Induction of autoantibodies against tyrosinase-related proteins following DNA vaccination: unexpected reactivity to a protein paralogue.
(17/94)
DNA vaccination against tissue-restricted antigens is a strategy for cancer therapy. Immune tolerance and ignorance of self antigens has been a hurdle for this approach. We have shown that immunization with xenogeneic DNA orthologues elicits tumor immunity. One model that we have developed entails immunization of mice against tyrosinase-related protein-2 (Tyrp2) using cDNA encoding homologous human Tyrp2. A subset of mice immunized with human Tyrp2 developed antibody responses to Tyrp1. Unexpectedly, this was not simply due to cross-reactivity, as mice with anti-Tyrp1 antibodies were not usually the same animals with anti-Tyrp2 antibodies. Although autoimmune vitiligo was frequently observed in mice that had been immunized with Tyrp2, its occurrence was not correlated with the development of antibodies to Tyrp1. This implies that the appearance of anti-Tyrp1 antibodies was not simply a consequence of the destruction of melanocytes by T-cells recognizing Tyrp2. This represents an example of intermolecular determinant recognition, but is not simply due to epitope spreading since antibodies against the antigen targeted by DNA vaccination are not typically detected. (+info)
Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1).
(18/94)
Griscelli syndrome (GS) is a rare autosomal recessive disorder that associates hypopigmentation, characterized by a silver-gray sheen of the hair and the presence of large clusters of pigment in the hair shaft, and the occurrence of either a primary neurological impairment or a severe immune disorder. Two different genetic forms, GS1 and GS2, respectively, account for the mutually exclusive neurological and immunological phenotypes. Mutations in the gene encoding the molecular motor protein Myosin Va (MyoVa) cause GS1 and the dilute mutant in mice, whereas mutations in the gene encoding the small GTPase Rab27a are responsible for GS2 and the ashen mouse model. We herein present genetic and functional evidence that a third form of GS (GS3), whose expression is restricted to the characteristic hypopigmentation of GS, results from mutation in the gene that encodes melanophilin (Mlph), the ortholog of the gene mutated in leaden mice. We also show that an identical phenotype can result from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern. This spectrum of GS conditions pinpoints the distinct molecular pathways used by melanocytes, neurons, and immune cells in secretory granule exocytosis, which in part remain to be unraveled. (+info)
Hypopigmentation in an African patient treated with imatinib mesylate: a case report.
(19/94)
Imatinib mesylate (STI 571, Gleevec) is a potent bcr-abl tyrosine kinase inhibitor. It also inhibits c-kit tyrosine kinase. Imatinib mesylate is active in the treatment of cronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). It is considered by some authorities to be the standard of care in newly diagnosed CML as well as patients in chronic phase who do not have a related match. C-kit and its ligand stem-cell factor regulate melanocyte development and survival. Hypopigmentation in patients receiving imatinib mesylate for CML has been reported recently. In this article, we report a black Nigerian male with GIST, who developed hypopigmentation of distal parts of digits, as well as generalized lightening of skin on the body three months after receiving imatinib mesylate. We believe that this is the first case of hypopigmentation reported in a black patient with GIST. (+info)
Melanoma-associated leukoderma.
(20/94)
A case is presented of a man with a history of melanoma treated with sentinel lymphadenectomy and interferon therapy, who subsequently developed diffuse hypopigmented patches thought to be consistent with a diagnosis of melanoma-associated leukoderma. Clinically, melanoma-associated leukoderma is a diffuse macular hypomelanosis or depigmentation, which often develops at sites distant to the location of the primary melanoma. The leukoderma may be hypomelanotic and mottled or depigmented and milk-white. Spontaneous repigmentation may occur. A recent study has demonstrated that T cells involved in the destruction of neoplastic melanocytes are identical clones of those that accumulate in melanoma-associated leukoderma. (+info)
Imatinib mesylate causes hypopigmentation in the skin.
(21/94)
BACKGROUND: Imatinib mesylate is a tyrosine kinase inhibitor that targets the BCR-ABL protein in CML, c-kit (KIT) and platelet-derived growth factor receptors. In clinical trials with imatinib mesylate, common side effects of nausea, emesis, diarrhea, periorbital edema, fluid retention, and myelosuppression have been documented. METHODS: In this case series, the authors describe unique clinical findings of skin hypopigmentation in six patients with CML who were treated with imatinib mesylate. RESULTS: Most patients developed onset of skin hypopigmentation within the first month of treatment and all of the patients experienced additional drug toxicity. Despite patient susceptibility to toxicity, the presence of hypopigmentation did not appear to predict leukemic cell response or clinical outcome. All six patients established a hematologic response but only two patients had a complete cytogenetic response. Imatinib mesylate induced hypopigmentation also appeared to be reversible and potentially dose related. CONCLUSION: Skin hypopigmentation is a benign side effect from imatinib mesylate treatment that appears to be reversible upon discontinuation or dose reduction. Several lines of evidence have previously reported that KIT and its ligand stem cell factor (SCF) have a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation. The signal transduction mechanism currently is believed to involve SCF ligand binding of KIT and downstream activation of MAP kinase (Erk-2). Microphthalmia (Mi), a basic helix-loop-helix leucine zipper (bHLHZip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73). Once phosphorylated, Mi transactivates the tyrosine pigmentation gene promoter and affects pigment production. (+info)
Characterization of melanosomes in murine Hermansky-Pudlak syndrome: mechanisms of hypopigmentation.
(22/94)
The Hermansky-Pudlak syndrome is a genetically heterogeneous autosomal recessive disorder affecting mice and humans, which causes oculocutaneous albinism, prolonged bleeding, and in some cases, pulmonary fibrosis or granulomatous colitis. We previously demonstrated that the gene defects causing murine Hermansky-Pudlak syndrome cause blocks in melanosome biogenesis and/or trafficking in 10 Hermansky-Pudlak syndrome strains. Here, we report an in vivo quantitative analysis on five additional murine models of the Hermansky-Pudlak syndrome. We demonstrate that all strains examined here except for ashen have defects in morphogenesis, the most severely affected is sandy, muted, and buff followed by subtle gray. The ashen strain only has a defect in secretion, as indicated by retention of melanosomes in melanocytes. We document three cellular mechanisms contributing to the hypopigmentation seen in the Hermansky-Pudlak syndrome: (1) exocytosis of immature hypopigmented melanosomes from melanocytes with subsequent keratinocyte uptake; (2) decreased intramelanocyte steady-state numbers of melanosomes available for transfer to keratinocytes; and (3) accumulation of melanosomes within melanocytes due to defective exocytosis, as seen in ashen. We also report that melanosomes in the DBA/2J strain, the parental strain of the Hermansky-Pudlak syndrome strain sandy, are abnormal, indicating that aberrant biogenesis of melanosomes may play a part in the pathogenesis of pigmentary glaucoma observed in these mice. (+info)
Colocalized nevus depigmentosus and lentigines with underlying breast hypoplasia: a case of reverse mutation?
(23/94)
Nevus depigmentosus (ND) is classically defined as a congenital nonprogressive hypopigmented macule, stable in size and distribution. There have been many reports of colocalization of ND and lentigines. We describe development of multiple lentigines over ND in a 9-year-old girl along with hypoplasia of the underlying breast. The case is being reported to highlight the phenotypic manifestation of reverse mutation and the coincidental breast hypoplasia that has not been reported before. (+info)
Electrophysiological characterisation and monitoring in the management of birdshot chorioretinopathy.
(24/94)
AIMS: To characterise patients with birdshot chorioretinopathy (BCR) clinically and electrophysiologically in order to monitor changes in retinal function before and after treatment with corticosteroids and/or immunosuppression. METHODS: 18 patients with BCR were characterised clinically and electrophysiologically. Serial studies were performed on 14 patients in order to monitor changes in retinal function before and after treatment with corticosteroids and/or immunosuppression. RESULTS: Most patients presented with characteristic subretinal pale spots, were HLA-A29 positive, and had diverse signs of ocular inflammation. Various electrophysiological abnormalities were present. Moderately severe bilateral pattern electroretinogram (PERG) abnormalities at presentation were common, reflecting macular dysfunction. Cone mediated 30 Hz flicker electroretinograms (ERGs) were consistently delayed before treatment, and were the most sensitive parameter of retinal dysfunction. Scotopic maximal ERG responses were abnormal in 13 patients; 10 had an electronegative maximal ERG or a reduced b:a ratio in one or both eyes. Single flash photopic ERGs were less often and less severely affected. Photopic ON and OFF ERG responses often revealed predominant ON response b-wave abnormalities with relative OFF response preservation. ERGs improved in treated cases, sometimes preceding clinical signs of recovery. Pattern ERG improvements occurred, possibly reflecting the resolution of macular oedema. CONCLUSIONS: The ERG data confirm that BCR frequently affects inner retinal function of cone and rod systems. Clinical features were not reliable indicators of functional deterioration or recovery. Objective electrophysiological assessment of retinal function demonstrated improvement following treatment and provides a reliable method of monitoring treatment efficacy, enabling management decisions to be taken with greater confidence and allowing early initiation or modification of treatment. (+info)