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Biomedical subjects

T P Gordon

Publications and source records attributed to T P Gordon.

At least 19 recordsLinked to original sources
PubMed2007

Autoantibody-mediated bladder dysfunction in type 1 diabetes.

Bladder dysfunction is a common complication of diabetic autonomic neuropathy; however, its cause remains uncertain. We have recently identified a novel IgG autoantibody (Ab) in patients with type 1 diabetes that acts as an agonist at the dihydropyridine (DHP) site of L-type voltage-gated calcium channels (VGCC), disrupting neuronal regulation of visceral smooth muscle. In the present study, passive transfer to mice of IgG from patients with type 1 diabetes was used to investigate the role of anti-VGCC Abs in mediating diabetic bladder dysfunction. Injection of mice with diabetic immunoglobulin (IgG) with anti-VGCC activity induced features of an overactive bladder, including phasic detrusor contractions and a loss of bladder wall compliance. The bladder overactivity is mimicked by the DHP agonist Bay K8644, reversed by the DHP antagonist nicardipine, but is insensitive to the motor nerve blocker tetrodotoxin, indicating that the anti-VGCC Ab acts at the level of the bladder detrusor itself. This study reports the first evidence of Ab-mediated bladder dysfunction in type 1 diabetes, which may be part of a wider spectrum of smooth muscle and cardiac abnormalities.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

Neo-epitopes are required for immunogenicity of the La/SS-B nuclear antigen in the context of late apoptotic cells.

Mechanisms responsible for the induction of anti-nuclear autoantibodies (ANA) following exposure of the immune system to an excess of apoptotic cells are incompletely understood. In this study, the immunogenicity of late apoptotic cells expressing heterologous or syngeneic forms of La/SS-B was investigated following subcutaneous administration to A/J mice, a non-autoimmune strain in which the La antigenic system is well understood. Immunization of A/J mice with late apoptotic thymocytes taken from mice transgenic (Tg) for the human La (hLa) nuclear antigen resulted in the production of IgG ANA specific for human and mouse forms of La in the absence of foreign adjuvants. Preparations of phenotypically healthy cells expressing heterologous hLa were also immunogenic. However, hLa Tg late apoptotic cells accelerated and enhanced the apparent heterologous healthy cell-induced anti-La humoral response, while non-Tg late apoptotic cells did not. Subcutaneous administration of late apoptotic cells was insufficient to break existing tolerance to the hLa antigen in hLa Tg mice or to the endogenous mouse La (mLa) antigen in A/J mice immunized with syngeneic thymocytes, indicating a requirement for the presence of heterologous epitopes for anti-La ANA production. Lymph node dendritic cells (DC) but not B cells isolated from non-Tg mice injected with hLa Tg late apoptotic cells presented immunodominant T helper cell epitopes of hLa. These studies support a model in which the generation of neo-T cell epitopes is required for loss of tolerance to nuclear proteins after exposure of the healthy immune system to an excess of cells in late stages of apoptosis.

Adjuvants, Immunologic↗
PubMed2004

Antibodies raised against the second extracellular loop of the human muscarinic M3 receptor mimic functional autoantibodies in Sjögren's syndrome.

Functional antimuscarinic M3 receptor (M3R) autoantibodies have been shown to inhibit cholinergic neurotransmission at the postsynaptic level and appear to mediate parasympathetic dysfunction, including sicca symptoms in Sjögren's syndrome (SS). The precise epitope(s) involved in the inhibition of M3R-mediated cholinergic neurotransmission has not been defined. In this study, an active immunization approach to raise antibodies with functional activity against the second extracellular loop of the M3R was used and their functional properties were compared with those of human autoantibodies. Peptides corresponding to the second extracellular loop of the M3R were used as immunogens in rabbits, and antisera were tested for inhibition of carbachol-evoked colon smooth muscle contraction in parallel with immunoglobulin G from a patient with SS. Anti-M3R antibodies were affinity purified on a peptide representing a dominant functional epitope at the COOH terminus of the second extracellular loop of the M3R and tested for concentration-dependent inhibition. Experimentally raised anti-M3R antibodies, like the human autoantibodies, showed concentration-dependent and noncompetitive inhibition of carbachol-evoked colon contractions. Inhibitory activity was detected by functional assays at concentrations as low as 3 ng/ml, which was below the threshold of detection of antibody by peptide enzyme-linked immunosorbent assay. It is concluded that the experimentally raised anti-M3R antibodies share the functional properties of autoantibodies in patients with SS.

Amino Acid Sequence↗
PubMed2004

Increased expression of the B-cell-regulatory molecule CD72 in primary Sjögren's syndrome.

To determine whether there is an intrinsic abnormality of B-cell signaling in primary Sjögren's syndrome (pSS), the expression of B-cell coreceptors was determined in patients with primary Sjögren's syndrome and healthy and disease controls. Peripheral blood mononuclear cells were labeled with monoclonal antibodies to CD21, CD22, or CD72, and then the pan B-cell marker CD19. The expression of these coreceptors on the total CD19(+) population was determined. There was a significant increased expression of CD72 on the B cells of pSS patients (MFI, 215 +/- 6) compared to normal controls (MFI, 141 +/- 6). The increased CD72 expression was disease specific for pSS, as it was not observed in systemic lupus erythematosus or rheumatoid arthritis. The effect of B-cell stimulation on coreceptor expression was determined by culturing cells with B-lymphocyte-activating factor (BAFF) and/or pokeweed mitogen (PWM) or without either. Following culture, CD72 expression was decreased in both pSS and normal controls, regardless of the presence of BAFF or PWM. The upregulation of CD72 in pSS might be a compensatory response to increased B-cell receptor stimulation or a primary abnormality leading to uncontrolled B-cell activation.

Aged↗
PubMed2004

Fas gene promoter polymorphisms in primary Sjögren's syndrome.

BACKGROUND: Fas mediated apoptosis may be important in the pathogenesis of primary Sjögren's syndrome (pSS). OBJECTIVE: To examine genetic variation in the promoter region of the Fas gene in pSS. METHODS: Two single nucleotide polymorphisms at positions -1377(G/A) and -670(G/A) in the Fas gene promoter were genotyped by PCR-SSP in 101 patients with pSS and 108 Caucasoid controls. RESULTS: No significant differences in allele or genotype frequencies were detected between the patients with pSS and controls. However, significant associations were observed with Ro/La autoantibody negative patients, who display milder and later onset disease. The -670A allele was more frequent in Ro/La autoantibody negative patients than in Ro/La autoantibody positive patients (p = 0.04). CONCLUSION: This study does not confirm an earlier report of an association between pSS and the Fas promoter -670G allele. However, the results suggest that genetically determined variability in Fas expression may modulate Ro/La autoantibody responses in patients with pSS.

Antibodies, Antinuclear↗
PubMed2003

Association of stress proteins with autoantigens: a possible mechanism for triggering autoimmunity?

Patterns of autoantibody production are diagnostic of many autoimmune disorders; the recent observation of additional autospecificities towards stress-induced proteins may also provide insight into the mechanisms by which such responses arise. Grp78 (also known as BiP) is a target of autoaggressive B and T cell responses in our murine model of anti-Ro (SS-A) autoimmunity and also in rheumatoid arthritis. In this report we demonstrate reciprocal intermolecular spreading occurs between Ro52 and Grp78 in immunized mice, reflecting physiological association of these molecules in vivo. Moreover, we provide direct biochemical evidence that Grp78 associates with the clinically relevant autoantigen, Ro52 (SS-A). Due to the discrete compartmentalization of Ro52 (nucleocytoplasmic) and Grp78 (endoplasmic reticulum; ER) we propose that association of these molecules occurs either in apoptotic cells, where they have been demonstrated indirectly to co-localize in discrete apoptotic bodies, or in B cells themselves where both Ro52 and Grp78 are known to bind to immunoglobulin heavy chains. Tagging of molecules by association with Grp78 may facilitate receptor mediated phagocytotsis of the complex; we show evidence that exogenous Grp78 can associate with cell surface receptors on a subpopulation of murine splenocytes. Given the likelihood that Grp78 will associate with viral glycoproteins in the ER it is possible that it may become a bystander target of the spreading antiviral immune response. Thus, we propose a model whereby immunity elicited towards Grp78 leads to the selection of responses towards the Ro polypeptides and the subsequent cascade of responses observed in human disease.

Animals↗
PubMed2002

Restricted specificity of intermolecular spreading to endogenous La (SS-B) and 60 kDa Ro (SS-A) in experimental autoimmunity.

Intermolecular spreading of humoral autoimmunity to different components of the Ro (SS-A) and La (SS-B) ribonucleoprotein (RNP) complex has been reported following immunization with a single component of the complex. Although the immune response to the immunizing antigen is polyclonal and diversified, little is known about the specificity of the recruited autoimmune responses to the endogenous Ro and La antigens which drive B-cell spreading. To determine the specificity of intermolecular spreading to La, we examined sera from 52 kDa Ro (Ro52)- and 60 kDa Ro (Ro60)-immunized C3H/HeJ mice for reactivity with recombinant fragments spanning endogenous mouse (m)La by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Sera from mice primed and boosted with recombinant Ro52 and Ro60 showed reactivity restricted to the COOH-terminal fragment of mLa (aa361-415). The recruited anti-La response was species-specific, cross-reacting weakly with the corresponding region on the human La molecule, and was abrogated by the preabsorption of the Ro-immune sera with mLa 361-415. Analogous experiments using recombinant mRo60 fragments spanning the mRo60 molecule revealed a similar pattern of oligoclonality in the specificity of anti-Ro60 autoimmunity following active immunization with La and Ro52. These results suggest that intermolecular-intrastructural T-B help is limiting in this model, and reveal unsuspected immunodominance of selected Ro-La epitopes in the spreading of the autoantibody response to these structures. The focusing of the recruited autoantibody response to these COOH-terminal regions of the Ro and La polypeptides may also reflect the surface accessibility of these regions in La-Ro RNP.

Animals↗
PubMed2001

Subcellular distribution of aquaporin 5 in salivary glands in primary Sjögren's syndrome.

Secretions from salivary and lacrimal glands are reduced in patients with primary Sjögren's syndrome (PSS). Since aquaporin 5 is involved in transport of water and is present in salivary and lacrimal glands, this protein was thought to have a major role in the pathogenesis of PSS. We used indirect immunofluorescence and an immunoperoxidase technique to assess expression and subcellular localisation of aquaporin 5 in patients and controls. Our results suggest that the distribution and density of aquaporin 5 in salivary glands does not differ between patients with PSS and those without. Thus, the role of aquaporin 5 in the pathogenesis of PSS needs to be reassessed and alternative pathogenetic mechanisms investigated.

Animals↗
PubMed2001

Cognate T cell help is sufficient to trigger anti-nuclear autoantibodies in naive mice.

The mechanisms involved in the initiation of anti-nuclear autoantibodies are unknown. In this study, we show that one factor allowing anti-nuclear autoantibodies to develop is the incomplete nature of immune tolerance to many of these proteins. Immune responses in mice toward the ubiquitous nuclear autoantigen La/SS-B are much weaker than responses to the xenoantigen, human La (hLa; 74% identical). However, in transgenic (Tg) mice expressing hLa, the Ab response to this neo-autoantigen was reduced to a level resembling the weak autoimmune response to mouse LA: Partial tolerance to endogenous La autoantigen was restricted to the T compartment because transfer of CD4(+) T cells specific for one or more hLa determinants into mice bearing the hLa transgene was sufficient to elicit production of anti-hLa autoantibodies. Notably, only hLa- specific T cells from non-Tg mice, and not T cells from hLa Tg mice, induced autoantibody production in hLa Tg mice. These findings confirm partial Th tolerance to endogenous La and indicate the existence in normal animals of autoreactive B cells continuously presenting La nuclear AG: Therefore, the B cell compartment is constitutively set to respond to particular nuclear autoantigens, implicating limiting Th responses as a critical checkpoint in the development of anti-nuclear autoantibodies in normal individuals.

Adoptive Transfer↗
PubMed2001

Can B cell epitopes of 60 kDa Ro distinguish systemic lupus erythematosus from Sjögren's syndrome?

Antibodies binding components of the Ro/La (or SSA/SSB) ribonucleoprotein particle are found in the sera of patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) as well as mothers who give birth to babies with neonatal lupus. Anti-La occurs in a subset of sera that contain anti-Ro, and anti-La is found more commonly in sera of patients with SS than in sera from SLE patients. The fine specificity of autoantibodies binding 60 kDa has been studied extensively. Recent data have suggested that there are disease-specific epitopes which identify patients with either SLE or SS. Alternatively, other data suggest that the B cell epitopes of 60kDa Ro vary according to the presence of anti-La. The present study was undertaken to determine whether binding of putative disease-specific 60 kDa Ro epitopes is associated with the diagnosis of SLE vs SS, or instead associated with the presence of anti-La. Anti-60 kDa Ro positive sera from 24 SLE patients and 44 SS patients were studied for antibodies binding two epitopes of 60 kDa Ro. We find the epitope defined by residues 171-190 is associated with anti-60 kDa Ro without anti-La, regardless of diagnosis. Meanwhile, binding of the epitope defined by residues 215-232 is not commonly found in anti-60 kDa Ro sera, especially in those sera with both anti-60 kDa Ro and anti-La. Thus, the fine specificity of antibody binding to 60 kDa Ro varies according to the presence of anti-La, not to the diagnosis of either SLE or SS.

Autoantibodies↗
PubMed2001

Autoantibodies in primary Sjögren's syndrome: new insights into mechanisms of autoantibody diversification and disease pathogenesis.

Characterisation of autoantibodies and their target autoantigens in primary Sjögren's syndrome (SS) is an important entry point for studying this common systemic autoimmune disease. Diversification of anti-Ro/La responses is believed to occur by a process of determinant spreading following initiation of an autoimmune response to one component, possibly 52-kD Ro (Ro52). Recent evidence supports the ER-resident chaperone Grp78 as a potential candidate in the initiation of an autoimmune response against Ro52, by binding to a Grp78 binding motif in the COOH-terminal region of Ro52. The subsequent diversification of the anti-Ro/La response is influenced by distinct HLA class II alleles. Anti-salivary duct autoantibodies have been revisited and shown to be mimicked by cross-reactive isoantibodies to AB blood group antigens. Identification of autoantibodies that act as antagonists at M3-muscarinic receptors represents an important advance. As well as contributing to the sicca symptoms, the functional effects of these autoantibodies may explain associated features of autonomic dysfunction in patients with SS. Anti-M3 receptor autoantibodies occur in both primary and secondary SS and allow Sjögren's syndrome to be viewed as a disorder of anti-receptor autoimmunity.

Animals↗
PubMed2000

Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjögren's syndrome.

OBJECTIVE: Sjögren's syndrome (SS) is an autoimmune disorder characterized by dry eyes and mouth (sicca syndrome) and lymphocytic infiltration of the lacrimal and salivary glands. Abnormalities of parasympathetic neurotransmission may contribute to the glandular dysfunction. In this study, we used a functional assay to investigate autoantibody-mediated effects on parasympathetic neurotransmission and smooth muscle contraction. METHODS: Serum and purified IgG were obtained from patients with primary and secondary SS and from control subjects. Contraction of isolated bladder strips in response to stimulation of M3-muscarinic receptors by a muscarinic receptor agonist, carbachol, or by endogenous acetylcholine released from postganglionic parasympathetic nerves was measured before and after the addition of patient serum or IgG. RESULTS: Sera from 5 of 9 patients with primary SS and from 6 of 6 patients with secondary SS inhibited carbachol-evoked bladder contraction by approximately 50%. Sera from these patients also inhibited the action of neuronally released acetylcholine at M3-muscarinic receptors. Sera from 7 of 8 healthy individuals, from patients with rheumatoid arthritis without sicca symptoms, and from patients with systemic lupus erythematosus had no effect. The anti-muscarinic receptor activity was localized in the IgG fraction, since purified IgG from patients with SS also inhibited agonist- and nerve-evoked contractions. In this preliminary study, the autoantibodies seemed to be associated with the presence of bladder symptoms and other autonomic features. CONCLUSION: Autoantibodies that act as antagonists at M3-muscarinic receptors on smooth muscle occur in a subset of patients with primary and secondary SS. Their presence in secondary SS was unexpected and provides new evidence for a common pathogenetic link between primary and secondary SS. These autoantibodies appear to contribute to sicca symptoms and may explain associated features of autonomic dysfunction in some patients.

Acetylcholine↗
PubMed2000

Epitope mimics and determinant spreading: pathways to autoimmunity.

Infectious microorganisms have evolved molecules which mimic the host in order to aid in their undetected propagation. In response, mammalian hosts have evolved a highly diverse immune repertoire designed to eradicate rapidly changing pathogens. The generation of diversity in the immune repertoire results in potentially damaging self cross-reactivities which require multiple regulatory controls to keep autoreactive lymphocytes in check. Here, we review how molecular mimicry at the T cell level might be important in the development of systemic autoimmunity.

Animals↗
PubMed2000

Current concepts on diagnosis, autoantibodies and therapy in Sjögren's syndrome.

Sjögren's syndrome is a chronic autoimmune and rheumatic disorder. Most patients have mild to moderate complaints and this may explain the great discrepancy in prevalence found in population studies compared to studies performed in the clinic. However, there is no straightforward and simple diagnostic test for Sjögren's syndrome, although several classification criteria have been designed. Initiatives have been taken to propose a new set of classification criteria in a joint effort by research groups in Europe and USA. A large number of autoantibodies have been reported in Sjögren's syndrome where, in some cases, the antibodies are correlated with the extent and severity of disease. The finding of serum autoantibodies directed against the muscarinic M3 receptor is an important advance in understanding the pathogenesis of not only the impaired glandular function but also associated features of autonomic dysfunction in some patients. The treatment of primary Sjögren's syndrome is still mainly symptomatic.

Autoantibodies↗
PubMed2000

Activity of the hypothalamic-pituitary-adrenal axis is altered by aging and exposure to social stress in female rhesus monkeys.

Age-related changes in glucocorticoid negative feedback inhibition of hypothalamic CRF and pituitary ACTH are observed in rodents. Attempts to study similar effects in humans have produced mixed results due in part to the difficulty in matching older subjects on social and lifestyle variables. The present study used female rhesus monkeys as a model for women by comparing young adult (n = 20) to old (n = 20) females to test the hypotheses that the hypothalamic-pituitary-adrenal axis is altered in older animals and that this difference is exacerbated by exposure to social stress. The effects of age on the response to two doses of dexamethasone and two doses of CRF were assessed in females living in a stable social environment (control) and in socially stressed females removed from their group and housed temporarily in a remote, nonsocial environment (separated). The suppression of serum cortisol was not different between the two doses of dexamethasone. Before dexamethasone administration (2100 h), serum cortisol was significantly higher in old control females than in either young or old separated females, who were not different from one another. The young control females had baseline cortisol concentrations significantly lower than all other groups. Serum cortisol was suppressed approximately 75% below baseline values in all groups by 10 h after dexamethasone administration. Age significantly affected serum cortisol after dexamethasone, as the old control group showed a release from suppression 19 h posttreatment compared to the young control group and compared to the separated groups. Social condition had a significant effect on the responses of serum cortisol and plasma ACTH to CRF administration. At baseline (0930 h), serum cortisol was significantly higher in young controls compared with older controls, with both separated groups having intermediate values. Similarly, plasma ACTH at baseline was significantly higher in young controls compared to all other groups. Social separation significantly diminished the elevation of both serum cortisol and ACTH after stimulation with either dose of CRF. Control females showed a prolonged increase in plasma ACTH through 60 min and an increase in serum cortisol through 120 min after CRF. In contrast, these hormones either declined by 60 min or did not increase in socially separated females after CRF administration. These data suggest that the circadian rhythm in serum cortisol may be affected by aging, as levels were higher in the evening and lower in the morning in old control compared to young control females. The effect of age on the response to dexamethasone treatment among the control groups lends support to the hypothesis that the sensitivity of glucocorticoid negative feedback diminishes with aging. Although age did not affect the response to CRF, social separation diminished the elevation in both serum cortisol and plasma ACTH. Whether this effect was due to stress-induced down-regulation of pituitary CRF receptors remains to be determined.

Aging↗