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PubMed2001

Analgesia elicited by OFQ/nociceptin and its fragments from the amygdala in rats.

The heptadecapeptide, orphanin FQ/nociceptin (OFQ/N), binds with high affinity to the ORL-1/KOR-3 opioid receptor clone, yet binds poorly with traditional opioid receptors. OFQ/N has a complex functional profile with relation to nociceptive processing, displaying pro-nociceptive properties in some studies, acting as an inhibitor of stress-induced analgesia in others, yet producing both spinal and supraspinal antinociceptive actions in other studies. Among the intracerebral sites at which OFQ/N might produce one or more of these actions is the amygdala which has been intimately implicated in both antinociceptive and stress-related responses. Therefore, the present study assessed whether microinjections into the amygdala of equimolar doses of OFQ/N(1-17) or its shorter-chained active fragments, OFQ/N(1-11) or OFQ/N(1-7), would produce analgesia as measured by either reactivity to high-intensity radiant heat or reactivity to electric shock, and produce hyperalgesia as measured by reactivity to lower-intensity radiant heat. OFQ/N(1-17) in the amygdala produced a dose-dependent and time-dependent increase in high-intensity tail-flick latencies with maximal effects observed at a dose range of 0.75-3 nmol, and lesser effects at lower (0.015-0.15 nmol) and higher (5.5-30 nmol) doses. Both OFQ/N(1-11) and OFQ/N(1-7) in the amygdala displayed lower magnitudes of analgesia than OFQ/N(1-17) on this measure, with OFQ/N(1-11) displaying maximal effects at higher (15-30 nmol) doses and OFQ/N(1-7) displaying maximal effects at lower (0.15-1.5 nmol) doses. In contrast to traditional mu and kappa opioids and beta-endorphin, none of the OFQ/N fragments in the amygdala exhibited any analgesic responses on the jump test. Finally, using a low-intensity radiant heat assay capable of detecting hyperalgesic responses, each of the OFQ/N fragments in the amygdala increased tail-flick latencies on this measure. Therefore, OFQ/N fragments appear to exert only analgesic responses in the amygdala with quantitative and qualitative differences relative to traditional opioid agonists.

Amygdala↗
PubMed2003

Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system.

Dyrk1A and its Drosophila orthologue, the protein minibrain (mnb), belong to a family of serine/threonine kinases involved in the development of the central nervous system (CNS). However, additional roles for Dyrk1A have to be proposed, as its expression is still prominent in the adult brain. To gain insight into Dyrk1A physiological roles we have studied the distribution of this kinase in the CNS of mice in adulthood. A homogeneous diffuse immunostaining of variable intensity was detected throughout the neuropile, with the white matter displaying faint Dyrk1A immunoreactivity. Dyrk1A immunostaining was strong in the olfactory bulb, the cerebellar cortex and functionally related structures, the spinal cord and most of the motor nuclei of the midbrain and brain stem. These data agree with a possible implication of this kinase in the physiology of olfaction and motor functions. Cellular and subcellular localisation of Dyrk1A was also studied in primary cell culture of cerebellum, one of the structures showing significant Dyrk1A immunostaining in the adult. The distribution of Dyrk1A in primary cell culture showed the presence of this protein in the nucleus and the cytoplasm of both neurons and astrocytes. Moreover, studies on the subcellular distribution of Dyrk1A in whole brain homogenates of adult mice showed the presence of this protein both in nuclear and cytoplasm-enriched fractions, thus supporting selective functions of this kinase in these two subcellular compartments. The present results showing the distribution of Dyrk1A in widespread areas of the adult CNS and in different subcellular compartments, together with previous reports demonstrating its implication in developmental events concur with the idea of several spatio-temporal functional profiles.

Animals↗
PubMed1999

Functional expression of an inactivating potassium channel (Kv4.3) in a mammalian cell line.

OBJECTIVE: The goal of this study was to characterize the electrophysiological properties of the Kv4.3 channels expressed in a mammalian cell line. METHODS: Currents were recorded using the whole-cell voltage clamp technique. RESULTS: The threshold for activation of the expressed Kv4.3 current was approximately -30 mV. The dominant time constant for activation was 1.71 +/- 0.16 ms (n = 10) at +60 mV. The current inactivated, this process being incomplete, resulting in a sustained level which contributed 15 +/- 2% (n = 25) of the total current. The time course of inactivation was fit by a biexponential function, the fast component contributing 74 +/- 5% (n = 9) to the overall inactivation. The fast time constant was voltage-dependent [27.6 +/- 2.0 ms at +60 mV (n = 10) versus 64.0 +/- 3.6 ms at 0 mV (n = 10); P < 0.01], whereas the slow was voltage-independent [142 +/- 15 ms at +60 mV (n = 10) versus 129 +/- 33 ms at 0 mV (n = 6) P > 0.05]. The voltage-dependence of inactivation exhibited midpoint and slope values of -26.9 +/- 1.5 mV and 5.9 +/- 0.3 mV (n = 21). Recovery from inactivation was faster at more negative membrane potentials [203 +/- 17 ms (n = 13) and 170 +/- 19 ms (n = 4), at -90 and -100 mV]. Bupivacaine block of Kv4.3 channels was not stereoselective (KD approximately 31 microM). CONCLUSIONS: The functional profile of Kv4.3 channels expressed in Ltk- cells corresponds closely to rat ITO, although differences in recovery do not rule out association with accessory subunits. Nevertheless, the sustained component needs to be considered with respect to native ITO.

Animals↗
PubMed2002

Pharmacological characterization of human NPFF(1) and NPFF(2) receptors expressed in CHO cells by using NPY Y(1) receptor antagonists.

Neuropeptide FF (NPFF) belongs to an opioid-modulatory system including two precursors (pro-NPFF(A) and pro-NPFF(B)) and two G-protein coupled receptors (NPFF(1) and NPFF(2)). The pharmacological and functional profiles of human NPFF(1) and NPFF(2) receptors expressed in Chinese hamster ovary (CHO) cells were compared by determining the affinity of several peptides derived from both NPFF precursors and by measuring their abilities to inhibit forskolin-induced cAMP accumulation. Each NPFF receptor recognizes peptides from both precursors with nanomolar affinities, however, with a slight preference of pro-NPFF(A) peptides for NPFF(2) receptors and of pro-NPFF(B) peptides for NPFF(1) receptors. BIBP3226 ((R)-N(2)-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-argininamide) and BIBO3304 ((R)-N(2)-(diphenylacetyl)-N-[4-(aminocarbonylaminomethyl)-benzyl]-argininamide trifluoroacetate), two selective neuropeptide Y (NPY) Y(1) receptor antagonists, display relative high affinities for NPFF receptors and exhibit antagonist properties towards hNPFF(1) receptors. The structural determinants responsible for binding of these molecules to NPFF receptors were investigated and led to the synthesis of hNPFF(1) receptor antagonists with affinities from 40 to 80 nM. Our results demonstrate differences in pharmacological characteristics between NPFF(1) and NPFF(2) receptors and the feasibility of subtype-selective antagonists.

Animals↗
PubMed2002

Electrophysiological actions of gamma-aminobutyric acid and clomethiazole on recombinant GABA(A) receptors.

Clomethiazole is a gamma-aminobutyric acid (GABA)-mimetic agent with anticonvulsant, sedative and neuroprotective properties. The pharmacological actions of clomethiazole that underlie its functional profile have not been fully explored, but are known to result from an interaction with the GABA(A) receptor. Here, we present a quantitative electrophysiological study of clomethiazole action at human recombinant GABA(A) receptors. Whole-cell currents were recorded from murine L(tk-) cells stably transfected with either alpha1, beta1 and gamma 2 or alpha1, beta2 and gamma 2 GABA(A) receptor subunits. Clomethiazole directly activated GABA(A) currents in alpha1/beta1/gamma 2- and alpha1/beta2/gamma 2-containing cells, with EC(50) values of 0.3 and 1.5 mM, respectively. A low concentration of clomethiazole (30 micro M) also potentiated the action of GABA in both cell types, equivalent to a 3-fold increase in potency and up to 1.8-fold increase in maximal current. Both direct activation and gamma-aminobutyric acid potentiation are likely to contribute to the in vivo profile of clomethiazole.

Animals↗
PubMed2001

RNA ligands generated against complex nuclear targets indicate a role for U1 snRNP in co-ordinating transcription and RNA splicing.

RNA ligands were generated against various gene products present in HeLa nuclear extract. Functional profiling was performed to identify RNA ligands that modulate RNA polymerase II (pol II)-mediated transcription. Unexpectedly, four of the eight inhibitor ligands identified by this screen contained an 11-nucleotide sequence identical to the 5'-splice site of eukaryotic pre-mRNAs. Such ligands were shown to impede pre-initiation complex assembly on a cytomegalovirus promoter. In addition, U1 small nuclear ribonucleoprotein particles (snRNP) and pol II had been co-immunoprecipitated in the absence of transcription. These results suggest a role for U1 snRNP in co-ordinating transcription and RNA splicing.

Base Sequence↗
PubMed2002

Functional selectivity for glycerol of the nodulin 26 subfamily of plant membrane intrinsic proteins.

The nodulin-like intrinsic protein (NIP) subfamily of water and solute channels in plants is named for nodulin 26 of legume nodules. Two NIPs, soybean nodulin 26 and Lotus japonicus LIMP2, show a distinct functional profile with a low intrinsic osmotic water permeability (P(f)) and the ability to flux uncharged polyols such as glycerol. NIPs have a conserved signature sequence within the 'aromatic/arginine' region that forms the selectivity filter for major intrinsic proteins. This sequence is a hybrid of glyceroporin and aquaporin residues as well as exhibiting substitutions unique to the NIP subfamily. Site-directed mutagenesis of a conserved tryptophan in helix 2 of LIMP2 shows that this is a major determinant of glycerol selectivity.

Amino Acid Sequence↗
PubMed1988

Sequential changes in pulmonary mechanics in the very low birth weight (less than or equal to 1000 grams) infant.

Pulmonary function tests were performed on 36 very low birth weight neonates (birth weight less than or equal to 1000 gm, gestational age less than or equal to 30 weeks, appropriate size for gestational age) from birth until 8 weeks of age. Tidal airflow was measured by means of a pneumotachygraph, and the transpulmonary pressure changes were determined by the esophageal balloon technique. Pulmonary mechanics and energetics were calculated by the least mean square analysis technique at 1/2, 1, 2, 4, 6, and 8 weeks of age. Compliance was lowest at 2 weeks and subsequently increased linearly (at approximately 0.1 ml/cm H2O/wk). When compliance was based on body weight, however, no change was noted with advancing age. Resistance was greatest at 2 weeks and subsequently decreased. The infants maintained a normal minute ventilation with a slightly increased resistive work of breathing. Despite our ability to wean 53% of the infants to room air by 8 weeks, none of them had pulmonary mechanics considered normal for term infants. Infants with and without bronchopulmonary dysplasia (BPD) had similar patterns of pulmonary development. At 8 weeks of age, the pulmonary mechanics in infants with BPD who had been weaned to room air were comparable to those in infants without BPD, an observation that calls into question the rationale for defining BPD at 4 weeks in this population. These data suggest that such pulmonary function profiles provide evidence of persistent lung parenchymal abnormalities.

Airway Resistance↗
PubMed1989

Factors affecting clearance of hepatitis B e antigen in hepatitis B surface antigen carrier children.

To understand the natural history of chronic hepatitis B virus infection in children, we studied factors affecting the clearance of hepatitis B e antigen (HBeAg). One hundred sixty-nine apparently healthy children whose sera were positive for HBeAg and hepatitis B surface antigen (HBsAg) and who were recruited by screening were followed prospectively to delineate the HBeAg clearance rate. Another 59 carrier children visiting the outpatient clinic because of symptoms or abnormal liver function were studied for comparison. The annual HBeAg clearance rate was low (less than 2%) during the first 3 years of life but increased with age. The HBeAg clearance rate in children older than 6 years of age was lower in those whose mothers had HBsAg positivity (14.3%) than in those whose mothers had no detectable HBsAg (35.3%). Children who were brought for medical care had higher HBeAg clearance rates (42.4%) than those who were recruited by screening (14.6%) because immune clearance of hepatitis B virus and hence HBeAg often led to hepatocellular damage manifested by abnormal liver function profiles or by symptoms that had caused the parents to seek medical care for their children. We conclude that age, source of subject recruitment, and maternal HBsAg status are important factors affecting HBeAg clearance rate in HBsAg carriers.

Adolescent↗
PubMed1998

Hepatitis B surface antigenemia at birth: a long-term follow-up study.

OBJECTIVE: To investigate the prevalence and outcome of hepatitis B surface antigenemia in newborns of hepatitis B e antigen (HBeAg)-positive hepatitis B surface antigen (HBsAg) carrier mothers under the current immunoprophylaxis program. STUDY DESIGN: From 1984 to 1993, 665 high-risk newborns born to HBeAg-positive HBsAg carrier mothers were prospectively recruited. The newborns were tested for HBsAg soon after birth, before hepatitis B immune globulin administration. All newborns received hepatitis B immune globulin within 24 hours after birth plus subsequent hepatitis B vaccination. Those who were seropositive for HBsAg at birth were regularly followed up for their hepatitis B virus (HBV) markers, liver function profiles, and alpha-fetoprotein levels from 1984 to 1996. RESULTS: Sixteen (2.4%) of the 665 subjects were found to be seropositive for HBsAg at birth, and all remained HBsAg-positive at 6 months of age. Twelve of the 16 received long-term follow-up care, and all were confirmed to have chronic HBV infection. Of the 12, 2 had HBeAg seroconversion, and 1 had alanine aminotransferase flares without HBeAg seroconversion. Delayed appearance of hepatitis B core antibody (anti-HBc) occurred in 2 without alanine aminotransferase elevation. CONCLUSIONS: Current immunoprophylaxis strategy does not protect newborns with surface antigenemia, apparently acquired in utero, from becoming HBV carriers. Immunologic attempts to eliminate HBV may occur in carrier children infected in utero, despite their profound immune tolerance to HBV.

Alanine Transaminase↗
PubMed1991

Neobladder construction using completely detubularized sigmoid colon after radical cystoprostatectomy.

To improve the quality of life of the patient we used completely detubularized sigmoid colon for bladder reconstruction along with radical cystoprostatectomy in 6 men with invasive bladder cancer. Followup was 8 to 20 months. Postoperatively, all of the patients were continent during the day but only 4 (66.7%) were continent at night, although they had to awaken twice to remain dry. Neocystourethroscopy in 4 of the 6 patients revealed no tumor and no stricture at the urethrocolonic anastomosis. However, a stone in the neobladder was found in 1 patients. Urodynamic study of the neobladder showed a low pressure (mean 16.7 cm. water) at the filling phase of water cystometry and an adequate maximal urethral closure pressure (mean 52.0 cm. water) and functional profile length (mean 3.8 cm.). The uroflow rate in all patients was good (1 patient even had a maximal uroflow rate of 31 ml. per second). There was no reflux in any patient. One patient had intestinal obstruction 5 months postoperatively and died 5 months later of widespread metastasis. The remaining 5 patients are alive with a satisfactory quality of life. In conclusion, use of completely detubularized sigmoid colon may be an ideal operation for neobladder construction after radical cystoprostatectomy.

Adult↗
PubMed1990

Pathophysiology of urinary incontinence after radical prostatectomy.

To define the origin of urinary incontinence after radical prostatectomy urodynamic studies in 24 incontinent patients were compared to those of 13 continent patients. A statistically significant difference between incontinent and continent patients was found for the mean functional profile length (2.1 versus 3.6 cm., respectively, p less than 0.001), maximal urethral closure pressure (39 versus 74 cm. water, respectively, p less than 0.001) and maximal urethral closure pressure during voluntary contraction of the external sphincter (107 versus 172 cm. water, respectively, p less than 0.002). The differences among maximal detrusor pressure, initial bladder volume at which a detrusor contraction occurs, maximal cystometric capacity and residual urine were not statistically significant between the 2 groups. Urethral instability was present in 1 of the 24 incontinent patients (4.2%) and in none of the 13 continent patients, while detrusor instability was present in 6 (25%) and 3 (23.1%), respectively. Urethral and detrusor instability correlated poorly with incontinence (correlation coefficients 0.123 and 0.021, respectively). The appearance of the bladder outlet on voiding cystourethrography was correlated with urodynamic parameters and the presence or absence of continence. Tubularization above the level of the external sphincter was present in continent but absent in incontinent patients. Continence after radical prostatectomy is dependent upon sphincteric efficiency, which may be influenced by the anatomical configuration of the reconstructed bladder outlet and the integrity of the distal urethral sphincteric mechanism.

Aged↗
PubMed1983

Possible use of indoramin in patients with chronic neurogenic bladder dysfunction.

Indoramin, which has great selectivity for alpha-1-receptors, was administered orally for 10 days to 21 patients with urinary retention or residual urine caused by neurogenic vesicourethral dysfunction. After indoramin therapy 17 patients were able to empty the bladder with residual urine less than 50 ml. There was a significant decrease in the maximum urethral pressure (23.87 plus or minus 4.13 cm. water) and in the functional profile length (0.53 plus or minus 0.19 cm.). A diminution in the sphincter electromyography activity was observed in 3 patients. Two paraplegics who were investigated during spinal shock could not achieve voiding after indoramin therapy. However, involuntary urine leakage associated with a change of posture occurred in 2 patients but subsided after the dosage of indoramin was decreased. No other side effect was observed. It may be desirable to use drugs with selective action upon alpha-1-receptors since blockade of noradrenergic autoreceptors (alpha-2) also by nonspecific alpha-adrenoceptor blocking agents, namely phentolamine, phenoxybenzamine and so forth, causes the overflow of norepinephrine, which would produce symptoms such as tachycardia by stimulating beta-receptors.

Adolescent↗
PubMed1998

Interaction of the anxiogenic agent, RS-30199, with 5-HT1A receptors: modulation of sexual activity in the male rat.

RS-30199 has been shown previously to have atypical interactions at 5-HT1A receptors. RS-30199 and RS-64459, an analogue of buspirone with a buspirone side chain, were compared with the classic, partial agonist at 5-HT1A receptors, 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) and buspirone. At human (h) 5-HT1A receptors in CHO cells, RS-30199-193 (racemate) and its enantiomers (-197, -198) inhibited [3H]-8-OH-DPAT binding (RS-30199-198, ki, 29.7 +/- 11.7 nM; RS-30199-197, ki, 74.1 +/- 11.7 nM) as did RS-64459 (ki, 24.9 +/- 6.0 nM), but RS-30199-197 and -198 were almost full agonists in a [35S]-GTPgammaS binding assay, whereas RS-64459 was a partial agonist, resembling buspirone and 8-OH-DPAT. RS-64459 and the enantiomers of RS-30199 had weaker affinity for 5-HT2C and 5-HT7 receptors. These compounds did not induce the 5-HT behavioural syndrome in male rats. However, in a model where naive male rats were introduced to estrogen-progesterone primed, sexually receptive female rats, RS-30199-197 (0.1, 1, 10 mg/kg, s.c.) had a profound inhibitory effect on sexual behaviour score. Neither buspirone nor 8-OH-DPAT reduced the sexual behaviour score. Unlike 8-OH-DPAT, which shortens intromission latency, RS-30199 prolonged intromission latency. RS-30199 (10 mg/kg s.c.) fully inhibited the facilitation of sexual behaviour caused by the alpha2-adrenoceptor antagonist, delequamine (0.1 mg/kg, p.o.). In contrast, RS-64459 (100, 250, 1000 and 4000 microg/kg, s.c.) failed to modify the sexual behaviour score and did not modify intromission latency. The differences between the effects of RS-30199 and RS-64459 in binding and functional experiments are supported by molecular models of the receptor-ligand interaction, where the compounds interact in different ways with the receptor; a model is proposed for the allosteric interaction of different agents with the receptor, resulting in different functional profiles. RS-30199 can be considered an atypical agonist at 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Dendritic cells: their significance in health and disease.

Dendritic cells (DCs) represent a heterogeneous population of professional antigen-presenting cells. Precursor cells move via the blood to peripheral tissues. These immature DCs can take up invading pathogens and then rapidly migrate to the draining secondary lymphoid organs. Converted into antigen-presenting mature DCs, these cells are able to prime naive T cells and to initiate an adoptive immune response. The extraordinary functional profile suggests that, under certain preconditions, DCs may represent an ideal vector in the immunotherapy of cancer and infectious diseases

Animals↗
PubMed2002

Cryptic determinants and promiscuous sequences on human acetylcholine receptor: HLA-dependent dichotomy in T-cell function.

Experimental autoimmune myasthenia gravis can be induced in some strains of mice and rats by immunizing with acetylcholine receptor. Also, epidemiologic studies demonstrate an MHC linkage of myasthenia gravis in the man. In order to obtain direct experimental evidence for the influence of the genes of the MHC complex in the development of myasthenia gravis, we used mice transgenic to individual HLA molecules. We observed an increased susceptibility to the disease in HLA DQ8 transgenic mice compared to HLA DQ6 transgenic mice ( J. Immunol. 160:4169; 1998). These mice lacked endogenous mouse class II molecules. In the present study we mapped the cryptic and dominant sequences on the extra cellular region of human acetylcholine receptor. Although some epitopes (e.g., alpha11-30, alpha141-160, alpha171-190) were common between DQ8 and DQ6 transgenic mice, several others were disparately recognized. We also found a functional dichotomy in T cells from mice differing by one MHC molecule (HLA DQ8 or DQ6) when primed by sequences immunodominant in DQ8 and DQ6 tg mice. Differential disease manifestation in the two different HLA transgenic mice could be explained not only by differential recognition of peptides by these antigen presenting molecules, but also by the difference in the functional profile of T cells generated when primed by promiscuous sequence regions.

Amino Acid Sequence↗
PubMed2001

[Gain, loss and agreement between respiratory specialists and generalists in the diagnosis of asthma].

OBJECTIVE: To determine and analyze the degree of agreement and disagreement in the diagnosis of bronchial asthma (BA) by respiratory disease specialists and generalists in regional hospital and primary care settings. MATERIAL AND METHODS: Ninety-six outpatients (16 to 70 years of age) were studied; all had been assigned a diagnosis of BA by the referring physician or by the respiratory disease specialist. We recorded 1) clinical symptoms, determining the initial probability of a diagnosis (IPD)of BA to be high, medium or low; 2) results of spirometry and bronchodilator testing (BDT), peak flow variability and methacholine challenge testing; 3) prick test results, eosinophil levels and total serum IgE levels. Three diagnoses were recorded: the initial diagnosis (ID) by the referring physician to whom follow-up data were unavailable; diagnosis by the respiratory disease specialist based only on clinical symptoms (RSS); and the final diagnosis(FD). To arrive at a FD of BA, it was necessary to have a high or medium IPD and a positive BDT. A Kappa test was used to analyze the degree of agreement among the three diagnoses. Group features associated with greater or lesser agreement were analyzed by chi-square tests and analysis of variance. RESULTS: Agreement was acceptable between RSS and FD (K = 0.63) but very low between ID and RSS and between ID and FD. In the latter two cases, agreement was greatest for patients diagnosed in hospital and for those with high IgE levels (p < 0.05), with high IPD, longer course of disease and a history of asthma (p < 0.01) (odds ratio =59.8). Diagnostic disagreement occurred mainly for patients for whom a BA diagnosis was gained later, the of under-diagnosis being 39%. The patients involved visited the physician only because they had observed an isolated symptom related to asthma (odds ratio = 119) and to arrive at a diagnosis bronchomotor tests other than BDT were required (p < 0.01). CONCLUSIONS: a) The degree of agreement for a diagnosis of BA is low. b)The functional profile of patients for whom diagnostic agreement exists differs from that of patients for whom diagnosis is gained through testing. c) In the context of this study, a high rate of under-diagnosis is evident.

Adolescent↗
PubMed2003

Immunosenescence, autoimmunity, and rheumatoid arthritis.

Current disease models of autoimmune syndromes, such as rheumatoid arthritis, propose that chronic inflammation is caused by 'forbidden T-cell clones' that recognize disease-inducing antigens and drive tissue-injurious immune reactions. Reappraisal of disease incidence data, however, emphasizes that rheumatoid arthritis is a syndrome of the elderly that occurs with highest likelihood in individuals in whom the processes of T-cell generation and T-cell repertoire formation are compromised. Thymic T-cell production declines rapidly with advancing age. Multiple mechanisms, including antigen-driven clonal expansion and homeostasis-driven autoproliferation of post-thymic T cells, impose replicative stress on T cells and induce the biological program of cellular senescence. T-cell immunosenescence is associated with profound changes in T-cell functional profile and leads to accumulation of CD4+ T cells that have lost CD28 but have gained killer immunoglobulin-like receptors and cytolytic capability and produce large amounts of interferon-gamma. In patients with rheumatoid arthritis, T-cell immunosenescence occurs prematurely, probably due to a deficiency in the ability to generate sufficient numbers of novel T cells. We propose that autoimmunity in rheumatoid arthritis is a consequence of immunodegeneration that is associated with age-inappropriate remodeling of the T-cell pool.

Adult↗