Since I graduated from medical school, new scientific developments in immunology have been occurring at a prodigious rate. I knew I could use a refresher course, and serendipity dropped one in my mailbox in the form of a review copy of the new book Immunity, by William E. Paul, MD, chief of the Laboratory of Immunology at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and a major player in many of the scientific discoveries he describes. It was just what I needed. It brought me up to date, and it left me in awe of the amazing things our bodies do to keep us alive.
We are bombarded with claims that something will “boost the immune system” but the people who say that have no understanding of how the immune system really works. We have anti-vaxxers who still deny the effectiveness of vaccines and the existence of herd immunity, and who imagine all kinds of hypothetical harms from vaccines, but who have little understanding of how vaccines actually work. This book itself could serve as a sort of vaccine to immunize readers against scientifically ignorant arguments.
The immune system is reminiscent of the Goldilocks story: it can do too much, too little, or just enough. When it does too much, it causes autoimmune diseases like type 1 diabetes and rheumatoid arthritis. When it does too little, as in AIDS, it fails to protect the person from infections that are normally easy to fight off. When it does just enough, it allows us to resist disease naturally and/or with the help of vaccines.
The smallpox vaccine is one of the greatest success stories of science. Dr. Paul explains how vaccines work, how Jenner’s experiments with cowpox and variolation paved the way for an effective vaccine, and how a public health campaign by the World Health Organization achieved global elimination of smallpox in an astonishingly short ten years.
The immune response is three-part
There are three main parts to the immune response: physical barriers (like the cilia and mucus in the airways that prevent bacteria from reaching and infecting their target cells), innate immunity, and adaptive immunity. Paul explains them all in depth.
Innate immunity is a built-in response that depends on the capacity of highly conserved molecules to recognize certain important microbial factors. Toll-like receptors on the surface of macrophages recognize bacterial components and trigger a chain of biochemical responses in the cell that result in production of cytokines like interleukin-1 that mobilize other cells to destroy the bacteria and are also responsible for symptoms like fever and chills. When bacteria get inside the cell, there are other recognition elements that stimulate the cell to produce more cytokines and recruit neutrophils that “know where to go” because they are attracted by chemokines secreted at the site of infection. Neutrophils ingest bacteria and secrete substances to kill them. When those neutrophils die, they release neutrophil extracellular traps (NETS) that catch and kill more bacteria. Infected cells also make interferons that help them control and destroy the bacteria.
All these events occur rapidly. When they are not sufficient to stop the infection, they still serve to reduce the numbers of pathogens long enough for the adaptive immune system to swing into action.
Adaptive immunity is the one most of us are more familiar with; it involves B lymphocytes that produce antibodies and T lymphocytes that provide cellular immunity. Vaccines are based on adaptive immunity. We can make antibodies to an unlimited number of different antigens. Adaptive immunity may sound simple in principle, but the reality is mind-bogglingly complex; the details are in the book.
The book simplifies the subject as much as possible, but it is still hard to grasp. We learn about haptens, adjuvants, helper T cells (Th1, Th2, and on up to Th22), MHC (major histocompatibility molecules), pattern recognition receptors (PRRs), pathogen-associated molecular patterns (PAMPs), 36 different interleukins, inflammasomes, NOD-like receptors, somatic hypermutation, clonal selection, molecular folding, dendritic cells (discovered only in 1973), complement, natural killer cells, how heavy and light chains combine in antibody-producing cells, the recombination machine that moves DNA segments into juxtaposition and can create cancer-causing oncogenes, etc.
The three laws of immunology
The law of universality: The immune system is capable of creating millions of different antibodies. It is theoretically possible to prepare a vaccine against any infectious agent and even against any three-dimensional molecular structure, for instance cocaine.
The law of tolerance: The immune system should not respond to the person’s own molecules; responses against host tissues can be very destructive.
The law of appropriateness: A complex series of sensors help determine when the immune system should mount a vigorous response against a foreign substance and when it should not.
Other topics: politics, evolution, the future of science, and more
Dr. Paul describes some of the ingenious experiments that researchers devised to tease out some of the secrets of the immune system. In his own research, a finding of unexpectedly low levels of radioactive thymidine uptake in tissue cultures led to the discovery of interleukin. Many of his fellow researchers won Nobel Prizes for their work; others didn’t but deserved them just as much (to his mind, history’s verdict outweighs prizes). He describes how fears of recombinant DNA delayed essential research in the US that was then done in other countries. He gives many examples of Big Pharma and Big Government funding basic science research that led to crucial discoveries and he argues for more government funding.
He talks about evolution. Fruit flies and other invertebrates had only an innate immune system, and he speculates about the survival advantages of the adaptive immune system for vertebrates. A failure of the innate system may be responsible in part for the honeybee colony collapse problem. He discusses the relationship between vitamin A deficiency and susceptibility to measles. He delves into antibiotic resistance. He explains why he is skeptical about the hygiene hypothesis as an explanation for allergies and autoimmune diseases.
He shows how a single gene can cause multiple illnesses. He covers immunosurveillance and its relationship to cancer. He describes the success of checkpoint therapy, which shows that the immune system can be used to prevent and treat cancer. He predicts a great future for monoclonal antibody drugs. He talks about bone marrow transplants and organ transplants. He explains both the critical importance of animal experimentation and its drawbacks.
He explains immunopathology: by killing too many virus-infected cells, the immune response can destroy vital organs. One example is hepatitis B infection, where it is the immune response, not the virus itself, that leads to liver damage and liver cancer. He tells us that after the hepatitis B vaccine was introduced in Taiwan, the rate of liver cancer in children dropped by 84%.
He predicts that with new tools like genetic analysis, the traditional path of scientific discovery will be altered. New discoveries are more likely to flow from the recognition of a heritable human disease to discovery of the genetic mutation, to analysis of the underlying biochemical pathway, to studies in genetically altered mice, and eventually to the application of this knowledge to the treatment of human autoimmune diseases. Big Data is another new tool that will be invaluable for assessing human variability and discovering causal effects. He says the most certain thing about the future is that it will produce the unexpected.
An excellent overview of what science knows about immunology today
This book is not an easy read, but it is well-organized, divided into short chapters, and enlivened by anecdotes about the scientists and the process of discovery. It includes a touching personal chapter about the author’s grandson Julien, whose short life “illustrates the hope and the reality of hematopoietic stem cell transplantation for the treatment of leukemia.”
The human immune system is essential to our survival, and it is incredibly complex. Simplistic attempts to manipulate a part of it based on a poor understanding of the science are likely to do more harm than good. I wish every anti-vaxxer and everyone who wants to “boost the immune system” could be persuaded to read this book. It shows what is glaringly wrong with their thinking
This article was originally published in the Science-Based Medicine Blog.