Aging in man. Linear increase of a novel T cell subset defined by antiganglioside monoclonal antibody 3G5.

A new human T cell subset defined by antineuronal ganglioside mAb 3G5 increases linearly with advancing age in man. The percentage of circulating 3G5+ T cells in 21 normal individuals, quantitated by cytofluorograph analysis, increases linearly from age 7 (23-30%) to age 84 (58%) (r = 0.85, p less than 0.001). The antigen on T cells has the biochemical properties of a ganglioside that migrates between GM1 and GM2 ganglioside markers on TLC. The 3G5 subset represents the first T cell subset that reflects aging in man.

Aggregation of subclinical autonomic nervous system dysfunction and autoantibodies in families with type I diabetes.

The purpose of our study was to evaluate the occurrence of autonomic nervous system autoantibodies (ANS) in the nondiabetic family members of insulin-dependent (type I) diabetic subjects. We studied 24 families, including 45 nondiabetic parents and 53 nondiabetic siblings of a type I diabetic proband. One hundred one nondiabetic population control subjects were also studied. Stored sera from nondiabetic family members and control subjects were evaluated for the presence of complement-fixing (CF) adrenal medullary antibodies (CF-ADM), sympathetic ganglia antibodies (CF-SG), and vagus nerve antibodies (CF-V) by indirect immunofluorescence. HLA-DR3 and -DR4 typing was performed on 42 nondiabetic family members and 104 diabetic subjects. One or more CF-ANS were in 45 of 93 (40%) nondiabetic family members compared to 2 of 70 (2.8%) control subjects. CF-SG were in 28 of 92 (30%) family members compared to 0 of 101 control subjects (P = 0.0001). CF-V were in 25 of 95 (26%) family members compared to 0 of 76 control subjects (P = 0.0001). CF-ADM were in 10 of 83 (12%) family members compared to 2 of 70 (2.8%) control subjects (P = 0.056). There was no HLA-DR3 or HLA-DR4 association with ANS. Subclinical autonomic dysfunction was demonstrated in 3 of 4 family members with autoantibodies compared to 0 of 4 family members without autoantibodies.

Anti-sympathetic nervous system autoantibodies. Diminished catecholamines with orthostasis.

The etiology of autonomic neuropathy in insulin-dependent diabetes mellitus (IDDM) is unknown. Previous studies have noted the presence of anti-adrenal medullary antibodies in IDDM. Recently, we have also demonstrated the presence of anti-sympathetic ganglia antibodies in IDDM. We initiated a study to evaluate whether subjects with complement-fixing anti-adrenal medullary (CF-ADM) and anti-sympathetic ganglia (CF-SG) antibodies have a decreased catecholamine response to change in posture. Seven IDDM subjects aged 19-41 yr with duration of disease 5-21 yr at the time of the posture study were evaluated. Serums collected longitudinally were evaluated for the presence of CF-ADM and CF-SG antibodies. Three IDDM subjects were CF-ADM- and CF-SG- at all testing intervals (Ab- group). Four IDDM subjects were CF-ADM+ and/or CF-SG+ on at least one testing date (Ab+ group). Baseline mean norepinephrine and epinephrine levels were not significantly different in Ab+ and Ab- subjects. Norepinephrine levels 5 min after standing were mean +/- SD 227 +/- 16 and 419 +/- 48 pg/ml for Ab+ and Ab- subjects, respectively (P less than .03). The means of the 5-min minus basal norepinephrine levels were 88 +/- 42 (Ab+) and 207 +/- 26 (Ab-) pg/ml (P less than .03). Mean epinephrine levels after 5 min of standing were 35 +/- 16 (Ab+) and 101 +/- 44 (Ab-) pg/ml (P less than .03). The means of the 5-min minus basal epinephrine levels were 1 +/- 5 (Ab+) and 43 +/- 38 (Ab-) pg/ml (P less than .03).(ABSTRACT TRUNCATED AT 250 WORDS)

Complement-fixing antibodies to sympathetic and parasympathetic tissues in IDDM. Autonomic brake index and heart-rate variation.

We describe herein complement-fixing anti-adrenal medullary (CF-ADM) and anti-sympathetic ganglia (CF-SG) antibodies in insulin-dependent diabetes mellitus (IDDM). This study describes complement-fixing anti-vagus (CF-V) nerve antibodies and their relationship to the cardiovascular autonomic brake index (a measure of transient decrease in heart rate during the 1st min after a tilt), and R-R interval variation with deep breathing. CF-V was detectable in 7 of 83 (8.4%) subjects with IDDM aged 1.5-65.5 yr (mean +/- SE 28.7 +/- 1.8 yr) and duration of diabetes 0-47 yr (11.8 +/- 1.4 yr). Seventy-six nondiabetic subjects (aged 10-65 yr) all had negative CF-V scores. CF-V scores correlated with CF-ADM (0-16 yr of IDDM, r = 0.61, P less than 0.0001) and CF-SG (r = 0.39, P less than 0.05). Seventy IDDM subjects (aged 28 +/- 5 yr, duration of diabetes 17 +/- 3 yr) without proteinuria or proliferative retinopathy were screened for CF-ADM, CF-SG, and CF-V antibodies. Five of 70 (7.1%) had CF-SG only (negative for CF-ADM and CF-V). Brake indices ranged from 14.7 to 51.3 (37.3 +/- 6.9). Three of 70 (4.2%) had CF-ADM only, with brake indices from 26.9 to 45.1 (32.9 +/- 6.1). Four of 70 (5.7%) had CF-V antibodies only, with brake indices of 12.7-17.3 (15.1 +/- 1.1). Subjects with CF-SG or CF-ADM (anti-sympathetic) had higher brake indices than subjects with CF-V (anti-parasympathetic) antibodies (P less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-adrenal medullary antibodies in IDDM subjects and subjects at high risk of developing IDDM.

Previous reports have noted the presence of anti-adrenomedullary antibodies in subjects with insulin-dependent diabetes mellitus (IDDM). We initiated a study to evaluate the presence of complement-fixing anti-adrenomedullary antibodies (CF-ADM) in the following subjects: group 1 (age 4-60 yr), anti-islet cell antibody-positive (ICA+) subjects at high risk of developing diabetes, in which 9 (32%) of 28 were positive for CF-ADM; group 2 (age 6-41 yr), anti-ICA negative (ICA-) subjects at high risk of developing diabetes, in which 0 (0%) of 15 were positive for CF-ADM; group 3 (age 1-58 yr), ICA+ diabetic subjects, in which 7 (30%) of 23 were positive for CF-ADM; group 4 (age 5-68 yr), ICA- diabetic subjects, in which 1 (4%) of 24 was positive for CF-ADM; group 5 (age 20-56 yr), volunteer blood bank donor controls, in which 2 (6%) of 32 were positive for CF-ADM; and group 6, known healthy controls, in which 0 (0%) of 14 were positive for CF-ADM. CF-ADM were increased in group 1 compared with group 2 (P less than .02) and both control groups (P less than .02). CF-ADM were increased in group 3 compared with group 4 (P less than .03) and both control groups (P less than .03 vs. group 5, P less than .05 vs. group 6). Presence of CF-ADM was associated with presence of ICA in group 1 (P less than .02) and group 3 (P less than .03).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal medullary fibrosis in IDDM of long duration.

We conducted a retrospective pathology study to determine whether subjects with long-standing insulin-dependent diabetes mellitus (IDDM) have abnormalities of the adrenal medulla compared with subjects with non-insulin-dependent diabetes mellitus (NIDDM) and nondiabetic individuals. Slides were scored from 0 (no fibrosis) to 3+ (complete fibrosis). Nineteen IDDM subjects aged 30-60 yr (mean +/- SE 44.9 +/- 2.5 yr) at autopsy and with duration of diabetes 13-45 yr (26.8 +/- 1.8 yr) were studied. Twelve NIDDM subjects aged 61-84 yr (73.3 +/- 2.5 yr) with duration of diabetes 17-33 yr (22.8 +/- 1.9 yr) were studied. Twenty-two nondiabetic subjects aged 32-77 yr (53.7 +/- 2.9 yr) were studied. Four of 19 (27%) IDDM subjects had moderate to severe fibrosis compared to 1 of 12 (8.3%) NIDDM subjects and 1 of 22 (4.5%) control subjects. Thirteen of 19 (68%) IDDM subjects had a score of 1, 2, or 3 compared to 3 of 22 (13.6%) control subjects (P less than .0005). There was an association between duration of IDDM and fibrosis score (r = .46, P less than .05) and between age and fibrosis score among IDDM subjects (r = .57, P = .01). No association between age or duration of diabetes and fibrosis score was observed for NIDDM or control subjects. Adrenal medullary fibrosis may be an anatomical correlate of the diminished epinephrine secretion that occurs in response to insulin-induced hypoglycemia in some IDDM subjects.

Anti-sympathetic ganglia antibodies and postural blood pressure in IDDM subjects of varying duration and patients at high risk of developing IDDM.

We examined the sera of 94 subjects with insulin-dependent diabetes mellitus (IDDM) for the presence of complement-fixing sympathetic ganglia (CF-SG) antibodies. In a cross-sectional analysis (duration 0-43 yr), 22% had detectable CF-SG antibodies. Subjects at high risk for IDDM were also studied. Four groups were studied: group 1 (aged 4-64 yr) islet cell antibody-positive (ICA+) prediabetic subjects, 10 of 19 (53%) were CF-SG+; group 2 (aged 6-14 yr) ICA- prediabetic subjects (first-degree relatives of IDDM subjects with either transient hyperglycemia, impaired oral glucose tolerance, and/or first-phase insulin release after intravenous glucose tolerance testing), 4 of 9 (44%) were CF-SG+ (2 of the 4 ICA- CF-SG+ subjects have progressed to IDDM); group 3 (aged 1.5-43 yr) ICA+ IDDM subjects (less than or equal to 1 yr duration) 6 of 10 (60%) were CF-SG+; and group 4 (aged 8-59 yr) ICA- IDDM subjects (less than or equal to 1 yr duration), 2 of 11 (18%) were CF-SG+. All groups had increased CF-SG compared with controls. Postural blood pressure and simultaneous CF-SG antibody measurements were performed in 28 IDDM subjects. The drop in systolic blood pressure was greater in the CF-SG+ subjects (P less than .05), and the frequency of CF-SG was greater in the mean to -2SD group (P less than .03) when data were analyzed within mean +/- 2SD of the normal blood pressure response.

beta-Endorphin stimulates plasma renin and aldosterone release in normal human subjects.

To determine the effect of beta-endorphin on the renin-angiotensin-aldosterone system, human synthetic beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg X min) was infused iv in normal subjects. Each dose was administered for 30 min, and a control infusion of 5% dextrose and water was given on another day. Ten subjects were studied recumbent and in balance while ingesting a 10-meq Na+ diet. Plasma renin activity (PRA), plasma aldosterone (PA), and plasma cortisol (F) were measured basally and every 30 min for 210 min. The increments in PRA and PA above basal significantly (P less than 0.05) increased (3.1 +/- 1.2 ng/ml X h and 12.2 +/- 5.3 ng/dl, respectively; P less than 0.05) at the end of the beta-endorphin infusion. beta-Endorphin also significantly (P less than 0.01) suppressed F levels. Since in the low salt study, beta-endorphin suppressed F release while stimulating renin secretion, an additional five subjects were pretreated with dexamethasone (0.5 mg every 6 h) and were studied in balance while ingesting a 200-meq Na+ diet to suppress the renin-angiotensin system. Significant (P less than 0.025) increments in PRA (2.1 +/- 0.7 ng/ml X h) and PA (4.1 +/- 1.7 ng/dl) levels above basal were again found during the sequential dose infusion of beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg X min). However, PA elevations were sustained for at least 120 min after the beta-endorphin infusion was stopped despite a drop in PRA 90 min earlier. In additional studies, an attempt was made to define the minimal effective dose of beta-endorphin by 60-min infusions (0.03, 0.1, and 0.3 micrograms/kg X min) in subjects on a 200-meq Na+ diet who were dexamethasone pretreated. The PRA and PA levels rose significantly (P less than 0.05) above basal at the 0.3 micrograms/kg X min dose, but not at the 0.03 or 0.1 micrograms/kg X min dosage levels. There were no changes in blood pressure or potassium during either the 10 or 200-meq Na+ studies. Thus, beta-endorphin stimulates aldosterone release in vivo. However, the underlying mechanisms are complex, since renin levels also increased. The data suggest that the early aldosterone rise may be secondary to an increase in renin release, but renin cannot account for the sustained postinfusion elevations of aldosterone.

Adrenal medullitis in type I diabetes.

To investigate whether cell-mediated immunity against the adrenal medulla occurs in type I diabetes (IDDM), we conducted a retrospective autopsy study of adrenal glands from IDDM and nondiabetic subjects using formalin-fixed tissue. Forty-four IDDM subjects, aged 4-67 yrs (mean +/- SD, 44.8 +/- 15.4) with a duration of IDDM from 0-55 yr (28.6 +/- 14.2), and 29 nondiabetic controls, aged 8-82 yr (51.8 +/- 18.6), were evaluated for a lymphocytic infiltrate using UCHL1, which recognizes a subpopulation of resting T-lymphocytes and most activated T-lymphocytes. Immunohistochemistry using antihuman B-cell antibody (L26) was also performed. Sections were scored for both lymphocytic infiltrates and fibrosis [none (0), small (1), moderate (2), or large (3)]. Blinded scoring was performed. A moderate to severe UCHL1 infiltrate was present in 9 of 44 (20%) IDDM, compared with 1 of 29 (3%) control subjects (P less than 0.04). Mild to severe fibrosis (score 1, 2, or 3) was present in 22 of 42 (52%) IDDM subjects compared with 4 of 25 (16%) control subjects (P = 0.003). Eight of 42 (19%) IDDM subjects had moderate to severe fibrosis (score 2 or 3) compared with 1 of 25 (4%) control subjects. Seventeen of 44 (39%) IDDM subjects had either a moderate to large cellular infiltrate or moderate to severe adrenal medullary fibrosis compared with 2 of 29 (7%) control subjects (P = 0.003). Staining of the adrenal medulla with L26 revealed a large cellular infiltrate in only one subject who was UCHL1 negative. Adrenal medullitis was observed in 20% of IDDM subjects, suggesting that the adrenal medulla may be another immunological target in IDDM.

Renin suppression by saline is blunted in nonmodulating essential hypertension.

We have reported that 50% of subjects with normal renin essential hypertension have both delayed suppression of the renin-angiotensin-aldosterone axis following sodium infusion and a delayed rate of excretion of an acute salt load. In another study we have also described a subset of patients with essential hypertension (called nonmodulators) who have several abnormalities, including a pressor response to salt loading. To evaluate whether the abnormalities described in these different groups of patients actually occur in the same patient, we assessed the renin-angiotensin-aldosterone axis response to short-term saline loading in 38 hypertensive patients. Their ability to modulate was determined by their renal vascular response to infused angiotensin II on a high salt diet (200 mEq Na). In response to a 3-hour infusion of saline, 75 mEq/hr, the reduction in plasma renin activity at both 60 and 120 minutes was significantly greater (p less than 0.008) in patients with normal modulation than in the nonmodulators. Plasma aldosterone levels were also significantly lower (p less than 0.001) in those with intact modulation. Thus, nonmodulating essential hypertensive patients have abnormalities in several systems that influence sodium homeostasis, including altered adrenal and renal vascular response to angiotensin II, altered renal blood flow response to salt loading, and a delayed suppression of the renin-angiotensin-aldosterone system with short-term saline infusion.

Congenital rubella. Monoclonal antibody-defined T cell abnormalities in young adults.

In order to determine if congenital rubella infection is associated with persistent T cell abnormalities, T cell subsets were quantitated in 16 non-institutionalized subjects (ages nine to 21) with the clinical stigmata and history of congenital rubella. Flow cytometric analysis revealed a decreased T4/T8 ratio (mean +/- SEM in subjects with rubella, 1.57 +/- 0.15, p less than 0.01; in normal subjects, 2.3 +/- 0.4; in subjects with type I diabetes, 2.3 +/- 0.3), decreased percent of T4-positive "helper" cells (42.6 +/- 2.3) different from that in both normal subjects (52.6 +/- 2.4, p less than 0.01) and subjects with recent-onset diabetes (51.5 +/- 2.4), and increased percent of T8-positive "suppressor/cytotoxic" T cells (29.9 +/- 1.4, p less than 0.02) relative to that in normal subjects (24.2 +/- 1.5) and subjects with type I diabetes (23.9 +/- 1.4). Five of 16 subjects with congenital rubella had an elevation of la-positive T cells. Approximately 20 percent had antimicrosomal antibodies. One subject had diabetes mellitus and hypothyroidism, one had hypoglobulinemia, and one had previously undiagnosed hyperthyroidism. Glycosylated hemoglobin levels were normal in all except the diabetic subject, and none of the subjects was islet cell antibody-positive. The T cell abnormalities documented may predispose persons with congenital rubella to the development of organ-specific autoimmunity.

Lymphocyte dysfunction in autoimmune oophoritis. Resumption of menses with corticosteroids.

In a 32-year-old woman with secondary amenorrhea and biopsy-proven oophoritis, the circulating T lymphocytes were examined utilizing monoclonal antibody L243 to the nonpolymorphic region of the Ia antigen. The percentage of peripheral T cells expressing the Ia "immune-associated' antigen was 5.6 percent (normal 3 percent or less). With corticosteroid therapy, the percentage decreased to 2 percent and menses resumed after secondary amenorrhea of two years' duration. Following cessation of steroid administration, the percentage of Ia-positive T cells rose to 7.0 percent and secondary amenorrhea redeveloped in the patient. After corticosteroid therapy was reinstituted, menses resumed and the percentage of Ia-positive T cells fell to normal. This report represents additional new evidence of immune dysfunction in patients with "autoimmune" oophoritis.

Ia-positive T lymphocytes in recently diagnosed idiopathic Addison's disease.

The Ia (DR, immune-associated) antigen is absent on normal circulating T lymphocytes, but present on activated T lymphocytes. Utilizing monoclonal antibody L243, the expression of this glycoprotein on circulating T lymphocytes was studied in five patients with recent-onset idiopathic Addison's disease, one patient with recent-onset adrenal hemorrhage, and nine patients with long-standing adrenal insufficiency (five with idiopathic Addison's disease and four after bilateral adrenalectomy for Cushing's disease). The patient with adrenal hemorrhage and the nine patients with long-standing adrenal insufficiency had percentages of circulating Ia-positive T cells within the normal range. All five patients with recent-onset idiopathic Addison's disease had an elevated percentage of circulating Ia-positive T cells (7 to 29 percent). The expression of Ia antigen on T cells in recent-onset idiopathic Addison's disease probably reflects immunologic activation, which may be of pathophysiologic importance.

Amiodarone therapy and autoimmune thyroid disease. Increase in a new monoclonal antibody-defined T cell subset.

T cell subsets in 10 patients receiving amiodarone were evaluated, and their thyroid function and antithyroid antibodies were assessed. A generalized increase in a recently discovered subset of T cells expressing a complex ganglioside antigen reacting with monoclonal antibody 3G5 was found. Two patients, one with hyperthyroidism and the other with euthyroid Graves' ophthalmopathy, had an additional T cell abnormality--marked increase in Ia-positive T cells (an abnormality typical of patients with spontaneous Graves' disease). In the hyperthyroid patient, the Ia-positive T cells disappeared within three weeks after amiodarone was discontinued. The other patients receiving amiodarone had normal numbers of Ia-positive T cells. These studies indicate that amiodarone alters a major resting T cell subset for almost all patients and is associated with T cells expressing the Ia antigen in selected patients. These T cell abnormalities suggest that amiodarone precipitates organ-specific autoimmunity in susceptible persons.

Does subclinical hypothyroidism explain the increased susceptibility of women to torsades de pointes?

Among 20 consecutive patients (65% women) with drug-associated torsades de pointes, chemical evidence for hypothyroidism was found in only 10% of both women and men. Subclinical hypothyroidism is therefore unlikely to account for the consistently observed sex difference in the propensity to torsades de pointes.

POEMS syndrome with myocardial infarction: observations concerning pathogenesis and review of the literature.

A 27-year-old white man with no significant risk factors for coronary artery disease presented with a 9-month history of progressive impotence, gynecomastia, lower extremity paresthesias, and extensive myocardial infarction and subsequently developed ulcerative proctitis. A diagnosis of POEMS syndrome was made based on the clinical presentation; additional physical findings of papilledema, clubbing, and hyperpigmentation; and laboratory findings of an immunoglobulin G M component of the lambda subtype, elevated cerebrospinal fluid protein, and typical sclerotic bone lesions. Abnormal in vitro binding of the patient's serum immunoglobulin to testicular tissue was also seen. Cardiac catheterization showed evidence of diffuse coronary artery narrowing and left ventricular wall motion abnormalities. Diffuse coronary involvement and ulcerative proctitis have not been previously described in POEMS syndrome. It is hypothesized that an abnormal immunoglobin (or fragment) is responsible for both findings. Furthermore, the detection of antitesticular autoantibodies suggests the possibility of an interaction between the antibody and Leydig cells, leading to an alteration in the synthesis and release of sex steroids and thereby explaining the gonadal failure seen in this syndrome. Long-term glucocorticoid therapy for the past 5 years has resulted in marked subjective and objective improvement.

Premature menopause: monoclonal antibody defined T lymphocyte abnormalities and antiovarian antibodies.

The presence of other organ-specific autoimmune disorders in some patients with premature menopause has supported the concept of an autoimmune etiology. The authors analyzed the peripheral blood of 23 women with the diagnosis of premature menopause to detect the presence of monoclonal antibody-defined T-lymphocyte abnormalities and/or antiovarian antibodies. All subjects were less than 40 years of age with the duration of menopause ranging from less than 1 year to 11 years at the time of study. Thirty-five percent of the subjects had an elevated percentage of Ia+ (Dr-activated) T cells using monoclonal antibody L243. The percent T4 (helper) T8 (suppressor/cytotoxic) T cells and T4/T8 ratio were normal in the study group. Four subjects (approximately 17%) had elevated percentages of the age-related 3G5+ T cell subset. Two of the subjects with increased 3G5+ T cells also exhibited increased Ia+ T cells. Antiovarian steroid cell antibodies and antiadrenal cortical antibodies were present in approximately 9% of subjects. Anti-islet cell antibodies were not present. Thyroid antimicrosomal antibodies were present in 17% of subjects. Study subjects exhibited immunologic abnormalities that the authors hypothesize may play a role in the development of premature menopause in a larger percentage of patients than was previously suspected.

Type I diabetes mellitus: a chronic autoimmune disease?

Currently defined categories of diabetes mellitus reflect our growing knowledge of the biochemical and immunologic basis of several disorders resulting in hyperglycemia. The authors discuss the autoimmune phenomenon and autoimmune diseases associated with Type I diabetes mellitus. Special focus is placed on the impact of immunologic assays on the current and future clinical care of patients with Type I diabetes and their genetically susceptible relatives.

Polyglandular autoimmunity.

Although target tissues or glands differ, several common threads have begun to emerge that link the diseases of the autoimmune endocrine syndromes. In the polyglandular syndrome type II, a defect resides in one of the genes of the major histocompatibility locus which, in concert with other gene(s), results in susceptibility. Genetic susceptibility is necessary but not sufficient to produce the disorder. This is illustrated by the lack of 100% concordance of disease in identical twins. This lack of concordance has led to the search for environmental influences or "triggers" of the autoimmune process. These "triggers" have not been well defined, but may include amiodarone or other iodine-containing medications for thyroid autoimmunity and congenital rubella for some patients with diabetes and thyroiditis. The autoimmune destruction of most target glands appears to be a slow process with a long preclinical prodrome that may last for years. During this period, autoantibodies, lymphocyte abnormalities, and subclinical endocrine defects are usually present. As knowledge of target antigens has progressed, it appears that despite polyendocrine disease, within each gland specific antigens are the targets of the autoimmune process. When the genetic defect(s) and environmental influences of organ specific autoimmunity are better understood, it may be possible to devise specific "replacement" or corrective therapies. In the absence of this knowledge, therapies directed at partial immunosuppression are currently being studied in Type I diabetes and Graves' ophthalmopathy. Given the similar features of many of the organ-specific autoimmune disorders, it is likely that if immunotherapeutic modalities are successful in one disease, they may be of benefit in related disorders.

Type I diabetes as a chronic autoimmune disease.

The realization that Type I diabetes is an autoimmune disease and, in particular, a chronic autoimmune disease is beginning to impact on clinical care and research directed at elucidating the cause and prevention of diabetes. For example, specialized laboratory evaluation can now be used to exclude potential renal donors who are at high risk of developing diabetes (by screening renal donor candidates who are relatives of Type 1 diabetics for cytoplasmic islet cell antibodies and evaluating first phase insulin secretion on intravenous glucose tolerance testing). The most important long-term consequence of the ability to predict Type 1 diabetes may be the development of effective immunotherapy to prevent the disease. Finally, the realization that Type 1 diabetes is an auto-immune disease and that some of the antigens expressed by islets (e.g., specific gangliosides identified with monoclonal antibodies) are expressed by renal glomerular cells, retinal microvascular pericytes, and neurons has renewed interest in searching for immunologic factors contributing to secondary complications.