Jo-Ann Latkowski

Regulatory T cells in spontaneous autoimmune encephalomyelitis.

Summary: Spontaneous experimental autoimmune encephalomyelitis (EAE) develops in 100% of mice harboring a monoclonal myelin basic protein (MBP)‐specific CD4+αβ T‐cell repertoire. Monoclonality of the αβ T‐cell repertoire can be achieved by crossing MBP‐specific T‐cell receptor (TCR) transgenic mice with either RAG−/− mice or TCR α−/−/TCR β−/− double knockout mice. Spontaneous EAE can be prevented by a single administration of purified CD4+ splenocytes or thymocytes obtained from wild‐type syngeneic mice. The regulatory T cells (T‐reg) that protect from spontaneous EAE need not express the CD25 marker, as effective protection can be attained with populations depleted of CD25+ T cells. Although the specificity of the regulatory T cells is important for their generation or regulatory function, T cells that protect from spontaneous EAE can have a diverse TCR α and β chain composition. T‐reg cells expand poorly in vivo, and appear to be long lived. Finally, precursors for T‐reg are present in fetal liver as well as in the bone marrow of aging mice. We propose that protection of healthy individuals from autoimmune diseases involves several layers of regulation, which consist of CD4+CD25+ regulatory T cells, CD4+CD25− T‐reg cells, and anti‐TCR T cells, with each layer potentially operating at different stages of T‐helper cell‐mediated immune responses.

Swift Entry of Myelin-Specific T Lymphocytes into the Central Nervous System in Spontaneous Autoimmune Encephalomyelitis

Strong evidence supports that CNS-specific CD4+ T cells are central to the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Using a model of spontaneous EAE, we demonstrated that myelin basic protein (MBP)-specific CD4+ T cells up-regulate activation markers in the CNS-draining cervical lymph nodes at a time when there is no T cell activation anywhere else, including the CNS, and before the appearance of clinical signs. In spontaneous EAE, the number of MBP-specific T cell numbers does not build up gradually in the CNS; instead, a swift migration of IFN-γ-producing T cells into the CNS takes place ∼24 h before the onset of neurological signs of EAE. Surgical excision of the cervical lymph nodes in healthy pre-EAE transgenic mice delayed the onset of EAE and resulted in a less severe disease. In EAE induced by immunization with MBP/CFA, a similar activation of T cells in the draining lymph nodes of the injection site precedes the disease. Taken together, our results suggest that peripheral activation of T cells in draining lymph nodes is an early event in the development of EAE, which paves the way for the initial burst of IFN-γ-producing CD4+ T cell into the CNS.

Keratinocyte growth factor and keratin gene regulation

Keratinocyte growth factor (KGF) is a stromally derived paracrine mitogen that belongs to the fibroblast growth factor (FGF) family. It is secreted by dermal fibroblasts and specifically promotes keratinocyte proliferation. We have recently shown that epidermal growth factor (EGF) and transforming growth factor beta (TGF beta), modulators of keratinocyte proliferation, regulate expression of specific keratin genes. However KGF, unlike EGF and TGF beta, allows keratinocytes to differentiate normally. With this in mind, we sought to determine whether KGF may be involved in keratinocyte differentiation through a mechanism that does not involve regulation of keratin gene expression. We transfected human epidermal keratinocytes with ten different keratin gene promoters linked to a reporter gene, and grew the transfected cells in the presence or absence of KGF. Interestingly, no significant change in keratin gene regulation was observed in the presence of KGF relative to control. The possibility that KGF influences the induction of keratin gene expression by other keratinocyte modulators, such as EGF, TGF beta and gamma interferon (IFN gamma), was also explored. In these experiments, the transformed keratinocytes were exposed simultaneously to KGF and another modulator. KGF did not significantly change the effects of EGF, TGF beta or IFN gamma on keratin gene expression. KGFs lack of ability to directly regulate keratin gene expression suggests that KGF affects keratinocyte growth and differentiation through a pathway independent of keratin gene regulation. These results illustrate that regulation of keratinocyte proliferation can be separated from the regulation of keratin gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

The ethics of the medical-pharmaceutical relationship

Physician interaction with the pharmaceutical industry raises many ethical concerns. This relationship is complex, owing to a pluralism of beliefs held by physicians, patients, and third parties. As a result, determining whether physicians fulfill their responsibilities to both the professional and public communities is an arduous endeavor. In an effort to clarify the situation and provide transparency to this complex relationship, medical and pharmaceutical organizations have enacted their own respective codes and guidelines. Even with adherence to these guidelines, questions remain regarding the codependent relationship that interweaves the pharmaceutical industry with the medical community. Owing to the ever-changing landscape enmeshing product development, scientific advancement, corporate realities and patient care, the proper choice for physicians is rarely obvious; however, to operate to the highest standards, those in the medical community must be candid about relations with the pharmaceutical industry and transparent in their financial interests. Further undertakings should focus not on the eradication of physician-pharmaceutical interaction, but instead on the education of physicians about industry marketing strategies and the delineation of boundaries of these interactions to benefit not the individual physician, but our patients.

Characterization of Two Distinct Lymphoproliferative Diseases Caused by Ectopic Expression of the Notch Ligand DLL4 on T Cells

Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass β-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity.

Molecular Origin of Endemic Leprosy in New York City

We report an indigenous case of leprosy in New York City in an immunocompetent patient who was infected with a Mycobacterium leprae genotype that is consistent with an exogenous origin. Physicians in the eastern United States should be alerted that, although most patients who develop leprosy in the United States are foreign born, native-born Americans are also susceptible to the infection.

55-year-old man with ulcers in inguinal fold and intergluteal cleft found to have systemic Langerhans cell histiocytosis

LCH: Langerhans cell histiocytosis INTRODUCTION This article describes the case of a patient with cutaneous ulcers who was found to have systemic Langerhans cell histiocytosis (LCH). This article includes the clinical, histology, and electron microscopy images, in addition to a description of the presentation, workup, and management of this rare disease in this patients, with a review of the literature.

Regression of pigmented lesions in a patient with metastatic melanoma treated with immunotherapy

CTLA-4: cytotoxic T-lymphocyteeassociated protein 4 PD-1: Programmed cell death protein