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Biomedical subjects

J A James

Publications and source records attributed to J A James.

At least 37 records · Page 2Linked to original sources
PubMed2001

Tacrolimus is not associated with gingival overgrowth in renal transplant patients.

BACKGROUND: Cyclosporin A is used extensively to prevent the rejection of allogenic renal transplants. However, it is associated with a variety of undesirable side effects including gingival overgrowth. Tacrolimus (FK506), has been marketed as an effective alternative immunosuppressant to cyclosporin A and recent subjective reports suggest patients taking it complain infrequently of gingival problems. This clinical investigation was undertaken to confirm whether or not tacrolimus adversely affected the gingival health of renal transplant recipients. METHODS: Renal transplant patients (RTPs) under the care of the Renal Transplantation Service at the Manchester Royal Infirmary, who had received a renal allograft at least 18 months earlier, were recruited for this study. All but one of the RTPs had been taking tacrolimus since transplantation. The other had commenced tacrolimus therapy two months after receiving her allograft. A hospital based control group was recruited from non transplanted individuals attending the Turner Dental School, Manchester. Each patient underwent a detailed dental assessment and had dental impressions taken. The extent of gingival overgrowth was determined from plaster models. RESULTS: 25 renal transplant recipients and 26 control patients were included in the study. None of the individuals in either the tacrolimus or control groups had clinically significant overgrowth. The patients in the tacrolimus group with the highest overgrowth scores were those also taking calcium antagonists as treatment for hypertension. CONCLUSION: This study demonstrates that tacrolimus has no adverse effects on the gingival tissues and thus has potential as an alternative immunosuppressant for individuals susceptible to developing cyclosporin A-induced gingival overgrowth.

Adult↗
PubMed2001

Role of viruses in systemic lupus erythematosus and Sjögren syndrome.

Systemic lupus erythematosus and Sjögren syndrome remain elusive in the description of their underlying etiologic causes and pathogenic mechanisms. Although underlying genetic predisposition appears to contribute to both diseases based on twin and other genetic studies, additional factors must play a role. Over the decades additional factors, such as hormonal influence, UV light, environmental exposures (e.g., silica, solvents), and infectious agents have been postulated to play a role. Over the past few years additional information has been published concerning roles of various infectious agents in both lupus and Sjögren syndrome. Although the understanding of this field is still incomplete, significant advances are being made.

Humans↗
PubMed2001

The influence of transforming growth factor-beta1 gene polymorphisms on the severity of gingival overgrowth associated with concomitant use of cyclosporin A and a calcium channel blocker.

BACKGROUND: The purpose of this study was to determine whether the prevalence and severity of gingival overgrowth in renal transplant recipients concomitantly treated with cyclosporin and a calcium channel blocker was associated with functional polymorphisms within the signal sequence of the transforming growth factor-(TGF)beta1 gene. METHODS: The extent and severity of gingival overgrowth for 164 renal transplant recipients immunosuppressed with cyclosporin A and concomitantly taking a calcium channel blocker since transplant were entered into the study (86 in Manchester, 78 in Belfast). Two biallelic polymorphisms of the TGF-beta1 gene were studied at position +869, codon 10 (leucine to proline substitution), and position +915, codon 25 (arginine to proline substitution). RESULTS: Subjects who were homozygous for proline at codon 10 had significantly higher overgrowth scores than those who were heterozygous (P= 0.03) or homozygous for leucine (P= 0.01). Subjects who were heterozygous (arginine/proline) at codon 25 had a significantly higher (P= 0.04) gingival overgrowth score than those who were homozygous for arginine. Logistic regression analysis indicated that for codon 25 independent predictors of severe gingival overgrowth were the heterozygous arginine/proline genotype (P= 0.009) and whether the individual was young (P= 0.05). CONCLUSIONS: Polymorphisms in the TGF-beta1 gene influence the expression of gingival overgrowth in renal transplant recipients concomitantly treated with cyclosporin and a calcium channel blocker. The polymorphism in the TGF-beta1 gene at codon 25 represented an independent genetic determinant of severe gingival overgrowth in the susceptible subjects studied.

Adult↗
PubMed2000

Delineation of the human systemic lupus erythematosus anti-Smith antibody response using phage-display combinatorial libraries.

The anti-Smith (Sm) autoantibody response is highly specific for systemic lupus erythematosus and is predominantly targeted to the Sm-B/B' and -D1 polypeptides. In all animal species thus far studied, anti-Sm Abs initially recognize proline-rich epitopes in the carboxyl terminus of the Sm-B/B' protein and subsequently to multiple other epitopes in B/B' and D. The absence of appropriate mAbs has limited our understanding of the genetic and structural basis of this autoimmune response. Using phage-display technology and lymphocytes from a systemic lupus erythematosus patient we have generated the first and only panel of human IgG anti-Sm mAbs thus far available. These Abs reproduced to a remarkable extent the serological reactivity of the patient. Epitope mapping and genetic studies revealed that the anti-Sm response is produced by distinct B cell clones with restricted epitope reactivity. All of the Abs in our study were exclusively encoded by different members of the V(H)4 gene family. On the aggregate, our results demonstrate that combinatorial libraries can recapitulate the immune repertoire of peripheral blood B memory cells and that epitope spreading appears to occur through the sequential recruitment of nonclonally related autoreactive B cell clones.

Amino Acid Sequence↗
PubMed2000

The calcium channel blocker used with cyclosporin has an effect on gingival overgrowth.

BACKGROUND/AIMS: To investigate whether the choice of calcium channel blocker, used in conjunction with cyclosporin A, affected the prevalence of gingival overgrowth. METHOD: A cohort of 135 renal transplant recipients who had been medicated with cyclosporin A in combination with either nifedipine (89) or amlodipine (46) since transplant, took part in the study. The inclusion criteria were that eligible subjects had been in receipt of a kidney transplant for at least 12 months, had at least 10 teeth and had not received specialist periodontal treatment. The age, gender, current drug regimen and dosage were recorded for each participant and alginate impressions taken of both arches. The presence and severity of gingival overgrowth were scored from plaster models. RESULTS: A higher proportion (72%) of the amlodipine group were categorised as having gingival overgrowth compared with only 53% of the nifedipine group, chi square=4.5, p<0.05. Logistic regression analysis was used to explore the relationship between the presence or absence of gingival overgrowth (dependent variable) and age, gender, time since transplant, dose of cyclosporin A, centre in which the patient was treated, and the calcium channel blocker used (independent variables). Independent predictors of gingival overgrowth in this multivariate analysis were whether the individual was treated with amlodipine or nifedipine (p=0.01) and whether the individual was young or old (p=0.01). Within the multivariate analysis, the odds ratio for amlodipine to be associated with gingival overgrowth compared with nifedipine was 3.0 (confidence interval 1.3-6.9). CONCLUSIONS: The prevalence of gingival overgrowth in renal transplant recipients maintained on cyclosporin A and nifedipine is lower than those treated with cyclosporin A and amlodipine.

Adult↗
PubMed2000

Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus.

BACKGROUND: Unsightly gingival overgrowth affects many individuals immunosuppressed with cyclosporin A (CsA). Current management involves repeated periodontal surgery and intensive hygienist support. Tacrolimus is an effective alternative immunosuppressive agent for renal transplantation which does not appear to produce gingival enlargement. AIMS: The purpose of the present study was to monitor the gingival response of 4 renal transplant patients (RTPs), with clinically significant CsA-induced gingival overgrowth, after their immunosuppressive therapy was switched to tacrolimus. METHODS: Intra-oral photographs and alginate impressions were taken both prior to the drug conversion and again, 6 to 9 months later. Gingival overgrowth scores were determined, from plaster models on both these occasions. RESULTS: All of the RTPs experienced significant resolution of their gingival enlargement within the time period studied; however, only one had complete regression. CONCLUSION: It is concluded that conversion of RTPs with gingival overgrowth from CsA to tacrolimus may provide an effective management strategy for this clinical problem.

Adolescent↗
PubMed1999

Induction of autoimmunity by multivalent immunodominant and subdominant T cell determinants of La (SS-B).

We investigated the consequences of altering the form and valence of defined autodeterminants on the initiation and spreading of experimentally induced La/Ro autoimmunity. Anti-La and Ro (SS-A) Ab responses were monitored following immunization of healthy mice with defined immunodominant and subdominant T cell determinants of the La (SS-B) autoantigen synthesized as either monomeric or multiple antigenic (MAP) peptides. Abs to mouse La (mLa) developed faster and were of higher titer in mice immunized with the subdominant mLa25-44 MAP compared with mice immunized with the 25-44 monomer. Rapid intermolecular spreading of the autoimmune response to 60-kDa Ro was observed in AKR/J mice immunized with mLa25-44 MAP, but not in mice immunized repeatedly with monomeric peptide. A/J mice immunized and boosted with the known tolerogenic mLa287-301 determinant delivered as monomeric peptide failed to develop Abs to either intact mLa or mLa287-301 peptide. However, immunization with the multivalent mLa287-301 peptide led to the rapid production of high titer mLa autoantibodies associated with a proliferative T cell response to the mLa287-301 peptide. The data suggested that the enhanced immunogenicity of MAPs was not due to augmented Ag presentation or T cell stimulation. However, MAP-, but not monomer peptide-, containing immune complexes were potent substrates for Ab-dependent fixation of complement. These results demonstrate that the form of Ag responsible for inducing autoimmunity can profoundly influence the nature and magnitude of the immune response. Thus, molecular mimicry of tolerogenic and nontolerogenic self determinants might trigger autoimmunity under conditions of altered valence.

Amino Acid Sequence↗
PubMed1999

Immunization of mice with human 60-kd Ro peptides results in epitope spreading if the peptides are highly homologous between human and mouse.

OBJECTIVE: Immunization with peptide fragments of autoantigens may lead to an immune response at both the T and B cell level that is directed not only at the immunogen, but also at the autoantigen from which the peptide came. In addition, a complex multicomponent particle may become the target of this expanded immune response. The purpose of this study was to determine the ability of several different peptides from 60-kd Ro to induce expansion of the immune response to the Ro/La RNP particle. METHODS: We immunized BALB/c mice with 3 different oligopeptides from human 60-kd Ro (or, SSA). RESULTS: Animals immunized with peptides either identical to or differing by only 1 amino acid developed autoimmunity to the entire Ro RNP particle. Animals immunized with a human peptide highly divergent from the corresponding mouse sequence developed an immune response to the immunogen only and showed little evidence of epitope spreading. Furthermore, these mice did not have antibodies that bound the poorly conserved mouse homolog peptide, and the antibody response to this peptide did not include IgG1. CONCLUSION: These data indicate that B lymphocytes specific for the self-peptide that is homologous to the immunogen are a critical determinant for spreading of the immune response to other components of self.

Animals↗
PubMed1999

Side-chain specificities and molecular modelling of peptide determinants for two anti-Sm B/B' autoantibodies.

Autoantibodies binding the Sm B and B' peptides (B/B') are commonly associated with systemic lupus erythematosus in man and in MRL lpr/lpr mice. The linear antigenic regions of two anti-Sm B/B' murine monoclonal auto-antibodies have been mapped using overlapping octapeptides. Unique epitopes are identified by each antibody. Monoclonal KSm-5 recognizes the peptide, PPPGMRPP, which is repeated three times in the Sm B polypeptide. KSm 3 preferably binds to two similar, almost neighboring octapeptides, PPPGIRGP and PGIRGPPP. The two monoclonal antibodies do not cross react. These regions of Sm B/B' are major areas of antigenicity in human sera. Amino acid deletion and substitution in antigenic octapeptides show that binding to the KSm-5 epitope is lost with most modifications. Molecular dynamic modelling suggests that when PPPGMRPP is substituted in the sixth position arginine, KSm/5 binding may be associated with a shared peptide backbone structure rather than charge or hydrophobicity of the substituted amino acid. In contrast, binding of KSm-3 to PPPGIRGP is abolished when the sixth position arginine is substituted by any other amino acid. Substitution at arginine and modelling experiments, therefore, suggest very different mech-anisms of binding. Autoantibodies may bind quite different features of similar peptide structures.

Amino Acid Sequence↗
PubMed1999

Immunization as a model for systemic lupus erythematosus.

BACKGROUND: Immunization of laboratory animals is a new model system for systemic lupus erythematosus (SLE) and the autoimmunity of SLE. OBJECTIVE: Review the published reports describing immunization as a model of SLE and describe the state of this research as well as future objectives as related to human illness. METHODS: Medline search for relevant articles as well as review of cited bibliographies. RESULTS: Either rabbits or mice can be immunized with proteins or oligopeptides that are lupus autoantigens with a resulting immune response not just to the immunogen but instead to a host of other self components that are also SLE-associated autoantigens. Several studies have noted clinical illness in these animals that resembles human SLE. In addition, injection of pristane (a component of mineral oil) also results in SLE-like autoimmunity, even though lupus autoantigens are not present. Pristane injected animals may also develop an SLE-like illness. There are reports of human SLE having its onset after immunization, but there have been no prospective studies. CONCLUSIONS: Studies are needed to determine whether human SLE tends to begin soon after immunization. Meanwhile, continued study of animal models developed after immunization is needed in order to determine the relevance of this model to human disease. RELEVANCE: SLE and/or SLE-like autoimmunity can be triggered after immunization of animals. This may be a model for an environmental trigger of human SLE.

Animals↗
PubMed1999

Shared early autoantibody recognition events in the development of anti-Sm B/B' in human lupus.

Many aspects of the immune maturation are uncharted. For ordinary human autoimmune systems there are no complete descriptions of the progression from an initial antigenic epitope to a maximally complex immune response. In this study we have exploited a large serial collection of human sera to investigate the development of the anti-Sm autoimmune response in systemic lupus erythematosus (SLE). The results suggest a similar, if not virtually identical, stepwise progression in the early humoral immune maturation of anti-Sm. The amino acid sequence PPPGMRPP comprises the first epitope in the anti-Sm B/B'response and its close relative, PPPGMRGP, the second. Epitopes are subsequently enlarged by the incorporation of neighbouring amino acids. The third and fourth epitopes are also recognised by an antibody in a nearly identical sequence in different lupus patients. A column absorption with PPPGMRPP demonstrates that the epitope spreading among the first four early epitopes appears to occur by the sequential generation of cross-reactive antibodies. Unexpectedly, epitope spreading in this system occurs in a predictable fashion by involving essentially the same sequence of antigenic structures from person to person. In addition, these data support the lupus anti-Sm antibodies originating against a single antigenic structure and, hence, strongly support a unifying mechanism in the generation of these autoantibodies.

Amino Acid Sequence↗
PubMed1999

Cyclosporin associated gingival overgrowth in renal transplant recipients.

OBJECTIVES: To investigate the prevalence and severity of gingival overgrowth in a group of renal transplant recipients treated in one centre in Northern Ireland. STUDY DESIGN: A consecutive group of patients who had had a renal transplant for at least 6 months and were attending the Renal Unit in Belfast City Hospital took part in the study. These were divided into a group of 84 subjects treated with cyclosporin since their transplant who were compared with a control group of 36 transplant recipients who had never received cyclosporin. Each subject had a periodontal examination and completed a questionnaire. The severity of gingival overgrowth was scored from plaster models. OUTCOME MEASURES: Clinically significant gingival overgrowth was equated with a score of > or = 30 using the index developed by Seymour et al (1985). RESULTS: 41 (49%) of the cyclosporin group had clinically significant gingival overgrowth compared with none of the controls. A significantly higher proportion of males had overgrowth than females. There were significant correlations between age at transplant, plaque, bleeding, pocketing and the severity of gingival overgrowth. Many patients with clinically significant gingival overgrowth were apparently unconcerned about this condition. CONCLUSIONS: It is concluded that gingival overgrowth is a significant problem for renal transplant patients treated with cyclosporin, particularly if they are also treated with a calcium channel blocker. None of the factors measured, in isolation, explained the variable expression of gingival overgrowth in those at risk.

Adult↗
PubMed1999

Possible potentiation of toxins from Prevotella intermedia, Prevotella nigrescens, and Porphyromonas gingivalis by cotinine.

BACKGROUND: Smoking is a recognized risk factor for the initiation and progression of periodontitis. However, the mechanism by which smoking induces its negative effects on the periodontium is not clear. This study aimed to test the hypothesis that synergy may occur between cotinine and bacterial products isolated from 3 putative periodontopathogens. METHODS: A chick embryo toxin assay was used to investigate bacterial toxins (cell-free extracellular toxins and cell-free cell lysates) from 5 species with and without cotinine. A total of 9 putative periodontopathogens (3 species) and 2 non-oral controls (2 species) were studied. The periodontal species were: Prevotella intermedia (n = 4), Prevotella nigrescens (n = 4), and Porphyromonas gingivalis (n = 1). The control species tested were: Staphylococcus aureus (n = 1) and Escherichia coli (n = 1). RESULTS: The toxicity kill was significantly greater than expected by simple addition alone (P <0.05, Fisher's exact test) between cotinine (800 ng/ml) and 1) the cell-free extracellular toxins of P. nigrescens MH1 and 2) the cell-free cell lysates of P. intermedia MH2. Synergy occurred with cotinine plus the cell-free extracellular toxins in all but 3 periodontal isolates, and the cell-free cell lysates in all but 2 periodontal isolates. Cotinine significantly (P <0.05, Fisher's exact test) enhanced the effects of cell-free extracellular toxins and cell lysates from one control species (E. coli), but not the other (S. aureus). CONCLUSIONS: These findings indicate that synergy in an in vitro assay can occur between cotinine and toxins from putative periodontopathogens. This may be one important mechanism by which smoking increases the severity of periodontitis.

Animals↗
PubMed1999

Effects of tobacco products on the attachment and growth of periodontal ligament fibroblasts.

BACKGROUND: Cigarette smoking is one of the most significant risk factors in the development and further advancement of inflammatory periodontal disease, however, the role of either nicotine or its primary metabolite cotinine in the progression of periodontitis is unclear. This study aimed to investigate the effects of nicotine and cotinine on the attachment and growth of fibroblasts derived from human periodontal ligament (PDL). METHODS: Primary cultures were prepared from the roots of extracted premolar teeth. Cells were used at both low (P3 to P5) and high (P11 to P13) passage. Cell numbers were determined over 14 days using either the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay or with a Coulter counter. Cultures were exposed to culture medium supplemented with 1) 15% fetal calf serum (FCS) only; 2) 1% FCS only; 3) 1% FCS and nicotine (concentration range 5 ng/ml to 10 mg/ml); or 4) 1% FCS and cotinine (concentration range 0.5 ng/ml to 10 microg/ml). RESULTS: Nicotine significantly (P <0.05, by ANOVA) inhibits attachment and growth of low passage cells at concentrations >1 mg/ml and high passage PDL fibroblasts at concentrations >0.5 mg/ml. Cotinine, at the highest concentration used (10 microg/ml), appeared to inhibit attachment and growth of both low and high passage fibroblasts but this was not statistically significant (P >0.05, by ANOVA). CONCLUSIONS: Tobacco products inhibit attachment and growth of human PDL fibroblasts. This may partly explain the role of these substances in the progression of periodontitis.

Analysis of Variance↗
PubMed1998

Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.

Animals↗
PubMed1998

A model of peptide-induced lupus autoimmune B cell epitope spreading is strain specific and is not H-2 restricted in mice.

Anti-Sm is a common and specific autoantibody found in systemic lupus erythematosus. The peptide PPPGMRPP from Sm B/B' is an early target of the autoimmune response in some anti-Sm-positive human patients. After immunization with this peptide on a MAP backbone, rabbits develop anti-Sm autoantibodies with B cell epitope spreading of the autoimmune response as well as other features of lupus autoimmunity. Various strains of inbred mice have been immunized with peptide PPPGMRPP or PSQQVMTP (nonantigenic region of Sm B/B') in Freund's adjuvant or with no peptide. All peptide-immunized mouse strains eventually develop high titers of specific anti-peptide of immunization Abs. Mice immunized with Freund's adjuvant alone have no measurable Ab binding to the PPPGMRPP peptide. With time, nearly half the mouse strains tested develop Abs that react with additional regions of Sm B/B' and Sm D. All the regions bound by mouse serum are major epitopes of the human systemic lupus erythematosus anti-Sm response. These same strains also develop significant anti-Sm and anti-nuclear ribonucleoprotein titers. In addition, some of these strains demonstrate positive anti-nuclear Abs and anti-dsDNA Abs. Experiments with congenic H-2 mice demonstrate that the H-2 region does not play a role in spreading the immune response from the peptide of immunization to other epitopes of the spliceosome. These results present a new murine model of B cell epitope spreading and lupus autoimmunity induced by peptide immunization that is strain specific and not apparently dependent upon the loci at H-2.

Animals↗
PubMed1998

A limited lupus anti-spliceosomal response targets a cross-reactive, proline-rich motif.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of large amounts of characteristic autoantibodies. Anti-Sm and anti-nRNP (also known as anti-spliceosome) autoantibodies are among these. Previous epitope mapping of anti-spliceosomal antibodies has identified multiple antigenic determinants within this complex immune response. In this report we describe an SLE patient with a relatively simple, long-lasting anti-spliceosomal response. In the earliest serum sample tested the autoimmune response appeared restricted to the similar peptides PPPGMR(P,G)P of Sm B/B', PAPGMRPP of nRNP C, and PPPGMIPP of nRNP A. Unlike all the other tested lupus patients with anti-spliceosomal autoantibodies, in this patient these proline-rich epitopes remained the primary target for humoral autoimmunity in subsequent serum samples collected over many years. Absorption of anti-PAPGMRPP antibodies also removed binding to PPPGMR(P,G)P and PPPGMIPP. Isolated antibodies to PAPGMRPP were capable of binding Sm B/B', nRNP C and nRNP A by Western blot. For this particular SLE patient the autoimmune response observed against these three proteins is a single cross-reactive response against a similar proline-rich motif. Also, this patient has failed to undergo the B cell epitope spreading, typically observed in the naturally arising autoimmune response against the spliceosome in human lupus patients.

Adult↗