Monocyte Function in IDDM Patients and Healthy Individuals

Abstract

Interleukin 1β(IL-1β) and tumour necrosis factor alpha (TNF-α) may be pathogenetically important in insulin-dependent diabetes mellitus (IDDM), which is associated with genes of the HLA region. Since a regulatory role of HLA region genes on monokine production may exist, we looked for an association between the monokine and prostaglandin E₂ (PGE₂) responses of monocytes (Mo) from 20 healthy males (18–50 years) with HLA-DR types relevant for IDDM susceptibility and resistance (DR 1,2, DR 1,3, DR 1,4, DR 3,4). Monokine assays were established and evaluated and the secretions of IL-1β, TNF-α, and PGE₂ measured in Mo cultures (2 h, 6 h, 20 h) prepared by endotoxin-free techniques and stimulated by low-dose E. coli lipopolysaccharides (LPS). There were no significant associations between Mo responses and HLA-DR phenotype. Likewise, Mo from DR2 (n=5) and DR4 (n= 5) homozygous healthy males demonstrated no significant differences in monokine and PGE₂ responses of Mo. In the HLA class III region a diallelic TNF-β gene Ncol polymorphism consisting of alleles of 5.5 kb and 10.5 kb was recently described and associated with susceptibility to autoimmune diseases including IDDM. We report that IL-1β and TNF-α responses of Mo from TNF-β 10.5 kb homozygous healthy individuals were significantly higher than for TNF-β 5.5/10.5 kb heterozygotes. IL-1β and TNF-α responses of Mo from males (18–35 years) with newly diagnosed (n= 10) and long-standing IDDM (n= 10) and from age- and HLA-DR-matched healthy males (n= 10) were studied. LPS, gamma interferon (IFN), and TNF-α-stimulated Mo cultures were investigated. No significant differences were found between Mo responses of IDDM patients and controls. IFN (1000 U/ml) in the presence of LPS significantly potentiated LPS-stimulated Mo TNF-α secretion and reduced the levels of IL-β immunoreactivity in Mo lysates. IFN and TNF-α did not have any effects on LPS-stimulated Mo secretion of IL-1 β immunoreactivity. We conclude that Mo IL-1β and TNF-α production is normal in patients with recent-onset and long-standing IDDM. The interindividual differences in monokine responses may be accounted for by the diallelic human TNF-β gene polymorphism rather than by HLA class II genes. This observation may be important for understanding the association of certain H LA haplotypes with autoimmune phenomena and disease.