Immunology

• 1. Introduction

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  Immunology began with thorns pushed into starfish larvae. The Russian biologist Ilya Ilyich Mechnikov pressed small thorns into the larvae and watched unusual cells gather around the wound. He was seeing the body trying to keep itself whole. That moment of observation gave a name to a whole branch of biology and medicine, the study of immune systems in all organisms. Mechnikov coined the term, and in 1908 he shared the Nobel Prize with Paul Ehrlich, honored for their work on immunity. But the questions that came after that prize are bigger than any single experiment. How does a body tell itself apart from an invader? Why does a newborn arrive almost defenseless, and where does its first protection come from? How did a single idea split scientists into rival camps for decades? And why do diseases we never thought of as immune, from heart conditions to Alzheimer's, now sit inside this field? The answers run through cells, antibodies, hormones, and even the eggs a butterfly chooses to lay.

• 2. Self And Non-Self

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  Phagocytosis was the phenomenon Mechnikov first observed, the body engulfing a foreign object to defend itself. That single process sits at the root of how the immune system recognizes friend from foe. The system can perform self and non-self recognition, telling the body's own constituents from everything else. A substance that ignites the immune response is called an antigen, defined as anything that elicits the generation of antibodies. The cells that recognize the antigen are lymphocytes, and once they recognize it, they secrete antibodies.

  Antibodies are proteins that neutralize disease-causing microorganisms, but they do not directly kill pathogens. Instead they mark antigens as targets for destruction by other immune cells, such as phagocytes or NK cells. The antibody response is the interaction between antibodies and antigens. Antibodies are specific proteins released from a class of immune cells known as B lymphocytes. Immunology rests on understanding these two biological entities and the cellular response to both.

  The immune system itself has been divided into a more primitive innate immune system and, in vertebrates, an acquired or adaptive immune system. That adaptive arm is further split into humoral, or antibody, and cell-mediated components. The earliest written mention of immunity reaches back to the plague of Athens in 430 BCE. Thucydides noted that people who had recovered from the disease could nurse the sick without catching it a second time. Many ancient societies recorded the same phenomenon, but it did not become scientific theory until the 19th and 20th centuries.

• 3. Cells Versus Humors

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  Elie Metchnikoff argued that cells, more precisely phagocytes, were responsible for immune responses. That was the cellular theory of immunity, and at the end of the 19th century it collided head-on with a rival. The humoral theory, held by Robert Koch and Emil von Behring among others, claimed the active immune agents were soluble molecules found in the organism's humors rather than its cells. Ehrlich had fed mice small but increasing doses of the poisons ricin and abrin until they became, in his words, "ricin-proof". He read this as immunization, noting it began abruptly after a few days and lasted for several months.

  Macfarlane Burnet broke the deadlock in the mid-1950s, inspired by a suggestion from Niels Jerne. He formulated the clonal selection theory of immunity. On that basis Burnet built a theory of how a response is triggered by the self/nonself distinction. "Self" constituents do not trigger destructive immune responses, while "nonself" entities like pathogens or an allograft do. The theory was later modified to reflect discoveries about histocompatibility and the complex two-signal activation of T cells.

  Polly Matzinger and colleagues offered a different lens with the danger model, sometimes called danger theory. It has proven very influential, drawing many comments and discussions. Other frameworks followed, including autopoietic views, cognitive immune views, and the discontinuity theory. The self/nonself vocabulary has been criticized, yet it remains deeply influential, a sign of how stubbornly these foundational ideas hold.

• 4. The Newborn Defense

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  Neonates are described as being in a state of physiological immunodeficiency. Both their innate and adaptive immune responses are greatly suppressed at birth. A newborn responds favorably to protein antigens but not as well to glycoproteins and polysaccharides. Many infections acquired by neonates come from low-virulence organisms like Staphylococcus and Pseudomonas. The mean level of C3 in a newborn is roughly 65 percent of the adult level, and the ability to activate the complement cascade is very limited.

  Phagocytic activity is also greatly impaired in newborns. Their monocytes are slow and produce reduced ATP, while diminished up-regulation of integrin and selectin receptors limits how neutrophils interact with adhesion molecules in the endothelium. Total lymphocyte numbers run significantly higher than in adults, yet cellular and humoral immunity is still impaired. A newborn's T cells proliferate poorly and make very small amounts of cytokines like IL-2, IL-4, IL-5, IL-12, and IFN-g. B cells develop early during gestation but are not fully active.

  Most of the immunoglobulin present at birth is maternal IgG, transferred across the placenta using the FcRn, the neonatal Fc receptor. IgM, IgD, IgE, and IgA do not cross the placenta and are almost undetectable at birth, though breast milk supplies some IgA. These passively acquired antibodies can protect the newborn for up to 18 months, but the response is short-lived and of low affinity. They can also dampen things. A child exposed to the antibody before the antigen will produce a weakened response, which is why passively acquired maternal antibodies can suppress active immunization. Between six and nine months a child begins responding more strongly to glycoproteins, but a marked response to polysaccharides usually waits until at least one year of age, helping explain the distinct time frames in vaccination schedules.

• 5. Hormones And Age

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  17-β-estradiol, an estrogen, is the most significant hormonal driver of immunological change in females during adolescence, while in males it is testosterone. Estradiol usually begins to act around the age of 10, with testosterone following some months later. These steroids do more than shape sexual characteristics. Evidence suggests they affect the development and regulation of the immune system, including an increased risk of developing pubescent and post-pubescent autoimmunity. Cell surface receptors on B cells and macrophages may even detect sex hormones in the system.

  17-β-estradiol has been shown to regulate the level of immunological response. Some male androgens, such as testosterone, appear to suppress the stress response to infection, while others, like DHEA, increase immune response. In both sexes, these hormones seem to exert more control over the immune system during puberty and post-puberty than during the rest of adult life. Physical changes such as thymic involution further alter immunological response, a reminder that the immune system keeps shifting as the body ages.

• 6. Immunity In The Wild

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  The Monarch butterfly often lays its eggs on certain toxic milkweed species when it is infected with parasites. Those toxins reduce parasite growth in the offspring of the infected Monarch. The behavior carries a cost. When uninfected Monarchs are forced to feed only on these toxic plants, they suffer reduced lifespan compared with other uninfected butterflies. This points to a costly behavior that probably evolved to reduce the severity of parasite infection. This is the territory of ecoimmunology, which explores the relationship between an organism's immune system and its social, biotic, and abiotic environment.

  Mark Schaller coined the phrase behavioural immunity to describe psychological pathogen avoidance, such as the disgust aroused by stimuli around infected individuals, including the smell of vomit. Recent ecoimmunological research has turned to defenses traditionally considered non-immunological, like pathogen avoidance, self-medication, and symbiont-mediated defenses. Aphids rely on several symbionts for defense from key parasites and can vertically transmit them from parent to offspring. A symbiont that successfully protects against a parasite is more likely to pass to the host's offspring, allowing coevolution with parasites in a way similar to traditional immunity. Even extinct species offer clues, since the preserved immune tissues of the thylacine, Thylacine cynocephalus, can provide insights into its biology.

• 7. Medicine At The Bedside

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  AIDS is the most well-known disease that affects the immune system itself. It is an immunodeficiency marked by the suppression of CD4+ helper T cells, dendritic cells, and macrophages by the human immunodeficiency virus, HIV. Clinical immunology studies diseases caused by disorders of the immune system, sorting them into two broad categories. Immunodeficiency is where parts of the system fail to provide an adequate response, as in chronic granulomatous disease and primary immune diseases. Autoimmunity is where the system attacks its own host, as in systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's disease, and myasthenia gravis. Other disorders include hypersensitivities such as asthma and allergies, where the body responds inappropriately to otherwise harmless compounds.

  Immunotherapy uses immune system components or antigens to treat a disease or disorder. It is most commonly used for allergies, autoimmune disorders like Crohn's disease, Hashimoto's thyroiditis, and rheumatoid arthritis, and certain cancers. It also serves patients who are immunosuppressed, such as those with HIV, and includes regulating factors like IL-2, IL-10, GM-CSF B, and IFN-α. The specificity of the bond between antibody and antigen makes the antibody an excellent diagnostic tool. Antibodies for a desired antigen can be conjugated with an isotopic or fluorescent label, or a color-forming enzyme, to detect it. Similar antigens, though, can cause false positives when antibodies cross-react with imperfect matches.

  When conditions worsen to emergency status, portions of immune organs can be surgically excised for examination while patients are still alive, including the thymus, spleen, bone marrow, lymph nodes, and other lymphatic tissues. Clinical immunologists also study how to prevent the immune system from destroying allografts, the problem of transplant rejection. Clinical immunology and allergy is usually a subspecialty of internal medicine or pediatrics, and fellows may rotate through rheumatology, pulmonology, otorhinolaryngology, dermatology, and the immunologic lab. The field's reach keeps widening, because immune responses now appear in metabolic, cardiovascular, cancer, and neurodegenerative conditions like Alzheimer's disease, diseases once thought to have nothing to do with immunity at all.