Chronic immune activation in common variable immunodeficiency (CVID) is associated with elevated serum levels of soluble CD14 and CD25 but not endotoxaemia

Abstract

Common variable immunodeficiency (CVID), the most frequent symptomatic immunoglobulin primary immunodeficiency, is associated with chronic T cell activation and reduced frequency of CD4(+) T cells. The underlying cause of immune activation in CVID is unknown. Microbial translocation indicated by elevated serum levels of lipopolysaccharide and soluble CD14 (sCD14) has been linked previously to systemic immune activation in human immunodeficiency virus/acquired immune deficiency syndrome (HIV-1/AIDS), alcoholic cirrhosis and other conditions. To address the mechanisms of chronic immune activation in CVID, we performed a detailed analysis of immune cell populations and serum levels of sCD14, soluble CD25 (sCD25), lipopolysaccharide and markers of liver function in 35 patients with CVID, 53 patients with selective immunoglobulin (Ig)A deficiency (IgAD) and 63 control healthy subjects. In CVID subjects, the concentration of serum sCD14 was increased significantly and correlated with the level of sCD25, C-reactive protein and the extent of T cell activation. Importantly, no increase in serum lipopolysaccharide concentration was observed in patients with CVID or IgAD. Collectively, the data presented suggest that chronic T cell activation in CVID is associated with elevated levels of sCD14 and sCD25, but not with systemic endotoxaemia, and suggest involvement of lipopolysaccharide-independent mechanisms of induction of sCD14 production.

Fig. 1

Levels of serum soluble CD14 (sCD14) correlate with the degree of T cell activation in common variable immunodeficiency (CVID) patients. (a,c,e,g) Percentages of cells expressing human leucocyte antigen (HLA)-DR or CD38 out of CD4⁺ (a,e) or CD8⁺ (c,g) lymphocyte populations in control subjects (Ctrl) and patients with selective immunoglobulin (Ig) A deficiency (IgAD) and CVID. Horizontal lines indicate group medians; intergroup differences were analysed using Kruskal–Wallis test with post-hoc comparisons of mean ranks of all pairs of groups; P-values were corrected for multiple comparisons using Bonferroni adjustment. (b,d,f,h) Correlations between serum sCD14 and the expression of activation markers (HLA-DR or CD38) on CD4⁺ or CD8⁺ lymphocytes in CVID patients. Lines represent linear regression analysis. R and P-values were determined using two-tailed Spearman's rank order correlation test. n.s.: not significant.

Fig. 2

Levels of serum soluble CD14 (sCD14) in common variable immunodeficiency (CVID) patients correlate with decreased numbers of circulating CD4⁺ T cells, natural killer (NK) cells and B cells but not CD8⁺ T cells. (a,c,e,g) Absolute counts of specified immune populations are presented as 10³ cells/μl. Horizontal lines indicate group medians. Intergroup differences were analysed using Kruskal–Wallis test. (b,d,f,h) Correlations between serum sCD14 and absolute counts of specified immune populations in subjects with CVID. Lines represent linear regression analysis. R and P-values were determined using two-tailed Spearman's rank order correlation test. n.s.: not significant.

Fig. 3

Serum soluble CD14 (sCD14) levels correlate with the concentration of C-reactive protein (CRP) but not lipopolysaccharide (LPS). (a,b,c) Serum levels of sCD14 (a), LPS (b), and CRP (c) in control subjects (Ctrl) and subjects with selective immunoglobulin (Ig) A deficiency (IgAD) or common variable immunodeficiency (CVID). Horizontal lines indicate group medians. Intergroup differences were analysed using Kruskal–Wallis test. (d) Correlation between serum sCD14 and CRP, in CVID patients. Lines represent linear regression. R and P-values were determined using two-tailed Spearman's rank order correlation test.

Fig. 4

Serum soluble CD14 (sCD14) and lipopolysaccharide (LPS) levels do not reflect clinical complications of common variable immunodeficiency (CVID) patients. Levels of sCD14 (a) and LPS (b) in CVID patients with and without chronic diarrhoea, bronchiectasis, splenomegaly and granuloma. Horizontal lines indicate group medians. Data were analysed using Mann–Whitney rank sum test. No statistically significant differences were observed.

Fig. 5

Common variable immunodeficiency (CVID) patients exhibit elevated concentration of serum soluble CD25 (sCD25). (a) Levels of sCD25 (sIL-2Rα) in control subjects (Ctrl) and patients with selective immunoglobulin (Ig) A deficiency (IgAD) and CVID. Intergroup differences were analysed using Kruskal–Wallis test. (b) Correlation between serum soluble CD14 (sCD14) and sCD25. (c) Correlation between serum sCD25 and the expression of human leucocyte antigen D-related (HLA-DR) on CD4⁺ T cells in CVID subjects. (d) Negative correlation between serum sCD25 and the absolute count of CD4⁺ CD25⁺ T cells in CVID subjects. Lines represent linear regression. R and P-values were determined using two-tailed Spearma's rank order correlation test.