Gastric-type adenocarcinoma of the uterine cervix presenting in urine cytology specimens: A case report and literature review.

Gastric-type endocervical adenocarcinoma (GEA) is a rare type adenocarcinoma of the uterine cervix that is unrelated to human papillomavirus (HPV). GEA is difficult to diagnose due to its bland-looking morphological characteristics and is therefore often underdiagnosed. Although abnormal cells may be seen on cervical cytology specimens, they are rarely diagnosed as malignant and are often classified as atypical glandular cells. As a result, GEA may be diagnosed at advanced stages, with cytology samples from other organs after it has already invaded adjacent organs. Here, we report a case of GEA diagnosed by both cytological and histological examinations of urinary bladder and uterine cervix, after being identified as a non-urothelial malignancy on a urine cytology. We also review and summarize the differential diagnoses for non-urothelial lesions, particularly for glandular lesions observed on urinary cytology specimens, as well as the cytological and histological characteristics of GEA.

Uterine rupture due to adenomyosis in an adolescent: A case report and review of literature.

BACKGROUND: Uterine rupture is a fatal medical complication with a high mortality rate. Most cases of uterine rupture occur in late pregnancy or during labor and are mainly related to uterine scarring due to previous surgical procedures. Adenomyosis is a possible risk factor for uterine rupture. However, spontaneous uterine rupture due to severe adenomyosis in a non-gravida-teenaged female has not been reported in the literature to date. CASE SUMMARY: A 16-year-old girl was referred to our hospital for acute abdominal pain and hypovolemic shock with a blood pressure of 90/50 mmHg. Radiologic studies revealed a huge endometrial mass with multiple nodules in the lung, suggesting lung metastasis. The patient underwent an emergency total hysterectomy and wedge resection of the lung nodules. Histologically, the uterus showed diffuse adenomyosis with glandular and stromal dissociation. Lung nodules were endometrioma with massive hemorrhage. Immunohistochemistry demonstrated that the tumor cells were positive for PAX8, ER, and PR expression, leading to a final diagnosis of pulmonary endometriosis and uterine adenomyosis. Following surgery, the patient remains in good condition without recurrence. CONCLUSION: This is the first case of spontaneous uterine rupture due to adenomyosis in a non-gravida adolescent.

Usefulness of the human papillomavirus DNA chip test as a complementary method for cervical cytology.

Objectives: As a convenient and economical method of screening cervical cancer and precancerous pathologies, the Papanicolaou smear (Pap smear) has been most widely used. Nevertheless, it requires cytological changes for making diagnoses and reportedly has a high false-negative rate. In this study, the usefulness of the human papillomavirus (HPV) DNA chip test as a complementary method that can compensate for the defect of the Pap smear was investigated. Material and Methods: Of the 6516 patients who simultaneously underwent a Pap smear and an HPV DNA chip test at Chonnam National University Hospital between January 2015 and December 2016, 1897, an initial PAP smear-negative patients who had undergone an additional Pap smear during their 2-year follow-up period were selected for this study. Of the subject patients, 281 underwent a cervical biopsy. Results: The Pap smear follow-up of an initial Pap smear-negative subjects showed 53 (75.7%) HPV high-risk positive cases in the cytology low-grade lesion group (70 cases) and 46 (97.8%) HPV high-risk positive cases in the cytology high-grade lesion group (47 cases). The 281 biopsy cases included 67 biopsy low-grade lesion cases and 74 biopsy high-grade lesion cases, of which there were 45 (67.2%) and 67 (90.5%) HPV high-risk positive cases, respectively. The follow-up cytology on the high-risk HPV-positive subjects showed that the ratio of their high-grade lesions was 260.8 times greater than that of the high-risk HPV-negative subjects (OR = 260.8 and 95% CI: 36.1 and 1886.1); and their biopsy showed that the ratio of their high-grade lesions was 102.7 times greater than that of the HPV-negative subjects (OR = 102.7 and 95% CI: 14.0 and 753.3). Conclusion: The complementary use of the HPV DNA chip test may be useful in increasing the accuracy of screening examinations for the early diagnosis of uterine cervix cancer when combined with the Pap smear.

Primary duodenal dedifferentiated liposarcoma: A case report and literature review.

BACKGROUND: Dedifferentiated liposarcoma (DDLPS) is an extremely rare neoplasm that exhibits various morphologies. The tumor is characterized by immunoreactivity to MDM2 and CDK4 and can be confirmed by detecting MDM2 amplification via fluorescence in situ hybridization (FISH). Herein, we report an unusual case of DDLPS arising from the duodenum. CASE SUMMARY: A 64-year-old man presented with repeated abdominal pain and weight loss. Radiologic studies revealed a mass of the duodenum involving the pancreas. The patient was treated with pylorus-preserving pancreaticoduodenectomy. Histologically, the tumor showed a high-grade sarcoma. Immunohistochemistry demonstrated that the tumor cells were positive for MDM2 and CDK4 expression. MDM2 amplification was detected via FISH, leading to the final diagnosis of DDLPS. Following surgery, the patient was treated in the intensive care unit due to peritonitis, and died 60 d after surgery. CONCLUSION: To the best of the authors' knowledge, this is the first case of primary duodenal DDLPS in Korea and the third case in the English-language literature. Care must be taken not to misdiagnose DDLPS as another high-grade tumor. Liposarcoma should be in the differential diagnosis list.

TFE3-expressing malignant perivascular epithelioid cell tumor of the mesentery: A case report and review of literature.

BACKGROUND: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor that exhibits an epithelioid and spindle cell morphology. The tumor is characterized by immunoreactivity for melanocytic and myogenic markers but can be misdiagnosed as more common tumors with similar characteristics, including gastrointestinal stroma tumors or leiomyosarcomas. Recently, a subset of PEComas has been reported to harbor a transcription factor binding to TFE3 fusion. Herein, we report a rare case of TFE3-expressing malignant PEComa arising from the mesentery. CASE SUMMARY: A 50-year-old woman presented with abdominal discomfort for 3 months. Results of laboratory tests were all within the normal ranges, and the patient had no notable medical history. Magnetic resonance imaging revealed a large tumor on the right side of the pelvic floor, which was originally suspected to be a primary ovarian tumor. However, during surgery, the tumor was revealed to have originated from the mesentery. Histologically, the tumor was composed of bundles of spindle cells and sheets of epithelioid cells. Extensive coagulative necrosis and numerous mitotic figures were observed. Immunohistochemistry revealed that the tumor cells were positive for smooth muscle actin, HMB-45, and TFE3 expression. Tumor involvement of the rectal serosa was identified, leading to a final diagnosis of malignant PEComa of the mesentery. Surgical resection was followed by adjuvant chemotherapy. No recurrence or metastasis was observed over a 6-month follow-up period. CONCLUSION: Malignant PEComa of the mesentery is extremely rare and should be distinguished from morphological mimics through differential diagnosis and immunohistochemistry.

ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes.

ETS1 has shown dichotomous roles as an oncogene and a tumor suppressor gene in diverse cancers, but its functionality in breast cancer tumorigenesis still remains unclear. We utilized the Cancer Genome Atlas (TCGA) database to analyze comprehensive functions of ETS1 in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. ETS1 expression was significantly diminished by hyper-methylation of the ETS1 promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, ETS1 high BRCA patients showed better prognosis and longer survival compared to ETS1 low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of ETS1 expression revealed direct as well as indirect mechanisms of ETS1 that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of ETS1 as a tumor suppressor in breast cancer cells.

Ets1 suppresses atopic dermatitis by suppressing pathogenic T cell responses.

Atopic dermatitis (AD) is a complex inflammatory skin disease mediated by immune cells of both adaptive and innate types. Among them, CD4+ Th cells are one of major players of AD pathogenesis. Although the pathogenic role of Th2 cells has been well characterized, Th17/Th22 cells are also implicated in the pathogenesis of AD. However, the molecular mechanisms underlying pathogenic immune responses in AD remain unclear. We sought to investigate how the defect in the AD susceptibility gene, Ets1, is involved in AD pathogenesis in human and mice and its clinical relevance in disease severity by identifying Ets1 target genes and binding partners. Consistent with the decrease in ETS1 levels in severe AD patients and the experimental AD-like skin inflammation model, T cell-specific Ets1-deficient mice (Ets1ΔdLck) developed severe AD-like symptoms with increased pathogenic Th cell responses. A T cell-intrinsic increase of gp130 expression upon Ets1 deficiency promotes the gp130-mediated IL-6 signaling pathway, thereby leading to the development of severe AD-like symptoms. Functional blocking of gp130 by selective inhibitor SC144 ameliorated the disease pathogenesis by reducing pathogenic Th cell responses. Our results reveal a protective role of Ets1 in restricting pathogenic Th cell responses and suggest a potential therapeutic target for AD treatment.

Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness.

Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (Ets1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and invasion of human breast cancer cells. However, underlying mechanisms of Ets1 gene expression is still ambiguous. Here, we identified a core-regulatory element (CRE) located in the Ets1 promoter region (-540/-80 bp from TSS) that contains elements responsible for associating with NFATs and NF-κBs. Compared with the less metastatic breast cancer cells, metastatic breast cancer cells (MDA-MB-231) show open chromatin configurations in the CRE, which facilitates direct binding of NFATc2 and/or NFKB1/RELA complex to trans-activate Ets1 transcription. Moreover, enhanced level of Nfatc2 and Nfkb1 positively correlated with Ets1 expression in the human breast cancer specimens. Deletion of the CRE region by CRISPR/Cas9 system resulted in significant reduction in Ets1 expression, which led to alterations of Ets1-mediated transcription programs including tumor invasiveness-related genes. Proper regulation of Ets1 gene expression by targeting the NFATc2 and NFKB1/RELA interaction could be a potential therapeutic target for Ets1-mediated metastatic breast cancer.

A case of large cell neuroendocrine carcinoma of the uterine cervix misdiagnosed as adenocarcinoma in Thinprep cytology test.

Large cell neuroendocrine carcinoma (LCNEC) of uterine cervix is a rare malignancy with aggressive behavior and poor clinical outcome even in its early stage. Few cytopathologic features of cervical LCNEC have been reported previously. A 57-year-old postmenopausal African American female, presented to the local health department with a chief complaint of heavy vaginal bleeding. A 45-year-old female presented with 20 months of vaginal pruritus and foul odor. Cervical malignancy was suspected by pelvis magnetic resonance imaging. Thinprep cytology test demonstrated ball-like tumor cell clusters in a necrotic background. Cytologic diagnosis of adenocarcinoma was rendered. However, the histologic and immunohistochemical examination of cervical biopsy revealed the LCNEC of the uterine cervix. Due to its rarity, LCNEC may pose a diagnostic challenge in cervical cytology. Cytopathologists should pay attention to the cytological features of cervical LCNEC, such as rosettoid pattern, nuclear molding, and thin nuclear membrane for differentiation from other mimics.

Transcription factor NFAT1 controls allergic contact hypersensitivity through regulation of activation induced cell death program.

Allergic contact hypersensitivity (CHS) is an inflammatory skin disease mediated by allergen specific T cells. In this study, we investigated the role of transcription factor NFAT1 in the pathogenesis of contact hypersensitivity. NFAT1 knock out (KO) mice spontaneously developed CHS-like skin inflammation in old age. Healthy young NFAT1 KO mice displayed enhanced susceptibility to hapten-induced CHS. Both CD4(+) and CD8(+) T cells from NFAT1 KO mice displayed hyper-activated properties and produced significantly enhanced levels of inflammatory T helper 1(Th1)/Th17 type cytokines. NFAT1 KO T cells were more resistant to activation induced cell death (AICD), and regulatory T cells derived from these mice showed a partial defect in their suppressor activity. NFAT1 KO T cells displayed a reduced expression of apoptosis associated BCL-2/BH3 family members. Ectopic expression of NFAT1 restored the AICD defect in NFAT1 KO T cells and increased AICD in normal T cells. Recipient Rag2(-/-) mice transferred with NFAT1 KO T cells showed more severe CHS sensitivity due to a defect in activation induced hapten-reactive T cell apoptosis. Collectively, our results suggest the NFAT1 plays a pivotal role as a genetic switch in CD4(+)/CD8(+) T cell tolerance by regulating AICD process in the T cell mediated skin inflammation.

Mesonephric Adenocarcinoma of the Uterine Corpus: A Case Report and Diagnostic Pitfall.

Mesonephric adenocarcinoma is a rare tumor type that is usually found in areas where the Wolffian duct was present during the fetal period. We report a case of mesonephric adenocarcinoma of the uterine corpus in a 66-year-old woman who presented with vaginal bleeding. Pelvic magnetic resonance imaging revealed a 2.7-cm-sized irregular thickening and enhancement of the uterine body. The diagnosis following endometrial curettage biopsy was endometrioid adenocarcinoma, and the patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. The tumor was composed of small tubular and ductal components, and a retiform appearance was also observed in the deeper areas. The tumor cells were immunopositive for cytokeratin, vimentin, CD10 with a luminal staining pattern, PAX2, and PAX8, and immunonegative for estrogen receptor and progesterone receptor, which was consistent with tumor of mesonephric origin. Mesonephric neoplasms reveal relatively low-grade nuclear feature, characteristic immunoprofiles (immunonegative for ER and PR, and immunopositive for CD10, PAX2, PAX8, and GATA3), and unique tumor location (myometrium), whereas Müllerian neoplasms such as endometrial adenocarcinoma show various morphology, immunopositivity for ER and PR, and primarily endometrial location. As described above, an integration of the clinical features, morphologic characteristics, and immunohistochemical profiles is needed to make a diagnosis.

Flagellin suppresses experimental asthma by generating regulatory dendritic cells and T cells.

BACKGROUND: Although the hygiene hypothesis suggests that microbial infections could subvert asthma and thus a microbial product might serve as a therapeutic adjuvant for asthma, the relationship between bacterial components and asthma is complex. Recently, low levels of flagellin, the Toll-like receptor (TLR) 5 ligand, have been reported to promote asthma. OBJECTIVE: We show that a therapeutic dose of flagellin suppresses asthma and that the effect occurs through generating regulatory dendritic cells (rDCs) and regulatory T (Treg) cells. METHODS: Ovalbumin (OVA)-induced wild-type and TLR5 knockout asthmatic mice were treated intranasally with a mixture of OVA and 10 µg of a flagellin B (FlaB; of Vibrio vulnificus). OVA/FlaB-treated rDCs were adoptively transferred to mice with OVA-induced asthma. Anti-CD25 mAb was used to deplete Treg cells. A mixture of house dust mite (HDM) and FlaB was used to treat mice with HDM-induced asthma. Blood CD14(+) monocyte-derived dendritic cells from HDM-sensitive asthmatic patients were treated with FlaB and incubated with autologous CD4(+) T cells. RESULTS: An OVA/FlaB mixture ameliorated OVA-induced asthma by inhibiting TH1/TH2/TH17 responses in a TLR5-dependent manner through generating rDCs and Treg cells. The adoptive transfer of OVA/FlaB-treated dendritic cells inhibited OVA-induced asthma, whereas the depletion of CD25(+) cells eliminated the inhibitory effect. A similar effect of FlaB was observed in mice with HDM-induced asthma. In patients with HDM-sensitive asthma, FlaB-treated rDCs inhibited HDM-stimulated TH1/TH2 responses while enhancing Treg cells in an IL-10-dependent manner. CONCLUSION: These findings collectively suggest that flagellin could be used as a tolerogenic adjuvant to treat allergic asthma.

Expression of matrix metalloproteinases and their inhibitors in different immunohistochemical-based molecular subtypes of breast cancer.

BACKGROUND: Metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification. METHODS: Tissue microarray sections were immunostained for estrogen receptor-α (ER-α), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-α, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected. RESULTS: Statistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival. CONCLUSION: We found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.

Insulin-like growth factor-II mRNA-binding protein 3 expression in effusion cytology: a marker for metastatic adenocarcinoma cells and a potential prognostic indicator in gastric adenocarcinoma.

OBJECTIVE: The aim of our study was to identify the diagnostic value of insulin-like growth factor-II mRNA-binding protein 3 (IMP3) in distinguishing metastatic adenocarcinoma cells (MAC) from reactive mesothelial cells (RMC) in effusions. We also investigated the role of IMP3 as a prognostic indicator for patients with malignant effusion. STUDY DESIGN: A total of 156 cell block specimens, including 116 malignant effusions with MAC and 40 benign effusions with RMC, were subjected to immunocytochemical staining for IMP3. RESULTS: Immunocytochemical studies showed positive staining for IMP3 in 91 of 116 (78.4%) cases of MAC and in 3 of 40 (7.5%) cases of RMC. With regard to distinguishing MAC from RMC, the IMP3 reactivity was found to be 78.4% sensitive and 92.5% specific with a positive predictive value of 96.8% and a negative predictive value of 59.7%. Diffuse IMP3 expression (>25%) in MAC from patients with gastric adenocarcinoma was associated with shorter survival (p = 0.001). CONCLUSION: Our data suggest that IMP3 is a helpful marker for differentiating MAC from RMC, and that diffuse IMP3 expression is a poor prognostic indicator in patients with gastric adenocarcinoma and malignant effusion.

Diagnostic Utility of a Clonality Test for Lymphoproliferative Diseases in Koreans Using the BIOMED-2 PCR Assay.

BACKGROUND: A clonality test for immunoglobulin (IG) and T cell receptor (TCR) is a useful adjunctive method for the diagnosis of lymphoproliferative diseases (LPDs). Recently, the BIOMED-2 multiplex polymerase chain reaction (PCR) assay has been established as a standard method for assessing the clonality of LPDs. We tested clonality in LPDs in Koreans using the BIOMED-2 multiplex PCR and compared the results with those obtained in European, Taiwanese, and Thai participants. We also evaluated the usefulness of the test as an ancillary method for diagnosing LPDs. METHODS: Two hundred and nineteen specimens embedded in paraffin, including 78 B cell lymphomas, 80 T cell lymphomas and 61 cases of reactive lymphadenitis, were used for the clonality test. RESULTS: Mature B cell malignancies showed 95.7% clonality for IG, 2.9% co-existing clonality, and 4.3% polyclonality. Mature T cell malignancies exhibited 83.8% clonality for TCR, 8.1% co-existing clonality, and 16.2% polyclonality. Reactive lymphadenitis showed 93.4% polyclonality for IG and TCR. The majority of our results were similar to those obtained in Europeans. However, the clonality for IGK of B cell malignancies and TCRG of T cell malignancies was lower in Koreans than Europeans. CONCLUSIONS: The BIOMED-2 multiplex PCR assay was a useful adjunctive method for diagnosing LPDs.

Diagnostic usefulness of MUC1 and MUC4 for distinguishing between metastatic adenocarcinoma cells and reactive mesothelial cells in effusion cell blocks.

OBJECTIVE: The aim of our study was to determine the diagnostic value of MUC1 and MUC4 for distinguishing between metastatic adenocarcinoma cells (MAC) and reactive mesothelial cells (RMC) in effusion fluids. STUDY DESIGN: A total of 237 cell block specimens from pleural and peritoneal effusions, including 196 malignant effusions with MAC and 41 benign effusions with RMC, were stained with antibodies against MUC1 and MUC4. Membranous staining with or without cytoplasmic staining was considered to be positive. RESULTS: MUC1 immunoreactivity was observed in 194 (99.0%) of 196 cases of MAC and in 20 (48.8%) of 41 cases of RMC. MUC4 immunoreactivity was observed in 174 (88.8%) of 196 cases of MAC and in 4 (9.8%) of 41 cases of RMC. For distinguishing MAC from RMC, the MUC1 reactivity was found to be 99.0% sensitive and 51.2% specific with a positive predictive value of 90.7% and a negative predictive value of 91.3%. The sensitivity of MUC4 for MAC was 88.8%, the specificity was 90.2%, the negative predictive value was 62.7%, and the positive predictive value was 97.8%. CONCLUSION: Our data suggest that MUC4 appears to be a sensitive and specific marker for differentiating between MAC and RMC.

Multiple peripheral typical carcinoid tumors of the lung: associated with sclerosing hemangiomas.

This study presents a first case of multiple peripheral typical carcinoid tumors associated with sclerosing hemangiomas in the lung. A 52-year-old male presented with incidentally detected multiple pulmonary nodules on a simple chest X-ray during routine health check-up. A computed tomography (CT) scan of the chest showed multiple nodular lesions in the middle and lower lobes of the right lung. These were initially suspected as inflammatory lesions due to miliary tuberculosis. However, possibility of malignancy could not be excluded and right lower lobe lobectomy was performed. Histopathologically, some nodules including two largest nodules were composed of small round to spindle shaped cells with fine chromatin pattern, whereas the rest of the sclerotic nodules were composed of two epithelial cell types- surface cells and round cells. The final diagnosis of this case was multiple peripheral typical carcinoid tumors associated with sclerosing hemangiomas of the lung. For past three years of post-surgery follow up period, no new lesions or changes in the right middle lobe have been identified.

Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response.

The immunomodulatory effect of probiotics has been shown mainly in gastro-intestinal immune disorders and little information is available on the inflammation of central nervous system. Recently we reported that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental inflammatory disorders. In this study, we evaluated the prophylactic and therapeutic effects of IRT5 probiotics in experimental autoimmune encephalomyelitis (EAE), a T cell mediated inflammatory autoimmune disease of the central nervous system. Pretreatment of IRT5 probiotics before disease induction significantly suppressed EAE development. In addition, treatment with IRT5 probiotics to the ongoing EAE delayed the disease onset. Administration of IRT5 probiotics inhibited the pro-inflammatory Th1/Th17 polarization, while inducing IL10(+) producing or/and Foxp3(+) regulatory T cells, both in the peripheral immune system and at the site of inflammation. Collectively, our data suggest that IRT5 probiotics could be applicable to modulate T cell mediated neuronal autoimmune diseases, including multiple sclerosis.