Suhayl Dhib-Jalbut

Hematopoietic progenitors express neural genes

Bone marrow, or cells selected from bone marrow, were reported recently to give rise to cells with a neural phenotype after in vitro treatment with neural-inducing factors or after delivery into the brain. However, we showed previously that untreated bone marrow cells express products of the neural myelin basic protein gene, and we demonstrate here that a subset of ex vivo bone marrow cells expresses the neurogenic transcription factor Pax-6 as well as neuronal genes encoding neurofilament H, NeuN (neuronal nuclear protein), HuC/HuD (Hu-antigen C/Hu-antigen D), and GAD65 (glutamic acid decarboxylase 65), as well as the oligodendroglial gene encoding CNPase (2′,3′ cyclic nucleotide 3′-phosphohydrolase). In contrast, astroglial glial fibrillary acidic protein (GFAP) was not detected. These cells also were CD34+, a marker of hematopoietic stem cells. Cultures of these highly proliferative CD34+ cells, derived from adult mouse bone marrow, uniformly displayed a phenotype comparable with that of hematopoietic progenitor cells (CD45+, CD34+, Sca-1+, AA4.1+, cKit+, GATA-2+, and LMO-2+). The neuronal and oligodendroglial genes expressed in ex vivo bone marrow also were expressed in all cultured CD34+ cells, and GFAP was not observed. After CD34+ cell transplantation into adult brain, neuronal or oligodendroglial markers segregated into distinct nonoverlapping cell populations, whereas astroglial GFAP appeared, in the absence of other neural markers, in a separate set of implanted cells. Thus, neuronal and oligodendroglial gene products are present in a subset of bone marrow cells, and the expression of these genes can be regulated in brain. The fact that these CD34+ cells also express transcription factors (Rex-1 and Oct-4) that are found in early development elicits the hypothesis that they may be pluripotent embryonic-like stem cells.

Testicular in vitro conversion of progesterone to testosterone and androstenedione in 17α-hydroxylase deficiency

Incubations of [3H]-progesterone with testicular tissue obtained from a new case of male with 17 alpha-hydroxylase deficiency were performed. The per cent conversion to androstenedione and testosterone was virtually absent when compared to that obtained from an identical incubation performed using testicular tissue from a normal male with cryptochordism. The findings provide an in vitro evidence in support of the existence of 17 alpha-hydroxylase testicular defect in this disorder.

Different virus antibodies in serum and cerebrospinal fluid of patients suffering from subacute sclerosing panencephalitis

Complement fixing (CF) antibody titers to measles, parainfluenza (PI) types 1 and 3, mumps, herpes type 1, and cytomegalovirus (CMV) in serum and cerebrospinal fluid (CSF) of 33 patients with subacute sclerosing panencephalitis (SSPE) were evaluated. Results were analyzed in comparison to 11 patients with neurological diseases other than SSPE and 7 normal subjects. All SSPE patients had elevated serum and CSF measles antibody titers. The number of SSPE patients manifesting elevated titers other than measles did not reach statistical significance when compared to controls, except for PI type 1. This suggests a possible dual infection with measles and PI in SSPE. The anticomplementary effect detected in the serum and CSF of some patients indirectly suggests the presence of immune complexes.

Introduction to a Special Issue on Cytokines in Neuroinflammation and Immunity

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating and degenerative disease of the central nervous system (CNS). It is pathologically characterized by infiltration of activated inflammatory cells across the blood–brain barrier into the brain and spinal cord tissue resulting in demyelination and loss of cells, including oligodendrocytes, neurons, and axons. The inciting antigen has not been characterized and is likely to be heterogeneous. Genetic and environmental risk factors have been identified and their interaction is believed to underlie the immune dysregulation that leads to MS. MS is clinically heterogeneous, but the most common phenotype is relapsing remitting (RRMS), which ultimately transitions into secondary progressive (SPMS) with accumulation of disability. Fewer patients begin with a progressive form of the disease from the outset without relapses or remissions, referred to as the primary progress form (PPMS). No consistent immune differences among the different forms of the disease have been identified. While currently available immunomodulatory drugs are relatively effective in RRMS; unfortunately, they do not impact the course of PPMS. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS induced either by active immunization of the animal with myelin proteins and complete Freund’s adjuvant, or by passive transfer of encephlitogenic T-cells. Although not a prefect model of MS, EAE is commonly used to study MS immunopathogenesis and to screen for potential therapies. In this special issue of Journal of Interferon & Cytokine Research ( JICR), leading experts in neuroimmunology address current hot topics in MS, including pathogenesis and disease triggers, relevant signaling pathways, biomarkers, and potential novel therapeutic targets. Ben Segal highlights MS as a dynamic disease with stage-specific immune alterations. He reviews potential biomarkers for different phases of the disease and how these biomarkers could be utilized as outcome measures in clinical trials. V. Wee Yong and colleagues discuss the interactions between microglia and T cells in MS. They present evidence for reciprocal stimulation between the two cell types that could result in injurious or neurotrophic outcomes. They propose that this interaction could be targeted therapeutically. Kiel and Kasper review gut commensalism and its relationship to CNS demyelination. They discuss the role of the gut microbiome in disease severity as well as in disease-free state and the contribution of T-helper, T-regulatory, and B cells to immune homeostasis within the gut. Two contributions to this issue highlight the importance of specific signaling pathways in MS. Benveniste and colleagues discuss the involvement of the JAK/STAT signaling pathway in MS and its animal model EAE and how this pathway mediates the biological effects of the cytokines believed to contribute to MS pathogenesis. Racke and colleagues propose that the transcription factor T-bet is critical for T-cell encephalogenecity and could be targeted therapeutically in MS. Interferon-beta (IFN-B) was the first drug to be approved for the treatment of MS more than two decades ago. Nallar and Kalvakolanu reviewed the known mechanisms of IFN action and the recently emerged ones in their article. Some of these signaling pathways are involved in neurotoxicity and others in neuroprotection. A number of experimental animal models that may have potential relevance to the CNS and IFN signaling have been identified in that review. However, a direct relevance of the proposed players needs to be established in the context of MS with more detailed studies. Thus, there is a great need to fill the gap between IFN action and its proand anti-CNS effects. Tony Reder discusses how IFN-B works in MS and comments on some unexpected mechanistic effects for IFNB in the context of risk factors and other therapeutic interventions in MS. Graber and Dhib-Jalbut review potential biomarkers to monitor clinical efficacy of IFN-B therapy in MS. Finally, Makar and colleagues discuss the role of neurotrophic factors—specifically, brain-derived neurotrophic factor—in EAE and how this molecule could be utilized therapeutically using genetically modified stem cell delivery into the CNS. We hope that this special issue of JICR will advance the reader’s appreciation of the cytokines and signaling pathways involved in MS and how knowledge of these intricate pathways can potentially lead to better therapies and animal models of the disease. We realize that this issue is not an

Kenneth P Johnson, MD 1932–2011

Dr Kenneth Johnson, an unquestioned leader in the field of multiple sclerosis (MS), succumbed to his year-long battle with multiple myeloma, on 3 September 2011 at the age of 79. Born in Jamestown, New York, he received his medical degree from Jefferson Medical College in 1959, and began his post-doctoral training at Buffalo General Hospital. His neurology residency was interrupted by military service at the Portsmouth Virginia Naval Hospital. He resumed training at Case Western Reserve University and went on to a neurovirology fellowship with Richard T Johnson. Ken was subsequently appointed to the attending staff of the Cleveland Metropolitan General and rose through the ranks to Associate Professor of Neurology at Case Western by 1971. Early on, Ken made seminal contributions to the understanding of slow and persistent viral infections of the CNS, and viral teratology. He moved to the University of California San Francisco in 1974 where he teamed with J Richard Baringer, MD, to help catapult the team based at Kenneth P Johnson, MD 1932–2011

Hillel Panitch, MD

Hillel Panitch, Professor of Neurology and Director of the Multiple Sclerosis Center at the University of Vermont died on December 23, 2010 at the age of 70 after a year-long battle with melanoma. He had devoted his life to the care of MS patients and research into the pathogenesis and treatment of MS. Hill, as we all know him, grew up in Albany, NY. He was exposed to medicine from an early age being the son of a family doctorwho had his practice on the first floor of their home. He did his undergraduate work at Wesleyan University where he graduated Phi Beta Kappa and received a Fulbright Scholarship which he used to study for a year in France. He earned his Medical Degree from the New York University School of Medicine and then completed a Residency in Neurology at the University of California, San Francisco (UCSF). He completed fellowships in neurovirology at the Johns Hopkins School of Medicine and neuroimmunology at the National Institutes of Health. He held academic positions, first at UCSF, then at the University of Maryland, and finally at the University of Vermont. He made many major scholarly contributions to the fields of MS research and neuroimmunology. While a fellow at the NIH with Dale McFarlin and Henry McFarland he carried out early studies showing that experimental allergic encephalomyelitis was cell mediated. While on the faculty of UCSF he joined a group of investigators, including Kenneth Johnson, Michael Oldstone, George Rice and Jack Sipe who did one of the first well designed studies of interferon in MS. After moving to the University of Maryland he conducted a trial of interferon gamma in patients with MS which showed that immune activation could worsen MS and resulted in a paradigm shift in our approach to research the immunopathogenesis of MS. Characteristically, itwas his careful laboratory studies of study subjects that provided the key insights. His work was recognized by his receipt of a Department of Veterans Affairs Medical Investigator Award in 1990. In addition, he was a major contributor to the development of many of the first line therapies used in the treatment of MS today. After he moved to the University of Vermont in 2000 he continued his research and in 2010 was recognized as the senior investigator of the year by the College of Medicine. Hill was a dedicated and caring physician. He is fondly remembered by the hundreds of patients whom he cared for over the course of his career. He was a tireless volunteer for the National MS Society and served on or chaired a number of committees and task forces that made crucial recommendations for the treatment of MS. In recognition of his contributions to MS, he was honored with the 2010 Partner in Progress Award from the Greater New EnglandMS Chapter. Hill will be remembered by many of us not only as a physician scientist and a critical thinker, but also as a mentor and a role model physician who cared deeply for his patients. A fund has been established in Hills memory at the University of Vermont, College of Medicine to support training in the area of neurotherapeutics.

Impaired measles-specific cytotoxic T-cell response in SSPE

Subacute sclerosing panencephalitis (SSPE) is a persistent infection of the nervous system related to measles virus (MV). I t is not known whether a defect in the host cel lular immune response to MV exists in this disease. The capacity to generate MV-specific cytotoxic T-Lymphocytes (CTLs) was examined in two SSPE patients and eight healthy controls, using autologous MV infected B-cell targets in a standard Cr-release assay. The ab i l i t y to generate influenza and mumps virus-specific CTLs was used as a control response. MVspecific CTL response was markedly reduced in both SSPE patients (<5%) compared to that in the healthy controls (24.1 ± 9.1%). Generation of influenza and mumps virus-specific CTLs, as well as MV induced NK act iv i ty were similar in the SSPE patients and controls. In addition, MHC class I I matched CTLs from healthy individuals lysed SSPE targets indicating a defect in the effector cell in SSPE.

Immune Complexes in Subacute Sclerosing Panencephalitis

Publisher Summary It has been observed that patients with Subacute Sclerosing Panencephalitis (SSPE) respond normally to skin test antigens, have normal isohemagglutinin titers, elevated serum IgG, IgA, and IgM levels, elevated cerebrospinal fluid (CSF) IgG levels and elevated serum and CSF measles antibody titers (MAT). It has also been observed that both serum and CSF IgG levels increase with progression of the disease, while the specific measles antibody titers remain at the same level. Findings have suggested that antigenic stimuli other than the measles virus may be involved in the disease. This chapter discusses the findings based on the studies conducted circulating immune complexes in patients with SSPE. The results indicate the presence of immune complexes (IC) in the circulation of patients suffering from SSPE and the presence of a specific blocking factor in the sera and CSF of SSPE patients. It is suggested that one of the sites at which IC can be deposited is the choroid plexus. This makes the supposition of the involvement of IC in the pathogenesis of SSPE more probable. Further studies are being conducted to elucidate the role of IC in the pathogenesis of SSPE.

Ophthalmoscopic findings in subacute sclerosing panencephalitis (SSPE). Report of 17 cases and review of the literature.

ABSTRACT The ophthalmoscopic findings in 17 patients suffering from subacute sclerosing panencephalitis (SSPE) are described and compared to those in the literature. At the time of the first examin...