Bakgrund: Människans försvar mot omvärlden och patogena mikrober består av ett väl utvecklat immunsystem innehållande det medfödda immunsystemet, innate, som inte förändras nämnbart över tid samt det adaptiva immunsystemet som skapar minnesceller efter immunrespons på peptidantigen. Det medfödda immunsystemets receptorer binder främmande strukturer och agerar snabbt genom att skapa inflammatorisk respons. Människans adaptiva immunsystem har celler som tar upp, bryter ned och via major histocompatibility complex (MHC) presenterar peptidantigen för T-celler. T-celler behöver flera stimuleringsvägar för att starta immunrespons. Immunsystemets celler kontrolleras så immunologisk tolerans upprätthålls. Autoimmunitet orsakas troligen av genetisk känslighet där den genetiska dispostitionen inte kan upprätthålla immunologisk tolerans vid trauma. Alopecia areata och vitiligo är de enda kända autoimmuna hudsjukdomarna som inte är antikroppsmedierade. Sjukdomarna drabbar 1 – 2 % av befolkningen. Hårfolliklar attackeras av autoreaktiva T-celler vid alopecia areata vilket ger håravfall. Vitiligo ger depigmenterade hudområden orsakat av autoreaktiva T-celler som förstört melanocyter. Sjukdomarna behandlas med immunsuppressiva läkemedel lokalt på huden eller systemiskt. Syfte: Examensarbetet syftade till att erhålla en djupare kunskap rörande likheter och skillnader i mekanism mellan de autoimmuna hudsjukdomarna alopecia areata och vitiligo samt undersöka och besvara frågeställningen vilken effekt olika typer av immunsuppressiv behandling har vid dessa sjukdomar.  Metod: Examensarbetet är en litteraturstudie som baseras på sex stycken vetenskapliga artiklar framsökta ur databasen PubMed genom flera sökningar. Sökningarna avgränsades genom användande av bl.a. sökorden alopecia areata, vitiligo, treatment, tacrolimus och janus kinase. Resultat: Studie 1 och 2 utvärderar systemisk puls-behandling med glukokortikoider. Patienterna i studie 1 hade alopecia areata med omfattande håravfall och behandlingsrespons sågs hos många patienter. Vitiligo-patienterna i studie 2 uppvisade minskad sjukdomsaktivitet vilket ses i färre nya lesioner samt repigmenterade lesioner, dock ses ingen repigmentering hos en del patienter. Studie 3 och 4 utvärderar lokal behandling med takrolimus-salva. Patienter med vitiligo i studie 3 fick viss repigmentering av lesionerna och patienterna med alopecia areata i studie 4 fick delvis håråterväxt. Effekten av oralt administrerade januskinas-hämmare utvärderas i studie 5 och 6. Studie 5 visar att många patienter med alopecia areata fått mycket håråterväxt vid behandlingens slut och studie 6 påvisar behandlingsrespons hos hälften av vitiligo-patienterna där repigmentering främst ses på hudområden exponerade för solljus. Slutsats: Litteraturstudien visar att olika typer av immunsuppressiv behandling kan lindra sjukdoms-utbrott samt förkorta sjukdomstid vid de autoimmuna hudsjukdomarna alopecia areata och vitiligo. Immunologiskt sett har sjukdomarna liknande sjukdomsmekanismer genom inflammatorisk respons som ger aktivering av autoreaktiva T-celler. Behandlingsresistensförekommer och därför behövs fortsatt forskning kring sjukdomsmekanismer och nya läkemedel. / Humans are depending on a functional immune system that provides defense against microbes and other things in our environment that can harm us. The skin is the largest and the heaviest of our organs. It’s important to have a barrier between the inner functions of the body and the world outside. The innate immune system specificities are recognition of microbes and damage. The adaptive immune system includes B and T cells which develops from stem cells in the bone marrow. The mature B and T cells are tested for self-tolerance before they are released. Having a functional immune system needs immunologic cells with immunologic tolerance. Immunologic tolerance demand B and T cells to know the difference between self antigens and pathogens.  Autoimmunity is probably caused by genetic susceptibility under influence of trauma such as local tissue injury and infection. The trauma cause imbalance in the immune system and gives an autoimmune response with activated T cells reacting on self antigens. Autoimmune diseases can be systemic or organ specific and different mechanisms cause the damage of tissue. Diseases caused by autoimmunity tend to be chronic, self-perpetuating and progressive. Alopecia areata and vitiligo are autoimmune skin diseases which gives hair loss and depigmentation. Hair loss in alopecia areata is caused by autoimmune T cells attacking hair follicles and depigmentation in vitiligo is caused by destruction of melanocytes by autoimmune T cells. The diseases can’t be cured but immunosuppressive therapy can reduce disease activity and give faster recovery.  The aim of this literature study was to get a deeper knowledge about the autoimmune skin diseases alopecia areata and vitiligo, and evaluate the efficiency of different immunosuppressive therapies used against alopecia areata and vitiligo. Found six scientific articles from the database PubMed through several searches. The searches were delimited by use of the keywords alopecia areata, vitiligo, treatment, tacrolimus and janus kinase.  Studies 1 and 2 evaluate systemic pulse management with glucocorticoids. The patients in study 1 had alopecia areata with extensive hair loss and treatment reactions were seen in many patients. Vitiligo patients in study 2 show reduced disease activity as seen in fewer lesions as well as repigmented lesions, however, no repigmentation seen in some patients. Studies 3 and 4 evaluate local treatment with tacrolimus ointment. Patients with vitiligo in study 3 received some repigmentation of the lesions and the patients with alopecia areata in study 4 received partial hair regrowth. The effect of orally administered janus kinase inhibitors is evaluated in studies 5 and 6. Study 5 shows that many patients with alopecia have received a lot of hair regrowth at the end of treatment and study 6 shows treatment response in half of vitiligo patients where repigmentation is mainly seen in sunlight exposed areas.  The literature study shows that different types of immunosuppressive treatment can relieve disease outbreaks and shorten disease in autoimmune skin diseases alopecia areata and vitiligo. Immunologically the diseases have similar disease mechanisms through inflammatory responses that provide activation of autoreactive T cells. Conclusion of this smallscale literature study is the need for further research on mechanisms of the diseases and research on therapies because therapy resistance is seen in both diseases although many patients responded to the immunosuppressive therapies.

Made available in DSpace on 2016-04-28T20:39:13Z (GMT). No. of bitstreams: 1 Dissertacao Marcia Yuri Funabashi.pdf: 436435 bytes, checksum: 05dd978753a97d140a232a0e634f0457 (MD5) Previous issue date: 2006-05-31 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A investigação psicanalítica das manifestações somáticas levanta o enigma acerca da sua causalidade psíquica ao apostar na associação entre as vicissitudes destas doenças e questões da subjetividade. O tema desta dissertação retoma este impasse a partir da construção psicopatológica no caso Flora. Flora procura análise com a demanda de um saber sobre a alopecia areata universal, manifestação somática que rompeu com a sua lógica, deixando-a num completo desamparo. Ao tecer uma construção simbólica em torno da doença, Flora vai nos revelando a especificidade deste fenômeno. O conteúdo desta dissertação é uma mostra possível de um trabalho de elaboração em busca da palavra representativa do vivido na clínica. A construção metapsicológica resultante desta trajetória segue o pensamento da psicopatologia fundamental, sendo um produto de inúmeras reformulações promovidas pela escuta clínica e pelo constante diálogo com a teoria freudiana, de seus contemporâneos e com o discurso médico. Ao longo deste percurso de pesquisa, o estudo sobre a topologia lacaniana produziu um sentido na vivência clínica, ao sustentar que o corpo se estrutura a partir da articulação dos registros real, simbólico e imaginário, estabelecendo uma lógica precisa. Sendo assim, encontramos neste pensamento um eixo teórico para a compreensão da alopecia areata no caso Flora, através da investigação da estrutura presente nesta manifestação somática. A fim de alcançarmos uma maior compreensão acerca desta topologia de Lacan, realizamos uma releitura da metapsicologia freudiana, buscando resgatar idéias que deram subsídios para a proposta lacaniana. Com isso, juntamente com o retorno a Freud, avançamos com a posição de Lacan

A general goal to my study was to promote an inclusive approach to baldness by sharing and centering women's experiences with baldness from skin and hair conditions, such as autoimmune alopecia areata conditions and monilethrix. Specifically, a main goal of my study was to her-storicize the lived experiences of women who are bald from skin and hair conditions by examining medical and cultural discourses surrounding these conditions, femininity, and female baldness. Additionally, my study considers strategies of accommodation and resistance that bald women perform in a given context, space, or time. For instance, I consider the ways participants manage their conditions and baldness within certain contexts. To achieve these goals, I interviewed four women who are bald from alopecia areata, alopecia totalis, alopecia universalis, and monilethrix by using an interactive approach to the interviews. Once the interviews were completed, I used interpretative phenomenological analysis to extract themes across the four interviews. Based on the analysis, I organized the findings into two overarching themes that include (a) navigating the feminine ideal and (b) negotiating the assumptions of illness and female baldness. In these themes, I discuss how participants' experiences demonstrate the significance of accommodating and/or resisting hegemonic notions of femininity and illness.

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.

Syftet med denna litteraturstudie var att beskriva sjuksköterskans omvårdnadsåtgärder gentemot patienter med cancer vid cytostatikarelaterat håravfall, fatigue, illamående och kräkning. De vetenskapliga artiklar som användes för denna litteraturstudie hämtades ur Högskolan Dalarnas databaser Elin@Dalarna och PubMed. Efter kvalitetsgranskning och betygsättning av artiklarna kvarstod 18 artiklar som ansågs relevanta och låg till grund för resultatet av denna studie. Samtliga artiklar bedömdes ha en god vetenskaplig kvalitet. Resultatet av denna litteraturstudie visade att behandling mot håravfall med kylmössa hade god effekt men att biverkningarna kunde vara svåra att uthärda. Information från sjuksköterskan om sminkningsteknik och användning av peruk, upplevdes av patenten vara viktig vid håravfall. Regelbunden träning och avslappningsövningar hade en positiv effekt på fatigue. Sjuksköterskans information till patienter om fatigue och egenvårdsåtgärder, visade sig också vara till hjälp för patienterna. Vidare lindrade akupressur besvären vid illamående och kräkning. Sjuksköterskornas regelbundna kontroller av cytostatikarelaterade biverkningar förbättrade omvårdnadens kvalitet

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.

Androgens are the main regulators of human hair growth stimulating larger, terminal hair development e.g. beard and causing scalp balding, androgenetic alopecia. Hair disorders cause psychological distress but are poorly controlled. Androgens probably act by altering regulatory paracrine factors produced by the mesenchyme-derived dermal papilla. This study aimed to investigate paracrine factors involved in androgen-regulated alopecia, particularly hepatocyte growth factor (HGF) family members, by investigating their in vivo status. Balding and non-balding scalp hair follicles and their component tissues were isolated and analysed by molecular biological methods (reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative PCR and DNA microarray analysis), cell culture and immunohistochemistry. Scalp follicles expressed a range of paracrine messenger genes. The dermal papilla, cultured dermal papilla cells and dermal sheath expressed several HGF family genes, while matrix cells only produced the receptor RON suggesting autocrine roles for HGF and MSP, but a paracrine route only for MSP. Comparing balding and non-balding follicles from the same individuals revealed the expected reduction in several keratin and keratin-related protein genes supporting this approach's validity. There were also significant differences in paracrine factors previously implicated in androgen action by in vitro studies. Several factors believed to increase during androgen stimulation of larger, darker follicles, e.g. IGF-I and SCF, were lowered in balding follicles, while putative inhibitory factors, e.g. TGFß-1, were increased. HGF and MSP and their receptors, c-Met and RON, were significantly reduced. These results increase our understanding of androgen action in human hair follicles; this could lead to better treatments for hair disorders.

Hair growth disorders cause significant psychological distress, but are poorly controlled. Since prostaglandin F₂α (PGF₂α) and prostamide F₂α analogue glaucoma treatments cause eyelash growth as side-effects, they may be useful for alopecia. How they function is unknown; possibilities include direct action on hair follicles or stimulating follicular blood flow. It is important to clarify whether scalp follicles can also respond as human follicle response to androgens differ with body site. Therefore, human scalp follicles were grown in vitro in organ culture with PGF₂α, latanoprost, a PGF₂α analogue, and bimatoprost, a prostamide F₂α analogue, with, or without, appropriate antagonists, and the presence of PGF₂α (FP) and prostamide F₂α receptors were investigated using molecular biological and immunohiostochemical methods. Each treatment significantly stimulated follicle growth rate, the percentage of growing follicles, and the amount of hair produced in a dose-responsive manner (10nM-1μM); the receptor antagonists blocked these effects. Immunohistochemistry of frozen scalp sections demonstrated FP protein only in dermal papillae and connective tissue sheaths. RT-PCR identified FP and various prostamide F₂α receptors in anagen follicles and isolated dermal papillae and bulbar connective tissue sheath, but not in bulb matrix or other epithelial tissues. Therefore, isolated human scalp hair follicles can respond biologically to PGF₂α and related pharmaceuticals in organ culture via follicular receptors and express the genes and protein for FP and prostamide F₂α receptors. PGF₂α-related drugs appear to act directly on follicles via receptors in the regulatory dermal papilla. They offer an exciting, novel approach for treating alopecia and merit clinical investigation.

Orientador: Lilia F. R. de Souza Li / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T11:10:27Z (GMT). No. of bitstreams: 1 Macedo_LuciaCosentinode_M.pdf: 2481805 bytes, checksum: 85ab094926dbe8ad65a47ec2c1c6fcf5 (MD5) Previous issue date: 2006 / Resumo: A 1,25-dihidroxivitamina D é de fundamental importância na homeostase do cálcio. A vitamina D exerce suas ações através da interação com o seu receptor. O receptor da vitamina D (VDR) é membro da superfamília de receptores nucleares. O raquitismo é uma doença causada por mineralização deficiente na matriz óssea ou osteóide, afetando o desenvolvimento e a formação do osso na fase de crescimento. Mutações no receptor da vitamina D causam raquitismo dependente de vitamina D tipo II. Neste tipo de raquitismo ocorre hipocalcemia e as concentrações séricas de 1,25-dihidroxivitamina D3 são elevadas e, na maioria das vezes não há resposta ao tratamento com doses altas de 1,25-dihidroxivitamina D. Pacientes apresentam raquitismo grave de inicio precoce, nos primeiros meses de vida e a maior parte dos indivíduos apresenta pouco ou nenhum pêlo corporal (alopecia). O objetivo principal deste projeto foi a análise molecular do receptor de vitamina D (VDR) em quatro pacientes com raquitismo dependente de vitamina D tipo n que manifestaram raquitismo e alopecia. Amostras de DNA destes pacientes foram usadas para sequenciar o gene do VDR. Os cromatogramas gerados foram analisados em programas específicos, visando a busca de mutações. A análise mostrou 2 novas mutações pontuais que resultam em mudança de aminoácido (Q259E e G319V) e uma mutação que introduz um codon terminal (R73X). A cultura primária de fibroblasto proveniente de biópsia de pele dos pacientes foi usada para análise funcional do receptor. Extrato proteico nuclear mostrou redução de expressão de todos os receptores mutados. O receptor truncado contendo apenas parte do domínio de ligação com o DNA perdeu o epítopo de interação com o anticorpo usado, não sendo identificado no Western blot pelo anticorpo utilizado, impossibilitando a avaliação de sua expressão. Tratamento da cultura primária de fibroblasto com doses crescentes de l,25(OH)2 vitamina D demonstrou que os VDRs mutados foram incapazes de ser ativado e aumentar a expressão de 24-hidroxilase. Este trabalho identificou mutações em quatro pacientes com raquitismo dependente de vitamina D tipo II e estas mutações resultaram em comprometimento funcional do VDR / Abstract: The 1,25-dihydroxyvitamin D plays a fundamental role in the calcium homeostasis. The vitamin D exerts its actions through the interaction with its receptor. The vitamin D receptor (VDR) is a member of the superfamily of nuclear receptors. Rickets is a disease caused by deficient mineralization in the bone matrix or osteoids, affecting the development and formation of the bone during the growth stage. Mutations in the vitamin D receptor are associated to the vitamin D-dependent rickets type II. The biochemical characteristics is hypocalcemia and increase levels of 1,25-dihydroxyvitamin D3, and most of time there is no answer to the treatment with high doses of 1,25-dihydroxyvitamin D. Patients present rickets and or osteomalacia of varying severity beginning in the first months of life and most of the individuals presents little or any body hair (alopecia). The main objective of this project was the molecular analysis of the vitamin D receptor (VDR) in four patients with vitamin D-dependent rickets type II that manifested with rickets and alopecia. DNA samples of these patients were used to sequence the VDR gene. The generated chromatograms were analyzed in specific programs, aiming the search of mutations. The analysis showed two novel missense mutation that result in amino acid change (Q259E e G319V) and one nonsense mutations (R73X). Fibroblast primary culture derived from the patients' skin biopsy was carried out for functional analysis of the receptor. Nuclear protein extract showed reduction of expression of all mutant receptors. The truncated VDR receptor containing only part of the DNA binding domain lost the region containing the epitopo which the antibody was raised against and it was not identified by the Western blot analysis. Treatment of the fibroblast primary culture treatment with increasing doses of l,25(OH)2 vitamin D showed that the mutant VDR were unable to be activated and to increase the expression of the 24-hydroxylase. It was found mutations in the four patients with vitamin D-dependent rickets type II studied. Functional analysis confirmed that the mutations impaired the VDR activation / Mestrado / Mestre em Farmacologia

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. / Medicine, Faculty of / Medicine, Department of / Experimental Medicine, Division of / Graduate