Serum levels of recently discovered circulating forms of adhesion molecules, ICAM-1 and L-selectin, were found to be elevated in IDDM patients and in subjects at risk for developing IDDM compared with 100 normal, nondiabetic blood donors. Both adhesion molecules were determined by sandwich ELISA. Serum concentrations of either clCAM-1 or cL-selectin were >2SD of normal mean in 10 of 14 recent-onset IDDM patients (P < 0.05). Serum levels of clCAM-1 and cL-selectin did not correlate. In first-degree relatives, elevated adhesion molecule levels were observed in the 6 ICA + individuals and in the ICA" individuals all (n = 14) with a genetic risk of IDDM (sharing HLA-DR3 and/or -DR4 with the diabetic relative) but not in the HLA-DR3" and/or -DR4" relatives (n = 13). We conclude that elevated clCAM-1 and cL-selectin levels occur independently of ICA status and probably reflect ongoing immune processes in recent-onset IDDM patients and first-degree relatives at risk for IDDM.
Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Th1 cytokines gamma-interferon (IFN-gamma) (P = 0.028) and tumor necrosis factor alpha (TNF-alpha) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Th1 and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Th1 or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-alpha and IL-4 than normal subjects (P = 0.001-0.006). However, when the balance between Th1 and Th2 cytokine production was analyzed in individuals, the ratio between IFN-gamma or TNF-alpha and IL-4 or IL-10 was clearly biased toward Th1 reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Th1) in IDDM or humoral immunity (Th2) in Graves' disease.
The prevalence of islet cell antibodies in children with Type 1 (insulin-dependent) diabetes was determined in a cohort of 678 children. The natural course of islet cell antibodies was followed in 375 children at 1 year, 252 and 135 children after 2 and 3 years respectively. Islet cell antibodies were determined by indirect immunofluorescence on cryostat sections of human pancreas. At diagnosis of diabetes 85% of the children had detectable islet cell antibodies (mean titre 10.4). After 3 years 62% of the children were still islet cell antibody positive (mean titre 2.9) indicating a greater persistence of islet cell antibodies than described in earlier studies. In this large cohort a significant correlation between islet cell antibody prevalence or persistence and sex, age or HLA-DR type was not observed except for a faster loss of islet cell antibodies in very young boys and in patients lacking HLA-DR types 3 and 4. Complement fixing islet cell antibodies correlated with high titre islet cell antibodies. Greater persistence of islet cell antibodies was seen for cases with high antibody titre and in children with diagnosis of diabetes during the first half of the year.
C4 is the only component of the human complement system that is coded for by two genes, C4A and C4B, showing 99% homology. The genes for the two C4 isotypes are located with the genes for the second component (C2), factor B (BF), and steroid 21-hydroxylase (21-OHA and 21-OHB) between HLA-B and -DR in the MHC on chromosome six (1-4). The C4 and 21-OH genes are tandemly arranged and have probably arisen by duplication (Fig . 1 a). Based on the direction of transcription, C4A is usually expressed at C4 locus I, whereas C4B is usually expressed at locus II (5).C4A and C4B are highly polymorphic with more than 35 alleles including null alleles (C4QO) at both loci (6). The polymorphism can be defined by electrophoretic mobility ofthe intact protein or its subunits (7-9), by serology of Rodgers (Rg) and Chido (Ch) determinants (10), and by functional studies of complement activation and binding characteristics (11,12). A sequence of four amino acids in the C4d region (Chido 4 determinant on C4B molecules) is responsible for the major structural and functional differences of the C4 isotypes (Fig. 1 c; 9, 11-13) . The antigenic determinants Rodgers and Chido are generally expressed on the C4A and C4B isotypes, respectively, but rare reversed associations have been described (14). Gene conversion has been discussed as a possible mechanism for the generation of aberrant allotypes (15,16).Null alleles of C4A or C4B (AQO or BQO) occur at frequencies of 0.1-0 .3 in the normal population (17), and are assessed by the absence of gene products. The structural analysis of the C4 genes at the DNA level has revealed that only a proportion of C4 null alleles result from gene deletions affecting an entire C4 gene and one adjacent 21-OH gene, and consequently other null alleles were due to nonexpressed genes (pseudogenes) (18,19). Alternatively, it has been suggested that null alleles represent the expression of two identical, and therefore undistinguishable, allotypes on a haplotype, and this results from gene conversion of C4A to C4B and the reverse (5, 20).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.