Timothy H. Schmidt

The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement

Mice deficient in sphingosine 1-phosphate receptor type 2 (S1P2) develop diffuse large B cell lymphoma. However, the role of S1P2 in normal germinal center (GC) physiology is unknown. Here we show that S1P2-deficient GC B cells outgrew their wild-type counterparts in chronically established GCs. We found that antagonism of the kinase Akt mediated by S1P2 and its downstream mediators Gα12, Gα13 and p115RhoGEF regulated cell viability and was required for growth control in chronically proliferating GCs. Moreover, S1P2 inhibited GC B cell responses to follicular chemoattractants and helped confine cells to the GC. In addition, S1P2 overexpression promoted the centering of activated B cells in the follicle. We suggest that by inhibiting Akt activation and migration, S1P2 helps restrict GC B cell survival and localization to an S1P-low niche at the follicle center.

CXCR4 Promotes B Cell Egress from Peyer's Patches

Chemokine receptor CXCR4 promotes B cell localization to CXCL12+ perilymphatic zones and egress from Peyer’s patches.

The Eph-related tyrosine kinase ligand Ephrin-B1 marks germinal center and memory precursor B cells.

Identification of germinal center (GC) B cells is typically reliant on the use of surface activation markers that exhibit a wide range of expression. Here, we identify Ephrin-B1, a ligand for Eph-related receptor tyrosine kinases, as a specific marker of mature GC B cells. The number of Ephrin-B1+ GC B cells increases during the course of an immune response with Ephrin-B1+ GC B cells displaying elevated levels of Bcl6, S1pr2, and Aicda relative to their Ephrin-B1– counterparts. We further identified a small proportion of recently dividing, somatically mutated Ephrin-B1+ GC B cells that have begun to down-regulate Bcl6 and S1pr2 and express markers associated with memory B cells, such as CD38 and EBI2. Transcriptional analysis indicates that these cells are developmentally related to memory B cells, and likely represent a population of GC memory precursor (PreMem) B cells. GC PreMem cells display enhanced survival relative to bulk GC B cells, localize near the edge of the GC, and are predominantly found within the light zone. These findings offer insight into the significant heterogeneity that exists within the GC B cell population and provide tools to further dissect signals regulating the differentiation of GC B cells.

Cutaneous Findings and Systemic Associations in Women With Polycystic Ovary Syndrome

IMPORTANCE Understanding of the associations among cutaneous findings, systemic abnormalities, and fulfillment of the diagnostic criteria in women suspected of having polycystic ovary syndrome (PCOS) is incomplete. OBJECTIVE To identify cutaneous and systemic features of PCOS that help distinguish women who do and do not meet the diagnostic criteria. DESIGN, SETTING, AND PARTICIPANTS Retrospective cross-sectional study of a racially diverse referred sample of women seen at the University of California, San Francisco, Polycystic Ovary Syndrome Multidisciplinary Clinic over a 6-year period between May 18, 2006, and October 25, 2012. Participants were 401 women referred for suspected PCOS. In total, 68.8% (276 of 401) met the Rotterdam PCOS diagnostic criteria, while 12.0% (48 of 401) did not. Overall, 11.5% (46 of 401) had insufficient data to render a diagnosis, 1.7% (7 of 401) were excluded from the study, and 6.0% (24 of 401) refused to participate in the study. EXPOSURE Comprehensive skin examination and transvaginal ultrasonography. All patients were tested for levels of total testosterone, free testosterone, dehydroepiandrosterone (DHEAS), androstenedione, luteinizing hormone, and follicle-stimulating hormone. Levels of serum cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were obtained, in addition to 0-hour and 2-hour oral glucose tolerance test (OGTT) results, with measurement of glucose and insulin levels. MAIN OUTCOMES AND MEASURES Findings from comprehensive skin examination, laboratory testing, and transvaginal ultrasonography. RESULTS In total, 401 women with suspected PCOS were included in the study. The median patient age was 28 years. Compared with women who did not meet the diagnostic criteria for PCOS, women who met the criteria had higher rates of hirsutism (53.3% [144 of 270] vs 31.2% [15 of 48], P = .005) (with higher mean modified Ferriman-Gallwey scores of 8.6 vs 5.6, P = .001), acne (61.2% [164 of 268] vs 40.4% [19 of 47], P = .004), and acanthosis nigricans (AN) (36.9% [89 of 241] vs 20.0% [9 of 45], P = .03). Cutaneous distributions also varied. Women who met the PCOS criteria demonstrated more severe truncal hirsutism and higher rates of axillary AN. Women who met the PCOS criteria had elevated total testosterone levels (40.7% [105 of 258] vs 4.3% [2 of 47], P < .001). Among women with PCOS, the presence of hirsutism (43.9% [54 of 123] vs 30.9% [34 of 110], P = .04) or AN (53.3% [40 of 75] vs 27.0% [40 of 148], P < .001) was associated with higher rates of elevated free testosterone levels as well as several metabolic abnormalities, including insulin resistance, dyslipidemia, and increased body mass index. Although the prevalence of acne was increased among women with PCOS, there were minimal differences in acne types and distribution between the women meeting vs not meeting the PCOS criteria. CONCLUSIONS AND RELEVANCE Hirsutism and AN are the most reliable cutaneous markers of PCOS and require a comprehensive skin examination to diagnose. When present, hirsutism and AN should raise clinical concern that warrants further diagnostic evaluation for metabolic comorbidities that may lead to long-term complications. Acne and androgenic alopecia are prevalent but unreliable markers of biochemical hyperandrogenism among this population.

Polycystic Ovary Syndrome: Special Diagnostic and Therapeutic Considerations for Children

Polycystic ovary syndrome (PCOS) is an endocrine syndrome with variable phenotypic expression and important systemic associations and sequelae, including obesity, insulin resistance, infertility, risk of endometrial cancer, and possible risk of cardiovascular events. PCOS is recognized as a condition influenced by genetic and environmental factors and distinct manifestations in all stages of life, including the prenatal period, childhood, adolescence, and adulthood. Identification of this disorder in childhood and adolescence has received growing attention, in part because of emerging evidence of the benefit of early intervention, but the diagnosis and management of PCOS in children and adolescents can be challenging. Diagnostic and therapeutic considerations of PCOS in children are reviewed to enhance identification and evaluation of patients suspected of having this disorder. When a diagnosis of PCOS is suspected in a child but cannot be confirmed, a provisional diagnosis is strongly recommended so as to prompt ongoing monitoring with an emphasis on important early interventions such as obesity reduction.

Successful treatment of mucous membrane pemphigoid with bortezomib

Mucous membrane pemphigoid (MMP) is a rare, autoantibody-mediated disease characterized by mucocutaneous blistering including oral, ocular, laryngeal, and skin involvement. Treating MMP is challenging, with few effective therapies available. We report successful treatment of a patient with treatment-refractory MMP with the proteasome inhibitor, bortezomib.

Chronic Helicobacter cinaedi cellulitis diagnosed by microbial polymerase chain reaction

PCR: polymerase chain reaction TMP-SMX: trimethoprim-sulfamethoxazole XLA: X-linked agammaglobulinemia INTRODUCTION Helicobacter cinaedi is an unusual cause of cellulitis in immunocompromised patients. The organism is fastidious, and blood cultures are often negative, making the diagnosis challenging, especially in those without systemic signs. We report a case of chronic H cinaedi cellulitis in a patient with X-linked agammaglobulinemia (XLA) diagnosed by universal microbial polymerase chain reaction (PCR).

Abstract A065: Oscillatory genes in lymphocyte retention and egress

The adaptive immune system attacks cancer cells by initiating immune responses in lymphoid organs and egressing of activated effector cells into circulation to reach the tumor. Several G protein-coupled receptors have been reported to recruit lymphocytes to the lymphoid organ or to promote exit. However, how these signals crosstalk to ensure efficient lymphocyte recruitment and transit is not well understood. To further define how cell transit through the lymphoid tissue is controlled, we designed two parallel RNAseq to identify novel regulators for lymphocyte transit. We compared the transcriptome of naive B cells from the blood and peripheral lymph node. Also, by utilizing photoconvertible proteins, we isolated naive B cells that newly enter the lymphoid organ and those that have been dwelling for several hours. We identified multiple genes whose transcript levels were correlated with lymphoid dwelling time. One of the genes, KLF11, encoding a transcription factor, is expressed more highly in the blood than in the lymph node, and the expression decreases with the dwelling time in the lymphoid organ. Analysis of the KLF11 knock-out mouse identified strong lymphocyte transit and developmental defects, but we found the strong phenotypes segregated independently of the KLF11 knock-out allele. The phenotypes were the result of a mutated DOCK2 allele in the commercial B6 background. We have now generated a KLF11 knock-out with wildtype DOCK2. The progress of characterizing the function of KLF11 in lymphocyte recruitment and egress will be reported. Citation Format: Hsin Chen, Timothy Schmidt, Ying Xu, Erick Lu, Jason G. Cyster. Oscillatory genes in lymphocyte retention and egress [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A065.