Inner Nature: Immunity — Autosurveillance

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By Vidya Rajan, Columnist, The Times

The immune system is the mechanism that protects and defends the body. Although its main purpose is defense against attack, the immune system is also a barrier, border patrol, soldier, police, doctor, parent, and amazingly, a fortune-teller, all in one package. Not only that, it exists in every living organism from bacteria to plants to animals to protect against infection. Before moving on, we need to define “infection”.

Living organisms are made of organic molecules. They all need material to build their own organic molecules, but only photosynthetic organisms can harvest light to make them from scratch using carbon dioxide. This sets up a system by which photosynthetic producers, bacteria, algae and plants – the producers at the bottom of the food chain – support the nutritional needs of the rest, the consumers. The consumers are predators who eat prey: either the producers themselves in which case they are called herbivores, or something higher up on the food chain (then called carnivores), or both (omnivores). To avoid being eaten prey produce deterrents, and the predators that consume them produce all manner of defense weapons to neutralize or overcome the deterrents. This sets up an arms race that steadily escalates in firepower traits such as speed or ferocity. But not all predators are large and attack in an obviously adversarial way. Predators can deploy trickery and stealth to sneak up unobserved. Some predators are not even visible to the naked eye. These predators are parasites such as bacteria, viruses, fungi, and worms are tiny, but their motivation is to obtain food. They attach themselves to the inside or outside of host bodies and absorb their nutrients. This constitutes an infection.

The hosts resist the entry of parasites by erecting barriers that are hard to penetrate. If the barriers fail, they fight the parasites off. This is the immune system’s fight. As I mentioned before, all host bodies, including plants and bacteria have an immune system of sorts. Here, I will look at the immune system of vertebrate animals such as ourselves and compare these to the immune systems of invertebrate animals such as insects.

Vertebrates are distinguished from invertebrates by the presence of an endoskeleton. In most animals, this endoskeleton is made of bone; in some fish such as sharks, it is made of cartilage. Bone is more than just a frame to hang muscles on: it is a living tissue with metabolic and physiological functions. Bones originate from mesodermal cells that were orginally sandwiched between endodermal cells which give rise to our digestive system and lungs, and ectodermal cells which give rise to our skin, brain and sensory organs. The rest of the filling of our body between the outside and inside layers – muscles, blood, bone, kidneys, heart, and gonads – well, that’s what the mesoderm becomes. Bones and blood are intimately linked with regard to the immune system. The bone marrow contains blood-cell-making, or hematopoietic, stem cells that give rise to two major lineages of blood cells – the myeloid lineage which produces red blood cells and phagocytic immune cells that are commonly called white blood cells, and the lymphoid lineage which produces the familiar T-cells and B-cells as well as a class of cells called natural killer cells (NK cells).

The immune system is loosely divided into inherent (innate) and induced (adaptive) responses. The innate system is a series of impediments to parasites setting up an infection: the skin and its outgrowths, corrosive secretions of acid and salt, sticky mucus and wax, and small antimicrobial chemicals including enzymes and peptides that non-specifically target a variety of bacteria and viruses. Significant among barriers is the microbial barrier of symbiotic bacteria and fungi that exists on all surfaces exposed to the outside – the skin, the digestive system, the mucus membranes of the eyes, mouth, nose, and urinogenital system – and block would-be parasites from accessing host tissues. If the barrier is breached anyway and an infection is imminent, the components of blood take over. Blood clots with fibrin which entangles the parasites and clogs the wound, phagocytic white blood cells gobble parasites up, complement marks them for destruction, interleukins broadcast a call for help from other immune cells, interferons send out alarms to uninfected host cells to shore up their defenses, and natural killer cells go on the hunt. NK cells search for signs of infection and sacrifice infected host cells as well as the parasites hiding in them for the common good by peppering them with destructive chemicals. The immune system really does not do things by halves when it is aroused. [Note: Therein lies a problem. Allergies and inflammation are the downsides of a too-enthusiastic surveillance system.]

Where the innate immune system is tactical, the adaptive immune system is strategic. To preempt future issues with known parasites, a class of phagocytic cells called antigen-presenting cells (APC) of the innate system liaise with a class of T-cells of the adaptive immune system called T-helper cells. The first time a predator enters the host body, the adaptive immune system is provided an antigen priming service, something akin to the T-helper cell interface being shown a “Wanted” poster by APC (see Figure 1). [Note: It would be a clever predator strategy to incapacitate T-helper cells; that is done by HIV, the virus which causes AIDS.] The real innovation that the adaptive system brings to vertebrate immune systems is the ability of the immune system to learn the features of new parasites and respond quickly. It is nimble and smart.There are two major effectors of the adaptive response: soluble proteins called antibodies which neutralize anything from toxins to pathogens, and cytotoxic T-cells which go after host cells that have been infected, or are otherwise compromised, by recognizing subtle cell surface changes that indicate that they have been subverted. [Note: The recognition system requires a whole article to describe,  but suffice it to say that it can recognize any shape in the Universe without first seeing it. This is one of the key reasons for the immune system’s success in recognizing new pathogens.] The second time that same predator enters the body, memory cells of the adaptive immune system recognize the “Wanted” predator. The adaptive system reacts instantly and with fury, annihilating all traces of the “Wanted” predator or anything that looks like it. This is the principle on which vaccinations and immune-based therapies are based, but it is also the principle of autoimmune diseases and anaphylactic shock. [Note: Many drugs that end with the suffix “-mab” are antibodies. T-cells’ ability to recognize intracellular changes have been harnessed for treatment by a process called chimeric antigen (car) T-cell therapy.]

Figure 1: Function of T-helper cells. T-helper cells liaise between the innate system and the adaptive system by releasing chemicals called interleukins that stimulate specific classes of cells. T-helper cells also help with tamping down the immune system by activating a class of cells called T-regulatory cells which mediate tolerance. Tolerance is not discussed in this article, but is important for preventing immune reactions to materials such as food. APC = antigen presenting cells; CD4 = molecule found on the surface of T-helper cells.
Figure from Häggström, Mikael (2014). “Medical gallery of Mikael Häggström 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.

Insects are invertebrates. They do not have endoskeletons, and therefore they lack an adaptive immune system resembling the vertebrate B- and T-cell system. This appears to subordinate insect immune systems in sophistication to bacteria, which do have an adaptive immune system. [Note: The bacterial immune system, Crispr-Cas, has been harnessed to provide a precision gene editing system which has revolutionized genetic engineering in the last few years.]

Insects have an innate immune system consisting, as in vertebrates, of barriers such as exoskeleton, microbial symbionts, chemicals such as antimicrobial peptides, and phagocytic cells chomping down on parasites [1]. Recall that invertebrates have an open circulatory system where hemocoel bathes the internal organs as I have described in an earlier article [2]. The hemocoel contains phagocytic cells called hemocytes and they are able to access all the nooks and crannies of the insect’s body to provide systemic surveillance. In addition, insects produce antimicrobial proteins, clotting factors, and cytokines. Wounding is accompanied by a response called “melanization” which involves the synthesis of melanin, the pigment which is associated with skin color. Melanization has many outcomes: it encapsulates parasites, provides wound healing and clot formation and produces reactive chemicals that kill invaders. The melanization process is even found in albino cave insect species otherwise lacking pigmentation.

Insects lack an adaptive immune system made of B- and T-cells. However, immune memory is not completely lacking. There is a distinct instinctual hardwired response, as well as a “primed” response that has features of adaptability: exposure of an insect to a predator seems to be passed on somehow to its offspring so that they are more resistant to the same predator [3].

The instinctual, hardwired response of the innate system was first discovered in insects. Animals have been around for a long time. The animal kingdom as a group is about 750 million years old, and entered an ecosystem dominated by the bacteria, which are about 3,500 million years old. Early and sustained existential pressures selected for an ability to quickly sense the presence of pathogen molecules produced by bacterial and viral parasites using a pathway called the Toll system. The Toll system was first discovered in insects, and parallels were found in other animals and also in plants. In humans, these are called Toll-like receptors (TLR) and are present on white blood cells which recognize bacterial molecules instantly and sound the alarm, causing inflammation attended by its four apocalyptic horsemen: Rubor, Calor, Tumor, and Dolor.

The next time you cut yourself, notice how quickly the wound reddens with blood (rubor), feels warm (calor), swells (tumor) and hurts (dolor). Then thank your evolutionary progenitors for their farsightedness – your TLRs have worked, and your immune system is dealing with parasites that entered with the cut.

  1. Vilmos, P. and É. Kurucz, Insect immunity: evolutionary roots of the mammalian innate immune system. Immunology letters, 1998. 62(2): p. 59-66.
  2. Rajan, V., Inner Nature – Respiration: The Breath of Life, in The Unionville Times, https://www.unionvilletimes.com/?p=42536. 2019.
  3. Cooper, D. and I. Eleftherianos, Memory and specificity in the insect immune system: current perspectives and future challenges. Frontiers in Immunology, 2017. 8: p. 539.
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