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Biomedical subjects

B O Boehm

Publications and source records attributed to B O Boehm.

At least 19 recordsLinked to original sources
PubMed2006

The serotonin transporter gene polymorphism is not associated with smoking behavior.

Nicotine increases serotonin release in the brain and symptoms of nicotine withdrawal may be modulated by diminished serotonergic neurotransmission. The promoter region of the serotonin transporter gene, solute carrier family neurotransmitter transporter member 4 (SLC6A4), contains a functional tandem repeat polymorphism. The long (L) variant is more actively transcribed than the short (S) variant and is associated with a higher serotonin uptake. To investigate the potential role of this polymorphism for smoking behavior, SLC6A4 genotypes were determined in two different studies, the SMOKING GENES case-control study (470 current smokers and 419 subjects who had never smoked) and the cross-sectional Ludwigshafen risk and cardiovascular health (LURIC) study (777 current smokers and 1178 subjects who had never smoked). In the SMOKING GENES case-control study, SLC6A4 genotype frequencies were not statistically different between smokers (LL: 30.9%; LS: 46.8%; SS: 16.4%) and non-smokers (LL: 36.3%; LS: 41.8%; SS: 14.3%; P=0.13). Similar results were obtained in the cross-sectional LURIC study (smokers: LL, 36.5%, LS, 45.6%, SS, 17.9%; non-smokers: LL, 33.6%, LS, 48.9%, SS, 17.6%; P=0.33). SLC6A4 genotypes were furthermore not associated with Fagerstrom Tolerance Questionnaire score, packyears, number of cigarettes smoked per day or previous attempts to quit smoking. We conclude that the SLC6A4 promoter polymorphism is not a major determinant of smoking behavior in Caucasian.

Adult↗
PubMed2005

Early hypoglycaemia after accidental intramuscular injection of insulin glargine.

AIM: Insulin glargine is a long-acting insulin analogue with favourable clinical characteristics. We studied a slim 24-year-old female with Type 1 diabetes who repeatedly experienced severe hypoglycaemia after switching from NPH insulin to insulin glargine at identical daily doses. METHODS: Clinical examination and high-resolution ultrasound. RESULTS: The patient frequently placed her injections into muscle tissue, followed by unexpected rapid insulin action. After correction of her injection technique, hypoglycaemia did not recur. CONCLUSIONS: The long-acting kinetics of insulin glargine require precipitation in the subcutaneous tissue. Therefore, each patient's injection technique should be carefully checked when treatment with insulin glargine is initiated, particularly in young and lean individuals.

Adult↗
PubMed2005

Association of polymorphisms of platelet membrane integrins alpha IIb(beta)3 (HPA-1b/Pl) and alpha2(beta)1 (alpha807TT) with premature myocardial infarction.

Conflicting results of an association of the human platelet antigen 1b (HPA-1b/PlA2), localized on the beta-subunit of the integrin alpha(IIb)beta3, and the alpha(2)807TT genotype of the integrin alpha2beta1 with coronary atherosclerosis and myocardial infarction have been reported. Both platelet receptor polymorphisms were genotyped in 3261 patients who had undergone coronary angiography, including 1175 survivors of a myocardial infarction, 1211 individuals with coronary artery disease but no history of myocardial infarction, and 571 control patients without angiographic coronary artery disease, and in 793 blood donors. In a case-control design, the prevalence of HPA-1b and alpha(2)807TT genotypes did not differ significantly between the patient groups with coronary artery disease or myocardial infarction and patient controls or blood donors. By contrast, using a multivariate case-only design, it was found that the median age of onset of myocardial infarction was 5.2 years earlier (P = 0.006) in carriers of the HPA-1b allele and 6.3 years earlier (P = 0.006) in carriers of the alpha(2)807TT genotype in the 264 survivors of myocardial infarction of recent onset with one- or two-vessel coronary artery disease. A significant interaction with the conventional risk factors hypercholesterolemia, smoking, diabetes, hypertension, and hyperfibrinogenemia was excluded. Human platelet antigen 1b and alpha(2)807TT are associated with premature myocardial infarction but not with coronary artery disease, suggesting a role of distinct integrin genotypes for increased platelet thrombogenicity. This association requires confirmation in follow-up studies.

Age of Onset↗
PubMed2004

The PlA1/A2 polymorphism of platelet glycoprotein IIIa is not associated with the risk of type 2 diabetes. The Ludwigshafen Risk and Cardiovascular Health study.

AIMS/HYPOTHESIS: The PlA1/A2 polymorphism of platelet glycoprotein IIIa (GPIIIa) has been implicated in the pathogenesis of type 2 diabetes. We studied this polymorphism in a homogenous, extensively phenotyped cohort using the candidate gene approach. METHODS: The PlA1/A2 polymorphism was determined in 1051 patients with type 2 diabetes and in 2247 individuals without type 2 diabetes. RESULTS: In patients with type 2 diabetes, genotype frequencies were as follows: PlA1/A1 71.4%, PlA1/A2 26.0%, and PlA2/A2 2.7%. In individuals without type 2 diabetes, genotype frequencies were 71.6%, 25.7% and 2.8%, respectively. The PlA2 allele was not associated with fasting and postprandial glucose, glycated haemoglobin, insulin, proinsulin, C-peptide and calculated indices of insulin resistance or pancreatic beta cell function. The PlA2 allele was also not significantly associated with angiographic CHD (adjusted odds ratio [OR] 1.13; 95% CI, 0.93-1.39) or with a history of previous myocardial infarction (adjusted OR 1.09; 95% CI, 0.87-1.37). CONCLUSIONS/INTERPRETATION: The GPIIIa PlA1/A2 polymorphism is not associated with type 2 diabetes, glucose metabolism, angiographic CHD or myocardial infarction.

Aged↗
PubMed2004

The advanced glycation end-product N epsilon-(carboxymethyl)lysine level is elevated in cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

Oxidative stress is involved in the aetiopathogenesis of amyotrophic lateral sclerosis (ALS), a fatal degenerative disorder. To test whether oxidative stress in ALS is increased and confined to the central nervous system, we have measured the glycoxidation product N(epsilon)-(carboxymethyl)lysine (CML) in serum and cerebrospinal fluid (CSF) samples by means of a novel enzyme immunoassay. Significant increases of CSF/serum ratio of CML in ALS patients (n = 25) as compared to normal controls (n = 20, p = 0.001) and to Alzheimer disease patients (n = 9, p = 0.029) suggest intrathecal production of this glycoxidation product. Measurement of CML levels may provide a novel diagnostic tool and may supplement current monitoring strategies in interventional trials.

Adult↗
PubMed2004

Association between the A-2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus.

AIMS/HYPOTHESIS: The molecular mechanisms of obesity-related insulin resistance are incompletely understood. Macrophages accumulate in adipose tissue of obese individuals. In obesity, monocyte chemoattractant protein-1 (MCP-1), a key chemokine in the process of macrophage accumulation, is overexpressed in adipose tissue. MCP-1 is an insulin-responsive gene that continues to respond to exogenous insulin in insulin-resistant adipocytes and mice. MCP-1 decreases insulin-stimulated glucose uptake into adipocytes. The A-2518G polymorphism in the distal regulatory region of MCP-1 may regulate gene expression. The aim of this study was to investigate the impact of this gene polymorphism on insulin resistance. METHODS: We genotyped the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort ( n=3307). Insulin resistance, estimated by homeostasis model assessment, and Type 2 diabetes were diagnosed in 803 and 635 patients respectively. RESULTS: Univariate analysis revealed that plasma MCP-1 levels were significantly and positively correlated with WHR ( p=0.011), insulin resistance ( p=0.0097) and diabetes ( p<0.0001). Presence of the MCP-1 G-2518 allele was associated with decreased plasma MCP-1 ( p=0.017), a decreased prevalence of insulin resistance (odds ratio [OR]=0.82, 95% CI: 0.70-0.97, p=0.021) and a decreased prevalence of diabetes (OR=0.80, 95% CI: 0.67-0.96, p=0.014). In multivariate analysis, the G allele retained statistical significance as a negative predictor of insulin resistance (OR=0.78, 95% CI: 0.65-0.93, p=0.0060) and diabetes (OR=0.80, 95% CI: 0.66-0.96, p=0.018). CONCLUSIONS/INTERPRETATION: In a large cohort of Caucasians, the MCP-1 G-2518 gene variant was significantly and negatively correlated with plasma MCP-1 levels and the prevalence of insulin resistance and Type 2 diabetes. These results add to recent evidence supporting a role for MCP-1 in pathologies associated with hyperinsulinaemia.

Adenine↗
PubMed2004

Elevated serum levels of N(epsilon)-carboxymethyl-lysine, an advanced glycation end product, are associated with proliferative diabetic retinopathy and macular oedema.

AIMS/HYPOTHESIS: Diabetic retinopathy is a frequent microvascular complication. In search of novel risk markers, we analysed the association between serum levels of the major advanced glycation end product N(epsilon)-carboxymethyl-lysine (CML) and prevalence of advanced stages of retinopathy in Type 2 diabetic patients without nephropathy. METHODS: We carried out a case-control study of Type 2 diabetic patients with and without advanced stages of diabetic retinopathy. Retinopathy and macular oedema were defined according to standard criteria. Serum levels of CML were estimated by means of a novel competition-based ELISA assay. RESULTS: Serum levels of CML were significantly different between age-matched controls (n=792; mean value +/- SD: 521+/-134 ng/ml), Type 2 diabetic patients without severe retinopathy (821+/-141 ng/ml; p<0.0001) and Type 2 diabetic patients with proliferative retinopathy (1182+/-346 ng/ml; p<0.0001). Levels of CML greater than 1000 ng/ml represented a 25-fold increase in risk of proliferative retinopathy. Receiver operating characteristics analysis revealed a CML threshold of 1087 ng/ml (100% sensitivity, 93% specificity) for clinically significant macular oedema. CONCLUSIONS/INTERPRETATION: High serum levels of CML were associated with advanced stages of retinopathy. Serum levels were shown to be a progressive risk marker, whereby a level of more than 1000 ng/ml induced a 25-fold increase in risk of proliferative retinopathy and clinically significant macular oedema. Our data suggest that serum levels of CML provide a novel risk marker for advanced stages of diabetic retinopathy in Type 2 diabetic patients.

Biomarkers↗
PubMed2004

Pro- and anti-inflammatory cytokine production by autoimmune T cells against preproinsulin in HLA-DRB1*04, DQ8 Type 1 diabetes.

AIMS/HYPOTHESIS: Preproinsulin is a target T cell autoantigen in human Type 1 diabetes. This study analyses the phenotype and epitope recognition of preproinsulin reactive T cells in subjects with a high genetic risk of diabetes [HLA-DRB1*04, DQ8 with Ab+ (autoantibody-positive) or without islet autoantibodies (control subjects)], and in HLA-matched diabetic patients. METHODS: A preproinsulin peptide library approach was used to screen for cytokine profiles and epitope specificities in human peripheral blood lymphocytes, and CD4(+)CD45RA(-) and CD4(+)CD45RA(+) T cell subfractions, representing memory and naive and recently primed T cells respectively. RESULTS: In CD4(+) T cell subsets we identified immunodominant epitopes and cytokine production patterns that differed profoundly between patients, Ab+ subjects and non-diabetic HLA-matched control subjects. In Ab+ subjects, a C-peptide epitope C13-29 and insulin B-chain epitope B11-27 were preferentially recognised, whereas insulin-treated Type 1 diabetic patients reacted to native insulin and B-chain epitope B1-16. In peripheral blood lymphocytes of Ab+ subjects, an increase in T helper (Th) 1 (IFNgamma, IL-2) and Th2 (IL-4) cytokines was detectable, wheras in CD45RA(+) and CD45RA(-) subsets, IL-4 and IL-10 phenotypes dominated, compatible with the contribution of non-CD4 cells to IFNgamma content. In insulin-treated Type 1 diabetic patients, naive and recently primed CD4(+) cells were characterised by increasd IFNgamma, TNFalpha, and IL-5. CONCLUSIONS/INTERPRETATION: Our data show that T cell reactivity to preproinsulin in CD45RA subsets is Th2-dominant in Ab+ subjects, challenging the Th1 paradigm in Type 1 diabetes. Characteristic immunodominant epitopes and cytokine patterns distinguish diabetic patients and Ab+ subjects from HLA-matched healthy individuals. This could prove useful in monitoring of T-cell immunity in clinical diabetes intervention trials.

Adolescent↗
PubMed2004

T-cell receptor repertoire and function in umbilical cord blood lymphocytes from newborns of type 1 diabetic mothers.

Recent observations show that the development of the human fetal immune system is susceptible to conditions of the maternal immune system and vice versa. To investigate the impact of type 1 diabetes mellitus in pregnant women on the maturation of the immune system of their newborn infants, the umbilical cord blood (UCB) T-cell repertoire at birth was analysed for clonal or oligoclonal expansions and TCRBV gene usage. Quantitative PCR using TCRBV family-specific probes and the spectratyping method were used. The extent of oligoclonal expansions observed in cord blood was markedly lower than in peripheral blood of the diabetic mothers and healthy adults. Functional analysis revealed that UCB T cells from newborns of both type 1 diabetic and gestational diabetic mothers are mature and can be readily stimulated by superantigens and phytohemagglutinin in vitro. No significant differences of the clonal contingent and the TCRBV usage were found in newborns of type 1 diabetic mothers when compared to newborns of gestational diabetic mothers, independent from the presence or absence of islet autoantigens. Our findings indicate that the immune system of type 1 diabetic mothers has no major effects on the TCR repertoire of the newborn infants. In that respect, no evidence was found for superantigen-activated T cells, nor was chronic hyperglycaemia per se found to alter either T-cell repertoire or functional activity.

Adult↗
PubMed2004

Genetic susceptibility and immunological synapse in type 1 diabetes and thyroid autoimmune disease.

Type 1 diabetes mellitus results from an immune mediated or idiopathic destruction of the pancreatic beta cells. Its aetiopathogenesis remains to be elucidated, despite great progress in the characterisation of beta-cell antigens, T-lymphocyte and antibody markers as well as whole genome screening. The incidence of type 1 diabetes is rising in most countries. Moreover, a considerable proportion of patients initially presenting with type 2 diabetes mellitus have an underlying type 1 diabetes with a latent course. A proportion of type 1 diabetes patients have concomittant thyroid autoimmune disease, either Hashimoto's thyroiditis or Graves' disease. Whereas Hashimoto's thyroiditis shares the same destructive immune process as type 1 diabetes, Graves' disease is unique in stimulating specifically the TSH-receptor through high-affinity immunoglobulins. However, both the thyroid autoimmune disorders and type 1 diabetes have susceptibility genes in common, implying shared pathways of immunopathogenesis. It has become clear that the genetic composition of a host at least partly determines the course of an immune response leading either to an organ-specific autoimmune disease or creating a state of balance where antibodies are hallmarks of (auto)immunity but normal function prevails. Genetic factors including MHC ( IDDM 1-genetic locus) and non-MHC genes (IDDM 2 - IDDM X) have been shown to determine susceptibility to autoimmunity in type 1 diabetes or lifelong tolerance. Currently the importance of the various diabetes associated genes is becoming clearer due to functional studies. Our review attempts to compile the relevant data that have accumulated in recent years and offers perspectives for prediction, prevention and possibly even therapy of immune-mediated endocrinopathies.

Autoimmune Diseases↗
PubMed2003

Therapy of osteoporosis in patients with Crohn's disease: a randomized study comparing sodium fluoride and ibandronate.

BACKGROUND: Osteoporosis is a frequent complication in Crohn's disease. Although the efficacy of both sodium fluoride and aminobisphosphonates in postmenopausal osteoporosis has been investigated in long-term therapy studies, no long-term results are available regarding the effect of these agents in the management of osteoporosis in patients with Crohn's disease. METHODS: Eighty-four patients with Crohn's disease and pathological bone mineral density findings were randomized to receive either vitamin D3 (1000 IU) and calcium citrate (800 mg) daily (group A) or sodium fluoride (25 mg b.d., group B) or intravenous ibandronate (1 mg every 3 months, group C) in addition to daily calcium/vitamin D substitution. On admission to the study and after 12 and 27 months, patients underwent dual-energy X-ray absorptiometry and radiological examination of the spine. RESULTS: Sixty-eight patients completed the 1-year observation period and were available for the intention-to-treat analysis. No new vertebral fractures were diagnosed. In group A, lumbar bone density increased by 2.6% (P = 0.066, N.S.), in group B by 5.7% (P = 0.003) and in group C by 5.4% (P = 0.003). Therapy with sodium fluoride was associated with an increase in osteocalcin (N.S.), whereas administration of ibandronate was associated with a decrease in the resorption parameter, carboxy-terminal cross-linked type-I collagen telopeptide (P < 0.05). Both sodium fluoride and ibandronate resulted in significant decreases in the serum concentration of osteoprotegerin after 9 months (P < 0.001). CONCLUSIONS: The findings of the present study show that both sodium fluoride and ibandronate are effective in combination with calcium and vitamin D substitution in the management of osteopenia and osteoporosis in patients with Crohn's disease. Both agents are safe and well tolerated, and induce continuous increases in lumbar bone density.

Bone Density↗
PubMed2003

Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy.

AIMS/HYPOTHESIS: Retinopathy is the most common microvascular complication of diabetes. Our aim was to address the predictive value of pro-angiogenic and anti-angiogenic markers for progression of retinopathy. METHODS: Aqueous humor was collected at cataract surgery from 32 diabetic patients who had no or very mild retinopathy (ETDRS stage </=20) and 33 normoglycaemic control subjects. Content of pro-angiogenic vascular endothelial growth factor and angiogenic inhibitor pigment epithelium-derived factor were determined. ANGIOGENIC activity was quantified by measuring its effect on the migration of capillary endothelial cells. The predictive value of the initial level of these markers for progression of retinopathy was studied by following the probands for a maximum of 75 months. RESULTS: In the aqueous fluid content of vascular endothelial growth factor was increased in diabetic patients (mean values 492 versus 292 pg/ml; p=0.0052), and pigment epithelium-derived factor values were decreased (mean values 1740 versus 3680 ng/ml; p=0.0058) compared to control subjects. Of the diabetic patients ten progressed during follow-up (ETDRS stage >47B). This subgroup showed lower pigment epithelium-derived factor content when compared to non-progressors and control subjects. Migratory activity in samples of patients from the control group and in diabetic patients without progression was generally inhibitory due to pigment epithelium-derived factor. Inhibition was blocked by neutralizing antibodies to pigment epithelium-derived factor. In diabetic patients initial angiogenic activity was higher in those who later developed retinopathy (vs. controls p=0.00005; vs. no progressors p=0.0003). Both pigment epithelium-derived factor and migratory response predicted progression. CONCLUSION/INTERPRETATION: Pigment epithelium-derived factor is an important negative regulator of angiogenic activity of aqueous humor. Its content in the aqueous humor of diabetic patients strongly predicts who among them will develop progression of retinopathy.

Aged↗
PubMed2003

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy.

Cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism. Single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were determined in 98 patients with untreated dyslipidemias and analyzed for associations with plasma CETP and plasma lipids before and during statin treatment. Individual CETP SNPs and haplotypes were both significantly associated with CETP enzyme mass and activity. However, only certain CETP haplotypes, but not individual SNPs, significantly predicted the magnitude of change in HDL cholesterol (HDL-C) and triglycerides. After adjusting for covariates and multiple testing, the TTCAAA haplotype showed a gene-dose effect in predicting the HDL-C increase (P=0.03), while the TTCAAAGGG and AAAGGG haplotypes predicted a decrease in triglycerides (P=0.04 both). This is the first study to demonstrate that SNP haplotypes derived from allelic SNP combinations in the CETP gene were more informative than single SNPs in predicting the response to lipid-modifying therapy with statins.

Aged↗
PubMed2003

Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. a pilot study.

Retinopathy is the most common microvascular diabetes complication and represents a major threat to the eyesight. The aim of this study was to address the role of pro- and anti-angiogenic molecules in diabetic retinopathy in the aqueous humor of the eye. Aqueous humor was collected at cataract surgery from 19 diabetic patients and from 13 age- and sex-matched normoglycemic controls. Levels of pro-angiogenic vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) were determined. Angiogenic activity of the aqueous humor was quantified by measuring its effect on the migration of capillary endothelial cells. In the aqueous fluid, VEGF levels were increased in diabetics (mean values: 501 vs. 367 pg/ml; p = 0.05), compared to controls. PEDF was found to be decreased in diabetics (mean values: 2080 vs. 5780 ng/ml; p = 0.04) compared to controls. In seven diabetic patients with proliferative retinopathy, the most profound finding was a significant decrease of the PEDF level (mean value: 237 ng/ml), whereas VEGF levels were comparable to diabetic patients without proliferation (mean value: 3153; p = 0.003). Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF. Likewise, in diabetics without proliferation, angiogenic activity was also blocked by antibodies to PEDF. We will demonstrate here that the level of the natural ocular anti-angiogenic agent PEDF is inversely associated with proliferative retinopathy. PEDF is an important negative regulator of angiogenic activity of aqueous humor. Our data may have implications for the development of novel regimens for diabetic retinopathy.

Aged↗
PubMed2002

Premixed insulin aspart 30 vs. premixed human insulin 30/70 twice daily: a randomized trial in Type 1 and Type 2 diabetic patients.

AIM: To compare the efficacy and safety of premixed insulin aspart (30% free and 70% protamine-bound, BIAsp 30) with human insulin premix (BHI 30) used in a twice-daily injection regimen in people with Type 1 and Type 2 diabetes. METHODS: People with Type 1 and Type 2 diabetes (n = 294) using twice-daily insulin were randomized to a 12-week open-label comparison of BIAsp 30 and BHI 30. Efficacy was assessed by analysis of variance of 12-week data, adjusted for baseline level. RESULTS: BIAsp 30 was as effective as BHI 30 based on the primary efficacy measure, HbA1c, mean difference -0.01 (90% confidence interval (CI) -0.14; 0.12) %Hb. Meal-time self-measured blood glucose increment averaged over the three main meals was significantly lower in the BIAsp 30 group than in the BHI 30 group (-0.68 (-1.20; -0.16) mmol/l; P < 0.02). Significant improvements were observed after breakfast, before lunch, after dinner and at bedtime (P < 0.02-0.05), with blood glucose around 1.0 mmol/l lower in the BIAsp 30 group. The number of major hypoglycaemic episodes with BIAsp 30 was half that with BHI 30. However, the overall risk of both minor and major hypoglycaemia did not differ significantly between treatments. CONCLUSION: Post-prandial glycaemic control was significantly improved, without increasing the risk of hypoglycaemia, and overall control was similar when people with Type 1 and Type 2 diabetes were treated on a twice-daily regimen with immediate premeal injections of BIAsp 30 compared with BHI 30.

Adult↗
PubMed2001

A T cell clone's avidity is a function of its activation state.

At present it is unclear how Ag dose-dependent T cell functions, such as cytokine production, reflect TCR affinity and how the signal strength afforded by the Ag dose affects the kinetics of cytokine production by the individual T cell. We used a computer-assisted ELISPOT approach to address these issues. IFN-gamma release by a clonal population of CD4 T cells was monitored on a clonal population of APC while titrating the nominal peptide. The frequency of cytokine-producing cells, the net per-cell output of cytokine, and the onset of cytokine production were each found to be functions of the signal strength. Sigmoidal dose-response curves were seen at the clonal population level, but the activation thresholds for the individual T cells followed a Gaussian distribution. Moreover, the overall dose-response curve of the T cell clone revealed cyclic changes, becoming increasingly shifted toward lower Ag concentrations with the duration of time that elapsed since the last restimulation with Ag. Therefore, responsiveness to Ag ("functional avidity") is not a constant parameter of a T cell clone but a function of the T cell's history of last Ag encounter. The implications of such shifting activation thresholds are discussed for autoimmune disease.

CD4-Positive T-Lymphocytes↗
PubMed2001

Frequencies of neuroantigen-specific T cells in the central nervous system versus the immune periphery during the course of experimental allergic encephalomyelitis.

Direct measurements of the frequency and the cytokine signature of the neuroantigen-specific effector cells in experimental allergic encephalomyelitis (EAE) are a continuing challenge. This is true for lymphoid tissues, and more importantly, for the CNS itself. Using enzyme-linked immunospot analysis (ELISPOT) assays, we followed proteolipid protein (PLP) 139--151-specific T cells engaged by active immunization of SJL mice. The total numbers of PLP(139--151)-specific CD4 cells were highest before disease onset. At this time, these cells resided in lymphoid and nonlymphoid tissues, but were not detected in the CNS. While the PLP(139--151)-specific cells reached high frequencies in the CNS during clinical EAE, in absolute numbers, less than 20% of them were present in the target organ, with the majority residing in the periphery throughout all stages of the disease. The numbers of PLP(139--151)-specific cells gradually declined in both compartments with time. While eventually this first wave of effector cells completely disappeared from the CNS, PLP(178--191)-specific cells became engaged, being detected first in the CNS. These data suggest that throughout all stages of EAE, the effector cells in the CNS are recruited from a vast peripheral reservoir, and that the second wave of effector cells is engaged while the first wave undergoes exhaustion.

Acute Disease↗