neuropeptide-y and Vitiligo

Vitiligo is an autoimmune disease characterized by depigmented patches of skin due to loss of the pigment-producing melanocytes. No cure exists for vitiligo. The available treatments are inefficient for many patients, suggesting that universal treatment approaches may be inappropriate. Deeper understanding of the mechanistic basis for variability in vitiligo aetiologies is necessary. Genetic mutations in neuropeptide Y (NPY), a widely distributed protein, are associated with increased NPY expression and increased susceptibility for vitiligo. NPY is also upregulated in the circulation and lesional skin of some vitiligo patients. However, the contributions of NPY to melanocyte pathology are not understood, and presently there are no models with which to investigate this possibility. In this study, we employed NPY-overexpressing mice to explore the role of NPY in melanocyte dysfunction. Our results show that NPY overexpression induces progressive hair greying (depigmentation) due to premature depletion of follicular melanocyte stem cells. Additionally, NPY transcripts and protein are elevated in the skin and melanocytes of these mice, respectively, suggesting that these effects may be mediated locally. Together, these results suggest that supraphysiological levels of NPY in the skin can induce melanocyte dysfunction, thus identifying this mouse line as a novel model to study NPY-mediated melanocyte pathology.

Topics: Animals; Disease Models, Animal; Female; Male; Melanocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Vitiligo

Vitiligo is a depigmenting disorder resulting from loss of functional melanocytes in the skin. NPY plays an important role in induction of immune response by acting on a variety of immune cells. NPY synthesis and release is governed by IL1B. Moreover, genetic variability in IL1B is reported to be associated with elevated NPY levels.. Aim of the present study was to explore NPY promoter -399T/C (rs16147) and exon2 +1128T/C (rs16139) polymorphisms as well as IL1B promoter -511C/T (rs16944) polymorphism and to correlate IL1B transcript levels with vitiligo.. PCR-RFLP method was used to genotype NPY -399T/C SNP in 454 patients and 1226 controls; +1128T/C SNP in 575 patients and 1279 controls and IL1B -511C/T SNP in 448 patients and 785 controls from Gujarat. IL1B transcript levels in blood were also assessed in 105 controls and 95 patients using real-time PCR.. Genotype and allele frequencies for NPY -399T/C, +1128T/C and IL1B -511C/T SNPs differed significantly (p<0.0001, p<0.0001; p = 0.0161, p = 0.0035 and p<0.0001, p<0.0001) between patients and controls. 'TC' haplotype containing minor alleles of NPY polymorphisms was significantly higher in patients and increased the risk of vitiligo by 2.3 fold (p<0.0001). Transcript levels of IL1B were significantly higher, in patients compared to controls (p = 0.0029), in patients with active than stable vitiligo (p = 0.015), also in female patients than male patients (p = 0.026). Genotype-phenotype correlation showed moderate association of IL1B -511C/T polymorphism with higher IL1B transcript levels. Trend analysis revealed significant difference between patients and controls for IL1B transcript levels with respect to different genotypes.. Our results suggest that NPY -399T/C, +1128T/C and IL1B -511C/T polymorphisms are associated with vitiligo and IL1B -511C/T SNP influences its transcript levels leading to increased risk for vitiligo in Gujarat population. Up-regulation of IL1B transcript in patients advocates its possible role in autoimmune pathogenesis of vitiligo.

Topics: Exons; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; India; Interleukin-1beta; Linkage Disequilibrium; Male; Neuropeptide Y; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; RNA, Messenger; Sex Factors; Vitiligo

In order to study the possible role of neuropeptide-Y (NPY) in the pathogenesis of vitiligo, the authors measured the levels of NPY in the plasma from 47 patients with vitiligo compared with 25 healthy volunteers, and the tissue fluids of skin lesions and uninvolved skin from 32 patients, employing a NPY 125I RIA Kit. The results showed that the levels of NPY in the patients with vitiligo of all of the generalized, local and segmental types were significantly higher than the normal controls. In both local and segmental type, the levels in progressive stage were significantly higher than those in stable stage, while in generalized type, there was no significant difference between those in progressive stage and stable stage. The levels of NPY in the tissue fluids from skin lesions were significantly higher than those from uninvolved skin in both the local type and segmental type, while in the generalized type, there was no significant difference between the NPY level in the tissue fluid from skin lesion and that from uninvolved skin. It is speculated that NPY may play certain roles in the pathogenesis of vitiligo, via neuro-immunity mechanism or neuronal affection on the melanocytes.

Topics: Adolescent; Adult; Aged; Blood; Body Fluids; Child; Female; Humans; Male; Middle Aged; Neuropeptide Y; Skin; Vitiligo

Skin distribution of substance P (SP)-, somatostatin (SOM)-, calcitonin-gene-related peptide (CGRP)- and neuropeptide-Y (NPY)-like immunoreactivity in vitiligo patients was studied by an indirect immunofluorescence technique. Immunocytochemical characteristics of the epidermis, dermoepidermal junction, papillary and reticular dermis, and skin appendages were analyzed in lesional and marginal vitiligo areas as well as in healthy skin. SP-, SOM-, CGRP-, and NPY-immunoreactive nerve fibers were observed in healthy pigmented skin, with patterns specific for immunoreactive distribution. Thin SP-containing fibers were observed in dermal papillae, extending into the epidermis, and SP-immunoreactive nerve fibers were seen around blood vessels and sweat glands. SOM-immunoreactive varicose nerve fibers were associated with Meissner's corpuscles in dermal papillae, while CGRP-like immunoreactivity was demonstrated in free subepidermal nerve terminals and sensory nerve fibers around blood vessels, hair follicles and sweat glands. Autonomic NPY-containing nerve fibers innervated eccrine sweat glands and blood vessels. The distribution of these neuropeptides was the same in healthy controls, except for an increased immunoreactivity to NPY and to a lesser extent to CGRP. These results suggest that NPY may serve as a neurochemical marker in the pathogenesis of the disease, thus supporting the neuronal theory of vitiligo.

Topics: Calcitonin Gene-Related Peptide; Female; Humans; Immunohistochemistry; Male; Nerve Fibers; Neuropeptide Y; Neuropeptides; Skin; Somatostatin; Substance P; Vitiligo

Skin distribution of substance P (SP)-, somatostatin (SOM)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (LI) in vitiligo patients was studied by an indirect immunofluorescence technique. Immunocytochemical characteristics of the epidermis, dermal-epidermal junction, papillary and reticular dermis and skin appendages were analyzed in lesional and marginal vitiligo areas, as well as in healthy skin. In healthy pigmented skin, SP-, SOM-, CGRP-, and NPY-LI nerve fibers were observed with specific distributional patterns. In uninvolved vitiligo skin, thin SP-containing fibers were evident in dermal papillae, extending into the epidermis, and SP-LI fibers were seen around blood vessels and sweat glands. SOM-LI varicose nerve fibers were associated with Meissner corpuscles in the dermal papillae, while CGRP-LI was demonstrated in the free subepidermal nerve terminals and in sensory nerve fibers around blood vessels, hair follicles and sweat glands. Autonomic NPY-nerve fibers innervated the eccrine sweat glands and blood vessels. The distribution of these neuropeptides in both marginal and lesional areas of vitiliginous skin was the same as in the skin of healthy control subjects, except for an increased immunoreactivity against NPY and, to a lesser extent, against CGRP in the skin depigmentation lesions. The elevated NPY levels in skin affected by vitiligo suggest that this peptide may serve as a neurochemical marker in the pathogenesis of the disease, thus supporting the neuronal theory of vitiligo.

Topics: Adult; Biomarkers; Blood Vessels; Calcitonin Gene-Related Peptide; Female; Fluorescent Antibody Technique, Indirect; Humans; Male; Melanocytes; Nerve Fibers; Neurons, Afferent; Neuropeptide Y; Skin; Skin Pigmentation; Somatostatin; Substance P; Sweat Glands; Vitiligo

Pioneering studies both in humans and animals have demonstrated an association between the peripheral nervous system and epidermal melanocyte destruction. The presence of certain neuropeptides and neuronal structural markers in peripheral nerve fibres was investigated in involved and uninvolved vitiligo skin and compared with normal healthy skin. A group of 18 vitiligo vulgaris patients and matched healthy volunteers participated in the investigation. The indirect immunofluorescence technique was employed. There was a tendency for a reduction in the number and intensity of low affinity (p75) nerve growth factor receptor immunoreactive (NGFr-IR) basal keratinocytes in involved vitiliginous skin (P < 0.06) compared with control skin, while the number of NGFr-IR nerve fibres was significantly increased (P < 0.01). The number of calcitonin gene-related peptide (CGRP)-IR nerve fibres in the epidermis and papillary dermis was dramatically increased in involved skin as compared with control skin (P < 0.01) and with uninvolved skin (P < 0.05). No clear difference could be found in the distribution of vasoactive intestinal polypeptide (VIP)- and neuropeptide tyrosine (NPY)-IR nerve fibres. A different structural appearance of the peripheral nervous system as well as a changed balance of neuropeptides in vitiliginous skin point to a critical role of the nervous system in the pathogenesis of vitiligo.

Topics: Adult; Animals; Calcitonin Gene-Related Peptide; Case-Control Studies; Female; Fluorescent Antibody Technique, Indirect; Humans; Keratinocytes; Male; Middle Aged; Nerve Endings; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Peripheral Nerves; Receptors, Nerve Growth Factor; S100 Proteins; Skin; Thiolester Hydrolases; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide; Vitiligo

Neuropeptide and neuronal marker immunoreactivity was studied in skin biopsies from lesional and marginal areas in 12 patients with vitiligo, and in seven normal controls. The vitiligo was active in seven, static in two, and of unknown activity in three. Antibodies against general neuronal marker PGP 9.5 (PGP 9.5), substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY), were used. The epidermis, dermo-epidermal junction, papillary and reticular dermis, and appendages, were assessed semiquantitatively for reactivity with each antibody. Staining with PGP 9.5 in the upper dermis was assessed quantitatively by image analysis. An increase in reactivity against NPY antibody was seen in five of 10 cases (three with active vitiligo) in the marginal areas, and in three of 12 subjects (all with active vitiligo) in the lesional vitiligo areas. VIP antibody reactivity showed a minimal increase in the marginal and lesional vitiligo areas (in two cases each, both of whom had active vitiligo). SP and CGRP reactivities did not differ from normal. PGP 9.5 staining was minimally increased at the dermo-epidermal junction and lower Malpighian layer in biopsies from marginal areas in three of 10 subjects (all with active vitiligo). Quantitative analysis of PGP 9.5 reactivity in the upper dermis showed no difference between vitiligo and normal biopsies. These findings support the concept of neuronal or neuropeptide involvement in vitiligo, and in particular suggest that NPY may have a role in the pathogenesis of the disease.

Topics: Biomarkers; Calcitonin Gene-Related Peptide; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neurons; Neuropeptide Y; Neuropeptides; Skin; Substance P; Thiolester Hydrolases; Tissue Fixation; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide; Vitiligo