Selective correlation of interferon-gamma, tumour necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor with immunoglobulin G1 and immunoglobulin G3 subclass antibody in leprosy.

Dysregulation of both B- and T-cell responses is observed in leprosy. Immunoglobulin G1 (IgG1) and IgG3 antibody subclasses are selectively elevated towards the lepromatous or disseminated form of the disease accompanied by a depression of T-cell responses. T-cell and macrophage cytokines influence antibody class switching, differentiation and proliferation of B cells. To understand the dynamic nature of the immune response in leprosy, we examined the relationship between circulating Mycobacterium leprae-specific antibodies and secreted cytokines [interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-5, IL-10, IL-6, tumour necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF)] in leprosy patients (19 lepromatous patients; 25 tuberculoid patients) and their exposed household contacts (HC=14) in response to M. leprae antigens. Paired comparison revealed a highly significant negative correlation between IFN-gamma and IgG (P=0.016), IgG1 (P<0.001) and IgG3 (P=0. 007) antibodies. No significant relationship was observed with other T-cell cytokines (IL-2, IL-5 and IL-10). These results strongly suggest that IFN-gamma may play a role in down-regulating antigen-specific IgG1 and IgG3 antibodies. Among the macrophage cytokines, TNF-alpha and GM-CSF which have not been shown to play a role in B-cell activation were positively associated with IgG1 (TNF-alpha, P=0.0005; GM-CSF, P=0.001) and IgG3 (TNF-alpha, P=0.001; GM-CSF, P=0.021) antibodies. Since macrophages have high-affinity Fc receptors for IgG1 and IgG3, it is possible that antigen uptake via these receptors may influence cytokine expression of TNF-alpha, a key modulator of disease pathogenesis in mycobacterial diseases. We are currently investigating the role of Fc receptors on activated macrophages, in expression of pro-inflammatory cytokines in mycobacterial diseases.

Induction of Th1 cytokine responses by mycobacterial antigens in leprosy.

Twelve mycobacterial antigens were compared for induction of gamma interferon (IFN-gamma) secretion by human blood mononuclear cells of patients with leprosy. Fractionated Mycobacterium leprae antigens containing cell wall proteins or cytosolic and membrane proteins induced good IFN-gamma responses in tuberculoid leprosy patients. Lipoarabinomannan from M. tuberculosis Erdman and M. leprae mycolylarabinogalactan peptidoglycan were the poorest IFN-gamma inducers.

Selective increases in antibody isotypes and immunoglobulin G subclass responses to secreted antigens in tuberculosis patients and healthy household contacts of the patients.

Mycobacterium tuberculosis-specific antibodies (immunoglobulin M [IgM], IgE, IgG, and IgG subclasses) were determined in 164 tuberculosis patients (pulmonary involvement, n = 135; lymph node involvement, n = 29), 59 healthy household contacts (HC), and 51 healthy endemic donors (EC) by a quantitative enzyme-linked immunosorbent assay for reactivity with culture filtrate. Among the isotypes, significant differences between tuberculosis patient groups with either pulmonary or lymph node involvement and healthy control groups (HC and EC) were detected only for IgG (P < 0.001) and IgG1 (P < 0.001) antibodies. Pulmonary patients also showed a significant difference with IgM (P < 0.01) and IgE (P < 0.05) antibodies. HC showed elevation of only IgM antibodies compared with EC, indicating that IgM antibodies may be an indicator of recent infection with M. tuberculosis. These results suggest that the switching of IgM antibody response to IgG1 is a critical event in disease progression. Polyclonal IgG1, IgG3, and IgE antibodies also showed significant elevation (P < 0.05) in patients compared with EC. A strong correlation (rho = 0.254; P < 0.003) was observed between M. tuberculosis-specific IgG1 and polyclonal IgG1 in patients, suggesting that activations of antigen-specific and polyclonal antibodies are related events. No correlation was found between IgG1 antibodies and purified protein derivative skin test results. Since IgG1 antibody responses to culture filtrate are present only after disease establishment, IgG1 responses could provide a useful diagnostic marker of disease.