Maintenance of Hair Follicle Immune Privilege Is Linked to Prevention of NK Cell Attack

Hair follicles (HFs) enjoy a relative immune privilege (IP) that is characterized by downregulation of major histocompatibility complex (MHC) class I and local expression of potent immunosuppressants. Normally, natural killer (NK) cells attack cells with absent/low MHC class I expression. However, because few perifollicular NK cells are found around healthy human anagen HFs, we asked how HFs escape from NK cell attack. This study suggests that this happens via an active NK cell suppression. Alopecia areata (AA), an organ-specific autoimmune disease thought to result from a collapse of HF-IP, in contrast, shows striking defects in NK cell inhibition/containment. We show that the NK cell inhibitor macrophage migration inhibitory factor is strongly expressed by the HF epithelium, and very few CD56+/NKG2D+ NK cells are observed in and around normal anagen HFs compared to AA with prominent aggregations of CD56+/NKG2D+ NK around AA-HFs. By flow cytometry, many fewer NK function-activating receptors (NKG2D, NKG2C) and significantly more killer cell Ig-like receptors-2D2/2D3 were found to be expressed on peripheral blood CD56+ NK cells of healthy controls than on those of AA patients. In addition, only weak immunoreactivity for MHC class I chain-related A gene was observed in normal anagen HFs compared to AA. To our knowledge, this defect is previously unreported and must be taken into account in AA pathogenesis and its management

A Bioinformatics Filtering Strategy for Identifying Radiation Response Biomarker Candidates

The number of biomarker candidates is often much larger than the number of clinical patient data points available, which motivates the use of a rational candidate variable filtering methodology. The goal of this paper is to apply such a bioinformatics filtering process to isolate a modest number (<10) of key interacting genes and their associated single nucleotide polymorphisms involved in radiation response, and to ultimately serve as a basis for using clinical datasets to identify new biomarkers. In step 1, we surveyed the literature on genetic and protein correlates to radiation response, in vivo or in vitro, across cellular, animal, and human studies. In step 2, we analyzed two publicly available microarray datasets and identified genes in which mRNA expression changed in response to radiation. Combining results from Step 1 and Step 2, we identified 20 genes that were common to all three sources. As a final step, a curated database of protein interactions was used to generate the most statistically reliable protein interaction network among any subset of the 20 genes resulting from Steps 1 and 2, resulting in identification of a small, tightly interacting network with 7 out of 20 input genes. We further ranked the genes in terms of likely importance, based on their location within the network using a graph-based scoring function. The resulting core interacting network provides an attractive set of genes likely to be important to radiation response

Neurocognitive impairment in relation to glutathione S-transferase enzyme polymorphisms among medulloblastoma patients

Background. Medulloblastoma is a type of brain cancer that accounts for approximately 7-8% of all intracranial tumors and 20-30% of pediatric brain tumors. It is the most common type of malignant brain tumor in childhood. It was reported that majority of survivors with medulloblastoma have social problems, endocrine deficits, and neurological complications. Furthermore, all had significant deficits in neurocognitive functioning. Glutathione S-transferases belong to a family of isoenzymes that catalyze the glutathione conjugation of a variety of electrophilic compounds. Objective. We aimed to determine whether the development of neurocognitive impairment is associated with GST polymorphisms among children and adolescents diagnosed with medulloblastoma (MB) after radiation therapy. Methods. A pilot study composing of 16 children and adolescents diagnosed with MB at Texas Children\u27s Cancer Center was conducted. The t-test was used to determine if the GST polymorphisms were related to neurocognitive impairment and logistic regression was performed to explore association between GST polymorphisms and gender, age at diagnosis, race/ethnicity, and risk group. Results. An association was observed between GSTT1 polymorphism and cognitive impairment one year after radiation and GSTM1 polymorphism two years after radiation. It was observed that patients with GSTT1 null genotype have lower performance IQ (p=0.03) and full scale IQ (p=0.02) one year after radiation and patients with GSTM1 null genotype have lower verbal IQ (p=0.02) two years after radiation. Patients under age 8 have a statistically non-significant higher risk of having not null genotypes compared to those older than age 8 (OR= 7.5, 95%CI: 0.62-90.65 and OR= 2.63, 95%CI: 0.30-23.00 for GSTT1 and GSTM1 respectively). Conclusion. There was a significant association between GSTT1 polymorphism and cognitive impairment one year after radiation and between GSTM1 polymorphism and cognitive impairment two years after radiation. Further large scale studies may be needed to confirm this finding and to examine the underlying mechanism of neurocognitive impairments after treatment of medulloblastoma patients

Evaluating novel risk factors for childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood leukemia accounting for 70- 75% of cases worldwide. Both genetic and environmental stressors are two major factors suspected to influence the occurrence of ALL. Therapeutic success in survival of childhood ALL has increased the risk of late occurring complications, and co-morbidities. These consequences have a large impact on the quality of a survivor\u27s life and society from continued medical care, ancillary services, and financial burden. In order to reduce the incidence and lessen the burden of childhood ALL, we aim to identify the association of two novel parental occupational exposures, asthmagens and endocrine disrupting chemicals (EDCs), and the risk of childhood ALL among children under the age of 15 years who were recruited at Texas Children\u27s Hospital (TCH), Houston, Texas between May 2007 and April 2012 using job exposure matrices (JEM). In the current study, I studied 129 ALL cases and 212 healthy controls from an ongoing epidemiological case-control study entitled Exploring Potential Risk Factors for Childhood Cancer and Hematological Disorders by Case-Control Studies . Descriptive statistics were used to assess the frequency distribution and differences between case and control parents using chi-squared tests (or Fisher\u27s exact test) for the categorical variables. We believe our findings helped to shed light on the underlying causes and mechanism of the disease, which might help in reducing the incidence of these conditions and the public health burden

Prior history of atopy or autoimmunity increases risk for alopecia areata

Background. The association between a prior history of atopy or other autoimmune diseases and risk of alopecia areata is not well established. ^ Objective. Purpose of this study was to use the National Alopecia Areata Registry database to further investigate the association between history of atopy or other autoimmune diseases and risk of alopecia areata. ^ Methods. A total of 2,613 self-registered sporadic cases (n = 2,055) and controls (n = 558) were included in the present analysis. ^ Results. Possessing a history of any atopy (OR = 2.00; 95% CI 1.50-2.54) or autoimmune disease (OR = 1.73; 95% CI 1.10-2.72) was associated with an increased risk of alopecia areata. There was no trend for possessing a history of more than one atopy or autoimmune disease and increasing risk of alopecia areata. ^ Limitations. Recall, reporting, and recruiting bias are potential sources of limitations in this analysis. ^ Conclusion. This analysis revealed that a prior history of atopy and autoimmune disease was associated with an increased risk of alopecia areata and that the results were consistent for both the severe subtype of alopecia areata (i.e., alopecia totalis and alopecia universalis) and the localized subtype (i.e., alopecia areata persistent).

Multiple cutaneous neuromas and macular amyloidosis associated with medullary thyroid carcinoma

Multiple cutaneous neuromas are rarely seen in dermatology practice. We report a case of multiple cutaneous neuromas, macular amyloidosis (MA), and medullary thyroid carcinoma (MTC) and discuss the interrelationship of the associated conditions. Multiple endocrine neoplasia 2 (MEN 2) is a hereditary syndrome that comprises MEN 2A, MEN 2B, and familial MTC. Germline mutations in the RET protooncogene is the underlying cause of the syndrome. MEN 2A and MEN 2B show some common endocrine manifestations including MTC and pheochromocytoma. There are reports of families with MA and MEN 2A. Multiple mucosal neuromas occur in 100% of patients with MEN 2B syndrome. Cutaneous neuromas are infrequently reported in MEN 2B syndrome. Our patient was a heterozygote carrier of GAG --> GAC mutation (Glu 768 Asp) in exon 13, codon 768 of the RET proto-oncogene. We speculate that our patient may represent an unusual presentation of MEN 2B or an overlap of MEN 2A and MEN 2B syndromes or a sporadic MTC case with unusual associations