Immunology: From Pioneering Discoveries to Opportunities

Immunology originates from the Latin word ‘immunis’, meaning 'exempt' signifying that a person contracting an infection develops protection from the same infection a second time (and is thus immune). The history of immunology dates back over 2000 years, and it was between 2000 and 1000 BC that there was possible smallpox in Egyptian mummies, including Ramses V, who died in 1157 BC. In 430 BC, the Greek historian Thucydides proposed that people who contracted and recovered from plagues - were protected from future infections, thus laying the groundwork for immunology.

Advancing further in time, in the 10th century CE, the Persian physician Al-Razi (Latinized as Rhazes) distinguished between smallpox and measles. He also authored significant works on allergy and immunology, including descriptions of allergic asthma. Subsequently, in the 11th century, the Persian polymath Ibn Sina (Avicenna) introduced theories on acquired immunity. By the 15th century, the Chinese and Turks had developed a technique of introducing dried crusts from smallpox pustules into minor cuts to induce protective immunity. However, the inhalation technique for inducing immunity was reported in China as early as the 10th Century CE.

In the 18th Century CE, British physician, Edward Jenner, noticed that milkmaids with cowpox seemed immune to deadly smallpox. He inoculated a boy with cowpox material who then showed immunity to smallpox, leading to the development of the first vaccine. This played a crucial role in the eradication of smallpox by the 20th Century CE and laying the foundation for modern immunology. In 1881 CE, Louis Pasteur, a French chemist and microbiologist, collaborated closely with Émile Roux, a physician, and successfully demonstrated a vaccine against anthrax in sheep. By 1885, the duo had developed a vaccine for rabies, with the first human trial conducted on a young boy named Joseph Meister after a rabid dog bit him - saving the boy's life and making a significant leap in preventive medicine.

In 1884, zoologist Metchnikoff, while studying starfish larvae, proposed the cellular theory of immunology, suggesting cells defend the body directly. This concept significantly influenced views on the immune system, but its full acceptance came much later. In 1890, von Behring and Kitasato reported that animals immunized with diphtheria and tetanus toxins generated neutralizing antitoxins in their blood, highlighting passive immunity, contrasting with the then-prevalent cellular theory of immunity centered on phagocytic cells. This groundbreaking discovery that circulating antitoxins mediated immunity, known as serotherapy, led to von Behring being awarded the first Nobel Prize in Medicine in 1901. However, Kitasato did not receive the Nobel with him. Several immunologists have been honored with Nobel Prizes - Richet in 1913 for his experimental demonstration of anaphylaxis; Bordet in 1919 for his immunity-related discoveries; and Landsteiner in 1930 for his discovery of human blood groups.

A significant turning point in the field of immunology was the clonal selection theory developed by Talmage in the 1950s and by Jerne and Burnet in the 1960s. It revolutionized our understanding of how the immune system recognizes and responds to antigens. Understanding the history of immunology provides a foundation to grasp the intricate mechanisms of our immune system.

At its most basic, the immune system defends the body by distinguishing between 'self' and 'non-self' and consequently mounting a response through its two fundamentally different lines of defense – the innate immune system, inherited from invertebrates, and the adaptive immune system, found only in vertebrates. The innate (natural) immune system's response includes physical, chemical, and microbiological barriers, which work rapidly to detect and destroy foreign invaders encountered in daily life. The acquired (adaptive) immune system's response involves specialized T and B cells, which can recognize and mount a rapid response (immunologic memory) after initial contact (immunologic priming) with the foreign invaders.

The immune system, through its innate and adaptive responses, works in a perfect symphony to maintain good health, which is essential for the survival of humans.

However, when the immune system malfunctions, it can lead to problems both by being underactive - resulting in severe infections and tumors due to immunodeficiency, such as microbial infections in the lungs; or overactive - leading to chronic inflammation and autoimmune diseases, such as autoimmune thyroiditis, Addison disease, and Kawasaki disease. The diseases that arise as a consequence of dysfunction of the immune system not only have a significant impact on the patients and their families but also have a wide-ranging effect on the healthcare system and costs, given the high morbidity and mortality for some of these diseases. The most common therapies for immune dysfunction diseases have usually involved non-specific immune-modulating or immunosuppressive agents such as systemic corticosteroids, which also have associated short- and long-term adverse events because of their non-specificity.

There was a need for scientists to target specific parts of an antigen, offering more precision and improving therapeutic outcomes. In 1975, Milstein and Kohler discovered a method to produce monoclonal antibodies through the hybridoma technique, revolutionizing the immune therapeutics field. In the 1980s, monoclonal antibodies were used in laboratories and were essential in identifying and isolating cells and proteins, and by 1986, they were used to prevent organ transplant rejection. The first breakthrough in monoclonal antibody treatment was achieved in 1997 with the regulatory approval of rituximab (a monoclonal antibody targeted against CD20 found on the surface of B cells) for non-Hodgkin's lymphoma. By the 2000s, monoclonal antibodies were being used for various autoimmune conditions like rheumatoid arthritis and Crohn's disease and also to lower cholesterol. The discovery and development of nanobodies in the 1990s has further revolutionized the field of immune therapeutics: these are smaller than monoclonal antibodies and thus expand the possibility of use in therapeutics and can be used in inhalable forms.

Thanks to the remarkable complexity, versatility, and accessibility of the immune system and the advances in molecular biological techniques, we have gained an unprecedented understanding of how the human immune system works. This knowledge, coupled with technological advances such as the development of monoclonal antibodies and nanobodies, has presented an exciting opportunity for developing vaccines for millions of people, treatments for patients without adequate therapeutic options, or those inadequately managed with conventional therapies. However, challenges remain as we still do not have vaccines for many diseases such as HIV, Hepatitis C, or malaria, and the danger of reemergence of previously eradicated diseases or bringing the world to a grinding halt, such as with the COVID-19 pandemic, looms large.

While we have made significant progress in understanding the human immune system and developing targeted therapies, it is evident that we have only scratched the surface, and much more is to be learned and discovered. The future of immunology offers numerous challenges but also promises discoveries that will advance our knowledge of the immune system and how we can harness it to maintain good health, prevent disease, and treat diseases when they occur. The rapid development and global cooperation seen in the creation of COVID-19 vaccines is undoubtedly a beacon of hope for future endeavors in the field of immunology.

Also, in developing these treatments, we must consider the differences and disparities in the demographic, socioeconomic, and environmental factors, as susceptibility to immunological diseases may be impacted by these factors. It is also essential to address questions regarding access to these medications. This would ensure that advances in the field of immunology benefit patients with high unmet needs, reduce the impact on health systems, and lead to an equitable and healthier future.