled cells in afferent lymph following contact with antigen.

Histiocyte differentiation.   Stem cell factors (SCF and Flt-3 Ligand) amplify histiocyte differentiation - especially DC. GM-CSF and TNF-alpha induce differentiation toward DC (interstitial DC and LC); TGF-beta influences the terminal stages of LC differentiation. M-CSF induces macrophage differentiation. Important and distinctive surface markers of each type of histiocyte are listed on the right. The pattern of expression of CD1 molecules is a major distinguishing feature between DC and macrophages. E-cadherin expression is unique (among DC) to Langerhans cells. Epidermal Langerhans Cells   Distinctive surface markers and chemokine receptors. Dermal (interstitial type) DC   Distinctive surface markers and chemokine receptors. DC Migration   The fate of dermal (interstitial type) DC and LC once they leave skin following encounter with antigen. Activation leads to changes in chemokine receptor expression (CCR7 upregulation) and migration under the influence of chemokines produced by lymphatic endothelium (SLC or CCL21) and stromal cells in the lymph node paracortex (MIP3-beta or CCL19 and CCL21). Origin of interdigitating DC in lymph nodes.   The majority of interdigitating DC arrive from blood as non activated cells whose differentiation is influenced by IL-3 and GM-CSF (and perhaps G-CSF - recent data). They are phenotypically relatively undifferentiated upon arrival, but can express CD1 and upregulate MHC II upon stimulation. The activation/migration route is taken by interstitial DC and LC which enter lymphatics and migarate to the lymph node paracortex following encounter with antigen - this migration provides the minority of interdigitating DC.