PPD-specific IgG1 antibody subclass upregulate tumour necrosis factor expression in PPD-stimulated monocytes: possible link with disease pathogenesisin tuberculosis

Cachexia is a prominent feature of advanced tuberculosis, in association wi th increased expression of the monokine tumour necrosis factor (TNF)-alpha. Monocytes, have high affinity receptors (mannose, complement and Fc gamma 1 and gamma 111) which mediate antigen uptake and subsequent cytokine activ ation. Several mycobacterial proteins, including PPD, can stimulate TNF-alp ha secretion from monocytes. However, the role of various receptors in stim ulating or regulating TNF-alpha secretion is still unclear. We have previou sly shown selective augmentation of opsonic antibodies (IgG1 and IgG3) in t uberculosis patients with advanced pulmonary disease. We now analyse the ro le of opsonizing antibodies in modulating TNF-alpha expression in antigen s timulated monocytes. PPD was used as the prototypic mycobacterial antigen t o stimulate monocytes from PPD skin test negative donors (n = 7) in the pre sence of plasma from tuberculosis patients (n = 8), containing known amount s of IgG1 and IgG3 anti-PPD antibodies. TNF-alpha secretion was enhanced in the presence of TB plasma (4/8) but not in the presence of control plasma. Using Spearman Rank analysis (two-tailed Fisher exact test), a significant correlation (rho = 0.762; P = 0.04) was observed between IgG1 antibodies a nd enhancement of TNF-alpha secretion. No significant association was obser ved with IgG2 (rho = 0.310; P = 0.41), IgG3 (rho = 0.089; P = 0.81) or IgG4 (rho = - 0.357; P = 0.347) subclass antibodies. Absorption of IgG1 with pr otein 'A' removed the enhancement of TNF-alpha secretion activity from the plasma samples. Our results therefore indicate that IgG1 antibodies may enh ance the chronic release of TNF-alpha in TB patients with progressive disea se and, for the first time, show a direct link between disease pathogenesis and raised antibody levels.