Before we dive into the nitty-gritty of the workings of the immune system, let's learn a little bit about how we came to discover it.
The field of Immunology started with the observations that individuals who had survived a deadly disease were the only ones who could nurse the ailing because they seemed to be protected from reinfection. The field of immunology thus got its name from the Latin word 'immunis' meaning 'exempt'.
The initial advances of immunology was led by works on vaccines. These works however, advanced purely on the basis of trial-and-error or accidentally since there was next to no knowledge of the mechanisms of the immune system. When Louis Pasteur developed vaccines for rabies and other life threatening illnesses, he still didn't understand the underlying mechanisms of the immunity resulting from these vaccines.
Two camps arose in the science community, each lead by their own postulate, postulates that attempted to hypothesize the mechanisms of immunity. One postulate was that of immunity mediated by soluble agents and the other, Cell-mediated Immunity.
In 1890, Emil von Behring and Shibasaburo Kitasato conducted experiments that were among the firsts to shed light on the workings of the immune system. They made the incredible observation that when the serum (noncellular component of the blood) of an animal immunized to diptheria is transferred into an unimmunized animal, the unimmunized animal could survive the infection.
In 1883, Elie Metchnikoff demonstrated that certain white blood cells, which he termed as 'Phagocytes' (later identified as monocytes and neutrophils), ingested microorganisms and foreign particles. He also observed that these phagocytes were more active in case of an immunized animal.
Experiments of von Behring and Kitasato supported the soluble agents hypothesis. These findings acted as a catalyst for more studies to be conducted on serum and its components to gain a better understanding about what exactly grants an organism immunity. In the early 1900s, various components of the serum were characterized according to the activity it exhibited. Antitoxin, preciptin and agglutinin were named according to the activity they expressed. In 1930s, Elvin Kabat established that these different components were in fact the same and named it Gamma Globulin (now Immunoglobulin or Antibodies). Since these antibodies are found in the body fluids or body humors, the immunity granted by them is also called as Humoral Immunity.
The findings of von Behring and Kitasato had such a profound impact on the field of immunology that even today certain treatments use transfer of immunoglobulins to susceptible individuals. These therapies are done in cases of emergency such as against snake, scorpion venoms or even to grant immunity to immunocompromised individuals. This type of immune protection that is transferred between individuals is known as Passive Immunity. Passive immunity is a quick solution but unlike vaccines, it does no provide long-term protection against infections.
The conflict between the two beliefs of Immunology raged on for several decades. While the Humoral immunity was gaining importance due to the several supporting observations and experiments, Cell-mediated Immunity lagged behind due to the lack of modern tissue culture techniques and genetically defined animal models. What helped renew the interest is the study conducted by Merrill Chase which revealed that white blood cells, when transferred between guinea pigs, could provide immunity against tuberculosis. With this new found evidence, cell-mediated immunity hypothesis gained more interest and more people started working on it.
As tissue culture techniques improved, lymphocytes were identified as the cell type responsible for cellular as well as humoral immunity in the 1950s. Bruce Glick established the two types of lymphocytes using chickens: T lymphocytes, developing from the Thymus and B lymphocytes, developing from the Bursa of Fabricius (in birds). It was later discovered that in mammals B lymphocytes develop in Bone marrow.
Thus the conflict between the two camps of humoral and cell-mediated immunities was resolved as both were found to be correct. The two systems were found to be interlinked and of paramount importance for the successful and efficient functioning of the immune system.
One of the great mysteries of immunology was 'How did the immune system manage to acquire such high specificity for the foreign particles (antigens)?'. In the 1900s, Jules Bordet shared findings that the immune system reacts to foreign substances such as the red blood cells of other species and not just pathogenic substances. Karl Landsteiner demonstrated that production of antibodies could be induced by any nonself organic chemical leading to the discovery that antibodies have an immense range of reactivity that covers even compounds that have only recently been synthesized in the laboratory. What was also remarkable was the specificity of the reaction. Molecules differing by as little as one amino acid would trigger different antibodies. To explain this phenomenon, two theories were proposed, and again, the researchers were split in two camps. But unlike conflict between postulates of mechanisms of immunity, there could only be one winner.
The two theories were The Selective Theory and The Instructional theory. Paul Ehrlich in 1900 proposed that blood cells express a diverse array of "side-chain receptors" (suggesting that the cells were pluripotent) which would bind to infectious agents and deactivate them. With the help of the concept of enzyme-substrate interaction proposed by Emil Fischer, he explained that the binding of a receptor and an infectious agent can be compared to the fit between a lock and a key. He also suggested that this binding would induce the cell to 'select' the specific receptor causing production and release of more receptors of the same specificity.
The selective theory was challenged in 1930s and 1940s by the instructional theory. Proposed by Friedrich Breinl and Felix Haurowitz in 1930s and redefined by Linus Pauling in 1940s, this theory postulated that the antibody moulded around the antigen resulting in a complementary configuration.
With new experimental data from F. Macfarlane Burnet, Niels Jerne, and David Talmadge in the 1950s, the selective theory was refined and re-established. Now called as Clonal Selection Theory, most of the aspects suggested by Ehrlich were found to be correct with a few modifications. According to the clonal selection theory, the T or B lymphocytes expresses several copies of the identical receptor on its surface (the cells are not pluripotent like Ehrlich suggested). The specificity of these receptors is determined before its interaction with the antigen. Upon the interaction, the cell proliferates, generating clone daughter cells with the same receptor. These clones then launch an attack on the invading antigen resulting in its elimination.
Thus, the clonal selection theory prevailed and the instructional theory was disproved in 1960s.
Though major concepts of the workings of the immune system have been established, there are still several conundrums waiting to be solved. However, to discuss these conundrums we must first understand the basics of the system. The next infodump will be focusing on the classification of the immune system and their functions.
Kuby, Janis. Kuby Immunology. New York : W.H. Freeman, 2013.