Distinct Monocyte Gene-Expression Profiles in Autoimmune Diabetes

Abstract

OBJECTIVE— There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes. RESEARCH DESIGN AND METHODS— We studied patterns of inflammatory gene expression in monocytes of patients with type 1 diabetes (juvenile onset, n = 30; adult onset, n = 30) and latent autoimmune diabetes of the adult (LADA) ( n = 30) (controls subjects, n = 49; type 2 diabetic patients, n = 30) using quantitative PCR. We tested 25 selected genes: 12 genes detected in a prestudy via whole-genome analyses plus an additional 13 genes identified as part of a monocyte inflammatory signature previously reported. RESULTS— We identified two distinct monocyte gene expression clusters in autoimmune diabetes. One cluster (comprising 12 proinflammatory cytokine/compound genes with a putative key gene PDE4B ) was detected in 60% of LADA and 28% of adult-onset type 1 diabetic patients but in only 10% of juvenile-onset type 1 diabetic patients. A second cluster (comprising 10 chemotaxis, adhesion, motility, and metabolism genes) was detected in 43% of juvenile-onset type 1 diabetic and 33% of LADA patients but in only 9% of adult-onset type 1 diabetic patients. CONCLUSIONS— Subgroups of type 1 diabetic patients show an abnormal monocyte gene expression with two profiles, supporting a concept of heterogeneity in the pathogenesis of autoimmune diabetes only partly overlapping with the presently known diagnostic categories.

Genetic and Environmental Influences on Pro-Inflammatory Monocytes in Bipolar Disorder

“…Some of the genes (CCL2, CCL7, EMP1, and CDC42) were clearly influenced by genetic factors, and interestingly in a previous study, 22 we found that CCL2, CCL7, EMP1, and CDC42 belong to a separate subcluster of motility/chemotaxis and adhesion genes, which are-though weaker-correlated with the core inflammatory genes (such as PDE4B, the cytokines, and inflammatory compounds). It is tempting to speculate that the expression of this subcluster of genes in monocytes is more under the control of genetic factors and that common environmental factors play a minor role.…”

Type 1 Diabetic Children and Siblings Share a Decrease in Dendritic Cell and Monocyte Numbers but are Differentiated by Expansion of CD4+T Cells Expressing IL-17

“…In light of these limitations and the associated potential for data misinterpretation, continuing efforts are required to re-evaluate blood DC and T Reg cell populations in diabetic and non-diabetic subjects. It is anticipated that ongoing immune activation induced by an array of proinflammatory cytokines produced by DC and monocytes [14][15][16] results in constant recruitment of CD4 + T and CD8 + T cells from the T naïve (T n ) and T central memory (T CM ) pools into the T effector memory (T eM ) and T terminally-differentiated effector (T eMRA ) pools. As such, the effect of immune activation on the dynamics of blood T n , T CM , T eM and T eMRA subsets is far from understood and may differ greatly between diabetic and non-diabetic subjects.…”

Monocyte Gene Expression Signatures in Rheumatic Diseases: Biomarkers for Disease Activity and Tools for Diagnosis and Classification

“…Our profiling of CD14+ monocytes resulted in the identification of gene expression signatures for T1D, pSjS and autoimmune thyroiditis [41,42,Drexhage et al unpublished results]. We detected two different signatures in T1D: a signature involving primarily cytokine/inflammatory compound genes and a second signature that involves genes of chemotaxis, adhesion, motility and metabolism [42].…”

“…Our profiling of CD14+ monocytes resulted in the identification of gene expression signatures for T1D, pSjS and autoimmune thyroiditis [41,42, Drexhage et al unpublished results]. We detected two different signatures in T1D: a signature involving primarily cytokine/inflammatory compound genes and a second signature that involves genes of chemotaxis, adhesion, motility and metabolism [42]. Interestingly, this latter gene expression signature is in line with our earlier observations on functional adhesion and chemotaxis abnormalities of monocytes of T1D patients [43,44] underscoring the usefulness of gene profiling for unraveling functional pathways.…”