It has been reported that an increasing number of people, especially elementary school and junior high school students, suffer from cedar pollen allergy. This phenomenon occurs despite improvements in living environments, diets, hygiene, medical and pharmaceutical conditions in modern society.

About 60 to 70 years ago, a running nose was a very common phenomenon among children, and I was probably no exception. Cedar pollen allergy and atopic dermatitis rarely developed at that time. I still remember that infectious diseases, including dysentery and parasitic diseases, pulmonary tuberculosis and hypertensive cerebral hemorrhage were common diseases. Cancer, however, was relatively rare. In the suburbs of cities at that time, cows and horses were still in the fields, and their excrement and human feces were used as organic fertilizers. I remember that paved roads were still uncommon and we walked to school on dirt roads. The environment was not as highly hygienic at that time as it is presently.

One study suggests a hypothesis compiled through examination of fieldwork data from the viewpoint of humoral and cellular immunity, which has provoked a world-wide discussion. This hypothesis was offered by Mr. Taro Shirakawa, a researcher at Kyoto University, and was called the “hygiene hypothesis.”

Allow me to explain this “hygiene hypothesis.” Mr. Shirakawa suggested that the high incidence of tuberculosis and parasitic infections among Japanese was due to an immune status in which humoral immunity was dominant. The conditions related to occurrence of infectious diseases greatly changed because of the availability of antibiotics. Mr. Shirakawa hypothesized that it caused a shift toward cellular immunity becoming dominant over humoral immunity in Japanese people. This means that the dominance in immune status may shift between cellular immunity and humoral immunity in responding to stimulation of antibody production from potential pathological exposure in the environment.

Immune systems of animals, including human beings, are equipped with two different mechanisms to eliminate invaders; one is to eliminate invaders mainly by immune cells reacting to antigens, and the other is by opsonization. In the opsonization process, an antibody is produced to form an immunocomplex of antigen, antibody, and complement, which is later phagocytized, that is, engulfed and dissolved by immune cells called macrophages. This process starts with signals from macrophages, which trigger the immune reactions. In a case when the antigen stimulation is an influenza virus, for example, phagocytosis by macrophages is followed by the activity of humoral immunity.

Macrophages present antigens to T and B lymphocytes, which trigger the immune responses of humoral immunity. At the same time, in a case when there is antibody stimulation from M. tuberculosis, macrophages are not able to destroy it to produce antibodies. Instead, the immune system reacts to M. tuberculosis by presenting a signal to T lymphocytes, which comprise a component of cellular immunity. M. tuberculosis has a unique “pellicle,” which contains more lipids than other bacteria, and the structure of its antigen is unique. Therefore, the mechanism to produce antibodies hardly functions against M. tuberculosis. This phenomenon makes it difficult to develop an M. tuberculosis vaccine. The immune system biologically defends against antigens of various invaders in these ways.

On the other hand, returning to the topic of cedar pollen allergy, when antigen stimulation from the environment changes, the dominance of the immune status also shifts accordingly between cellular and humoral immunity, like a seesaw. Immunity gradually alters when antigen stimulation by M. tuberculosis or parasites decreases. Cedar trees were extensively planted in suburban mountains after World War II. In addition, our living environments have changed. Various chemicals, including fungicides and lumber preservatives like formalin and toluene, are now in widespread use in construction lumber. Furthermore, the air-tightness of houses has increased. In traditional Japanese houses, rooms were divided with “shōji,” which were sliding doors or screens consisting of a wooden frame and paper; in addition, windows at that time allowed easier ventilation. Modern Japanese houses, by contrast, have airtight sashes and windows, which inhibit antigenic substances from diffusing to the outside.

The younger generation of Japan supposedly has different immune defenses from the older generation, like us. Young Japanese are considered to have type I hypersensitivities, which may trigger excessive reactions resulting in anaphylaxis. This is the ultimate alarm reaction to the environment. These reactions include cedar pollen allergy, food allergy, bee venom allergy, penicillin shock, contrast agent allergy, as well as bronchial asthma, allergic rhinitis, atopic dermatitis, metal allergy, and others. Repeated antigenic stimulation to the skin, nasal mucosa, respiratory mucosa, oral mucosa, or digestive mucosa largely impacts the immune system and triggers systemic reactions. I regard this kind of allergic reaction, in a sense, as the ultimate evasive responce.

In this type of allergic reaction, IgE (Immunoglobulin E) plays a major role in humoral immunity. Immunoglobulins that are invoked to develop “resistance” in this case are IgM (innate immunity), IgG (adaptive immunity), and IgA (mucosal immunity). IgM, which is a component of innate immunity leads to “immunoglobulin class switching” in consecutive antigen stimulation. In immunoglobulin class switching, various kinds of immunoglobulin are produced by plasmatocytes, which trigger antibody production. Immunoglobulin class switching randomly occurs, and may be caused by environmental factors. This is considered to be one of the factors that has led to the contemporary immune status in which humoral immunity is dominant.

When our skin is transplanted to other parts of our body, it generally doesn’t result in rejection and functions normally. However, transplantation of human skin from another person’s body results in failure in most cases. German biochemist Paul Ehrlich, in the 19th century, investigated this phenomenon with profound insight, and described it as “horror autotoxicus” (the horror of self-toxicity). He characterized the genius of immunity as “self and non-self.” This theory led to discovery of the immunological phenomenon expressed as “tolerance and rejection.” I would like to write about the common cold, smallpox, SARS, and MERS in the next column.