Self & Other · When the System Is Quiet

Why It’s Hard to See

The general principle worth holding onto is that “always being sick” is sometimes a normal feature of having young children at home, or working in a school, or having recently moved to a new climate, or going through a particularly stressful year. But sometimes it is a sign of something specific and nameable, which a primary immunodeficiency clinic can identify with a few blood tests, and which has a treatment that can substantially change a person’s life. If a person is getting infections that are unusually frequent, unusually severe, unusually long-lasting, or unusual in type, the question to ask is not “how do I boost my immune system” — a question we have been pushing back against throughout this book — but “is something specific going on?”

Why It’s Hard to See

Primary immunodeficiency is, in many ways, the opposite of autoimmune disease in how it sits in the public imagination, and the contrast is worth naming.

Autoimmune disease, as we discussed in the last chapter, attracts a great deal of moralizing about lifestyle. Patients are told, often, that their disease is the result of choices they could have made differently. The science does not support this, but the cultural pressure persists.

Immunodeficiency attracts the opposite kind of error. Patients are often told that nothing is wrong, that they should just take more vitamin C, that they need to “boost their immunity” through any of a thousand wellness products, that the problem is their habits or their stress. The science does not support this either. A person with CVID cannot eat their way to functional B cells. A person with selective IgA deficiency does not need a stronger immune system; they need a specific missing antibody class that no diet will provide. A person with X-linked agammaglobulinemia has no B cells at all and never will, no matter how clean their diet is.

Both of these errors share a root assumption: that immunity is something you can dial up or down by behavior, and that anyone whose immune system is not behaving correctly is, in some sense, responsible. We have spent ten chapters arguing that this is wrong. The immune system is set up before you were born and shaped over your life by factors that are, for the most part, not under your conscious control. Some people, through factors entirely outside their control, have immune systems that overreact. Some people, through factors entirely outside their control, have immune systems that underreact. Both deserve specific medical attention. Neither deserves the standard moralizing.

This applies, with particular force, to people whose immune systems are intentionally suppressed by medication. People who have had organ transplants, people on immunosuppressive drugs for autoimmune disease, people on chemotherapy — all of them are functionally immunodeficient, often profoundly so. They are vulnerable to infections that healthy people brush off. They cannot mount full responses to many vaccines. They depend, in a real and underappreciated way, on the immunity of the people around them — on the fact that the diseases they cannot fight are mostly not circulating, because most other people have been vaccinated against them or have already had them and developed memory cells.

This is the concept sometimes called herd immunity, and although the phrase has become politically charged in recent years, the underlying idea is simple. A pathogen needs susceptible hosts to spread. If most of a population is immune to a particular disease, the pathogen runs out of people to infect long before it can reach the people who, for medical reasons, cannot defend themselves. The vulnerable are protected, in part, by the choices of the people around them. This is not metaphor; it is straightforward epidemiology. It is the reason, for example, that measles outbreaks in recent years have so disproportionately affected children too young to be vaccinated and people undergoing immunosuppressive treatment. Their protection has always been borrowed.

A person with CVID, a child on chemotherapy, an elderly relative on biologic therapy for rheumatoid arthritis — these people are part of every community and almost every family. The immunity of the people around them is, for them, not an abstraction. It is, sometimes, the difference between a manageable life and a devastating one.

What Treatment Looks Like

Treatment for immunodeficiency varies by condition, but a few major approaches keep recurring.

Replacement. For conditions where a specific component is missing or insufficient — antibodies in CVID, the ADA enzyme in some forms of SCID — the missing component can sometimes be supplied from outside. IVIG (intravenous immunoglobulin) and SCIG (subcutaneous immunoglobulin) provide pooled antibodies from healthy donors. They are given regularly, they do not cure the underlying condition, and for many patients they are transformative.

Cell replacement. For SCID and some other severe primary immunodeficiencies, a bone marrow transplant from a matched donor can rebuild the entire immune system from scratch. The patient’s own bone marrow cells are largely destroyed; the donor cells engraft; the new immune system is, immunologically, the donor’s. The procedure is intense but, in capable hands, often curative.

Gene therapy. For some specific genetic immunodeficiencies, the patient’s own bone marrow cells can be removed, corrected outside the body using a viral vector that delivers a working copy of the broken gene, and reinfused. The corrected cells then produce normally functioning immune cells for the rest of the patient’s life. This has been done for several forms of SCID and is being explored for other primary immunodeficiencies. It is among the more remarkable accomplishments of modern medicine, and it represents the most direct version of a treatment we will keep encountering throughout this book: the body’s own cells, edited and returned.

Antimicrobials. For people with chronic immunodeficiency, prophylactic antibiotics or antiviral drugs can be used to prevent infections that the immune system cannot reliably stop. This is part of the standard of care for many primary immunodeficiencies. It is also, in a slightly different form, the basis of HIV treatment: antiretroviral drugs that suppress the virus and allow the immune system to recover.

Vaccination, with care. People with immunodeficiency can usually receive most vaccines safely, although they may not respond as strongly. Live attenuated vaccines (the kind we discussed in Chapter 4) can sometimes be dangerous in severely immunocompromised people, because the weakened pathogen can occasionally cause infection in someone with no defenses. Inactivated and subunit vaccines are generally safe. mRNA vaccines, as we will discuss in Chapter 17, are also generally safe in immunocompromised patients, though the response may be weaker. Vaccination decisions in immunodeficient patients are individualized, often with the input of a specialist.

Borrowed Immunity

We can’t quite leave this chapter without saying one more thing, because it ties immunodeficiency back to the ordinary biology that everyone shares.

Almost every newborn baby in the world spends its first six months of life with a partially borrowed immune system. The mother passes antibodies across the placenta during the last trimester of pregnancy, and continues to pass them through breast milk if the baby is breastfed. These maternal antibodies do not belong to the baby — they were made by the mother’s B cells, against pathogens the mother had encountered. The baby is, in essence, briefly running on the mother’s immunological memory.

This is why a healthy newborn can survive in a world full of pathogens its own immune system has never met. The baby’s adaptive immune system is functional but inexperienced; its memory library is empty; it has not yet had time to make memory cells against anything. The mother’s antibodies fill the gap. Over the first six months of life, the maternal antibodies fade, and the baby’s own immune system takes over — building memory, encounter by encounter, the same way every immune system always has.

The process is part of why vaccinating pregnant women against certain diseases (whooping cough, influenza, more recently RSV) protects newborns: the antibodies cross the placenta and protect the baby for the first crucial months. It is also why, biologically, the mother’s prior infections and vaccinations matter for the child. The library you inherit from the body that carried you is real. It does not last. But for the months when you needed it most, it was there.

Every human being, in this small specific way, begins life as someone whose immune defense was loaned by another body. The fact that we forget this, by the time we are old enough to read about immunology, does not make it any less true.

So this is the other side of the disorder. Not an immune system that is mistakenly attacking, but an immune system that is missing something it should have — because of a single gene, because of a virus that found exactly the wrong target, because of a treatment we are giving on purpose to manage another disease, because of any of a hundred specific reasons that medicine can usually identify if it looks.

The people in this chapter are not weak. They have not failed to do something. They are people whose immune systems are, in some specific way, not making something they should be making, or not eliminating something they should be eliminating. The treatments work, increasingly, because we understand specifically what is wrong. The lifestyle moralizing that gets directed at them is, if anything, even more out of place than it is in the autoimmune chapter, because here the relevant biology is often a single missing enzyme, a single missing antibody class, a single virus targeting a single cell type.

The same permission applies that we offered at the end of the last chapter. If you are someone who gets every infection going around, who has a child who keeps getting unusual pneumonias, who has been quietly worrying for years that something might be a little wrong, the most useful thing the science has to offer is the suggestion that “something specific” is sometimes a real category, that it is sometimes nameable, and that nameable things sometimes have nameable treatments. It is worth asking. It is worth getting tested. The answer is sometimes nothing, and sometimes it is a clinic visit and a blood draw away.

The next chapter takes us to the third great category of immune-related disease, which is in some ways the most counterintuitive. It is about a disease in which the immune system is not attacking something foreign, and not failing to attack something foreign, but failing to recognize something that came from inside the body itself. The disease is cancer. The story of how the immune system has finally, in the last fifteen years, been turned against it is one of the most extraordinary in modern medicine.

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