Heterogeneous Antibody Responses in Tuberculosis

K Lyashchenko

R Colangeli

M Houde

H Al Jahdali

D Menzies

M Gennaro

Public Health Research Institute, New York, New York 10016,^{and BioChem ImmunoSystems Inc.}^{and Montreal Chest Institute,}^{Montreal, Quebec, Canada}

^{Corresponding author. Mailing address: Public Health Research Institute, 455 First Ave., New York, NY 10016. Phone: (212) 578-0844. Fax: (212) 578-0804. E-mail:}ude.uyn.irhp@oranneg.

Editor: S. H. E. Kaufmann

Received 1998 Mar 5; Revisions requested 1998 Apr 14; Accepted 1998 Apr 30.

Abstract

Antibody responses during tuberculosis were analyzed by an enzyme-linked immunosorbent assay with a panel of 10 protein antigens of Mycobacterium tuberculosis. It was shown that serum immunoglobulin G antibodies were produced against a variety of M. tuberculosis antigens and that the vast majority of sera from tuberculosis patients contained antibodies against one or more M. tuberculosis antigens. The number and the species of serologically reactive antigens varied greatly from individual to individual. In a given serum, the level of specific antibodies also varied with the antigen irrespective of the total number of antigens recognized by that particular serum. These findings indicate that person-to-person heterogeneity of antigen recognition, rather than recognition of particular antigens, is a key attribute of the antibody response in tuberculosis.

Abstract

Tuberculosis (TB) is the leading cause of death from a single infectious agent. Worldwide, one third of the population is infected with Mycobacterium tuberculosis; each year, 8 million cases of disease arise, and 3 million people die (4, 17). Immunological research on TB has focused largely on cell-mediated immunity because this part of the immune system mediates acquired resistance to TB (8). Much less effort has been placed on the characterization of the nonprotective, humoral immune response. It has often been suggested but never firmly established that different clinical outcomes are related to the fact that some patients show a stronger cell-mediated response and others show a stronger humoral response (12). It has also been conjectured that antibodies and immune complexes play an immunosuppressive role in TB (7, 23). Clearly, a full understanding of immune responses in TB and the use of such information to develop TB control measures require knowledge of humoral immunity in the infected host.

Most of our current knowledge on humoral immunity in TB derives from serodiagnostic studies. In the search for appropriate antigens, it has been repeatedly observed that single-antigen-based assays never achieve satisfactory serodiagnostic performance (reviewed in references 11 and 29), leading to the view that up to 30% of patients with TB are seronegative (15). However, complex antibody binding patterns are usually observed with immunoblot analyses of sera from TB patients (28). Thus, it has not been clear whether the poor performance of serodiagnostic assays reflects a lack of antibody responses in a large number of patients or a lack of appropriate reagents to measure the responses. An answer to this question requires the availability of a broad set of serologically active M. tuberculosis antigens.

We looked for antigens that elicit antibody responses in TB by focusing on the extracellular proteins of M. tuberculosis (operationally referred to as culture filtrate proteins), since these proteins are known to induce strong immune responses in TB (reviewed in references 1 and 10). Using a panel of 10 culture filtrate proteins purified from recombinant Escherichia coli, we found that person-to-person heterogeneity of antigen recognition, rather than recognition of particular antigens, is the signature of humoral immunity in TB.

ACKNOWLEDGMENTS

We thank Clemence Desputeau and Stephane Francoeur for excellent technical assistance. We also thank Tom Daniel, Karl Drlica, Sam Kayman, and Carol Lusty for comments on the manuscript.

This work was supported in part by NIH grant AI-36896 (to M.L.G.). R.C. was the recipient of an AIDS training fellowship from the Istituto Superiore di Sanitá, Rome, Italy.

ACKNOWLEDGMENTS

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