Thesis (M.Med. (Dermatology))--University of the Witwatersrand, Faculty of Health Sciences, 2013. / A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment of the requirements for the degree of Masters of Medicine in Dermatology by coursework and research report Johannesburg 2013

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.

Langerhans’ cells (LC) are the dendritic cells (DC) of the epidermis and, as sentinels of the immune system, act as a bridge between the innate and adaptive immune responses. When LC, and other DC, recognise an antigen or pathogen they mature and are stimulated to migrate to the lymph nodes, where they orchestrate immune responses. Pathogen derived toll-like receptor (TLR) ligands, and chemical allergens, are recognised as being potentially harmful and stimulate LC to mobilise and mature. Cytokine signals, including tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-18, all induce LC migration and are required for initiating LC mobilisation in response to certain contact allergens. Subsequently, chemokines promote the migration and localisation of LC within the draining lymph nodes. Chemokines are also involved in shaping the adaptive immune response by promoting differential T cell activation, such as T helper (Th)1 or Th2 responses, which are involved in immunity against different pathogens, and also in the development of different types of chemical allergy. The hypothesis is that LC phenotype (activation, migration and chemokine production), is dependent on the nature of the challenge ligand. The murine LC-like cell line XS106 was used to investigate the response of LC following stimulation with TLR ligands and chemical allergens. In addition, LC migration in response to these stimuli was investigated in vivo and the role of TNF-α was examined using mice deficient in either one of the two TNF-α receptors; TNF-R1 or TNF-R2.XS106 cells and freshly isolated LC were associated with a selective type 2 immune response, as determined by preferential expression of type 2 associated chemokines. Furthermore, XS106 cells responded to type 2, but not to type 1, associated TLR ligands. In contrast, all of the TLR ligands tested induced the migration of LC from the epidermis in vivo. Similarly, chemical allergens failed to induce a maximal response of XS106 cells, but did induce the migration of LC in vivo. There were differences in LC migration between the two mouse strains tested, with C57/BL6 strain mice being less responsive to administration of TNF-α and the contact allergen oxazolone compared with BALB/c strain mice. However, C57/BL6 and BALB/c strain mice responded similarly after exposure to the contact allergen 2,4-dinitrochlorobenzene (DNCB). Furthermore, DNCB was able to induce LC migration in mice deficient in TNF-R2, the TNF-α receptor expressed by LC.Collectively, these data suggest a paradigm in which keratinocytes and LC in the epidermis have distinct roles in promoting type 1 and type 2 immune responses, respectively. Therefore, LC may not be activated directly by certain TLR ligands or chemical allergens that are associated with type 1 responses. Consequently the migration of LC in vivo after encounter with these stimuli may be secondary to interaction with keratinocytes, or with other skin resident cells. Together, LC and keratinocytes allow the epidermis to respond to a range of pathogens, in addition to developing the necessary type 1 and type 2 responses. Chemical allergens may have divergent cytokine signalling requirements for the induction of LC migration as, unlike other contact allergens (and other stimuli such as irritant and ultraviolet [UV]B exposure), DNCB may induce LC migration independently of TNF-α.

No description available.

With increasing age, aspects of the innate and adaptive immune systems show functional decline. In the skin this is associated with an increased incidence of epidermal malignancies and infections, a decreased incidence of contact allergy, and the development of autoimmunity. The mechanisms underlying these clinical effects in aged skin are poorly understood. Langerhans’ cells (LCs), which are members of the wider family of dendritic cells (DCs), reside in the epidermis where they act as sentinels of the immune system by processing and presenting antigen and inducing T cell responses. Previous investigations have suggested that the number of epidermal LCs is reduced, and that the motility of LCs is impaired in aged skin. A series of investigations was performed to characterise the mechanistic basis for the reduced frequency and restricted mobility of epidermal LCs in the skin of the elderly. Initially LC-like cells were cultured from circulating monocyte precursors and characterised using flow cytometry. The ability of precursors to differentiate into LC-like cells was not impaired in the aged; furthermore there were no age-associated differences in expression of markers of LC activation at baseline or upon stimulation. The phenotype of epidermal LCs was assessed using flow cytometric analysis of epidermal cell suspensions and did not appear altered in aged individuals. In addition, using the same techniques with dermal cell suspensions the dermal DC population was not altered with age. Langerhans’ cell migration from epidermal explants prepared from the skin of aged individuals was impaired but could be restored with exogenous interleukin (IL)-1β. There was no age-related reduction in the epidermal levels of IL-1β or caspase-1 (IL-1β converting enzyme which converts pro-IL-1β to the active form) or the expression of the IL-1 receptor I (IL-1RI), to account for this observation. However, the amount of IL-1 receptor antagonist was reduced in aged skin suggesting a change in the overall local cytokine balance. Based on previous reports that topical retinoic acid (RA) can increase cutaneous IL-1 production, a 4-day patch test assay was performed using 0.025% all-trans RA cream to explore whether this could restore LC migration in the aged. There was no effect on LC migration from epidermal explants prepared after treatment with RA in the aged.These data demonstrate that changes in LC function in the elderly may not be associated with changes in systemic DC biology. Age related changes in the cutaneous microenvironment are likely to be more relevant.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Michigan, 1985.

Thesis (M.S.)--University of Michigan, 1985.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20976号 / 医博第4322号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 岩田 想, 教授 中川 一路 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM