Understanding Germinal Centers
What are scientists learning about the structures within which antibody-producing cells develop and mature?
By Kristen Jill Kresge
Researchers are investigating multiple ways to develop a vaccine capable of preventing HIV infection. One of the main approaches relies on the induction of infection-fighting proteins known as antibodies. These typically Y-shaped proteins can work against viruses in various ways and are the reason most, if not all, vaccines provide protection. Some antibodies work by binding to viruses and preventing them from infecting cells, thereby marking the virus particles for destruction. This type of antibody is referred to as a neutralizing antibody (see Understanding Neutralizing Antibodies).
Researchers are pursuing many different strategies to induce neutralizing antibodies against HIV through vaccination. And because HIV is so variable, with multiple subtypes circulating globally, researchers are interested in antibodies that can neutralize a broad swath of HIV variants, which are referred to as broadly neutralizing antibodies.
In 2009 researchers identified a slew of new, more potent broadly neutralizing antibodies. Since then new antibodies have been identified at nearly break-neck speed. Now researchers have isolated more than 200 broadly neutralizing antibodies from blood samples collected from HIV-infected individuals. Close study of these antibodies is providing researchers with valuable information about how these antibodies form in response to HIV infection and clues about how they might induce such antibodies through vaccination.
Not your mother’s antibodies
Although many antibodies have been isolated, development of broadly neutralizing antibodies is still a rare occurrence—only a minority of HIV-infected individuals develop them and only after years of infection. HIV has a furious mutation rate and outpaces the immune system’s response. By the time antibodies are generated, HIV has mutated enough to avoid them, thereby escaping neutralization. This process of mutation and escape is necessary for the production of broadly neutralizing antibodies, researchers surmise.
Analysis of the hundreds of antibodies isolated so far shows that they are not just rare, they are also unique. These antibodies are highly mutated and have various other characteristics that make them unusual compared to other antibodies. These highly optimized antibodies are the result of a two-step process known as affinity maturation (see Understanding How Broadly Neutralizing Antibodies Evolve). Through affinity maturation the B cells that make and secrete antibodies accumulate multiple mutations in their genes that allow them to more efficiently bind to and neutralize HIV. After this process occurs, the more superior B cells that bind the strongest to HIV undergo additional cycles of mutation and differentiation. With each round, the B cells are said to become more mature. The more mature these B cells become, the antibodies they make become better and better at neutralizing HIV.
Germinal center dynamics
This process of affinity maturation takes place in germinal centers. Germinal centers are unique structures that form within lymph nodes or other peripheral lymphoid organs such as the spleen. Optimized B cells that leave germinal centers can go on to become antibody-secreting plasma cells or long-lived memory B cells, which are the type researchers hope to induce through vaccination (see Understanding the Immune System, Part I).
While researchers may not know precisely how antibody maturation in germinal centers unfolds, they know it is terribly important. Given the high level of affinity maturation seen in all of the broadly neutralizing antibodies against HIV identified so far, researchers think that formation of these antibodies must require optimal germinal center dynamics. For this reason, trying to better understand the processes that occur in germinal centers and figuring out ways to manipulate these reactions to improve the protection afforded by vaccines is now a major area of research.
The selection of vaccine adjuvants is one way that researchers are attempting to manipulate the complex process of affinity maturation in germinal centers. There is some evidence from studies in animals that suggest certain adjuvants—components that are added to vaccines to boost immune responses—can directly stimulate B cells and drive their accumulation of genetic mutations (see Understanding How Adjuvants Boost Immune Responses).
Researchers are also focused on understanding how a specialized subset of helper T cells that resides in germinal centers may also influence the affinity maturation process of B cells in germinal centers.
Part of the reason germinal centers and the processes that occur within them is such a mystery is that these sites are difficult to study. In some ways researchers are groping in the dark when it comes to analyzing germinal centers. Researchers can only access germinal centers that are hidden within lymph nodes by biopsy, which makes studying them less feasible in human volunteers.
Despite major gaps in understanding how germinal center reactions occur, this is a burgeoning field of research, and one that has seen quite a few advances in recent years, according to researchers. Next year, for the first time, HIV vaccine researchers will be mingling with immunology experts at a meeting solely on this topic, evidence of the growing importance of understanding and influencing germinal center reactions.