How defects in a signaling protein sabotage the immune system in multiple, seemingly contradictory ways

November 21, 2012
Immunology: Making sense of contradictions
TACI-deficient mice (KO) produce far fewer antibody-secreting plasma cells in response to an immune challenge relative to normal, wild-type (WT) animals. Credit: 2012 A*STAR Bioprocessing Technology Institute

The antibody response to immune threats is managed by cells known as B lymphocytes. The differentiation and function of B cells are tightly regulated to ensure a prompt response to confirmed dangers, such as viruses or bacteria, and also to prevent the emergence of harmful autoimmune responses that can damage healthy tissues in the body.

Many express a protein called TACI on their surface, but its specific function has remained ambiguous. "Human patients with TACI manifest two seemingly opposing conditions—immunodeficiency as well as autoimmunity," says Kong-Peng Lam, a researcher at the A*STAR Bioprocessing Technology Institute. By exploring the roots of these contradictory effects, Lam and his team have provided an explanation.

Much of the antibody response is marshaled at sites known as germinal centers (GCs), where so-called 'follicular helper T (Tfh) cells' essentially 'train' GC B cells to respond to infectious threats. Lam and co-workers examined mice that lack TACI, and found that these mice generated considerably greater numbers of both Tfh and GC B cells. A pathway driven by a signaling protein called BAFF plays a major role in driving GC B ; the researchers determined that this pathway is hyperactive in TACI-deficient mice, and proposed a model wherein TACI normally sequesters excess BAFF to limit cellular expansion of GCs.

In spite of the increased GC B cells, TACI-deficient mice generally failed to mount an efficient antibody response against an immune challenge. Upon closer examination, Lam and co-workers found that these animals had fewer (see image), the class of B lymphocytes that secretes , and determined that TACI acts as a 'survival factor' that enables these cells to flourish.

Although these two effects would seem to counteract each other, the researchers' proposed model links these physiological changes with the unusual immune defects observed in human patients. Lam notes that B cell selection in the GC also entails elimination of harmful B cells that recognize host antigens. "Absence of TACI increases the population of GC B cells, and this probably has the follow-on effect of reducing the stringency of the selection process, such that autoimmunity may arise," he says.

Thus, while the drop in the number of plasma cells would result in overall immunodeficiency, the 'quality' of surviving plasma cells would also drop. "The few antibody-secreting cells that manage to survive may be autoreactive," says Lam, "and this explains the two seemingly opposing conditions that are found in TACI-deficient patients."

Explore further: Awaiting orders to retaliate

More information: Ou, X., Xu, S. & Lam, K.-P. Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival. Proceedings of the National Academy of Sciences 109, 15401–15406 (2012). www.pnas.org/content/early/2012/08/28/1200386109.abstract

Related Stories

Awaiting orders to retaliate

June 24, 2011

(Medical Xpress) -- When immune system B cells are alerted to the presence of a threat within the body, they form structures called germinal centers, which serve as ad hoc headquarters for marshaling a targeted immune response. ...

Ensuring the persistence of immune memory

September 16, 2011

Structures within the lymph nodes known as germinal centers (GCs) help the body to maintain long-term immune defense against foreign threats. The GCs essentially act as sites where antibody-producing B cells undergo a process ...

Unsung heroes of antibody production

August 3, 2012

B cells are the body’s antibody factories, standing by to churn out molecules that selectively target foreign threats as a component of the humoral immune response. However, this process also requires T cells to secrete ...

Recommended for you

Epigenomic changes are key to innate immunological memory

August 31, 2015

A research team led by Keisuke Yoshida and Shunsuke Ishii of the RIKEN Molecular Genetics Laboratory has revealed that epigenomic changes induced by pathogen infections, mediated by a transcription factor called ATF7, are ...

Team finds early inflammatory response paralyzes T cells

August 18, 2015

In a discovery that is likely to rewrite immunology text books, researchers at UC Davis have found that early exposure to inflammatory cytokines, such as interleukin 2, can "paralyze" CD4 T cells, immune components that help ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.