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Kevin J McElwee

Publications and source records attributed to Kevin J McElwee.

13 recordsLinked to original sources
PubMed2004

Apoptosis resistance in peripheral blood lymphocytes of alopecia areata patients.

Alopecia areata (AA) is a putative, cell-mediated autoimmune disease of anagen stage hair follicles. Inter- and intra-follicular lymphocytic infiltrates are associated with alopecia that may progress from an initially patchy presentation to extensive, even universal, hair loss. We previously noted in a mouse model of AA that regulatory T cells (Treg) are absent from draining lymph nodes and that expression of CD44v7 is transiently upregulated. Both features might explain autoreactive T cell persistence. Here we explored whether similar changes are seen in AA patients' peripheral blood mononuclear cells (PBMC). There was no clear evidence for a reduction in Treg as a possible means to support sustained T cell activation. However, progressive AA patients' PBMC displayed increased resistance towards apoptosis, which was accompanied by a decrease in CD95L+ and an increase in CD44v7+ cells. Notably, an expanded population of CD4+CD25+CD154+ T cells in progressive AA patients' PBMC was apoptosis resistant and expressed CD44v7. Thus, survival of activated T cells in progressive AA patients' PBMC is apparently sustained by downregulation of CD95L and upregulation of CD44v7 which is known to be associated with anti-apoptotic gene expression.

Adolescent↗
PubMed2004

Macrophage-stimulating protein promotes hair growth ex vivo and induces anagen from telogen stage hair follicles in vivo.

Hepatocyte growth factor (HGF) is a promoter of hair follicle growth. We examined another HGF family member, macrophage-stimulating protein (MSP), for its hair follicle-modulating properties. Western blotting revealed presence of mature MSP in cultured human dermal papilla (DP) cells and bulbar dermal sheath (DS) cells, but not non-bulbar DS cells. Immunohistology demonstrated expression of MSP receptor RON in the outer and inner root sheaths, hair matrix cells, DP, and bulbar DS whereas non-follicular epithelium and some cells of the sweat glands exhibited low-level receptor expression. Human hair follicles exposed in vitro for 8 d to 0.1, 1, 10, and 100 ng per mL MSP all yielded a mean net increase in hair follicle length in excess of the mean baseline growth observed in controls. MSP was incubated with agarose beads and injected subcutaneously into mice all 70 d old when a uniform telogen state in dorsal skin was apparent. All eight mice receiving 1 microg MSP, and four of eight receiving 100 ng MSP showed induction of anagen hair growth at the site of bead implantation by 16 d whereas eight mice implanted with saline incubated beads had no hair growth. The data identify MSP as a modulator of hair growth.

Adult↗
PubMed2004

The progressive state, in contrast to the stable or regressive state of alopecia areata, is reflected in peripheral blood mononuclear cells.

Alopecia areata (AA) is a putative autoimmune disease of the skin with an inflammatory component that can be treated by the local application of contact sensitizers. Here, we explored whether responsiveness toward diphenylcyclopropenone (DPCP) is reflected by the composition and the activation state of peripheral blood mononuclear cells (PBMCs). PBMCs of 43 AA patients, 26 treated and 17 untreated, and of 31 healthy volunteers were tested. AA patients' PBMCs differed from that of healthy donors by a slight increase in CD16- and tumor necrosis factor-alpha (TNF-alpha)-expressing cells. These features were independent of the disease state and treatment. Additional changes in the activation state of PBMCs, upregulation of the costimulatory molecules CD40 and CD80, of the accessory molecule CD154, and of interferon-gamma expression were identified only in AA patients where the disease was advancing, i.e. these changes were independent of the extent of hair loss and were not seen in patients with spontaneous or DPCP treatment-induced, regressing AA. Thus, the progressive state of AA is accompanied by a systemic activation of T cells, and the therapeutic efficacy of treatment can be estimated by restoration of the non-activated state. Furthermore, an increase in CD16(+)- and TNF-alpha-expressing cells may contribute to AA susceptibility.

Adolescent↗
PubMed2003

Alopecia areata susceptibility in rodent models.

With our current view of alopecia areata as an autoimmune disease, it is probable that disease development in an individual is dependent on multiple genetic and environmental factors interacting in a complex system. Rodent models afford the opportunity to investigate alopecia areata development and to define the significance of the different factors involved. Recently, rodent model characterization has been conducted using flow cytometry, microarray analysis, and functional studies. From these a pattern of events in alopecia areata development has emerged. Although the preliminary activation events for the onset of alopecia areata remain unknown, the response of the immune system is characterized by antigen presentation and costimulation of lymphocytes in the lymph nodes and skin, a deficiency of CD4+/CD25+ regulatory cells, and an action of activated lymphocytes on hair follicles via Fas/FasL signaling and cytokines. Thus, onset of disease may require appropriate (or inappropriate) expression of stimulatory antigens within the hair follicle, the breakdown of the putative hair follicle immune privilege, the presentation of antigens to the immune system, a failure of immune system regulation, and the ability of the activated immune system to disrupt anagen-stage hair follicles. Once the sequence of events is initiated, it may become a self-perpetuating cycle, with epitope spreading leading to a wider range of targets in chronic alopecia areata. Rodent model studies have provided significant insight into alopecia areata, but much more remains to be explained about the mechanisms of disease development.

Alopecia Areata↗
PubMed2003

Major locus on mouse chromosome 17 and minor locus on chromosome 9 are linked with alopecia areata in C3H/HeJ mice.

Alopecia areata is an autoimmune disease that targets actively growing (anagen) hair follicles in humans, mice, rats, dogs, horses, and cattle. C3H/HeJ mice spontaneously develop alopecia areata from 5 mo of age and older in females and later in males. Frequency of disease approached 20% in a colony by 18 mo of age. C57BL/6J mice do not develop alopecia areata. A segregating F2 population of female mice (n=1096) was generated from crossing these two strains. Alopecia areata (n=138) and clinically normal (n=214) mice were genotyped at 12 mo of age using 211 microsatellite probes. The peak logarithm of odds ratio score on mouse chromosome 17 (10.9) was around marker D17Mit134 at 16.9 cM from the centromere. The mouse histocompatibility locus, H2, the mouse equivalent of human leukocyte antigen in humans, was a likely candidate. Twelve-month-old C3H.SW-H2b/SnJ mice (C3H/HeJ congenic mice in which the H2k purported susceptibility locus was replaced with the H2b purported resistance locus) did not develop alopecia areata, supporting this locus as being important in alopecia areata. A suggestive linkage was also found on mouse Chromosome 9 (logarithm of odds ratio score 2.0) around D9Mit206, 20 cM from the centromere. The interval on mouse Chromosome 17 contains several orthologous genes potentially associated with human alopecia areata.

Alopecia Areata↗
PubMed2003

The pathogenesis of alopecia areata in rodent models.

Rodent models of human disease provide an important tool in the investigation of genetic and environmental activation factors, disease pathogenesis, and the development of new and improved treatments. Up to 20% of aged C3H/HeJ mice and 70% of Dundee Experimental Bald Rats (DEBR) develop alopecia areata (AA), a nonscarring, inflammatory hair loss disease with a suspected autoimmune pathogenesis. These rodent models are currently employed in determining the genetic basis of AA, understanding the mechanisms of disease initiation and progression, and defining potential endogenous and environmental influences. Induction of AA by skin graft transfer between affected and unaffected mice has been employed to examine skin and immune system changes during AA pathogenesis. Manipulation of inflammatory cells in vivo indicates AA is primarily a cell mediated disease with auto-antibody production as a secondary event. Whether the AA activating factors are exogenous or endogenous antigens, or involve normal or aberrant epitope expression remains to be elucidated. However, current research suggests a self contained disease cycle involving four key events: (1) Failure of the putative anagen stage hair follicle immune privilege and exposure of hair follicle located AA inciting epitopes to the immune system; (2) Antigen presentation, costimulation, and activation of responsive lymphocytes by antigen presenting cells; (3) Activated inflammatory cell migration to, and infiltration of, hair follicles; (4) The subsequent disruptive actions of the inflammatory cell infiltrate on the hair follicles. Each of these events is vulnerable to therapeutic intervention, and rodent models will be fundamentally involved in developing new treatments for AA.

Adjuvants, Immunologic↗
PubMed2003

Alopecia areata: treatment of today and tomorrow.

It is the aim of this article to review and appraise available data on treatments for alopecia areata (AA) according to the demands of evidence based medicine. Studies evaluating the efficacy of a treatment for AA should include appropriate controls, use cosmetically acceptable hair regrowth as a parameter for treatment success, include patients with AA totalis, universalis or extensive patchy AA, and exclude patients suffering from AA for less than 3 months. Moreover, the treatment must be safe over a prolonged period of time. Among the various therapeutic approaches presently available for AA, only treatment with contact sensitizers such as diphenylcyclopropenone or squaric acid dibutylester has been shown to be effective in studies that fulfill these criteria. Improved future treatments may be immunosuppressive or immunomodulatory targeting of the autoimmune pathogenesis of AA, or they may otherwise protect hair follicles from the injurious effects of inflammation. Such possible future therapeutic approaches include the incorporation of immunomodulatory agents into liposomes as an improved vehicle; inhibition of apoptosis mediated by the Fas-FasL system; inhibition of the lymphocyte homing receptor CD44v10; induction of tolerance.

Adjuvants, Immunologic↗
PubMed2003

Fas-deficient C3.MRL-Tnfrsf6(lpr) mice and Fas ligand-deficient C3H/HeJ-Tnfsf6(gld) mice are relatively resistant to the induction of alopecia areata by grafting of alopecia areata-affected skin from C3H/HeJ mice.

Alopecia areata is suspected to be a T cell-mediated autoimmune disease of the hair follicle, where Fas is expressed on hair follicles and Fas ligand on perifollicular infiltrates. To elucidate whether the Fas/Fas ligand pathway is of pathogenetic significance in alopecia areata, we investigated whether alopecia areata can be induced in Fas-deficient and Fas ligand-deficient mice and whether alopecia areata develops in Fas-deficient and Fas ligand-deficient skin. Therefore, we induced alopecia areata by grafting alopecia areata-affected C3H/HeJ mouse skin on to C3H/HeJ mice (control), on to Fas ligand-deficient C3H/HeJ-Tnfsf6(gld) mice or Fas-deficient C3.MRL-Tnfrsf6(lpr) mice. All control mice developed alopecia areata, whereas no Fas-deficient mice showed hair loss and two of seven Fas ligand-deficient mice developed only transitory, limited alopecia areata. Moreover, skin from C3H/HeJ mice (control), C3H/HeJ-Tnfsf6(gld) mice, and C3.MRL-Tnfrsf6(lpr) mice was grafted on to C3H/HeJ mice with extensive alopecia areata. Skin grafts from control mice developed hair loss, whereas Fas-deficient and Fas ligand-deficient skin grafts were spared from alopecia areata. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling and immunofluorescence studies revealed an increased number of apoptotic cells and expression of Fas on hair follicles as well as expression of Fas ligand on cells of the perifollicular infiltrate in C3H/HeJ mice with alopecia areata, whereas in Fas-deficient and Fas ligand-deficient mice apoptotic cells were virtually absent in hair follicles. The results suggest that the Fas/Fas ligand pathway plays an important pathogenetic role in alopecia areata.

Alopecia Areata↗
PubMed2003

Cultured peribulbar dermal sheath cells can induce hair follicle development and contribute to the dermal sheath and dermal papilla.

Green fluorescent protein (GFP)-expressing wild-type, and nontransgenic mouse vibrissa follicle cells were cultured and implanted to mouse ears and footpads. Dermal papiller (DP)-derived cells and cells from the peribulbar dermal sheath "cup" (DSC) induced new hair follicles in both implanted ears and footpads, while nonbulbar dermal sheath cells did not. Confocal microscopy revealed that GFP-expressing DP and DSC cells induced hair growth associated with the formation of DP exclusively comprised of fluorescent cells. In mouse ears, but not footpads, fluorescent DP and DSC cells could also be identified in DP along with nonfluorescent cells. DSC cells were characterized in vivo and in vitro by low alkaline phosphatase activity in contrast to high alkaline phosphatase in DP cells. The results indicate transplanted DP and DSC cells were equally capable of DP formation and hair follicle induction. This suggests the DP and peribulbar DSC may be functionally similar. In addition to observing papillae exclusively composed of GFP-expressing cells, DP and DSC cells may also have combined with resident cells to form papillae composed of implanted GFP-expressing cells and host-derived non-GFP-expressing cells. Alkaline phosphatase expression may be utilized as a simple marker to identify hair follicle mesenchyme derived cells with hair follicle inductive abilities.

Alkaline Phosphatase↗
PubMed2002

Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopecia areata.

Alopecia areata, an autoimmune disease affecting anagen stage hair follicles, can be induced by grafting spontaneous alopecia areata affected skin to normal-haired C3H/HeJ mice. As the onset of alopecia areata can be significantly retarded by anti-CD44 variant isoform 10 treatment, it was interesting to explore the underlying disease mechanism. Two weeks after transplanting alopecia areata affected skin, expression of CD44 variant isoforms 3, 6, 7, and 10 was strikingly upregulated as compared with sham-grafted mice. By 6 wk after grafting, CD44 variant isoform levels had returned to normal, whereas in draining lymph nodes, CD44 variant isoform expression was slightly decreased. Leukocytes in the skin of mice with chronic alopecia areata expressed a hematopoietic isoform of CD44 and CD44 variant isoform 6 at an elevated level, but CD44 variant isoform 3 expression was reduced. Cytokine expression in leukocytes of chronic alopecia areata affected skin was higher than in normal-haired controls. Cytokine expression also increased postsurgery in sham and alopecia areata grafted mice, but remained elevated only in mice receiving alopecia areata affected skin. Finally, from the skin of mice with chronic alopecia areata and of mice transplanted with alopecia areata affected skin, an increased number of CD4(+) and CD8(+) cells, but a strongly decreased number of CD4(+)/CD25(+) regulatory T cells was recovered. Thus, expression of CD44 variant isoforms is important for the migration of leukocytes during the initial period of alopecia areata. CD44, however, is apparently not involved in the maintenance of the disease state, which is characterized by high cytokine expression levels, an increased number of CD4(+) and CD8+ cells, but a low level of CD4(+)/CD25(+) suppressor cells.

Alopecia Areata↗
PubMed2002

Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans.

Alopecia areata is a suspected autoimmune hair loss disease. In a rodent model, alopecia areata can be induced in normal haired C3H/HeJ mice by transfer of skin grafts from mice with spontaneous alopecia areata. At weeks 2, 4, 6, and 10 after surgery, grafted mice were euthanized, skin collected and processed for histology, and RNA extracted. Age-matched sham-grafted mice, and mice with and without spontaneous alopecia areata, were similarly processed. For comparison, skin biopsies from alopecia areata and androgenetic alopecia affected humans were also collected. Skin mRNA processed to cDNA was analyzed using Affymetrix mouse 11K and human 6800 gene chip(R) array technology. Microarray results indicated 42 known genes upregulated or downregulated during onset of mouse alopecia areata consistent with an inflammatory cell-mediated disease pathogenesis involving antigen presentation, costimulation, and a T helper 1 lymphocyte response. In contrast, 114 genes, many regulating immunoglobulin response, were altered late in disease development. In alopecia areata affected humans, 95 genes were significantly modulated. As confirmation of microarray analysis results, lymph node and spleen cells from alopecia areata affected mice injected into normal haired littermates transferred the alopecia areata phenotype. Alopecia areata onset could be inhibited in skin-grafted mice by modulation with B7.1- and B7.2-specific monoclonal antibodies. In addition, depletion of CD4+ CD8+ expressing cells in chronic alopecia areata affected mice using monoclonal antibodies permitted hair regrowth. The results consistently demonstrated the importance of an immune cell-mediated disease mechanism in alopecia areata pathogenesis and suggested targeting antigen-presenting cells and reactive lymphocytes may be effective in alopecia areata treatment.

Adoptive Transfer↗
PubMed2002

Resistance to alopecia areata in C3H/HeJ mice is associated with increased expression of regulatory cytokines and a failure to recruit CD4+ and CD8+ cells.

Grafting alopecia areata affected C3H/HeJ mouse skin to littermates induces alopecia areata, but high dietary soy oil reduces alopecia areata susceptibility. Alopecia areata affected and resistant mice were characterized to evaluate possible mechanisms involved in alopecia areata resistance. Of 44 mice that received alopecia areata affected skin grafts but failed to develop alopecia areata, only two of 22 receiving further alopecia areata affected skin grafts developed alopecia areata, whereas 39 of 44 controls developed alopecia areata. Alopecia areata affected skin contained increased numbers of CD4+ and CD8+ cells, increases in pro inflammatory T helper 1 and T helper 2 type cytokines, and upregulation of CD28, CD40L, and their ligands. In draining lymph nodes, a relatively high number of antigen-presenting cells was recovered, whereas several CD44v variants were downregulated. In contrast, alopecia areata resistant mouse skin did not display increased numbers of CD4+ and CD8+ cells, whereas counter-regulatory cytokines interleukins 4 and 10 were upregulated. High expression of CD28, CD80, CD86, CD40, CTLA4, CD44v variants, and FasL occurred in alopecia areata resistant mouse spleens. In vitro, lymph node cells of susceptible and resistant mice responded equally to a mitogenic stimulus, but only lymph node cells from alopecia areata affected mice displayed an increased response with T cell receptor stimulation via anti-CD3 cross-linking. These results suggest alopecia areata is a cell-mediated autoimmune disease, but alopecia areata affected skin graft hosts may resist alopecia areata onset through active counter-regulatory mechanisms. Because alopecia areata resistant mice showed unimpaired responsiveness and a transient inflammatory response towards the graft, it is suggested that alopecia areata develops as a consequence of an inappropriate immune response regulation.

Alopecia Areata↗