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dc.contributor.advisorSmith, Peter G
dc.contributor.authorDoss, Argenia Lanisha Necole
dc.date.accessioned2013-01-20T17:54:34Z
dc.date.available2013-01-20T17:54:34Z
dc.date.issued2011-12-31
dc.date.submitted2011
dc.identifier.otherhttp://dissertations.umi.com/ku:11844
dc.identifier.urihttp://hdl.handle.net/1808/10692
dc.description.abstractSkin disorders are often associated with immune and nervous system dysfunction. Intraepidermal nerve fibers (IENFs) detect mechanical, thermal, and noxious stimuli. Although immune cells such as mast and T cells can alter IENFs, it is unclear whether Langerhans cells (LCs), the resident antigen-presenting cell of the skin, do so as well. These studies examine the relationship between IENFs and LCs. LCs are intimately associated with IENFs, and in vitro studies suggest they possess neurotrophic properties. The objective of the first study was to determine if LCs regulate IENFs in skin by ablating LCs using diphtheria toxin in Lang-DTR mice, a strain genetically engineered to express the diphtheria toxin receptor selectively on LCs. In 1 month old mice, LC depletion resulted in 31% and 43% decreases in IENFs immunoreactive (ir) for the pan-neuronal marker PGP9.5 and calcitonin gene-related peptide (CGRP). CGRP-negative (non-peptidergic) IENFs were unchanged. Therefore, LCs are necessary for maintaining CGRP-ir IENFs. Since IENFs are modulated by neurotrophic factors, we determined if LC depletion results in reduced epidermal neurotrophin gene expression. LC depletion decreased NGF and GDNF gene expression by roughly 75% and 90%, respectively whereas BDNF did not change. Thus, LCs are likely to play a substantial role in epidermal NGF and GDNF production, and loss of CGRP-ir IENFs after LC depletion is likely due to diminished trophic support. Behavioral testing was performed to determine if LC depletion alters thermal and mechanical sensitivity. LC depletion increased mechanical sensitivity but did not affect thermal sensitivity. Therefore, LCs play an essential role in maintaining CGRP-ir IENFs and determining mechanical sensitivity in 1 month old mice. Because age can alter LCs and IENFs, we examined LCs and IENFs in 10 month old control and LC-depleted mice. LC and PGP9.5-ir IENF numbers were reduced in older mice. LC depletion further reduced PGP9.5-ir IENF density by 52%. Numbers of CGRP-ir IENFs did not change, but LC depletion reduced non-peptidergic IENFs by 98%. This implies that LCs exert age-dependent influences on different IENF subtypes, changing from CGRP-ir to non-peptidergic with age. LC depletion did not alter NGF, GDNF or BDNF gene expression in older mice. LCs therefore play a major, age dependent role in determining cutaneous innervation density, neurotrophic factor expression, and mechanical sensitivity. Neuro-immune cell interactions are altered in individuals with diabetes, which may contribute to cutaneous complications. The objective of the second study was to determine if the relationship between LCs and IENFs is altered in the rat with streptozotocin-induced diabetes. Footpad LC density was reduced after 4 weeks of diabetes, and LC density and size were reduced at 16 weeks. We examined if age influenced LCs and IENFs and found the proportion of skin occupied by LCs was increased by 141%, while IENFs were reduced by 37% in older rats. The increase in cutaneous LCs with age may have occurred in response to IENF reductions. PGP9.5-ir IENFs were not affected by diabetes in our rats; however, reductions in LCs apparently preceded nerve reductions reported by others at later times. Overall, this study shows that diabetes reduces LCs, which may lead to decreased immunosurveillance and increased susceptibility to infections, as well as reduced innervation in the later stages of diabetes. Collectively, these data show that LCs are essential in maintaining cutaneous innervation. They appear to play a major, previously unidentified role in determining cutaneous neurotrophin production, shedding light on a new function for these classical `immune' cells. Their importance is underscored by the finding that eliminating LCs substantially reduces cutaneous innervation. Moreover, this is functionally significant given that mice showed pronounced mechanical hypersensitivity after LC depletion. Interestingly, this nerve loss and allodynia are quite reminiscent of the clinical picture in many types of peripheral neuropathies. Further, the findings that LCs are altered by both diabetes and aging is consistent with the idea that factors that contribute to neuropathies also alter LCs. Clearly, additional study is warranted to further define the roles of these neuro-immune cells in regulating peripheral innervation.
dc.format.extent108 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsThis item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
dc.subjectNeurosciences
dc.subjectBiology
dc.subjectIntraepidermal nerve fiber
dc.subjectLangerhans cells
dc.titleTHE DYNAMIC RELATIONSHIP BETWEEN LANGERHANS CELLS AND INTRAEPIDERMAL NERVE FIBERS IN THE MOUSE AND RAT FOOTPAD
dc.typeDissertation
dc.contributor.cmtememberGeiger, Paige C
dc.contributor.cmtememberMcCarson, Kenneth E.
dc.contributor.cmtememberSmirnova, Irina V
dc.contributor.cmtememberWright, Douglas E.
dc.thesis.degreeDisciplineMolecular & Integrative Physiology
dc.thesis.degreeLevelPh.D.
kusw.oastatusna
kusw.oapolicyThis item does not meet KU Open Access policy criteria.
kusw.bibid7643203
dc.rights.accessrightsopenAccess


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