Just got back from a departmental conference up in Massachusetts. LOTS of great talks (I gave one myself). But one in particular stuck in my mind. It was a talk by Juan Jose Lafaille, who got his degree from the University of Sao Paulo and is currently a professor at the NYU School of Medicine.

He studies a particular white blood cell called a regulatory T-cell. Many T-cells are active participants of our immune response and loss of T-cells leads to severe immune deficiencies. Regulatory T-cells are somewhat different. They actually, though closely related to the T-cells that actively participate in the immune response, actually suppress the immune response.

Many people will think this is a bad thing. We LIKE our immune response. It prevents each bite we take, each breath we take from making us sick. And we think about those who cannot mount an effective immune response, the so-called "bubble babies" who have to be isolated from the outside world because they can be so easily made sick by even the weakest of germ. Or we think of AIDS where a virus destroys our immune system. But our immune system, when it gets out of hand, can kill us as surely as any germ. Think of multiple sclerosis, for example, a classic autoimmune disease.

Dr. Lafaille's main take home message from his talk at this week's conference was that it is WORSE to have an out of control immune system than no immune system at all. If you have no immune system, you can live for many years as a so-called bubble baby, isolated from the world. In many labs they have strains of mice that are raised completely germ free so that mouse strains unable to mount an effective immune response can live for extended periods. As an aside, other talks at the meeting discussed how this influences the immune response as well...a "normal" immune response requires exposure to germs and a sterile environment is NOT something we evolved to live in. Think about that next time you bleach every surface your kid touches. He or she may NEED some exposure to germs to develop a normal immune system.

So in the modern world a person (or mouse) can live with no immune system (or at least a severely impaired one). Dr. Lafaille's point is that if the immune system is too active, you will die no matter what, so, at least in the modern world, it is worse than having no immune system.

Multiple sclerosis may seem bad enough. That is an example of a case where your immune system, for reasons no one has yet figured out, starts attacking your own body. But Dr. Lafaille discussed how if you have no regulatory T-cells, the ones that actually inhibit your immune response, you die much faster than most other diseases could kill you. And, at least so far, there is nothing you can do about it. If you can't make regulatory T-cells, you develop a disease called Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome. The X-linked means mostly boys get it. The rest means your immune system attacks your own body and kills you. A description of IPEX:

IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly as insulin-dependent diabetes mellitus. Most children have other autoimmune phenomena including Coombs positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy The majority of affected males die within the first year of life of either metabolic derangements or sepsis; a few survive into the second or third decade.

In the modern world a bubble baby, with almost no immune system (or, technically, no adaptive immune system) can live for years. If you have no regulatory T-cells, and so an out of control immune system, you probably will die before your first birthday from a whole host of horrible symptoms. And so far there has been little hope of treatment short of a bone marrow transplant (which effectively replaces your immune system with someone elses, a risky and painful procedure). From the same IPEX website:

Treatment of [IPEX] manifestations: immunosuppressive agents (e.g., cyclosporin A, FK506) alone or in combination with steroids; sirolimus (rapamycin) for persons in whom FK506 therapy is toxic or ineffective; granulocyte colony stimulating factor (G-CSF, filgrastim) for autoimmune neutropenia; nutritional support; standard treatment of diabetes mellitus and autoimmune thyroid disease. If performed early, bone marrow transplantation (BMT) using non-myeloablative conditioning regimens can resolve clinical symptoms. Prevention of primary manifestations: BMT [bone marrow transpant]. Prevention of secondary complications: prophylactic antibiotic therapy for those with autoimmune neutropenia or recurrent infections; aggressive management of the dermatitis with topical steroids and anti-inflammatory agents to prevent infection. Surveillance: periodic evaluation of complete blood count, glucose tolerance, thyroid function, kidney function, and liver function for evidence of autoimmune disease. Testing of relatives at risk: if the family-specific mutation is known, FOXP3 sequence analysis in at-risk males immediately after birth to permit early diagnosis and BMT before significant organ damage occurs; otherwise, monitoring at-risk males for symptoms to enable early diagnosis and treatment.

It is absolutely true that our species would never have made it if our immune system wasn't so damned complicated. But that complexity comes at a price. We have had to evolve many ways to suppress our own immune responses or we would have died before one year old. IPEX is actually a mutation in a single gene coding for a protein that interferes with the production of a single class (maybe two classes) of immune cells. And yet a single mutation in that one gene kills kids within a year unless you replace their bone marrow with that of a properly matched normal person. Which is not easy or pleasant to do.

I should note that regulatory T-cells may keep us alive, but they also can keep cancer cells alive. There have been some fairly effective cancer treatments that targeted regulatory T-cells. Problem is, they also trigger autoimmune diseases, so are not likely to be commonly used for cancer treatment, no matter how effective.

Dr. Lafaille is working on ways to classify different subsets of regulatory T-cells in the hopes of finding ones that can be targeted to help treat cancer without too aggressively triggering autoimmune side effects.

Here is a rundown of Dr. Lafaille's work from his NYU profile:

Although most normal immune responses against pathogens require the action of T-lymphocytes, their improper control lies at the heart of two types of disease: autoimmunity and allergy. Our laboratory uses transgenic and knockout mice to study the molecular mechanisms responsible for the normal control of T-lymphocyte reactivity and the changes that occur when T-lymphocytes become either aggressive against self antigens or inappropriately reactive against substances (allergens) normally present in the environment.

Currently, we are examining the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, in transgenic mice bearing antimyelin basic protein (MBP) T-lymphocytes. Mice harboring large numbers of anti-MBP T-lymphocytes in addition to other lymphocytes seldom develop EAE spontaneously. However, when these mice are crossed with RAG-l KO mice, thereby producing only anti-MBP T-lymphocytes, they all develop spontaneous EAE. The sharp contrast in susceptibility to EAE between the two types of anti-MBP transgenic mice, one carrying regulatory lymphocytes and the other not, enables us to pursue identifying and characterizating those cells. We also focus on a transgenic mouse model for asthma to determine in vivo the factors controlling the synthesis of important interleukins involved in the asthmatic process such as IL-4 and IL-5 and the increased production of immunoglobulin E.

I think the take home messages here are:

1. evolution is comlpicated! Something as complex as the immune system can have massively positive and massively negative effects all bundled together, and evolution finds a reasonable balance that doesn't go too far one way or the other...but the consequence is that in individuals, you will see BOTH defects, either a defective immune response or an immune response that will kill you.

2. curing diseases can be hard because an effective mechanism may have horrible side effects that may or may not be possible to separate. We evolve as a balance of conflicting problems: cell aging vs. cell immortality (a major part of cancer), too weak vs. too aggressive an immune system, etc. Trying to cure a disease that errs one way, could trigger an opposite problem and hence be a problem in itself.

3. The immune system in particular is a double edged sword. Our ability to fight (as a species if not always as individuals) such a wide range of diseases comes at the price of allergy, asthma and autoimmunity and these are inseparable from our ability to fight disease. So in treating one thing, we are working with a delicate balance. We need an immune system, but even more importantly we need a way to keep that immune system in check.