While the mouse and human H proteins are structurally and functionally similar, they differ in their genetics. Whereas there is no evidence in humans for more than one gene; in mice the H locus is complex. Based on cDNA sequence and hybridization analysis of genomic cosmid clones, there are at least three distinct genes, all highly related to one another. The consensus repeating unit that comprises this molecule has obviously been duplicated numerous times, since it is present in many other molecules. Thus, it is not surprising to discover that there are several genes related to H in the mouse. A similar case has been described for two other members of this family. In humans, CR1 cDNA hybridizes to two distinct genomic clusters in the CR1 locus (Wong et al. 1989), and in mice, mCRY hybridizes to two regions in the genome, one on chromosome 1 and another on chromosome 8 (Aegerter-Shaw et al. 1987). It will be of interest to see if any other members of this family display as complex a genetic locus as murine H.
In spite of major research efforts, cancer of the colon remains the second commonest cancer killer in North America. Epidemiologic studies on large populations have implicated numerous dietary factors which encourage the appearance of these tumors but a clear cause — effect relationship for individuals has not been established (Armstrong and Dou, 1975; Kinlen, 1983; Review, 1982; Walker, 1976; Weisberger et al, 1982; Willett and MacMahou, 1984) . The large majority of colon cancers are classified as idiopathic. There are notable exceptions, however, such as the “cancer families”, familial polyposis, Gardner’s syndrome and others where the genetic background of the host appears to play an important role (Lynch et al, 1973; Lynch and Lynch, 1980) . In the majority of cases the problem remains of explaining why some individuals, given similar environments, develop colon cancer and others do not. One possibility is that subtle genetic factors are present, causing one individual to be susceptible and another resistant to developing colon cancer. Very little work appears to have been done, at an experimental level, to explore this possibility.
Recent studies have demonstrated that introduction of sense gene constructs in plants can result in transgenic plants which express the transgene but also in plants with suppressed levels of transgene expression (reviewed by Jorgensen 1991; Kooter and Mol 1993; Matzke and Matzke 1993). In many silencing cases, the transgene and homologous host genes are coordinately suppressed in the plants, a phenomenon called co-suppression (Napoli et al. 1990). Although the underlying mechanism(s) are unknown, co-suppression has been reported in different plant species, and thus may represent a new approach to the manipulation of gene expression in plants. The finding that the presence of transgenes can influence the expression of resident genes via a homology-based mechanism opens up the possibility that this type of gene regulation may be naturally occurring in plants. A major challenge now is to unravel the molecular mechanism(s) responsible for transgene-induced gene silencing in plants.
We and others reported that hybrids of spleen cells and the lymphoma line BW5147 express the Thy1.2 antigen of the splenic donor (1–3). Whether only T cells were the splenic parent of these hybrids could not be concluded from the hybrid phenotypes. We report here that either Ig+ (B) cells or Ig− (T and other) cells give hybrids with BW5147 that express the Thy1.2 allele in the genome of the spleen cell whether or not that allele was expressed on the spleen cell parent.
Transcriptional activation of cellular oncogenes has been shown to be associated with the integration of replication-competent retroviruses in a variety of tumors. Activation of the c-myc oncogene by viral integration within or near the gene has been shown to occur in several tumor systems including bursal B-cell lymphomas of the chicken and murine T-cell lymphomas.
Viruses are associated with insects in a variety of host-pathogen relationships. The viruses may be specific pathogens of insects, as for example, are the polyhedrosis viruses; or they may be pathogens of higher animals or of plants, with the insects only the intermediate hosts and the vectors. Because of these diverse relationships, there is considerable interest among research workers in many areas of biology in the use of insect tissue culture as a tool for the study of viruses. Indeed the interest has often outdistanced progress in the field of insect tissue culture. Therefore, some discussion of several of the problems involved in the culture of insect tissue seems justified before reviewing the history and present status of the study of viruses.
Centrocytic lymphoma is a CD5-positive B cell neoplasm defined in the Kiel classification (Figure 1) . This lymphoma, composed of cells resembling centrocytes (cleaved follicular center cells), is distinguished from other small cleaved cell lymphomas by the lack of transformed cells, the diffuse, vaguely nodular, or mantle zone growth pattern, and immunophenotypic differences (CD5+, CD10-, and strong surface IgM and/or IgD expression) [1, 2]. Transformation to non-cleaved or centroblastic (large cell) lymphomas is rare. Patients are usually males 50&3x2013;70 years of age, who generally present with diffuse lymphadenopathy, splenomegaly, and marrow involvement, and have a median survival > 4 years.
Translocations involving chromosome band 11q23, found in acute lymphoid and myeloid leukemias, disrupt the MLL gene. This gene encodes a putative transcription factor with regions of homology to several other proteins including the zinc fingers and other domains of the Drosophila trithorax gene product, and the “AT-hook” DNA-binding motif of high mobility group proteins. We have previously demonstrated that MLL contains transcriptional activation and repression domains using a GAL4 fusion protein system (2l). The repression domain, which is capable of repressing transcription 3-5-fold, is located centromeric to the breakpoint region of MLL. The activation domain, located telomeric to the breakpoint region, activated transcription from a variety of promoters including ones containing only basal promoter elements. The level of activation was very high, ranging from 10-fold to more than 300-fold, depending on the promoter and cell line used for transient transfection.
In translocations involving MLL, the protein produced from the der(ll) chromosome which contains the critical junction for leukemogenesis includes the AT-hook domain and the repression domain. We assessed the DNA binding capability of the MLL AT-hook domain using bacterially expressed and purified AT-hook protein. In a gel mobility shift assay, the MLL AT-hook domain could bind cruciform DNA, recognizing structure rather than sequence of the target DNA. This binding could be specifically competed with Hoechst 33258 dye and with distamycin. In, a nitrocellulose protein-DNA binding assay, the MLL AT-hook domain could bind to AT-rich SARs, but not to non-SAR DNA fragments. The role that the AT-hook binding to DNA may play in vivo is unclear, but it is likely that DNA binding could affect downstream gene regulation. The AT-hook domain retained on the der(ll) would potentially recognize a different DNA target than the one normally recognized by the intact MLL protein. Furthermore, loss of an activation domain while retaining a repression domain on the der(11) chromosome could alter the expression of various downstream target genes, suggesting potential mechanisms of action for MLL in leukemia.
The skin is positioned at the interface between an organism's internal milieu and an external environment characterized by constant assault with potential microbial pathogens. While the skin was formerly considered an inactive physical protective barrier that participates in host immune defense merely by blocking entry of microbial pathogens, it is now apparent that a major role of the skin is to defend the body by rapidly mounting an innate immune response to injury and microbial insult. In the skin, both resident and infiltrating cells synthesize and secrete small peptides that demonstrate broad-spectrum antimicrobial activity against bacteria, fungi, and enveloped viruses. Antimicrobial peptides also act as multifunctional immune effectors by stimulating cytokine and chemokine production, angiogenesis, and wound healing. Cathelicidins and defensins comprise two major families of skin-derived antimicrobial peptides, although numerous others have been described. Many such immune defense molecules are currently being developed therapeutically in an attempt to combat growing bacterial resistance to conventional antibiotics.
CD1 proteins present self and microbial glycolipids to CD 1-restricted T cells, or in the case of CD1d, to NKT cells. The CD1 family in humans consists of group I proteins CDla, CDlb, CDlc, and CDle and the group II protein CDld. Rodents express only CDld, but as CD1d is broadly expressed and traffics to all endosomal compartments, this single CD1 family member is thereby able to acquire antigens in many subcellular compartments. A complete understanding of the CD 1 family requires an appreciation of which cells express CD1 and how CD1 contributes to the unique function of each cell type. While group I CD 1 expression is limited to thymocytes and professional APCs, CD1d has a wider tissue distribution and can be found on many nonhematopoietic cells. The expression and regulation of CD1 are presented here with particular emphasis on the function of CD1 in thymocytes, B cells, monocytes and macrophages, dendritic cells (DCs), and intestinal epithelial cells (IECs). Altered expression of CD 1 in cancer, autoimmunity, and infectious disease is well documented, and the implication of CD 1 expression in these diseases is discussed.
The PLZF gene is one of five partners fused to the retinoic acid receptor alpha in acute promyelocytic leukemia. PLZF encodes a DNA-binding transcriptional repressor and the PLZF-RARalpha fusion protein like other RARalpha fusions can inhibit the genetic program mediated by the wild tpe retinoic acid receptor. However an increasing body of literature indicates an important role for the PLZF gene in growth control and development. This information suggests that loss of PLZF function might also contribute to leukemogenesis.
Based on cytogenetic studies, chromosome band 11q23 was predicted to contain an important gene, disruption of which was suspected to play a crucial role in leukemogenesis. Within the past 3 years, one of these disrupted genes, HRX (also known as Htrxl, MLL or ALL-1), and ten of its fusion partner genes have been cloned. Insights into the physiological role of the HRX protein and the leukemogenic consequences of its disruption are beginning to emerge from the observations that HRX is a homologue of the Drosophila homeotic regulator trithorax and may exert its effects through recognition and modification of chromatin structure.
Although substantial progress has been made in understanding the biochemical properties of 11S regulators since their discovery in 1992, we still only have a rudimentary understanding of their biological role. As discussed above, we have proposed a model in which the alpha/beta complex promotes the production of antigenic peptides by opening the exit port of the 20S proteasome (Whitby et al. 2000). There are other possibilities, however, that are not exclusive of the exit port hypothesis. For example the alpha/beta complex may promote assembly of immunoproteasome as suggested by Preckel et al. 1999, or it may function as a docking module and conduit for the delivery of peptides to the ER lumen (Realini et al. 1994b). There are also unanswered structural and mechanistic questions. Higher resolution data are needed to discern important structural details of the PA26/20S proteasome complex. The models for binding and activation that are suggested from the structural data have to be tested by mutagenesis and biochemical analysis. What is the role of homolog-specific inserts? Will cognate regulator/proteasome complexes show conformational changes that are not apparent in the currently available crystal structures, including perhaps signs of allosteric communication between the regulator and the proteasome active sites?
Cell lines have been established from 8 species of Lepidoptera representing 5 different families (Table 2). The line from Antheraea eucalypti (Grace, 1962) was the first insect cell line to be established and is still in culture after 9 1/2 years. The primary explants from which the eight lines originated were larval, pupal, and adult ovaries; larval and pupal hemocytes; and embryonic tissue. Larval, pupal and adult explants seem to follow the same general pattern when cultivated. For a period of several weeks, cell migration or proliferation occurs. Following this initial growth, cell multiplication ceases or decreases drastically. After a period of 6–9 months, cell growth resumes and subculturing may be initiated.
Resistance of mice to influenza viruses is governed by the Mx gene locus on chromosome 16 (Lindenmann 1964; Haller 1981; Staeheli et al. 1986). Mice of the inbred laboratory strain A2G carry the resistance allele Mx
+and are highly resistant to most influenza A viruses examined, including neurotropic (Lindenmann 1964), pneumotropic (Haller et al. 1979) and hepatotropic strains (Haller et al. 1976). In contrast, all other laboratory mouse strains tested so far are Mx
- (lacking the influenza virus resistance allele) and are uniformely susceptible to influenza viruses (Haller 1981). Resistance of Mx
+ mice selectively affects influenza viruses; susceptibility to other viruses is not influenced by the Mx gene (Haller et al. 1980). The expression of the resistance phenotype requires the action of interferon (IFN) (Haller et al. 1979, 1980). Murine IFN alpha or beta (but not IFN gamma) induces in Mx
+ cells the synthesis of a 75,000 dalton protein, termed Mx protein (Horisberger et al. 1983; Staeheli et al. 1984). The Mx protein accumulates in the cell nucleus (Dreiding et al. 1985) and inhibits influenza virus replication presumably by affecting influenza viral mRNA synthesis (Krug et al 1985).
The majority of inflammation-induced peritoneal BALB/c plasmacytomas (approximately 90%) harbor a balanced T(12;15) chromosomal translocation that deregulates the expression of the proto-oncogene c-myc. Recent evidence suggests that the T(12;15) is an initiating tumorigenic mutation that occurs in early plasmacytoma precursor cells. However, plasmacytomas take a long time to develop (average tumor latency approximately 220 days), which suggests that additional tumor progression events may be required to complete oncogenesis. We hypothesized that such tumor progression events may take the form of secondary chromosomal aberrations that can be detected by spectral karyotyping (SKY). We screened the entire chromosome complement of 18 primary BALB/c plasmacytomas carrying the T(12;15) and found in nine tumors (50% recurrence) secondary cytogenetic aberrations that involved bands D, E and F chromosome (Chr) 5. The Chr 5D-F rearrangements were manifested predominantly as unbalanced translocations with various partner chromosomes. This finding led us to propose the existence of an important plasmacytoma progression locus in the central region of Chr 5, which presumably becomes involved in peritoneal plasmacytoma development by promiscuous chromosomal translocations.
Multiple myeloma (MM) is characterized by a tremendous “genomic chaos” unique to this hematopoietic neoplasm. The lack of readily identifiable dominant cytogenetic abnormalities has presented an obstacle to molecular genetic research attempting to define lesions critical for myelomagenesis (Sawyer, et al., 1995). In addition, due to the hypoproliferative nature of this malignancy presenting with a terminally differentiated phenotype, informative karyotypes are available in only one-third of patients studied. Yet, DNA cytometric and, more recently, fluorescence in situ hybridization (FISH) studies of interphase cells have revealed genetic alterations in virtually all myeloma cases examined (Latreille et al., 1980; San Miguel et al., 1995; Flactif et al., 1995; Drach et al., 1995). The frequent involvement of chromosome 14q32, the site of the Ig heavy chain genes, in chromosome translocations of myeloma has led several groups to identify the partner chromosomes involved. Unlike most B-cell leukemias and lymphomas in which 14q32 translocations have recurrent partner chromosomes, molecular investigations of these translocations in myeloma have revealed considerable heterogeneity of partner loci (Bergsagel et al., 1996; Chesi et al., 1997; Iida et al., 1997; Chesi et al., 1998; Stec et al., 1998). None of these 14q32 translocations has yet been associated with a distinct clinical disease course in myeloma. Thus, it is unclear whether these translocations play a critical role in myelomagenesis.
Many of the genes found to be altered in cancer cells encode proteins with regulatory effects on the pattern of gene expression. Some, like growth factor receptors and adapter molecules, do so indirectly by interfering with signaling pathways that eventually converge on a nuclear target. Others are more directly associated with regulation of gene expressions, being either DNA-binding transcription factors or proximate regulators of transcription factor function.
Active locomotion by invading tumor cells is thought to be a prerequisite step in the establishment of secondary neoplasms. Successful metastasis requires the invasion of surrounding normal tissue and crossing of vascular and/or lymphatic boundaries (Nicolson 1988; Fidler 1990) and it has been suggested that motility of individual cells or groups of cells at the leading edge of a tumor protrusion might be responsible for such invasive movement (Strauli and Weiss 1977). Analysis of previously characterized high- and low-metastatic variant melanoma subpopulations has demonstrated that low-metastatic cells are largely immobile, while their high-metastatic counterparts exhibit profoundly greater locomotory activity (Raz and Geiger 1982; Volk et al. 1984; Geiger et al. 1985; Zvibel and Raz 1985; Raz and Ben-Ze’ev 1987). Similar findings were obtained using the Lewis lung carcinoma (Young et al. 1985) and a rat mammary adenocarcinoma model (Badenoch-Jones and Ramshaw 1984), while more recent work in the Dunning R-3327 rat prostatic adenocarcinoma model has further corroborated the relationship between motility and metastatic potential (Mohler et al. 1987, 1988; Partin et al. 1989).
The E1A oncogene of human adenoviruses cooperates with other viral and cellular oncogenes in oncogenic transformation of primary and established cells. The N-terminal half of E1A proteins that form specific protein complexes with pRb family and p300/CBP transcriptional regulators is essential for the transforming activities of E1A. Although the C-terminal half of E1A is dispensable for the transforming activities, it negatively modulates the oncogenic activities of the N-terminal region. Mutants of E1A lacking the C-terminal half or a short C-terminal region exhibit a hyper-transforming phenotype in cooperative transformation assays with the activated ras oncogene. The E1A C-terminal region implicated in the oncogenesis-restraining activity interacts with a 48-kDa cellular phosphoprotein, CtBP, that functions as a transcriptional corepressor. It appears that the C-terminal region of E1A may suppress E1A-mediated oncogenic transformation by a dual mechanism of relieving repression cellular genes by CtBP, and also by antagonizing the oncogenic activities of the N-terminal half of E1A.
The characteristics of natural populations result from different stochastic and deterministic processes that include reproduction with error, selection, and genetic drift. In particular, population fluctuations constitute a stochastic process that may play a very relevant role in shaping the structure of populations. For example, it is expected that small asexual populations will accumulate mutations at a higher rate than larger ones. As a consequence, in any population the fixation of mutations is accelerated when environmental conditions cause population bottlenecks. Bottlenecks have been relatively frequent in the history of life and it is generally accepted that they are highly relevant for speciation. Although population bottlenecks can occur in any species, their effects are more noticeable in organisms that form large and heterogeneous populations, such as RNA viral quasispecies. Bottlenecks can also positively select and isolate particles that still keep the ability to infect cells from a disorganized population created by crossing the error threshold.
Friend virus induces rapid progressive erythroleukemia in susceptible mice. To oncologists and to cell biologists, this disease has provided a fascinating model for analyzing neoplastic progression, the role of host genes in controlling susceptibility to cancer, and the differentiation of erythroid cells in culture. However, to molecular biologists, Friend virus (and the closely related Rauscher and Cas virus complexes) has been generally viewed as a relatively complex anomaly. The virus lacks a classical oncogene of the sort typified by the src gene of Rous sarcoma virus. Such classical viral oncogenes (v-oncs) are modified versions of normal cellular genes (proto-oncogenes or c-oncs) and they are present in all of the other known retroviruses that cause rapidly developing neoplasms (Bishop 1983, 1985; Weinberg 1985). The c-oncs have been highly conserved throughout evolution, and there, is evidence that they perform important cellular functions. Because Friend virus lacks such a modified cellular gene and contains only retroviral-specific nucleic acid sequences, and because it induces a progressively developing neoplasm rather than an immediate cancer, it has been widely assumed that it is relatively “different” and “complex,” perhaps too different to provide general insights and too complex for molecular biological analysis.
I would like to introduce my presentation with two slides published II years ago (Ohno et al. 1979). They illustrate the MPC associated 12:15 and 6:15 translocations. I do not intend to describe how successfully the whole story developed in the hands of molecular biologists. From the cytogenetic point of view, however, one intriguing question has remained unsolved (illustrated in Fig. 1).
Acute promyelocytic leukaemia (APL; FAB AML M3, Bennett et al. 1976) represents a unique example of a disease in which a successful treatment approach, in the form of all-trans retinoic acid (ATRA), has been developed that directly addresses and overcomes the causative molecular abnormality. For over a decade, retinoids have been noted to possess therapeutic activity which is virtually specific to the acute promyelocytic form of acute myeloid leukaemia (AML) (Breitman et al. 1981). Subsequent clinical trials have shown that ATRA can achieve remission rates of over 90% in APL (Huang et al. 1988; Castaigne et al. 1990; CHOMIENNE et al. 1990), representing an apparent significant improvement on results obtained with conventional chemotherapy; indeed a number of patients in these studies were chemoresistant or treated in relapse. Parallel in vitro studies have demonstrated that remission is achieved by terminal differentiation of the leukaemic clone rather than by a cytotoxic effect (Huang et al. 1988; Castaigne et al. 1990; Chomienne et al. 1990). This has been confirmed using clonal analysis of APL blasts and peripheral blood neutrophils following ATRA therapy (ELLIOTT et al. 1992).
A characteristic pericentric inversion of chromosome 16 [inv(l6)(p13q22)] is consistently associated with acute myelomonocytic leukemia with eosinophilia (AML M4Eo). This type of leukemia comprises 8% of AML cases and affects approximately 2,000 people each year in the United States. In addition to inv(l6), a number of other unique features are associated with AML M4Eo, including the presence of morphologically and histochemically abnormal eosinophils, a relatively good prognosis, and possibly frequent involvement of the central nervous system (for review see Liu etal. 1995)
Molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either several linear amino acids or their conformational fit may be shared, even though their origins are separate. Hence, during a viral or microbe infection, if that organism shares cross-reactive epitopes for B or T cells with the host, then the response to the infecting agent will also attack the host, causing autoimmune disease. A variation on this theme is when a second, third, or repeated infection(s) shares cross-reactive B or T cell epitopes with the first (initiating) virus but not necessarily the host. In this instance, the secondary infectious agents increase the number of antiviral/antihost effector antibodies or T cells that potentiate or precipitate the autoimmune assault. The formation of this concept initially via study of monoclonal antibody or clone T cell cross-recognition in vitro through its evolution to in vivo animal models and to selected human diseases is explored in this mini-review.
The innate immune system provides many ways to quickly resist infection. The two best-studied defenses in dendritic cells (DCs) are the production of protective cytokines-like interleukin (IL)-12 and type I interferons-and the activation and expansion of innate lymphocytes. IL-12 and type I interferons influence distinct steps in the adaptive immune response of lymphocytes, including the polarization of T-helper type 1 (Th1) CD4+ T cells, the development of cytolytic T cells and memory, and the antibody response. DCs have many other innate features that do not by themselves provide innate resistance but are critical for the induction of adaptive immunity. We have emphasized three intricate and innate properties of DCs that account for their sentinel and sensor roles in the immune system: (1) special mechanisms for antigen capture and processing, (2) the capacity to migrate to defined sites in lymphoid organs, especially the T cell areas, to initiate immunity, and (3) their rapid differentiation or maturation in response to a variety of stimuli ranging from Toll-like receptor (TLR) ligands to many other nonmicrobial factors such as cytokines, innate lymphocytes, and immune complexes. The combination of innate defenses and innate physiological properties allows DCs to serve as a major link between innate and adaptive immunity. DCs and their subsets contribute to many subjects that are ripe for study including memory, B cell responses, mucosal immunity, tolerance, and vaccine design. DC biology should continue to be helpful in understanding pathogenesis and protection in the setting of prevalent clinical problems.
The most proximal portion of mouse chromosome 17 occurs in a variant form known as a t haplotyper which is present at a high frequency in wild populations of mus domesticus and mus musculus. While t haplotypes have been studied by a number of investigators over the last 50 years, it is only within the last 5 years that we have begun to appreciate the true nature of these unusual genetic elements (for a recent review, see Silver, 1986). A large body of new data from a number of laboratories indicates that all naturally occurring t haplotypes are closely related to each other with a characteristic genomic organization that differs from the wild-type organization of this chromosomal region. (The “wild-type chromosome 17” refers to the non-t-haplotype form normally found in mus domesticus or mus musculus). Within the structurally variant region that defines t haplotypes (approximately 20–30,000 kb of DNA encompassing the T locus and the entire MHC), are many normally functioning genes interspersed with a number of independent “mutant loci” that mediate the characteristic t haplotype effects on fertility and development.
Proteins need help to fold and attain their functional conformation (Ellis and Hemmingsen 1989), and mechanisms have evolved to prevent the accumulation of misfolded protein aggregates within cells (Pelham 1988). These mechanisms fail to prevent the formation of protease-resistant, misfolded forms of PrP (ScPrP) during the development of scrapie and other transmissible spongiform encephalopathies, and ScPrP is a biochemical marker of these diseases. Much is now known about the structure and expression of the PrP gene, but the physiological function of the PrP protein and the mechanism by which the TDE pathogen replicates and specifically interferes with PrP metabolism remain a mystery--a mystery which will entertain prion-ophiliacs for some time yet.
The isolation and physical mapping of a class of mutants designated large plaque (Ip) mutants of adenovirus (Ad) type 2 (group C) within the E1B 19 kDa- coding region provided initial clues about the functions of E1B 19-kDa protein (Chinnadurai et al. 1979; Chinnadurai 1983). A class of mutants designated the cytocidal (cyt) mutants of Ad12 (group A) isolated by Takemori and colleagues (Takemori et al. 1968) which also produce large plaques on infected cell monolayers was subsequently mapped to the E1B 19 kDa-coding region by intertypic mutant complementation (Subramanian et al. 1984b). The cyt mutants of Ad12 induce extensive cytopathic effect on infected cells (Takemori et al. 1968). As expected, subsequent studies revealed that several Ad2 and Ad5 mutants defective in the 19-kDa protein (19K mutants) also induced severe cytopathic effects (Subramanian et al. 1984b; Takemori et al. 1984). In accordance with an observation by Mak and colleagues (Ezoe et al. 1981 ) that viral DNA is extensively degraded in cells infected with Ad12 cyt mutants, several Ad2/Ad5 19K mutants were also found to induce fragmentation of cellular and viral DNA (deg) in infected cells (Subramanian et al. 1984a; Pilder et al. 1984; White et al. 1984a). Genetic studies have indicated that the cyt and deg phenotypes are linked, thereby indicating that the fragmentation of cellular and viral DNA is a consequence of the cytopathic effect induced by the 19K mutants (Subramanian and Chinnadurai 1986).
Subacute sclerosing panencephalitis is an inflammatory, progressive, slowly evolving disorder of the central nervous system, affecting children and young adults. The disease has been known for almost forty years and described during this period under various designations by many neuropathologists. Each name, being based on different neuropathological findings, suggested a distinct nosological entity. Thus Bodechtel and Guttmann (1931) described one case under the heading “diffuse encephalitis with sclerosing inflammation of the hemisphere white matter”, Dawson (1933, 1934) used the term “inclusion body encephalitis” Pette and Döring (1939) named the disease “pan-encephalomyelitis” and van
Bogaert (1945) introduced the term “subacute sclerosing leukoencephalitis”. Only during the last twenty years have various investigators, after careful studies, come to the conclusion that these conditions were actually the same disease—one that can result in a broad variety of neuropathologic changes. At the present time the descriptive term “subacute sclerosing panencephalitis”, or SSPE, has been generally accepted as the designation for this disease.
The region of murine chromosome 1 surrounding the biochemical markers, Idh-1 and Pep-3 (band C) contains segments of homology with genes on human chromosomes 1, 2 and 18 (Lalley and McKusick 1985; Mock et al., in press). This 27 cM region of chromatin contains sites of endogenous proviral loci (Emy-16,17; Buchberg et al., 1986), an oncogene (bcl-2; Mock et al., 1987; in press) which, in man, is consistently rearranged in follicular lymphomas (Bakshi et al., 1985; Cleary and Sklar 1985; Tsujimoto et al., 1985), a cytolytic T-cell associated sequence (Ctla-4; Brunet et al., 1987) and genes involved in the serum complement system (Cfh and C4bp; Seldin in press; D’Eustachio et al. 1986), murine embryogenesis (En-1; Joyner et al. 1985), muscle development (Myl-1; Robert et al. 1984), the repair of chromatin breaks (Rep-1, Potter et al. in press) and the resistance/ susceptibility to Leishmania (Lsh, Bradley et al. 1979), Salmonella (Ity, Plant and Glynn 1976; Taylor and O’Brien 1982) and Mycobacterium (Bcg, Gros et al. 1981).
The homeobox is a conserved DNA sequence of about 183 nucleotides identified within a number of Drosophila genes which regulate certain aspects of early development. The homeobox sequence encodes a 61 amino acid homeodomain containing a helix-turn-helix motif which is probably involved in DNA binding. Drosophila genes containing a homeobox include some segmentation genes which are involved in generating a metameric pattern, and many homeotic genes (Gehring 1987). Homeotic genes have roles in establishing segment identity, which involves the specification of positional values along the anteroposterior body axis — a process which must occur in the embryos of all bilateral animals, not only those with a segmented body plan. It is therefore significant that several Drosophila homeobox-containing genes are expressed in patterns which suggest roles in positional specification independent of the process of segmentation (Doyle 1986; Hoey et al., 1986; Akam 1987; Gehring 1987).
Around 2008 or 2009, an influenza A virus that had been circulating undetected in swine entered human population. Unlike most swine influenza infections of humans, this virus established sustained human-to-human transmission, leading to a global pandemic. The virus responsible, 2009 pandemic H1N1 (H1N1pdm), is the result of multiple reassortment events that brought together genomic segments from classical H1N1 swine influenza virus, human seasonal H3N2 influenza virus, North American avian influenza virus, and Eurasian avian-origin swine influenza viruses. Genetically, H1N1pdm possesses a number of unusual features, although the genomic characteristics that permitted sustained human-to-human transmission are yet unclear. Human infection with H1N1pdm has generally resulted in low mortality, although certain subgroups (including pregnant women, people with some chronic medical conditions, morbidly obese individuals, and immunosuppressed people) have significantly higher risk of severe disease. As H1N1pdm has spread throughout the human population it continued to evolve. It has also reentered the swine population as a circulating pathogen, and has been transiently identified in other species such as turkeys, cats, and domestic ferrets. Most genetic changes in H1N1pdm to date have not been clearly linked to changes in antigenicity, disease severity, antiviral drug resistance, or transmission efficiency. However, the rapid evolution rate characteristic of influenza viruses suggests that changes in antigenicity are inevitable in future years. Experience with this first pandemic of twenty-first century reemphasizes the importance of influenza surveillance in animals as well as humans, and offers lessons to develop and enhance our ability to identify potentially pandemic influenza viruses in the future.
In contrast to our detailed knowledge of prokaryotic proteasomes, we have only a limited understanding of the prokaryotic regulators and their functional interaction with the proteasome. Most probably, we will soon learn more about the molecular structure and the mechanism of action of the prokaryotic regulators. Nevertheless, it still remains to be unravelled which signals or/and modifications transform an endogenous prokaryotic protein into a substrate of the proteasomal degradation machinery.
Murine plasmacytomas (MPCs) consistently exhibit chromosomal translocations involving chromosome 15 (t(12;15) or t(6;15)) (Ohno et al. 1979, 1984, 1988). These translocations of chromosomes juxtapose the proto-oncogene c-myc to the one of Ig gene loci (Cory 1986) . The juxtaposition of c-myc and the Ig gene strongly suggests that they play a critical genomic role in the development of MPCs probably by deregulating the c-myc gene expression.
Retroelements constitute approximately 45% of the human genome. Long interspersed nuclear element (LINE) autonomous retrotransposons are predominantly represented by LINE-1, nonautonomous small interspersed nuclear elements (SINEs) are primarily represented by ALUs, and LTR retrotransposons by several families of human endogenous retroviruses (HERVs). The vast majority of LINE and HERV elements are densely methylated in normal somatic cells and contained in inactive chromatin. Methylation and chromatin structure together ensure a stable equilibrium between retroelements and their host. Hypomethylation and expression in developing germ cells opens a "window of opportunity" for retrotransposition and recombination that contribute to human evolution, but also inherited disease. In somatic cells, the presence of retroelements may be exploited to organize the genome into active and inactive regions, to separate domains and functional regions within one chromatin domain, to suppress transcriptional noise, and to regulate transcript stability. Retroelements, particularly ALUs, may also fulfill physiological roles during responses to stress and infections. Reactivation and hypomethylation of LINEs and HERVs may be important in the pathophysiology of cancer and various autoimmune diseases, contributing to chromosomal instability and chronically aberrant immune responses. The emerging insights into the pathophysiological importance of endogenous retroelements accentuate the gaps in our knowledge of how these elements are controlled in normal developing and mature cells.
Following the discovery by Gross in 1950 of type C murine leukemia virus (MuLV) (Gross, 1951), considerable knowledge about these viruses in laboratory strains of mice has accumulated (for review, see Sarma and Gaidar, 1974). Only in the last few years, however, has information been obtained about type C viruses in outbred, feral-living Mus Musculus, the progenitor of the laboratory mouse. An understanding of the natural history of these viruses in wild mice is important because in laboratory mice they could represent to some extent an artifact of inbreeding and laboratory selection. The wild mouse might also prove a useful model for humans, an outbred species in which some involvement with RNA tumor virus genomes is suspected (for review, see Hehlman, 1976). The first indication that these viruses were present in wild mice was the detection of virus group specific antigen in the tissues of Maryland wild mice bred in captivity (Huebner et al., 1970). Type C viruses were subsequently found in multiple populations of wild mice in southern California and were shown to be lymphomagenic under natural and experimental conditions. Completely unanticipated, however, was the discovery of an independent etio-logic involvement of these agents with a naturally occurring neurogenic hind leg paralytic disease of wild mice, which in several aspects is similar to amyotrophic lateral sclerosis in humans.
For quite a long time, the paucity of immune system elements in the central nervous system (CNS) and its tight enclosure by the blood—brain barrier (BBB) have led to the assumption that this organ is an immunologically privileged site of the body that is rigorously excluded from immune surveillance. However, data accumulated in recent years suggest that this view has to be revised substantially, since the healthy as well as the injured CNS performs an intense and permanent cross-talk with the immune system resulting usually in a well tuned and gradually adapted immune response in the brain (Cserr and Knopf 1992; Fabry et al. 1994).
NF-kB elements mediate control of a number of important growth regulatory genes (rev. in Baeuerle, 1991). We have identified two functional NF-kB elements within the murine c-myc gene. The upstream regulatory element or URE is located -1101 to -1091 b.p. upstream of the PI promoter (Duyao et al. 1990). The internal regulatory element or IRE is at +440 to +459 b.p., within exon 1 (Kessler et al. 1992b). Activation of NF-kB by IL-1 in human dermal FS-4 fibroblasts (Kessler et al. 1992a) or by the tax protein of the HTLV-1 virus in T lymphocytes (Duyao et al. 1992) leads to induction of transcription of the c-myc promoter through binding to the URE and IRE. NF-kB is now known to be a family of dimeric transcription factors, whose subunits all contain an amino terminal rei homology domain, which mediates both dimerization and DNA binding. Classical NF-kB is a heterodimer composed of a p50 and a p65 subunit (Ghosh et al. 1990; Ruben et al. 1991). The c-rel gene encodes a 75 kDa protein (Simek and Rice 1988). Various combinations of these Rei family of proteins bind as dimers to NF-kB elements, but their activity has been found to be element specific.
The c-myc oncogene has been implicated in control of cell proliferation, differentiation, as well as neoplastic transformation. More recently, overexpression or inappropriate time of expression of the c-myc gene has been found to promote apoptosis. Cleveland and coworkers observed that addition of a vector expressing c-Myc protein accelerated apoptosis following IL-3 deprivation of the 32D Independent myeloid cell line . Similarly Evan and coworkers  found that transfection of 3T3 fibroblast cells with c-myc expression vectors led to enhanced levels of apoptosis upon growth arrest either by serum or isoleucine deprivation, or a thymidine block. These findings have been further extended using c-myc antisense oligonucleotides. Green and coworkers have shown that addition of these oligonucleotides to immature T cells and some T cell hybridomas, inhibited c-myc expression and prevented T cell receptor mediated apoptosis . Together these results strongly suggest that inappropriate overexpression of c-myc promotes apoptosis in some cell systems.
The germline content of immunoglobulin (Ig) heavy and light chain variable region genes is one important source of antibody diversity; thus a large germline repetoire of these genes provides a potential capability to respond to a wide variety of antigens independent of subsequent somatic diversification. Immunoglobulin variable region genes appear to have evolved at a more rapid rate than many other proteins (Wilson 1977), which might be expected in a system where selection favors increased diversity. Examining evolutionary changes in immunoglobulin multigene families provides an opportunity to study the rate at which this system is evolving and permits an examination of the relative contribution of point mutations, recombinational events and gene duplications to the generation of germline diversity. The Ig repetoire of inbred Mus musculus, which has been extensively studied (for a review, see Honjo 1985, Hood 1985), represents an ideal model for such studies.
It is generally accepted that the primary immune response to an antigen involves the formation of long-lived, antigen-specific memory cells, in addition to effector cells. These memory cells are thought to be responsible for the heightened immune response that follows secondary exposure to an antigen. As the secondary antibody response is generally characterized by the production of increased levels of antibodies having higher avidity for antigen (Eisen and Siskind 1964), it has been proposed that immunologic memory at the B-cell level includes both an increased frequency of antigen-reactive lymphocytes and a greater mean avidity of their antigen receptors (Andersson 1970; Celada 1971; Davie and Paul 1972). In the case of T-cell responses, little is known about the formation of memory cells during immunization. There is evidence that the frequency of antigen-specific T lymphocytes may increase after immunization (MacDonald et al. 1980). In addition, indirect evidence has been provided showing that T cells in immunized animals bear higher avidity antigen receptors compared with normal animals (MacDonald et al. 1982; Marrack et al. 1983). However, detailed analysis of memory T cells has been hampered by the lack of suitable surface markers allowing identification and isolation of these cells. As discussed below, recent studies from our laboratory indicate that murine memory T cells can be identified phenotypically by the surface marker Pgp-1. A more comprehensive review of T-cell memory will be presented elsewhere (Cerottini and MacDonald 1989).