The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Cl inic a l I m pl ic a t ions of B a sic R e se a rch

ElizabethG. Phimister, Ph.D., Editor

Antibodies to Mycobacterium tuberculosis

Arturo Casadevall, M.D., Ph.D.
Antibodies are time-honored reagents in the diagnosis, prevention, and treatment of infectious
diseases. Depending on the disease in question,
the presence of antibody in serum can be correlated with infection, immunity, or progression
of disease. For example, the presence of antibody to hepatitis B surface antigen in a vaccinated person connotes immunity, whereas the
presence of antibody to human immunodeficiency virus heralds infection and, if untreated,
a high likelihood of progression to the acquired
immunodeficiency syndrome.
Mycobacterium tuberculosis infection and its progression to tuberculosis are accompanied by brisk
antibody responses, but it has been difficult to
use serologic information reliably in clinical
practice.1 Similarly, harnessing the antimicrobial
properties of antibodies for the prevention and
treatment of tuberculosis has not been fruitful.
Numerous attempts in the early 20th century to
treat tuberculosis with serum therapy produced
inconsistent results,2 and vaccine development
has been focused on making vaccines that protect by inducing cell-mediated responses. There
is a long-simmering controversy about whether
humoral immunity contributes to host defense
against M. tuberculosis.3
Two recent studies4,5 show functional differences in antibodies to M. tuberculosis, which translate into differences in protective efficacy in vitro.
Overall, these findings imply tremendous complexity in structurefunction relationships for
antibodies to M. tuberculosis, which could have
contributed to the historical difficulties in exploiting humoral immunity in the diagnosis,
prevention, and treatment of tuberculosis.
Lu et al.4 found that antibodies that are produced in persons with latent tuberculosis are
more effective at inhibiting growth of M. tubercu-

losis in vitro than those that are produced in

persons with active disease. Specifically, the investigators found that IgG obtained from persons with latent infection was superior to IgG
obtained from persons with active infection with
regard to the promotion of inflammasome activation, phagolysosomal fusion, and the killing
of phagocytized mycobacteria by macrophages,
and they observed an association between these
effects and differences in immunoglobulin glycosylation (Fig.1). The finding of functional differences between IgG obtained from healthy
persons infected with M. tuberculosis and IgG
obtained from persons infected with M. tuberculosis who have active disease is intriguing because it suggests a role for humoral immunity in
the control of infection. However, this association does not imply causation, and it is possible
that the functional differences reflect qualitative
differences emerging from the progression of
disease, given differences between the healthy
infected state and the diseased state with regard
to mycobacterial antigenic load and immune
function.
Zimmermann et al.5 also studied antibody
responses in healthy persons who had been exposed to M. tuberculosis and in persons with active pulmonary disease. They analyzed serum
antibodies and recombinant monoclonal antibodies that were made by cells isolated from
these persons and found that IgA to M. tuberculosis inhibited the mycobacterial infection of
human epithelial-like and macrophage-like cells
derived from cell lines, whereas IgG promoted
infection (Fig.1). This finding suggests that
antibody efficacy may differ according to isotype
and body compartment. In the mucosa, where
IgA predominates, this isotype may be particularly important for protection against infection.

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283

The

n e w e ng l a n d j o u r na l

M. tuberculosis

IgA

Lu et al.
study
IgG

Active tuberculosis

Zimmermann
et al. study

M. tuberculosis

M. tuberculosis

IgG

Macrophage

Epithelial cell

IgA inhibits M. tuberculosis

infection of epithelial-cell line

m e dic i n e

Latent tuberculosis

Zimmermann
et al. study

of

Lu et al.
study
IgG

M. tuberculosis

Macrophage

Epithelial cell

IgG promotes macrophage

control of M. tuberculosis

IgG promotes infection

of epithelial-cell line

M. tuberculosis replicates
in macrophages

Figure 1. Tackling Tuberculosis.

Antibodies that have been obtained from persons with latent tuberculosis and from those with active tuberculosis
have functional differences in vitro. Lu et al.4 and Zimmermann et al.5 studied the efficacy of antibodies present in
persons with latent disease and in those with active disease by cloning antibodies from peripheral-blood cells and
investigating their efficacy with regard to the inhibition of Mycobacterium tuberculosis infection in macrophages and
epithelial cells. Lu et al. focused on serum IgG and found that IgG from persons with latent disease was more effective at inhibiting mycobacterial growth in macrophages than IgG from persons with active disease. The activity of
IgG (inhibitory vs. not inhibitory) was correlated with glycosylation status (aqua circles indicate latent tuberculosis
in a healthy person, and purple circles active pulmonary disease). Zimmermann et al. compared IgA monoclonal
antibodies with IgG monoclonal antibodies and found that the IgA isotypes inhibited infection of an epithelial cell
line and that the IgG isotypes promoted infection.

Although these investigators also noted that IgG

was potentially detrimental because it promoted
mycobacterial infection of cells of a human epithelial-cell line, it is important not to extrapolate
from their findings that this isotype is deleterious: as Lu et al. observed, different results may
be observed with different types of cell.
These studies are complementary in establishing functional differences among antibodies

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to M. tuberculosis, and together the studies help

explain why it has been so difficult to show
unequivocally that there is a role for humoral
immunity in defense against M. tuberculosis. It is
noteworthy that the two groups found considerable variation in the functionality of antibodies
made in healthy infected persons and in those
with active disease. The emerging picture is one
of great complexity, which in turn suggests that

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Clinical Implications of Basic Research

negative results in the historical attempts to establish a role for antibody immunity were possibly false and stemmed from the functional
variation in antibody responses to M. tuberculosis,
rather than from an inherent limitation in humoral immunity to protect against this pathogen.
The discovery of functional differences in the
efficacy of antibodies to M. tuberculosis could have
substantial clinical implications if developed
further in subsequent studies. If the functional
differences between antibodies in persons with
latent tuberculosis and the antibodies in those
with active tuberculosis are shown to have a
cause and effect, it may be possible to use serologic testing to identify persons at risk for disease. For example, the identification of persons
with effective antibody responses could allow
the stratification of infected persons such that
only those with nonprotective antibody responses
are given prophylaxis. In the prechemotherapy
era, it was known that a considerable proportion
of persons with pulmonary tuberculosis either
healed or had stabilized disease. If these different outcomes were associated with differences
in humoral immune responses, serologic testing
could also provide prognostic information that
could help improve therapy. If these findings are
replicated and a cause-and-effect relationship is
determined, they are likely to stimulate the search
for new vaccines that prevent tuberculosis by eliciting antibody responses that promote latency or
the elimination of infection.

The establishment of the clinical relevance of

functional differences in human antibodies to
M. tuberculosis will require prospective studies of
the antibody response during infection to establish a temporal relationship between the production of certain antibody responses and some
infection outcomes. Given that antibodies are
protective against most infectious diseases, including other intracellular pathogens, there is a
high likelihood that future studies will establish
causative relationships between functional differences in antibodies to M. tuberculosis and such
states of infection as latency and disease.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore.
1. Achkar JM, Ziegenbalg A. Antibody responses to mycobacte-

rial antigens in children with tuberculosis: challenges and potential diagnostic value. Clin Vaccine Immunol 2012;19:1898-906.
2. Glatman-Freedman A, Casadevall A. Serum therapy for tuberculosis revisited: reappraisal of the role of antibody-mediated
immunity against Mycobacterium tuberculosis. Clin Microbiol
Rev 1998;11:514-32.
3. Achkar JM, Chan J, Casadevall A. B cells and antibodies in
the defense against Mycobacterium tuberculosis infection. Immunol Rev 2015;264:167-81.
4. Lu LL, Chung AW, Rosebrock TR, et al. A functional role for
antibodies in tuberculosis. Cell 2016;167(2):433-443.e14.
5. Zimmermann N, Thormann V, Hu B, et al. Human isotypedependent inhibitory antibody responses against Mycobacterium
tuberculosis. EMBO Mol Med 2016;8:1325-39.
DOI: 10.1056/NEJMcibr1613268
Copyright 2017 Massachusetts Medical Society.

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