Antigen-receptor degeneracy and immunological paradigms

This paper discusses some consequences of the discovery that antigen receptors are degenerate: Immune specificity, in contrast to the tenets of the clonal selection paradigm, must be generated by the immune response down-stream of initial antigen recognition; and specificity is a property of a collective of cells and not of single clones.     

The tyrosine-based YXXØ targeting motif of murine leukemia virus envelope glycoprotein affects pathogenesis

Retroviruses, such as human and simian immunodeficiency viruses (HIV and SIV), and murine leukemia viruses (MuLV), harbor a tyrosine-based motif in the intracytoplasmic domain of their envelope glycoprotein. This motif can act as an endocytosis signal or as a targeting signal, restricting viral budding at specific cell surface membrane domains. In the present study, proviral DNA of the ecotropic Cas-Br-E strain of MuLV was modified by substitution or deletion of the critical tyrosine residue. Mutant viruses lost basolateral targeting in polarized MDCK epithelial cells while expression level of the glycoprotein at the cell surface was not affected. This suggests that the tyrosine-based motif in MuLV does not act as an endocytosis signal. Only a small delay in the appearance of disease was observed in inoculated mice. In contrast, a striking change in the pathology was observed with enlarged thymus and lymph nodes in animals inoculated with mutant viruses.     

Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study

In an exploratory study, 11 common polymorphisms were examined for contributing to longevity including: apolipoprotein E (apoE), methylenetetrahydrofolate reductase (MTHFR), cathepsin D (CAD), superoxide dismutase 2 (SOD2), angiotensinogen (AGT) and insulin-like growth factor 2 (IGF2), Leiden factor 7, p53 oncogene, dopamine D4 receptor (DRD4) and the serotonin transporter (SERT). Genotype and allele frequencies of these genes were compared in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity to a group of 441 younger subjects (22 years). Nominally significant results provide suggestive evidence in the Ashkenazi group that apoE, MHTFR, SOD2, IGF2 ApaI, and factor VII are risk factors for a single outcome, survival to 75. Overall, the more genetically homogenous Ashkenazi ethnic group showed evidence for association in five genes examined suggesting that future studies in this population would gainfully focus on this ethnic group.     

Frequency of MMPI profile types in three chronic illness populations

Clinical interpretation of the MMPI most often utilizes configural or profile analysis. However, most MMPI research has focused only on single scale comparisons. In this study sorting rules to identify four common MMPI configurations were developed and applied to four S populations (N = 157): Chronic low back pain patients, migraine headache patients, hypertensives, and diabetics. No differences in frequencies of these profile types were found among the groups, although the chronic low back pain patients did have more elevated profiles. Variables of age, chronicity of illness and gender did not seem to influence profile type, while some differences were found between patients who rated themselves high and low in activity limitation due to the illness.     

Detection of the homology among proteins by immunochemical cross-reactivity between denatured antigens. Application to the glyceraldehyde 3-phosphate dehydrogenases from different species

It was previously proposed that an immunological cross-reaction between two denatured proteins is evidence for an homology betweeen their amino sequence (Arnon &; Maron, 1971; Arnheim et al., 1971) and that detection of such a cross-reaction could then be a rapid method to detect sequence homologies (Zakin et al., 1978). In order to test the possibilities of such a methodology, using proteins of known structure, glyceraldehyde 3-phosphate dehydrogenases from different sources are compared by immunochemical techniques. The antibodies raised against the native enzyme from E. coli K 12 can only recognize the homologous antigen, the glyceraldehyde 3-phosphate dehydrogenase from B. stearothermophilus and to a lesser extent that from halibut. In contrast, the antibodies raised against the denatured enzyme from E. coli K 12 can recognize the glyceraldehyde 3-phosphate dehydrogenases from man, ostrich, chicken, sturgeon, halibut, lobster and yeast, when in their denatured state. The present results show unambiguously that through exposure of buried sequences, the immunochemical detection of sequence homologies among proteins is more discriminating when unfolded proteins are used, rather than native ones. It is also proposed that the use of denatured proteins both as immunogens and antigens would be a useful tool in studying biochemical evolution.     

Habituation and adaptation of the vestibuloocular reflex: a model of differential control by the vestibulocerebellum

Summary We habituated the dominant time constant of the horizontal vestibuloocular reflex (VOR) of rhesus and cynomolgus monkeys by repeated testing with steps of velocity about a vertical axis and adapted the gain of the VOR by altering visual input with magnifying and reducing lenses. After baseline values were established, the nodulus and ventral uvula of the vestibulocerebellum were ablated in two monkeys, and the effects of nodulouvulectomy and flocculectomy on VOR gain adaptation and habituation were compared. The VOR time constant decreased with repeated testing, rapidly at first and more slowly thereafter. The gain of the VOR was unaffected. Massed trials were more effective than distributed trials in producing habituation. Regardless of the schedule of testing, the VOR time constant never fell below the time constant of the semicircular canals (5 s). This finding indicates that only the slow component of the vestibular response, the component produced by velocity storage, was habituated. In agreement with this, the time constant of optokinetic after-nystagmus (OKAN) was habituated concurrently with the VOR. Average values for VOR habituation were obtained on a per session basis for six animals. The VOR gain was adapted by natural head movements in partially habituated monkeys while they wore ×2.2 magnifying or ×0.5 reducing lenses. Adaptation occurred rapidly and reached about ±30%, similar to values obtained using forced rotation. VOR gain adaptation did not cause additional habituation of the time constant. When the VOR gain was reduced in animals with a long VOR time constant, there were overshoots in eye velocity that peaked at about 6–8 s after the onset or end of constant-velocity rotation. These overshoots occurred at times when the velocity storage integrator would have been maximally activated by semicircular canal input. Since the activity generated in the canals is not altered by visual adaptation, this finding indicates that the gain element that controls rapid changes in eye velocity in the VOR is separate from that which couples afferent input to velocity storage. Nodulouvulectomy caused a prompt and permanent loss of habituation, returning VOR time constants to initial values. VOR gain adaptation, which is lost after flocculectomy, was unaffected by nodulouvulectomy. Flocculectomy did not alter habituation of the VOR or of OKAN. Using a simplified model of the VOR, the decrease in the duration of vestibular nystagmus due to habituation was related to a decrement in the dominant time constant of the velocity storage integrator (1/h ₀). Nodulouvulectomy, which reversed habituation, would be effected by decreasing h ₀, thereby increasing the VOR time constant. Small values of h ₀ would cause velocity storage to approach an ideal integrative process, leading the system to become unstable. By controlling the VOR time constant through habituation, the nodulus and uvula can stabilize the slow component of the VOR. VOR gain adaptation was related to a modification of the direct vestibular path gain g ₁, without altering the coupling to velocity storage g ₀ or its time constant (1/h ₀). The mismatched direct- and indirect-pathway gains simulated the overshoots in the dynamic response to a step in velocity, that were observed experimentally. We conclude that independent distributed elements in the VOR modify its dynamic response, under control of separate parts of the vestibulocerebellum.     

Mitogen-activated Xenopus laevis lymphocytes produce a T-cell growth factor.

Mitogen-free and serum-free supernatants (SNs) from cultures of phytohaemagglutinin (PHA)-stimulated Xenopus splenocytes, co-stimulated thymocytes, induced proliferation of splenic and thymic lymphoblast and supported growth of alloreactive T-cell lines. These SNs had no effect on 'resting' splenocytes, as measured by uptake of tritiated thymidine ([3H]TdR). Growth-promoting activity was also detected in SNs of cultures containing alloreactive T-cell lines and either PHA or irradiated stimulator cells that expressed the original priming alloantigens. Thus, T lymphocytes appear to be involved in producing, as well as responding to, a Xenopus T-cell growth factor (TCGF). TCGF activity could be absorbed from these active SNs with PHA-activated splenic blasts. No functional cross-reactivity among different mammalian interleukin-2 (IL-2) and Xenopus TCGF preparations was detected.