Our immune system defends us from attack by foreign agents such as viruses and bacteria, in most cases without our even knowing. Much of the work is done by the B and T cells, known as lymphocytes. They produce proteins that recognize antigens and trigger the appropriate immune responses to remove the invaders.
To combat a wide variety of pathogens, an individual’s defensive proteins, known as immunoglobulins and T-cell receptors, have to be extremely diverse in their molecular structure. It is estimated that a healthy individual carries 10 million different versions of these proteins. As the Nobel Prize–winning scientist Susumu Tonegawa explained in 1976, this diversity is the result of special genetic recombination and mutation at work in lymphocytes when they divide. The variety of defensive proteins an individual harbors at one time is known collectively as the immune repertoire.
A person’s immune repertoire is dynamic, changing continuously under the influence of genetic background, age, vaccinations, environmental exposure, and diseases such as immune disorders. One reason some elderly people are more susceptible to infections is that the diversity of their repertoire declines.
Immunologists have long wanted a way to document the diversity of a person’s immune repertoire. Only today is this becoming possible. Directly identifying the immune proteins in all their variety proved too challenging, but the discovery of the genetic machinery that creates those proteins suggested that sequencing the genes would be an easier alternative. In the last five years, advances in massively parallel sequencing technologies have made that feasible. Scientists can now affordably and quickly examine the genes from millions of lymphocytes taken from a single individual to understand the range of different proteins these can produce, obtaining a broad statistical catalogue of the subject’s immune repertoire and its diversity.
High-throughput sequencing of a person’s immune repertoire has many potential applications in medicine. The first clinical tests based on it have recently become available as a way to monitor lymphoma and leukemia patients for relapse. As scientists begin to study the repertoires of many different individuals over time, they may discover novel markers that could be used to assess the efficacy of vaccinations, the progress of autoimmune disorders, and the response of cancers to immunotherapy. The immune repertoire may also become an important part of the coming age of personalized medicine, since evidence suggests that autism, chronic fatigue syndrome, and other poorly understood conditions may be related to immune-system dysfunction. In the far future, knowledge about the immune repertoire could even inform genetic engineering to give a person super-immunity or to reverse immune disorders.
Christina Fan is a research scientist with ImmuMetrix, a company working on techniques for immune-repertoire sequencing.