Impact of Social Confrontation on Rat CD4 T Cells Bearing Different CD45R Isoforms

The impact of social defeat on lymphocyte subpopulations and T helper subsets was investigated in Long Evans rats. CD4 T helper cell subsets with distinct functional properties and different cytokine profiles can be distinguished by using the mAbs OX-22 (anti-CD45RC) and OX-7 (anti-CD90, Thy1.1). Male intruders were exposed for 2, 6, or 48 h to aggressive resident pairs. All intruders were attacked upon introduction and were defeated as indicated by frequent display of full submissive postures. After 2 and 48 h of confrontation, drastic but differential effects on blood leukocyte numbers, CD4 and CD8a cells, and CD4 subsets were evident. However, after 6 h of confrontation most lymphocyte subset numbers corresponded to baseline levels. Focusing on CD4 subsets after 2 h of confrontation, we demonstrated that only the number of the CD45RC⁻CD90⁻subset declines, whereas neither the number of the CD45RC⁺CD90⁻subset nor the number of the CD45RC⁻CD90⁺subset (recent thymic emigrants) was influenced. Con A stimulation of sorted subsets identified the CD45RC⁻CD90⁻as a poor producer of IFN-γ. The data clearly demonstrate that social factors might differentially influence not only T cell subsets but also T helper cell subsets with distinct cytokine profiles in a possibly time-dependent manner. Such a stress-induced shift toward a CD45RC⁺CD90⁻-dominated milieu may have important consequences in interpreting results obtained from mitogenic stimulation of blood lymphocytes and cytokine production profiles measured after such a stimulation. In addition, a shift toward a CD45RC⁺CD90⁻dominance may modify the type and magnitude of immune response, at least temporarily.     

Quality of life in inflammatory bowel disease.

Quality of life with inflammatory bowel disease has not been well examined. Recently, a questionnaire to determine subjective health status for patients with inflammatory bowel disease has been developed and verified. To examine the quality of life in a group of "well" outpatients with inflammatory bowel disease, we developed a self-administered form of this questionnaire containing 36 questions identifiable to five dimensions: systemic symptoms, bowel symptoms, functional impairment, social impairment, and emotional function. We identified outpatients with inflammatory bowel disease through the local chapter of the Ileitis and Colitis Foundation and distributed 396 questionnaires, by mail, with 182 being returned completed (46% response rate). Forty-eight age- and sex-matched controls filled out and returned an identical questionnaire. Response options for each question were framed on a seven-point scale in which 7 represented best function and 1 represented worst function. Male-to-female ratio and mean age were similar to those of controls for the inflammatory bowel disease group. In each dimension, as well as globally, the quality of life of patients with inflammatory bowel disease was significantly worse than that for their age- and sex-matched controls. In conclusion, this survey demonstrates that inflammatory bowel disease adversely affects quality of life in a highly motivated group of "well" outpatients when compared to an age- and sex-matched population.     

Identification of two point mutations and a one base deletion in exon 19 of the dystrophin gene by heteroduplex formation

Two thirds of the Duchenne muscular dystrophy population haveeither gene deletions or duplications. The nondeletion/duplicationcases are most likely the result of point mutations or smalldeletions and duplications that cannot be easily identifiedby current strategies. The major obstacle in identifying smallmutations is due to the large size of the dystrophin gene. Weselectively screened 5 DMD exons containing CpG dinucleotidesin 110 DMD patients without detectable deletions or duplications.Nonsenses mutations are frequently due to a C- to -T transitionwithin a CG dinucleotide pair. To screen for the nonsense mutations,we used the heteroduplex method. Utilizing this approach, weidentified 2 different nonsense mutations and a single basedeletion all occurring in exon 19. This is the first reportof a clustering of small mutations in the the dystrophin gene.     

Congruent effects of estrogen and T-cell receptor peptide therapy on regulatory T cells in EAE and MS

Both estrogen (E2) and T-cell receptor (TCR) peptides have beneficial effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and possibly multiple sclerosis (MS) that involve distinct but congruent mechanisms. Of interest, these two approaches share an ability to enhance expression of the FoxP3 gene and associated activity of regulatory T (Treg) cells. E2 increases the number and activity of FoxP3(+) T cells through Esr-1 signaling during TCR activation of CD4(+)CD25(-) T cells. In contrast, TCR peptide therapy appears to increase the frequency of regulatory FoxP3(+) T cells specific for self-TCR determinants expressed by targeted pathogenic T cells. The combined effects on Treg expansion and activation induced by these distinct immunoregulatory approaches may account for their potent effects on clinical EAE and argue for a similar combined therapeutic approach for MS.     

Amide molecular clocks in drosophila proteins: potential regulators of aging and other processes

After synthesis and folding, peptides and proteins undergo changes in charge and conformation through nonenzymatic deamidation of asparaginyl and glutaminyl residues. Each amide has a specific deamidation rate that is genetically determined by the sequence of residues immediately adjacent in the peptide chain and by secondary, tertiary, and quaternary structure. By means of experimentally verified computations, we have determined the deamidation rates of 49 Drosophila peptides and proteins. These rates demonstrate that deamidation provides molecular clocks that are suitable for the regulation of Drosophila aging, development, and other biochemical processes. We have also determined the rates of deamidation for 17,886 other proteins from a wide variety of organisms. The distribution function of these deamidation rates demonstrates the suitability of amide residues as biomolecular clocks.     

Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-alpha and IL-1beta

We previously demonstrated the therapeutic effects of ethinyl estradiol (EE), an orally active estrogen and a component of birth control pills, in encephalitogenic autoimmune encephalomyelitis (EAE). In this study, we report the effectiveness of EE in treating collagen-induced arthritis (CIA) induced with bovine type II collagen (bCII) in DBA/1LacJ mice, a CIA susceptible strain. Both low and high doses of EE notably suppressed clinical and histological signs of CIA in a dose-dependent manner compared to vehicle-treated controls. Oral treatment with EE decreased proliferation and secretion of pro-inflammatory factors, TNF-alpha IFN-gamma, MCP-1 and IL-6 by bCII peptide-specific T cells, production of bCII-specific IgG2a antibodies, and mRNA for cytokines, chemokines and chemokine receptors in joint tissue. This is the first report demonstrating effective treatment of joint inflammation and clinical signs of CIA with orally administered ethinyl estradiol, thus supporting its possible clinical use for treating rheumatoid arthritis in humans.