Monocyte Function in IDDM Patients and Healthy Individuals

Abstract

Interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha) 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 (DR1,2, DR1,3, DR1,4, DR3,4). Monokine assays were established and evaluated and the secretions of IL-1 beta, TNF-alpha, and PGE2 measured in Mo cultures (2h, 6h, 20h) 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-beta gene NcoI 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-1 beta and TNF-alpha responses of Mo from TNF-beta 10.5 kb homozygous healthy individuals were significantly higher than for TNF-beta 5.5/10.5 kb heterozygotes. IL-1 beta and TNF-alpha 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-alpha-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-alpha secretion and reduced the levels of IL-1 beta immunoreactivity in Mo lysates. IFN and TNF-alpha did not have any effects on LPS-stimulated Mo secretion of IL-1 beta immunoreactivity. We conclude that Mo IL-1 beta and TNF-alpha 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-beta gene polymorphism rather than by HLA class II genes. This observation may be important for understanding the association of certain HLA haplotypes with autoimmune phenomena and disease.

Cytokine overproduction in healthy first degree relatives of patients with IDDM

“…This suggests that these ªdiabetogenicº alleles do not exert a major influence upon cytokine production in diabetic children or in their relatives. This finding is in agreement with the study of Mùlvig et al [37] who did not find a significant association between production of IL-1b and TNF-a by monocytes and HLA DR phenotype.…”

TNF-? gene polymorphism: Clinical and biological implications

“…It was found that HLA-DR3, DR1, DR4, and DR7 were all associated with higher TNF-␣ synthesis (Bendtzen et al, 1988, Jacob et al, 1990, Pocoit et al, 1993. By contrast, HLA-DR2 and DR5 were found to be associated with lower TNF-␣ responses (Bendtzen et al, 1988, Jacob et al, 1990, Molvig et al, 1990, Pocoit et al, 1993. It is fair to assume that these associations are due to linkage disequilibrium between the TNF-␣ gene and the HLA-DR genes.…”

Polymorphisms IL10-819 and TLR-2 are potentially associated with sepsis in Brazilian patients

“…Furthermore, Schueller et al (2006) suggested the likelihood that this polymorphism does not serve as a prognostic marker for elevated sepsis risk in preterm infants. Some studies demonstrate that LTA [AA] individuals are high producers of TNF in vitro (Mølvig et al 1990, Pociot et al 1993. A previous study showed that individuals with the LTA [AA] polymorphism had a significantly reduced survival rate along with high TNF concentrations in comparison to heterozygous patients (Stuber et al 1996).…”