Seroconversion of reticulin autoantibodies predicts coeliac disease in insulin dependent diabetes mellitus.

Serum IgA class reticulin autoantibody test was performed prospectively once a year on 238 children and adolescents with insulin dependent diabetes mellitus (IDDM). At the initial testing, within one year after onset of IDDM, five were positive and 233 were negative. During follow up a further 11 of the initially antibody negative children became positive (6.7%). Jejunal biopsy was performed at the appearance of the autoantibodies and silent coeliac disease was shown in nine (3.8%). One of these children showed on initial biopsy after the onset of IDDM to have normal jejunal mucosal architecture deteriorating later to a flat lesion. Jejunal immunohistochemical studies of another of the patients positive for reticulin autoantibodies but normal on routine biopsy showed an increased density of intraepithelially located gamma/delta T cells and aberrant HLA-DR expression in the crypts pointing to ongoing mucosal inflammation and potential coeliac disease. This study shows that in IDDM patients, reticulin autoantibody negative subjects become antibody positive, which may be followed by coeliac disease. Repeated serological screening and rebiopsy should be considered to detect late developing clinically silent coeliac disease among patients with IDDM.

Apolipoprotein E phenotypes and plasma lipids in diabetic children and adolescents.

Apolipoprotein E (apoE) polymorphism is a genetic determinant of serum lipoprotein levels and coronary heart disease risk. ApoE appears in three major isoforms E2, E3 and E4, coded by corresponding alleles epsilon 2, epsilon 3 and epsilon 4. These give six different phenotypes. Patients with insulin dependent diabetes (IDDM) have been reported to have increased incidence of E2/2 homozygosity. We studied the frequencies of apoE phenotypes and their association with plasma lipids in 201 diabetic children, aged 2-17 years, and in 216 healthy controls with the same age range. Phenotyping was performed directly from plasma by iso-electric focusing and immunoblotting. Plasma total and high density lipoprotein (HDL) cholesterol (C) and triglycerides were determined by routine laboratory methods. Apolipoprotein A1 (apoA1) and B (apoB) were measured by turbidometry. There were no differences in apoE phenotype or allele distributions between the diabetic and control subjects. The frequencies of epsilon 2, epsilon 3, and epsilon 4 in the diabetic and control children were 0.08 versus 0.07, 0.73 versus 0.72 and 0.19 versus 0.21. The difference in apoE2/2 frequencies (2.0 in diabetic and 0.5% in normal children) was not statistically significant. In the diabetic children, there was a distinct relation between apoE phenotype and plasma lipids; presence of apoE2 was associated with the lowest and that of apoE4 with the highest concentrations of total and low density lipoprotein (LDL) C, and apoB. Ratios of HDL-C/LDL-C and apoA1/apoB showed on opposite trend. The influence of apoE polymorphism on plasma lipids was less clear in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Defective HLA class II expression in monocytes of type 1 diabetic patients. The Childhood Diabetes in Finland Study Group.

Activation of T-helper cells is modulated by the intensity of HLA class II expression on antigen-presenting cells. We evaluated whether any abnormalities could be found in the expression of HLA-DR and -DQ molecules on monocytes in type 1 diabetic subjects. DR and DQ molecules were induced by human recombinant interferon-gamma on cultured peripheral blood monocytes obtained from children with type 1 diabetes (N = 28), their siblings (N = 18) and unrelated healthy controls (N = 21). The response in DQ induction varied considerably between different individuals, but the average responsiveness was significantly lower in patients compared to siblings and unrelated controls. In addition to the diabetic subjects deficient DQ induction was also observed in three siblings. One of them had high levels of islet cell antibodies and presented with diabetes 6 months later, and another had active rheumatoid arthritis. The response in DR induction was also slightly lower in patients than in siblings, but did not differ from that in unrelated controls. The results suggest abnormalities in the regulation of HLA class II expression in type 1 diabetic subjects possibly reflecting the ongoing autoimmune process.

Decreased antibody reactivity to Epstein-Barr virus capsid antigen in type 1 (insulin-dependent) diabetes mellitus.

In this study, antibody levels to Epstein-Barr virus (EBV) capsid antigen (VCA) and EBV early antigens (EA) were analysed by enzyme immunoassay in 54 newly diagnosed type 1 diabetic children and in matched controls. The patients had significantly lower EBV VCA IgG-class antibody levels (p less than 0.02). This was true particularly in young patients and in boys (p less than 0.005). VCA IgA-class antibody levels were also decreased in young patients (p less than 0.02). VCA IgM-class antibodies were observed in two of the patients only. IgG- and IgA-class antibodies to EBV EA or rubella virus antigen showed no differences between patients and controls. The results suggest that EBV infections coincide with the onset of clinical diabetes relatively rarely. However, the abnormally low antibody response to EBV VCA in diabetic children suggests abnormalities in the EBV-specific immune response.

Suppression of autologous mixed leukocyte reaction in type 1 diabetes mellitus by in vivo-activated T lymphocytes.

In vivo-activated interleukin 2 receptor-positive T lymphocytes (Tac cells) are demonstrable and the autologous mixed leukocyte reaction (AMLR) is impaired in several autoimmune diseases, including type 1 insulin-dependent diabetes mellitus (IDDM). We investigated AMLR in greater detail, together with possible relationships between AMLR and Tac lymphocytes in IDDM. Coculture experiments with HLA identical patient-healthy sibling pairs revealed that both responder and stimulator cells of diabetic patients function abnormally in AMLR. Suppressive Tac lymphocytes among responder T cells seemed to impair their proliferation. The removal of Tac cells by immunomagnetic beads led to a striking enhancement of proliferation, while the restoration of AMLR cultures with enriched Tac cells was accompanied by a diminished response. The reasons for the poor stimulatory capacity of patient cells are at present unknown but may be due to altered function and/or structure of HLA-DR molecules.

Mumps infections in the etiology of type 1 (insulin-dependent) diabetes.

The epidemiology of Type 1 (insulin-dependent) diabetes was studied during a period starting after an unusually sharp epidemic of mumps. The number of diabetic cases increased significantly 2-4 years after the epidemic. Incidence rates were highest in geographical areas with the highest incidence of mumps and lowest in areas with the smallest numbers of reported mumps cases. Serological studies employing EIA-assays indicated recent mumps infections more often among newly diagnosed diabetic children than among matched controls although the incidence was low (13% of patients and 4% of controls had serological markers of recent mumps). Those patients, who had had serologically verified recent mumps had more often HLA-DR4 associated risk antigens (Dw4 and Dw14) than other patients. Also clinical history of mumps was obtained more often from diabetic children than from controls as 27% of the patients and 14% of the controls had had clinical mumps during the five years preceding the diagnosis of diabetes. These results confirm several earlier reports suggesting a connection between mumps and Type 1 diabetes and that the onset of diabetes may be delayed by several years.

Defective autologous mixed leukocyte reaction in newly diagnosed type 1 diabetes mellitus.

We studied autologous mixed leukocyte reaction (AMLR) in type 1 (insulin-dependent) diabetes mellitus (IDDM) patients, their healthy siblings and healthy schoolchildren, Blood samples from the patients were drawn within 1 week after hospitalization and 2 months later. AMLR was significantly depressed in the patients when compared to healthy siblings or other healthy controls. In addition, the mean AMLR responsiveness of the healthy control group exceeded that of healthy siblings. The production of IL-2 in AMLR was impaired in the patient group and the defective AMLR could be restored by addition of exogenous IL-2 in 7-10 patient cultures. However, in 3-10 patients addition of IL-2 induced no enhancement of proliferation. While the patients in general had raised levels of activated T lymphocytes these three patients had higher numbers of activated T cells than other patients. Defective AMLR and presence of activated T cells may be related and may play a role in the pathogenesis of IDDM.

Visible corneal nerve fibers and neuromas of the conjunctiva--a syndrome of type-3 multiple endocrine adenomatosis in two generations.

A case report of multiple mucosal neuroma syndrome (multiple endocrine adenomatosis type 3) is presented in a mother and her two children. In all of them the eye involvement consisted of highly visible corneal nerves, neuromas of the conjunctiva, and thickened eye lids. The mother had mucosal neuromas of the tongue, and in the 4-year-old girl these were seen to appear during the follow-up period. The mother and children had medullary carcinoma of the thyroid. Marfanoid physiognomy was also one characteristic clinical feature.

Humoral immunity against viral antigens in type 1 diabetes: altered IgA-class immune response against Coxsackie B4 virus.

A group of 210 pediatric Type 1 diabetic patients with long duration of illness and their matched controls (age range 2-19 years) were analysed for Coxsackie B4 antibodies in IgG-, IgM- and IgA-antibody classes by enzyme-linked immunosorbent assay (ELISA). About 60% of both patients and controls were seropositive. However, patients had higher prevalence and mean levels of IgA-class antibodies compared to controls. No such difference was found in IgG- or IgM-antibody classes. The elevation of IgA-class antibody levels was evident early after the Coxsackie B4 infection and seemed to persist for several years. IgA-class antibody levels did not differ between sexes in either patients or controls. The elevated levels of IgA-antibodies against Coxsackie B4 virus did not correlate with the elevated IgA antibodies against mumps virus, which served as control antigens. Thus it seems that in IDDM patients the abnormal IgA response against both Coxsackie B4 and mumps virus is antigen-specific.

Metabolic control in adolescent insulin-dependent diabetics referred from pediatric to adult clinic.

The metabolic control of 61 consecutive cases of adolescent diabetes was followed 1 year before and 1 year after the patients were referred from a pediatric to adult clinic. The level of control of the disease was determined by measurements of haemoglobin A1 made on visits to the out-patient clinic. No significant deterioration of the disease was noted on the first visit to the adult clinic. Boys and patients with a shorter disease history coped better with the transition period. During the first year of treatment at the adult clinic the metabolic control of the disease improved significantly (p less than 0.001). Girls and diabetics with a long disease history should be well-prepared for referral to adult clinics.

Humoral immunity against viral antigens in insulin-dependent diabetes mellitus (IDDM): altered IgA class immune response against mumps virus.

Two hundred and ten pediatric IDDM patients with long duration of illness and their matched controls (age range 2-19 years) were analysed for mumps antibodies in IgG, IgM and IgA antibody classes by enzyme linked immunosorbent assay (ELISA). About 70% of both patients and controls had antibodies against mumps virus. However, IDDM patients had higher mean levels of IgA class antibodies than the controls, while no difference was found in IgG or IgM class antibodies. The elevated IgA class mumps antibodies did not correlate with elevated levels of IgA class Coxsackie B4 or cytomegalovirus antibodies. This elevation of IgA antibody levels was evident already early after mumps infection and seemed to persist several years, since the difference was most pronounced in the oldest age group. Female patients as well as female controls had significantly higher IgG and IgM antibody levels compared to males. This may at least in part be explained by a difference in the age distribution in females compared to males and may suggest different age-dependent epidemiology of mumps between boys and girls in this material. No such difference was found in IgA levels between the sexes.

Increased prevalence of coeliac disease in diabetes.

A total of 215 diabetic children were screened for coeliac disease by determination of class specific serum reticulin antibody. Nine children were positive for reticulin antibody and all underwent biopsy of the small intestine. Four new cases of coeliac disease were found; all of these children had IgA reticulin antibody. Two of three other children with a low titre of IgA reticulin antibody had partial villous atrophy. It was concluded that IgA class reticulin antibody was a good marker of coeliac disease in diabetic children. The prevalence of coeliac disease in these children was 1:43 (including one previously diagnosed case) and we suggest that diabetic children be screened routinely for reticulin antibody.

A follow-up EEG study in diabetic children.

498 electroencephalograms (EEGs) were recorded from 195 diabetic children during a follow-up study. The children were divided into stable and labile groups according to diabetes control. The labile group was further subdivided into hypoglycaemic, ketoacidotic and mixed groups. In general it was found that the labile children had significantly more abnormal findings in their EEGs than the stable children, as expected. This applied particularly to generalized discharges with spikes and sharp waves or focal findings, but not to cases with only a diffuse-slowing. Nonstatistical differences in EEG abnormality were seen between the hypoglycaemic and ketoacidotic group--an unexpected finding. During the follow-up the labile group more often had an increasing EEG abnormality than the stable group. For those children who had an EEG abnormality but without an increasing tendency, there was no difference in the EEGs between the labile and stable children. It was concluded tht some of the EEG abnormalities are acquired, and apparently produced by a metabolic disturbance caused by diabetes. However, other causes may be of genetic or perinatal origin, or perhaps a combination of different causes. Because of the multifactorial aetiology of the abnormalities, EEG cannot at present be recommended for routine testing of the effects of metabolic disturbance in diabetics.