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Immunization against viral infection has saved countless lives, but how it works long remained a mystery. The discovery of antibodies at the end of the nineteenth century revealed one mechanism. Antibodies are proteins made by the immunized or infected animal that bind specifically to infectious agents or their toxic products (antigens) and inactivate them. The magical power of producing an infinite repertoire of antibodies seemed to imply an infinite repertoire of genes to code for them, which opened the way to an understanding of how a class of white blood cells known as T cells kill virus-infected cells in the body and so prevent the spread of viruses. This cell-mediated immunity complements the antibody response to infection. T-cell immunity is indeed profoundly different from B-cell immunity. Knowledge of it has transformed the prospects for designing new and effective vaccines.

The non-Hodgkin lymphomas (NHL) are a heterogeneous group of over forty lymphoid neoplasms that have undergone a major redefinition over the last twenty-five years, in part due to advances in immunology and genetics as well as implementation of the WHO classification system. NHLs are considered clonal tumors of B-cells, T-cells, or natural killer (NK) cells arrested at various stages of differentiation, regardless of whether they present in the blood (lymphoid leukemia) or lymphoid tissues (lymphoma). In the United States, the age-standardized NHL incidence rate (per 100,000) doubled from 1973 (10.2) to 2004 (21.4) and then stabilized, while five-year relative survival rates improved from 42% in 1973 to 70% in 2004. Established risk factors for NHL or specific NHL subtypes include infectious agents (HTLV-1, HIV, EBV, HHV8, HCV, H. pylori), immune dysregulation (primary immunodeficiency, transplantation, autoimmunity, and immunosuppressive drugs), family history of lymphoma, and common genetic variants identified by genome-wide association studies.

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of malignancies originating from B- or T-lymphocytes and engaging lymphoid tissue. Clinically, NHL subtypes range from chronic indolent to aggressive life-threatening diseases. The incidence of NHL overall increased dramatically worldwide during the latter half of the twentieth century but has now leveled off in many countries. Although some etiologic factors have been identified, most newly diagnosed cases of NHL as well as the previous rise in incidence remain largely unexplained. Well-established risk factors include severe immune suppression following HIV/AIDS and organ transplantation, autoimmune and inflammatory disorders, some infectious agents, and family history. More recently, lifestyle factors have also been linked with certain subtypes of NHL. Through the work of the international InterLymph consortium, several subtype-specific genetic susceptibility variants have also been revealed, promising to shed further light on mechanisms of lymphomagenesis.

A primary aim of functional genomics in pharmaceutical applications is to identify genes whose function is critical to maintaining a disease state and to determining whether therapeutic modulation of this function results in a beneficial clinical response. However, although many genomic approaches can identify disease-associated genes, lengthy follow-up studies are usually required to determine which genes are functionally important and are causally linked to a given disease. In contrast, retrovirally mediated functional genetic screening approaches enable rapid identification of physiologically relevant targets. Genetic screens are designed to detect functional changes that result in changes in cellular function that correlate with disease amelioration. Retroviruses possess unique properties that allow delivery of complex libraries of potential genetic effectors to a variety of cell types. These effectors can perturb specific interactions required to achieve a complete functional response and establish a direct relationship with a cellular function. Functional screens are employed to select for cells endowed with a desired genetic effector–induced change in phenotype. Identification of a genetic effector that causes an altered cellular phenotype that correlates with clinical benefit can explicate critical signaling components suitable for therapeutic intervention. Flow cytometry represents a uniquely powerful methodology to monitor complex multiparametric changes of individual cells in large populations. In conjunction with recent advances in retroviral expression systems, the sensitivity and speed of flow cytometry enables a highly efficient functional screening of complex libraries in a wide range of cell-based assays. In this chapter, we discuss the process of functional genetic screening and show specific examples of its implementation. We focus particularly on the critical parameters involved in the design and execution of functional genetic screening approaches based on FACS (fluorescence activated cell sorter). Retroviruses provide a powerful method of introducing genes into mammalian cells in an efficient and stable manner. Recent advances in retroviral vector technology and packaging systems have extended their application to allow efficient and stable delivery of highly diverse libraries encoding various types of genetic effectors, including cDNAs, peptides, and ribozymes, into a broad range of cell types.

Two types of pertussis vaccines are currently available: the first-generation, whole-cell (wP) and more recent, acellular (aP) vaccines. The aP vaccine has replaced the wP vaccine in most industrialized countries, based on an improved safety profile and comparable efficacy of the former compared to the latter. As both vaccines, as well as prior infection, protect well against whooping cough disease, albeit by different mechanisms, the human immune responses to natural infection and vaccination have been extensively studied over the last decades. Shortly after the discovery of the causative agent Bordetella pertussis, both agglutinating antibodies and complement-binding antibodies have been identified in the serum of convalescent patients. However, how much they contribute to protection against disease or infection is still not known. Nevertheless, passive transfer of convalescent serum can significantly attenuate the disease and placental transfer of maternal antibodies induced by vaccination during pregnancy has recently been shown to provide strong protection against severe disease in the offspring. Natural infection and wP vaccination have both been shown to induce a strong Th-1-oriented T-cell response, whereas administration of aP vaccine shifts the response to a Th-2 profile, which may be a reason for the fast waning of immunity upon aP vaccination, compared to wP vaccination and natural infection. None of the current vaccines induce sterilizing immunity and limit circulation of B. pertussis. Therefore, new vaccines are needed that protect both against disease and infection. One such candidate, live attenuated BPZE1, designed to prevent B. pertussis infection, is currently in clinical development.

This chapter discusses myeloma, a clonal B cell disorder that afflicts the elderly with a median age of 69 and with a median survival of three years from diagnosis. Myeloma results from the malignant proliferation of plasma cells in the bone marrow, the production of monoclonal immunoglobulin by malignant plasma cells in the blood and/or immunoglobulin light chains (Bence Jones protein) in the urine, and the bony destruction due to lytic lesions and osteoporosis. Staging of myeloma is determined through paraprotein levels, clinical parameters, and the extent of bone disease. Newer methods to assess the disease include cytogenic analysis for monosomy 13 or deletion of chromosome 13 and magnetic resonance imaging of bones.

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A 56-year-old woman with terminal breast cancer and spinal metastases comes to the emergency department. She complains of lower back pain and neuopathic pain going down her lefit leg. Current analgesia includes paracetamol and oramorph. On examination her BP is 145/82, pulse is...

This chapter discusses some of the barriers viruses must overcome in order to complete their life cycle. To survive, viruses must penetrate host cells before they can begin the process of reproducing their genetic material, and here again viruses appear remarkably resourceful. By carrying a molecular key on their surface, they can disguise themselves as normal body constituents, and latch on to and enter any cell which bears the complementary lock. As such, viruses infect only those cells which display the particular molecular lock that their key fits into, and this restriction dictates the type of cell a virus infects and therefore the symptoms it will cause. Since there are several hundred molecules to choose from, viruses cause a great variety of diseases. However, viruses are not fighting a one-sided battle. Even the simplest organisms have ways of dealing with viruses, but the sophistication and subtlety of the human immune system is unrivalled. The chapter then considers the vital role B and T cells play in the body’s defences. It also traces how viruses and their hosts have co-evolved. Finally, the chapter outlines the threats viruses may pose, including viral mutation and the use of viruses in biological warfare.