Biomedical subjects

E Kaplan

Publications and source records attributed to E Kaplan.

At least 73 records · Page 4Linked to original sources

PubMed1997

Response variability and timing precision of neuronal spike trains in vivo.

We report that neuronal spike trains can exhibit high, stimulus-dependent temporal precision even while the trial-to-trial response variability, measured in several traditional ways, remains substantially independent of the stimulus. We show that retinal ganglion cells and neurons in the lateral geniculate nucleus (LGN) of cats in vivo display both these aspects of firing behavior, which have previously been reported to be contradictory. We develop a simple model that treats neurons as "leaky" integrate-and-fire devices and show that it, too, can exhibit both behaviors. We consider the implications of our findings for the problem of neural coding.

Animals↗

PubMed1997

Thyrotropin-receptor and thyroid peroxidase-specific T cell clones and their cytokine profile in autoimmune thyroid disease.

We studied the cytokine profile and the immune responses to thyroid antigens of specific T cell clones (TCC) isolated from patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD). Antigen-specific TCC were reactive to thyroid peroxidase (TPO), thyroglobulin (Tg) or human recombinant TSH-receptor extracellular domain (TSH-R), and/or their respective peptides. Of the 43 clones derived from HT patients, 65% were reactive to TPO, and 59% of the 32 clones derived from GD patients were reactive to TSH-R. TPO epitopes 100-119 and 625-644 were recognized by 75% of HT-derived clones, whereas TSH-R epitopes 158-176, 207-222, and 343-362/357-376 were recognized by 85% of GD-derived TCC. The TCC were classified according to their cytokine profile into T helper cell (Th)0 [secreting interleukin (IL)-4, IL-5, interferon (IFN)-gamma], Th1 (secreting IFN-gamma) and Th2 (secreting IL-4 and/or IL-5). Tumor necrosis factor-beta and IL-10 were produced by all subsets. The specific TCC were predominantly Th1-like cells in HT, and were Th0- and Th1-like cells in GD. Fifty three percent of Th0 clones were derived from GD patients and were reactive to TSH-R, whereas 50% of Th1 clones were derived from HT patients and were reactive to TPO or Tg. Most Th2 clones (82%) were reactive to TPO and were established from peripheral blood. All these clones produced IL-5, and 64% produced IL-4 and IL-10. Interestingly, IFN-gamma was highly produced by TPO- or Tg-specific clones established from HT thyroid tissue. These results confirm at the clonal level our previous studies regarding T cell epitopes on TPO and TSH-R molecules and support the concept that immunodominant T cell epitopes are located on amino acid residues 100-119 and 625-644 of TPO in HT and amino acid residues 158-176, 207-222 and 343-362/357-376 of TSH-R in GD. Our studies also demonstrate that thyroid-specific T cells can be classified into Th0, Th1, and Th2 subsets. TPO- or Tg-specific clones with Th1 phenotype appear to be involved in the pathogenesis of HT, mediating thyroid tissue destruction, whereas TSH-R clones with Th0 phenotype may induce thyroid-stimulating autoantibodies in GD.

Autoantigens↗

PubMed1997

Fractal character of the neural spike train in the visual system of the cat.

We used a variety of statistical measures to identify the point process that describes the maintained discharge of retinal ganglion cells (RGC's) and neurons in the lateral geniculate nucleus (LGN) of the cat. These measures are based on both interevent intervals and event counts and include the interevent-interval histogram, rescaled range analysis, the event-number histogram, the Fano factor, Allan factor, and the periodogram. In addition, we applied these measures to surrogate versions of the data, generated by random shuffling of the order of interevent intervals. The continuing statistics reveal 1/f-type fluctuations in the data (long-duration power-law correlation), which are not present in the shuffled data. Estimates of the fractal exponents measured for RGC- and their target LGN-spike trains are similar in value, indicating that the fractal behavior either is transmitted form one cell to the other or has a common origin. The gamma-r renewal process model, often used in the analysis of visual-neuron interevent intervals, describes certain short-term features of the RGC and LGN data reasonably well but fails to account for the long-duration correlation. We present a new model for visual-system nerve-spike firings: a gamma-r renewal process whose mean is modulated by fractal binomial noise. This fractal, doubly stochastic point process characterizes the statistical behavior of both RGC and LGN data sets remarkably well.

Animals↗

PubMed1996

Conformal technique dose escalation for prostate cancer: biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen > or = 10 NG/ML.

PURPOSE: Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer. METHODS AND MATERIALS: We report the biochemical freedom from disease (bNED) rates (bNED failure is Prostate Specific Antigen (PSA) > or = 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (< 10, 10-19.9, and > or = 20 ng/ml). Dose was stated to be at the center of the prostate gland. RESULTS: There was significant improvement in bNED survival for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10-19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA > or = 20 ng/ml (p = 0.003 and 0.02, respectively). CONCLUSIONS: Increasing dose above 71 or 73 Gy did not result in improved bNED survival for patients with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in these patients. A significant improvement in bNED survival was noted for patients with pretreatment PSA > or = 10 ng/ml treated above 71 or 73 Gy; further dose escalation studies are warranted.

Aged↗

PubMed1996

Pulmonary function in children treated for rhabdomyosarcoma.

Chemotherapy, radiation therapy, and surgical intervention have markedly improved the survival of patients treated for rhabdomyosarcoma. Unfortunately, the therapy may have deleterious effects on the lung. Pulmonary functions tests were obtained from 17 patients treated for rhabdomyosarcoma because of our concern regarding potential pulmonary dysfunction in this group of patients who had received bleomycin, which is known to be associated with lung injury. Mean age at the time of the diagnosis of rhabdomyosarcoma was 10.1 (+/- 7.2) years (range 0.01-23.5 years). The mean age at the time of pulmonary function testing was 17.0 (+/- 7.5) years (range 5.8-34.0 years). Study patients reportedly had no pulmonary symptoms. Approximately 87% of study patients had a restrictive ventilatory impairment on pulmonary function testing as measured by total lung capacity (TLC) values less than the lower limit of normal. Approximately 70% of study patients had carbon monoxide diffusing capacity (DLCO) values less than the lower limit of normal. There were no significant differences in pulmonary function parameters when male study patients were compared to female study patients. There was a statistically significant lower forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio (P=0.03) and percent predicted forced expiratory flow at 25-75% of the FVC (FEF25-75; P=0.03) in the group of patients diagnosed with rhabdomyosarcoma over 8 years of age as compared to those individuals diagnosed under 8 years of age. In addition, there were no statistically significant differences in pulmonary function when the variables of sex and age at diagnosis (as outlined above) were studied in combination. In summary, we identified a high incidence of restrictive ventilatory abnormalities in a group of individuals (predominantly children) treated for rhabdomyosarcoma as well as a significantly lower FEV1/FVC ratio and percent predicted FEF25-75 in the group of patients diagnosed with the neoplasm over 8 years of age. Individuals caring for such patients are encouraged to obtain pre- and sequential posttreatment pulmonary function tests.

Adolescent↗

PubMed1996

The practice of surgical staging and its impact on adjuvant treatment recommendations in patients with stage I endometrial carcinoma.

A survey of American gynecologic oncologists was undertaken to assess their compliance with current surgical staging criteria in patients with early endometrial carcinoma. One hundred forty-four members of the Society of Gynecologic Oncologists responded to the survey. Respondents treated an average of 22 new cases annually. Tumor grade and intraoperative determination of depth of myometrial invasion were demonstrated to influence the frequency of lymphatic dissection. In grade 1, 2, and 3 lesions, 76, 60, and 34% of responders, respectively, indicated that depth of invasion influenced their decision to perform lymphadenectomy. In addition, depth of invasion was important in determining type and extent of lymphatic resection. Further, the impact of pathologic lymph node status on postoperative adjuvant radiation therapy recommendations was evaluated for various stratifications of endometrial adenocarcinoma confined to the corpus. The greatest differences in treatment recommendations were noted in the 50-66% invasion category. For grade 1 and 2 cancers, adjuvant therapy recommendations were reduced by 23 and 16% respectively when comparing pelvic and combined therapy versus none and vaginal therapy. The effect of surgical staging data on clinical decisions is clearly evident. The knowledge of pathologically negative lymph node status reduces the recommendation for postoperative adjuvant radiotherapy in patients with adenocarcinoma otherwise confined to the uterine corpus.

Chemotherapy, Adjuvant↗

PubMed1996

Tailoring of variability in the lateral geniculate nucleus of the cat.

Variability is usually considered an unwanted component in a sensory signal, yet the visual system does not seem to filter out the noise. On the contrary, noise is 'tailored' to scale with the signal size. We show that this tailoring occurs in the lateral geniculate nucleus, preferentially in X-cells, which are the cells most likely to transmit pattern information. Tailoring the variability to the signal size may be the visual system's way of providing the right amount of variability for a signal of any magnitude at all times during the computation.

Animals↗

PubMed1996

Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.

Iron deficiency may develop in hemodialysis patients, especially when erythropoietin is given. The role of iron deficiency in the anemia of predialysis chronic renal failure (CRF), however, is much less clear. We have intravenously (IV) administered iron as ferric saccharate in a total dose of 200 mg elemental iron monthly for 5 months to 33 CRF patients who remained anemic despite oral iron supplementation and who had no laboratory signs of iron overload. None was receiving erythropoietin therapy. In 22 of the patients there was an increase in the hematocrit values by the end of the study. These patients were considered responders to intravenous iron (IV Fe) therapy. In 11 patients the iron administration was not associated with improvement of the anemia (nonresponders). Before onset of the IV Fe therapy there were no differences between the responders and nonresponders with regard to degree of anemia, serum ferritin, iron saturation, renal function, or blood pressure. One additional patient was excluded from the study because of a mild reaction during an IV test dose before the study. No worsening of kidney function and no other side effects were noted. In four patients (three responders and one nonresponder) the control of blood pressure necessitated antihypertensive drug therapy adjustment. In conclusion, IV Fe supplementation in two thirds of anemic CRF patients not receiving dialysis resulted in a significant improvement of the anemia, thus avoiding the necessity of erythropoietin or blood administration. This could be achieved by increasing the plasma ferritin levels to 200 to 400 microns/L and/or increasing the iron saturation to 25% to 35%. Intravenous ferric saccharate appears to be a safe and effective method of administering iron for the correction of anemia in CRF patients not receiving dialysis.

Administration, Oral↗

PubMed1996

T-cell recognition of residue 158-176 in thyrotropin receptor confers risk for development of thyroid autoimmunity in siblings in a family with Graves' disease.

Twenty-two subjects in a family with Graves' Disease and 20 normal subjects unrelated to the family were examined for T-cell responses to rec h TSHR-ECD and its synthetic peptides. Seven of the family members and none of the controls responded positively to rec h TSHR-ECD. Peptide 158-176 was the only residue that showed a high percentage of response among family members, no responses in spouses, and a significant difference compared to unrelated controls. Family members under age of 6 did not differ from spouses in response to rec h TSHR-ECD or any individual peptide. Family members ages 6-12 years were significantly different from spouses in response to peptides 30-49, 158-176, and 172-186. The reactivity of adult family members including 3 Graves' patients was significantly different from spouses in response to peptides 44-62, 132-150, 158-176, and 248-263. The responses of female members of the family were higher than that of the male members and significantly different for peptide 272-291. These data suggest that recognition of peptide 158-176 may be an early event in the pathogenesis of the disease and that recognition of both 158-176 and 248-263 residues may be the cornerstone for establishment of the disease.

Adolescent↗

PubMed1996

Intravenous ferric saccharate as an iron supplement in dialysis patients.

In the present prospective study we examined the long-term effect of intravenous supplementation with ferric saccharate (IV Fe) in the treatment of the anemia of chronic dialysis patients. All patients, 64 on chronic hemodialysis (HD) and 9 on chronic ambulatory peritoneal dialysis (CAPD), were treated intravenously with this preparation in a dose of 100 mg elemental iron twice monthly. There were five groups. Group 1: 41 HD patients who were receiving erythropoietin (EPO) for at least 6 months prior to the addition of IV Fe. In this group, when IV Fe was given over 6 months, the hematocrit (Hct) increased from a mean of 28.7 to 33.7%. Over the next 6 months, the EPO dose was gradually reduced by a mean of 61.1%, but the mean Hct remained unchanged. Group 2: 11 HD patients who started IV EPO simultaneously with the IV Fe. In this group, over 6 months, the mean Hct increased from 28.1 to 34.1. Over the next 6 months, the EPO dose was gradually reduced by 75.7%, but the mean Hct remained unchanged. Group 3: 12 HD patients who received IV Fe alone for 12 months. The mean Hct increased from 30.5 to 37.9%. Group 4: 4 CAPD patients who had been receiving subcutaneous EPO for at least 6 months prior to IV Fe therapy. Over the subsequent 6 months of IV Fe, the mean Hct increased from 28.4 to 33.3%. Group 5: 5 CAPD patients not on EPO who received IV Fe for 6 months. The mean Hct increased from 27.7 to 35.6%. No adverse effects were seen in any patients throughout the study. In conclusion, adequate Fe supplementation may allow the target Hct of about 33% to be reached without, or with only very low doses of EPO. IV Fe as ferric saccharate is a new and safe form of parenteral iron therapy of the anemia of chronic dialysis patients.

Adult↗

PubMed1995

Contrast sensitivity and spatial frequency response of primate cortical neurons in and around the cytochrome oxidase blobs.

The striate cortex of macaque monkeys contains an array of patches which stain heavily for the enzyme cytochrome oxidase (CO blobs). Cells inside and outside these blobs are often described as belonging to two distinct populations or streams. In order to better understand the function of the CO blobs, we measured the contrast sensitivity and spatial frequency response of single neurons in and around the CO blobs. Density profiles of each blob were assessed using a new quantitative method, and correlations of local CO density with the physiology were noted. We found that the CO density dropped off gradually with distance from blob centers: in a typical blob the CO density dropped from 75% to 25% over 100 microns. Recordings were confined to cortical layers 2/3. Most neurons in these layers have poor contrast sensitivity, similar to that of the parvocellular neurons in the lateral geniculate nucleus. However, in a small proportion of layers 2/3 neurons we found higher contrast sensitivity, similar to that of the magnocellular neurons. These neurons were found to cluster near blob centers. This finding is consistent with (indirect) parvocellular input spread uniformly throughout layers 2/3, and (indirect) magnocellular input focused on CO blobs. We also measured spatial tuning curves for both single units and multiple unit activity. In agreement with other workers we found that the optimal spatial frequencies of cells near blob centers were low (median 2.8 c/deg), while the optimal frequencies of cells in the interblob regions were spread over a wide range of spatial frequencies. The high cut-off spatial frequency of multi-unit activity increased with distance from blob centers. We found no correlation between spatial bandwidth and distance from blob centers. All measured physiological properties varied gradually with distance from CO blob centers. This suggests that the view of blob cells subserving visual functions which are entirely distinct from non-blob cells may have to be reevaluated.

Animals↗

PubMed1995

Receptive fields of P and M ganglion cells across the primate retina.

We studied the receptive field organization and contrast sensitivity of ganglion cells located within the central 80 (radius of 40) deg of the macaque retina. Ganglion cell activity was monitored as synaptic (S) potentials recorded extracellularly in the lateral geniculate nuclei of anesthetized and paralyzed monkeys. Receptive field center and surround regions of magnocellularly-projecting (M) and parvocellularly-projecting (P) cells increase in area with distance from the fovea, with the center radii of M cells being about twice those of neighboring P cells. Peak sensitivities of center and surround regions are inversely proportional to the regions' areas, so that integrated contrast sensitivities (contrast gains) are constant across the visual field, with the gain of M cells being, on average, six times that of P cells. For both M and P cells, the average ratio of surround/center gain is 0.55. Constant gain of P cells across the visual field is achieved by increasing sensitivity to stimuli falling on the peripheral retina to an extent that counteracts the aberrations introduced by the eye's optics.

Animals↗

PubMed1995

Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument.

The FACT-L (version 3) is a 44-item self-report instrument which measures multidimensional quality of life. Available in eight languages, it is currently being used in several Phase II and III lung cancer clinical trials. Reliability and validity of the 33-item version 2 of the FACT-General (FACT-G) have previously been published. This paper reports further validation data on the FACT-G with a subsample of lung cancer patients from the original publication and, more importantly, presents data on the Lung Cancer Subscale (LCS). The nine LCS questions were administered along with the FACT-G to 116 patients with lung cancer. Internal consistency (coefficient alpha) was improved from 0.53 to 0.68 by dropping two questions which were uncorrelated with the others. A subset of 41 patients was tested again at 2 months to evaluate sensitivity to change in performance status rating (PSR) and to obtain estimates of a clinically meaningful change score for the FACT-G and the 7-item LCS. Using a linear test for trend, sensitivity to change in performance status rating (PSR) was obtained with the Total score (P = 0.03), the Physical Well Being (PWB) subscale (P = 0.02), the Functional Well Being (FWB) subscale (P = 0.05), and the LCS (P = 0.03). A 21-item Trial Outcome Index (TOI), combining scores on PWB, FWB and LCS, was highly reliable (coefficient a = 0.89) and sensitive to change in PSR F(1,38) = 4.84 (P = 0.01). This TOI is probably the most relevant and precise indicator of patient-reported quality of life available for lung cancer patients who complete the FACT-L while participating in an oncology clinical trial. The FACT-L may also be of benefit in evaluating quality of life in patients with lung diseases other than cancer.

Adult↗

PubMed1995

Assessment of plutonium exposures in Rongelap and Utirik populations by fission track analysis of urine.

A nuclear device, code-named Bravo, detonated at Bikini Atoll at 6:45 a.m. on 1 March 1954, unexpectedly released a large amount of radioactivity. Over 40 years after this incident, the study of its impact on the radiological health and environmental safety of the residents of Rongelap and Utirik Atolls continues. In 1987, researchers at Brookhaven National Laboratory established a fission track analysis (FTA) method for low-level 239Pu urinalysis. Two years later, a new shipboard protocol was developed for collecting 24-h radiologically clean urine samples. The purpose of this paper is to update information on the FTA method for measuring low-levels of plutonium, and to summarize results on the distribution of 239Pu in the populations of Rongelap and Utirik between 1981-1991. Plutonium detection levels (99% confidence level) in these samples were 2-3 microBq, which is equivalent to 0.2-0.3 mSv effective dose equivalent (EDE) to age 70 for Marshallese. The latest 1991 FTA data indicate average EDE of 0.62 mSv and 1.6 mSv for the people of Rongelap and Utirik, respectively, which both are the highest values since 1988.

Adolescent↗

PubMed1995

Dynamics of neurons in the cat lateral geniculate nucleus: in vivo electrophysiology and computational modeling.

1. We investigated the time domain transformation that thalamocortical relay cells of the cat lateral geniculate nucleus (LGN) perform on their retinal input, and used computational modeling to explore the biophysical properties that determine the dynamics of the LGN relay cells in vivo. 2. We recorded simultaneously the input (S potentials) and output (action potentials) of 50 cat LGN relay cells stimulated by drifting sinusoidal gratings of varying temporal frequency. The temporal modulation transfer functions (TMTFs) of the neurons were derived from these data. The burstiness of the LGN spike trains was also assessed using objective criteria. 3. We found that the form of the TMTF was quite variable among cells, ranging from low-pass to strongly band-pass. The optimal temporal frequency of band-pass neurons was between 2 and 8 Hz. In addition, the TMTF of some cells was nonstationary: their temporal tuning changed with time. 4. The temporal tuning of a cell was directly related to the degree of burstiness of its spike train. Tonically firing relay cells had low-pass TMTFs, whereas the most bursty neurons exhibited the most sharply band-pass transfer functions. This was also true for single cells that altered their temporal tuning: a shift to more band-pass tuning was associated with increased burstiness of the spike train, and vice versa. 5. We constructed a computer simulation of the LGN relay cell. The model was a simplified five-channel version of the thalamocortical neuron model of McCormick and Huguenard. It incorporated the quantitative kinetics of the Ca2+ T channel, as well as the Hodgkin-Huxley Na+ and K+ channels, as the only active membrane currents. To simulate the in vivo dynamics of the relay cell, the input to the model consisted of trains of synaptic potentials, recorded as S potentials in our physiological experiments. 6. When the resting membrane potential of the model neuron was relatively depolarized, the model's TMTF was low-pass, with no bursting evident in the simulated spike train. At hyperpolarized resting membrane potentials, however, the modeled TMTF was band-pass, with frequent burst discharges. Thus the biophysical model reproduced not only the range of dynamics seen in real LGN relay cells, but also the dependence of the overall dynamics on the burstiness of the spike train. However, neither of these phenomena could be simulated without the T channel. Thus the simulations demonstrated that the T-type Ca2+ channel was necessary and sufficient to explain the LGN dynamics observed in physiological experiments.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

T-cell reactivity to recombinant human thyrotropin receptor extracellular domain and thyroglobulin in patients with autoimmune and nonautoimmune thyroid diseases.

Grave's disease and Hashimoto's thyroiditis are common organ-specific disorders characterized by an immune response toward a number of thyroid proteins, including TSH receptor (TSHR), thyroid peroxidase, and thyroglobulin (Tg). Although considerable progress has been made in understanding and mapping the autoantibody response to TSHR, much less is known about recognition of TSHR by pathogenic T-cells in human disease. To identify such reactions, we analyzed the T-cell proliferative responses of peripheral blood lymphocytes (PBMC) to human recombinant TSHR extracellular domain (hrecTSHR-ECD amino acids 19-417) expressed in Escherichia coli and to Tg. Forty-two patients with autoimmune thyroid disease (AITD), 13 patients with non-AITD, and 20 normal subjects were studied. PBMC from 40% of patients with AITD and 46% of patients with non-AITD reacted significantly to hrecTSHR-ECD. The reactivity to Tg was less than that to TSHR-ECD in both groups. Five percent of normal subjects showed a response to hrecTSHR-ECD and none to Tg. TSHR-specific T-cell lines were developed in 16 of 26 AITD patients and 3 of 10 non-AITD patients. CD8-positive T-cell depletion from PBMC of 8 patients with AITD by the indirect panning method did not enhance the reactivity to hrecTSHR-ECD, except in 1 patient. We conclude that TSHR-specific T-cells are present in the circulation of patients with AITD and are presumably involved in the pathogenesis of thyroid autoimmunity. The lower, but positive, reactivity to hrecTSHR-ECD found in patients with non-AITD was unexpected and may be related to lymphocytic infiltrates in the thyroid of 7 of the 11 patients.

Adult↗

PubMed1995

Graves' disease in severe combined immunodeficient mice.

Graves' disease (GD) is an autoimmune thyroid disorder involving an antibody (TSAb) directed against the TSH receptor (TSHR) producing thyroid stimulation. We have developed an animal model of GD by engrafting peripheral blood mononuclear cells or T cell lines plus autologous thyroid tissue into severe combined immunodeficient (SCID) mice. We xenografted Graves' thyroid tissue from six patients into six groups of SCID mice. Autologous PBMC and T cell lines reactive to recombinant human TSHR extracellular domain and non-TSHR lines were injected ip into the designated groups. In some of the studies, thyroid tissue was irradiated with 2000 rads before xenografting. Irradiation of xenografts induced thyroid tissue damage and release of thyroid antigens and hormones. Mice reconstituted with peripheral blood mononuclear cells or nonspecific T cell lines did not simulate GD. However, we achieved production of TSAb, elevation of serum T3, and TSAb-dependent survival and function of human Graves' thyroid tissue in SCID mice reconstituted with TSHR-specific T cell lines. We reconstituted SCID mice with PBMC and TSHR-specific T cell lines that recognized TSHR peptide 158-176. This may be in vivo evidence of the importance of peptide 158-176 as an immunodominant epitope on the TSHR extracellular domain.

Adult↗

PubMed1995

T-cells recognize multiple epitopes in the human thyrotropin receptor extracellular domain.

In Graves' disease (GD), the TSH receptor (TSHR) is believed to be the major target of an autoimmune response. T-Lymphocytes regulate the immune system. To assess the interaction of T-cells with TSHR in the pathogenesis of GD, we tested the T-cell response of peripheral blood mononuclear cells and T-cell lines to the recombinant human TSHR extracellular domain (rhTSHR-ECD) and 31 synthetic peptides corresponding to the entire TSHR-ECD in 20 patients with GD, 8 patients with Hashimoto's thyroiditis, 7 with colloid nodular goiter (CNG), and 20 normal controls. Comparing patients from different groups with normal subjects, there was a significant response to rhTSHR-ECD and thyroglobulin in GD patients (P < 0.001) and HT patients (P < 0.05), but not in CNG patients (P > 0.1). All 20 patients with GD responded to at least one peptide. The reactivity in GD patients was heterogeneous and spanned the entire TSHR-ECD. However, the reactivity was significantly different from that in controls for peptide regions 44-88, 119-176, 227-263, and 343-376, and the stimulation index (SI) values were significantly different for peptides 272-291 and 301-320. Significant differences were confined to peptides 158-176 and 343-362 and the region 227-263 for comparison of the number of positive responses in patients and controls to individual peptides. Forty-six percent of human leukocyte antigen-DQA1 0501 allele-positive Graves' patients responded to peptides 158-176 and 248-263 (SI = 3 or more) compared to 14% of allele-negative patients. In HT and CNG patients, the response was mainly to peptides in the carboxy-terminal half of the TSHR-ECD. Concordance of the reactivity in T-cell lines and peripheral blood mononuclear cells was observed in 36% of direct comparisons in GD. Eighty-five percent and 90% of GD patients were positive for microsomal antibody and TSHR antibody, respectively, and 59% of microsomal antibody-positive and 67% of TSHR antibody-positive patients responded to rhTSHR-ECD (SI = 2 or more). However, there was no significant correlation between antibody-positive patients and reactivity to specific peptides. Using multiple criteria to define immunodominance, peptides 158-176, 237-252, 248-263, and 343-362 seem to be important epitopes and may be critical for T-cell triggering in GD.

Adult↗