Alopecia areata (AA) is a chronic inflammatory disease of hair follicles manifesting as
patchy areas of hair loss on the scalp and body. Development of AA is associated with
pen- and intra-follicular inflammation of anagen stage hair follicles, primarily by CD4+
and CD8+ cells. We hypothesized that if cell-mediated cytotoxicy against hair follicles is
to be a component of the hair loss disease mechanism, increased expression of genes and
products typical of cytotoxic cells, as well as increased apoptosis activity within affected
hair follicles, would be expected to occur in the lesional skin compared to the normal
skin. Furthermore, we studied gene expression levels of multiple cytokines and
characteristic chemokines, using the C3FI/HeJ mouse model of AA. mRNA expression
levels of granzyme A, granzyme B, perform Fas, Fas ligand, TNF-cL, TNF-aRl and R2,
TRAIL, TRAILR, TRAMP, Thi-, Th2-, and Th17-associated cytokines, as well as
multiple chemokines were compared between the skin, draining lymph nodes, thymus
and spleens of normal and AA-affected mice using quantitative reverse transcriptase
PCR. FasL, granzyme A, granzyme B, pro- and anti-inflammatory cytokines were all
highly up-regulated in the skin of AA-affected mice. Immunohistochemical studies of the
skin revealed that, although greater numbers of granzyme B and FasL expressing cells
were present in AA affected skin, the cells were morphologically diffusely distributed
and not exclusively located within the focal pen- and intrafollicular infiltrate. The
majority of these cells were further characterized as mast cells, which were also found in
substantially greater numbers in the skin of mice with AA compared to their normal
haired controls. Almost no perform expressing cells were identified in AA affected
mouse skin and TUNEL staining suggested relatively limited apoptosis activity in hair
follicle keratinocytes. In conclusion, while granzymes and FasL may play important roles
in disease development, the profiles and patterns of expression are not consistent with
direct cell-mediated cytotoxic action against the follicular epithelium in chronic mouse
AA. Potentially, hair growth inhibiting cytokines may play a more dominant role in AA
development than previously thought. Furthermore, mast cells, with their increased
presence around hair follicles in the AA affected mouse skin and their ability to express
granzyme B and FasL, are suggested as potential key players in the pathogenesis of AA.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU./4063 |
| Date | 05 1900 |
| Creators | Barekatain, Armin |
| Publisher | University of British Columbia |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | 3671758 bytes, application/pdf |
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