Serum acute phase protein and inflammatory cytokine network correlations: comparison of a pre-rheumatoid arthritis and non-rheumatoid arthritis community cohort

Abstract

Serum concentrations of acute phase proteins, inflammatory cytokines, and other immunological components were individually assayed using high-sensitivity ELISA in a com-munity-based cohort of preclinical rheumatoid arthritis (pre-RA) and matched non-RA control (CN) subjects. Bivariate correlations of the biomarker panel concentrations were compared in pre-RA versus CN and female versus male subjects. Clinically elevated CRP levels (8+ mg/l) occurred in a higher (p = 0.010) frequency in 46 pre-RA (n = 8, 17.4%) subjects than in 179 CN (n = 9, 5.0%), and were independent of age, gender, smoking behaviors, and serum rheumatoid factor. Selected age and gender differences were found in levels of the immunological network factors. In each study group, the ratio of sTNF-RI to IL-2sRα mean concentrations was 2-fold higher in men than in women. Aging correlated positively with CRP, ASAA, and TNF-α levels, but negatively with IL-1β. Bivariate correlations were similar in pre-RA subjects versus CN and by gender, with few exceptions. Factor loadings in principal component analysis of the total subjects indicated that age- and gender-related variables constituted the two main components. Using multiple regression analyses, an integrative working model of all variable interrelations was generated. The tentative, directional model supports a concept of gender dimorphism of the ratio of sTNF-RI to IL-2sRα serum concentrations and displays differing effects of age on TNF-α versus IL-1β levels. These findings indicate complex age, gender, and cytokine interrelations in control of the immune systems network. Future research in testing such inflammatory pathways promises a better understanding of predisposition to diseases, like RA.

Fig. 1

Outline of subject enrollment in the 1974 CLUE I cohort and the sequential distributions of their baseline sera to referral laboratories for immunoassays in the female and male study groups.

Fig. 1

Outline of subject enrollment in the 1974 CLUE I cohort and the sequential distributions of their baseline sera to referral laboratories for immunoassays in the female and male study groups.

Fig. 2

A working integrative model of the complex interrelations of baseline serum inflammatory biomarkers observed in a cross-sectional cohort, using the sequential MRA technique. Age and gender are assumed to be the highest level directional effectors of the other variables and the inflammatory cytokines to influence APP and receptor concentrations. For the inflammatory cytokine interrelations, age, but not gender, was entered in the models, since IL-6 was assayed only in females. Except for the IL-6 interrelations, other connecting lines were derived from values in total subjects, with the results being consistent in both genders. Straight lines were used for directional effectors and curved lines for intercorrelations among the reactor variables. The relative strengths of MRA-derived correlations are reflected in the line thicknesses: thinnest, p < 0.050; medium, p < 0.010, and thickest, p < 0.001. This integrated model of immune systems network interrelations needs further research testing.

Fig. 2

A working integrative model of the complex interrelations of baseline serum inflammatory biomarkers observed in a cross-sectional cohort, using the sequential MRA technique. Age and gender are assumed to be the highest level directional effectors of the other variables and the inflammatory cytokines to influence APP and receptor concentrations. For the inflammatory cytokine interrelations, age, but not gender, was entered in the models, since IL-6 was assayed only in females. Except for the IL-6 interrelations, other connecting lines were derived from values in total subjects, with the results being consistent in both genders. Straight lines were used for directional effectors and curved lines for intercorrelations among the reactor variables. The relative strengths of MRA-derived correlations are reflected in the line thicknesses: thinnest, p < 0.050; medium, p < 0.010, and thickest, p < 0.001. This integrated model of immune systems network interrelations needs further research testing.