Animal immune systems

An animal must keep itself distinct from its environment, recognizing its own tissues and keeping them from being invaded or mixed with tissues of other organisms. There are two types of protection used by animals in keeping out invaders and resisting foreign substances, nonspecific and specific defenses. In both types, the body distinguishes between cells that belong to the animal, which are “self,” and anything that does not belong, or “nonself.”

Nonspecific Defenses

Even animals as primitive as sponges have the ability to recognize and maintain self-integrity. Scientists have broken apart two different sponges of the same species in a blender, intermixing the separated cells in a dish. Cells crawled away from nonself cells and toward self cells, reaggregating into clusters of organized tissues containing cells of only one particular individual. Phagocytic cells that engulf and destroy foreign invaders were first identified by a scientist who had impaled a starfish larva on a thorn. He observed that, over time, large cells moved to surround the thorn, apparently trying to engulf and destroy it, recognizing it as nonself. Even earthworms can recognize and reject skin grafts from other individuals. If the graft comes from another worm of the same population, the skin is rejected in about eight months, but rejection of skin from a worm of a different population occurs in two weeks. Phagocytic cells in earthworms have immunological memory, enabling a worm to reject a second transplant from the same foreign source in only a few days.

Barriers, chemicals, and phagocytic cells are nonspecific protective mechanisms that do not distinguish among different kinds of invaders. Tough outer coverings such as skin, hide, scales, feathers, or fur provide surface barriers. Nonspecific defenses also include secretions of mucus, sweat, tears, saliva, stomach acid, and urine, as well as body-fluid molecules, such as complement and interferon. Damaged tissues or bacterial invaders signal other cells to produce inflammation, a nonspecific response characterized by heat, redness, swelling, and pain. Cellular defenses associated with inflammation include phagocytes, such as neutrophils and macrophages, which engulf and digest bacteria and debris, and natural killer cells, which destroy cancer cells or virally infected cells by poking holes in them.

Immunity

The only specific defense in vertebrates is provided by the immune system, in which the component parts react against particular antigens on invaders, such as individual strains of bacteria or types of viruses. This more sophisticated protection is produced by lymphocytes that provide either cell-mediated or humoral immunity against particular antigens. Cell-mediated immunity depends on T lymphocytes (T cells) that become mature as they pass through the thymus, from which they get the “T” of their name. Humoral immunity is the function of antibodies, proteins released by B lymphocytes (B cells) that have matured and developed into plasma cells. The B lymphocytes reach maturity in the bursa of Fabricius in birds, where they were first recognized and from which they were named. Other vertebrates lack the bursa of Fabricius, and B cells mature in the bone marrow instead, so the name “B lymphocyte” still applies.

Antigen molecules are usually proteins or glycoproteins (proteins with sugars attached) that generate either an antibody response or a cellular immune response when they are foreign to the responding animal. So-called self-antigens are molecules on cell membranes that identify the cells as belonging to the animal itself. An animal would not normally produce an immune response against its own antigens, but the same antigens would generate an immune response if placed in another animal to whom they were foreign. These antigens are the means by which self and nonself distinctions are made by the immune system, so the system can determine whether to ignore cells or attack them. Occasionally, self-antigens, for some reason, are no longer recognized by the animal’s immune system and are attacked as if they were foreign. This causes an autoimmune disease, where the immune system destroys the body’s own tissues. For example, Knut, the famous orphaned polar bear cub who died prematurely at the Berlin Zoo in 2011, died of a previously unknown autoimmune disorder that caused encephalitis, leading to his drowning. Further research into autoimmune diseases in animals implies a link to gender, but the underlying mechanisms of these relationships remain unclear.

Scientific understanding of how the immune system functions is largely dependent on work done using laboratory animals, including rabbits, mice, zebrafish, and hamsters. Laboratory mice have been highly inbred into strains where all the animals are genetically identical, and their genes and antigens are well known. Studies on these mice have been essential in determining how the immune system normally works, how it fails to work in autoimmune diseases, and the inability to prevent cancer cells from proliferating. Research has also focused on the adaptive nature of animals' immune systems as they adapt to urban life and the role antigen recognition genes play in such adaptations. Additionally, scientists at the University of Wisconsin–Madison successfully imaged the adaptive immune system of a zebrafish in the early 2020s—the first non-mammal species to be visualized in such a way.

Antigen Presentation and Receptors

Central to the functioning of the immune system in mammals is a system of genes called the major histocompatibility complex (MHC). These genes encode a collection of cell-surface glycoproteins that are the self-antigens by which the immune system recognizes its own body cells. Class I MHC molecules are expressed on the surfaces of all nucleated cells, while Class II MHC markers are produced only by specialized cells, including cells of the thymus, B lymphocytes, macrophages, and activated T lymphocytes. Both Class I and Class II MHC molecules identify the cells bearing them as self, and these also serve as the context in which the immune system recognizes foreign antigens that are presented on the cell surface. Cells with self-antigens are tolerated by the immune response of that individual animal, while cells that show foreign antigens are attacked and destroyed. Rejection of a graft or transplanted organ is reduced with more closely matched tissues, which are better tolerated by the immune system.

When bacteria evade protective barriers and chemicals to enter an animal’s body, the animal’s macrophages attack, engulfing and digesting the invaders. One bacterium may have thousands of different antigenic segments that can be recognized on its surface or inside the cell. Small parts of these digested cells, the individual antigens, are joined to the macrophage’s newly formed MHC Class I and Class II before they are exposed on the cell surface. The foreign antigens fit into a space or pocket within the MHC molecule and are recognized by T cells that have the same MHC molecules and can respond specifically to the foreign antigen. Cytotoxic T cells (T) react to antigens held in the pocket of a Class I molecule, while helper T cells (T) respond to those presented by Class II molecules. T cells are the agents of cellular immunity, producing perforin molecules that puncture and kill cells bearing the foreign antigen against which the T cells are specific. T cells, when activated by encountering their specific antigens presented with Class II molecules, release cytokines that help to activate both T_C cells and B lymphocytes. Activated B cells divide to produce memory B cells and lymphocytes that mature into plasma cells, which secrete about two thousand antibody molecules per second over their active lifespan of four or five days.

Both T and B lymphocytes can react with their specific foreign antigens because the antigen-MHC complex binds to receptor molecules on the lymphocyte surfaces. Each clone of lymphocytes has the genetic ability to respond to a particular shape that fits its receptors. There may be millions of different receptors among the lymphocytes of a single animal, capable of binding millions of different antigens, even artificial chemicals not existing in nature. This enormous variability in response capability makes the immune system of each animal protective against many kinds of foreign invaders. Since each individual has its own set of immune responses, a population is less likely to have all its members die in an epidemic. Certain animals will be more resistant to the pathogens, so some will survive to reproduce and keep the population from extinction.

Using mice, researchers at Stanford University discovered an immune system treatment that addressed all negative aspects of an aging immune system. In older mice, the treatment decreased the level of inflammatory proteins, increased regeneration in B and T lymphocytes, improved immunity to fight deadly infections, and increased the efficacy of vaccines. This breakthrough may have applications for humans.

Primary and Secondary Immune Responses

When a foreign antigen is encountered by an animal for the first time, both T and B cells that can bind to the antigen are activated, but not immediately. In a series of reactions, macrophages first break down the antigen-bearing cell, processing and presenting the antigen on its surface with MHC. The T cell specific to that antigen then encounters the antigen-MHC complex on the macrophage and divides to produce a clone of memory T cells and a clone of effector (activated) T cells. Activated T cells release cytokines that activate T and B cells so that they can attack the same foreign antigen. The first encounter with antigen produces a slow primary response, taking more than a week to reach peak effectiveness. During the time needed to generate this response, pathogenic bacteria or viruses can produce disease in the animal under attack. The memory T and memory B cells remain alive but inactive until the same foreign antigen is encountered again, even years later. The secondary response that results immediately when these memory cells are activated occurs so quickly that the disease process does not recur.

The importance of the immune system is evident in humans who lack its function—those with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). HIV is the causative agent of AIDS and is similar to viruses that attack other species in the same way. Most who die from AIDS succumb to one of many opportunistic infections that cause diseases in HIV-positive individuals but which are eradicated by the immune system in individuals without HIV/AIDS. Researchers have successfully prevented HIV-like infections in monkeys using an experimental mRNA HIV vaccine, permanently eliminated HIV markers in mice using dual gene-editing therapy, and identified specific antibodies that aid in preventing HIV infections in vulnerable populations. These discoveries in animals help guide therapy and prevention methods in humans.

Principal Terms

Antibody: protein produced by lymphocytes, with specificity for a particular antigen

Antigen: chemical that stimulates the immune system to respond in a very specific manner

Cell-Mediated Immunity: production of lymphocytes that specifically kill cells with foreign antigens on their surfaces

Humoral Immunity: production of antibodies specifically reactive against foreign antigens carried in body fluids (humors)

Lymphocyte: white blood cell that produces either cell-mediated or humoral immunity in response to foreign antigens

Macrophage: mature phagocytic cell that works with lymphocytes in destroying foreign antigens

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