Seventeen years ago, my young family and I emigrated from South Africa to start a new life in the United Kingdom, and in that time, we have grown to love much about our adopted land. We now live in farmland in the North-East region, known for its striking natural beauty and history, with many waves of Viking and Scots invasions passing through the area, and Hadrian’s wall being an amazing feature that goes past a mile above our home in the hills behind where we live. We still battle with the cold and wet winters, but love spring and summer, and the soft warmth, flowers, and green hills and fields which it brings. Sadly, for me the beauty of spring and summer have a real downside, in that I suffer from bad hay fever and pollen allergies and spend a lot of the beautiful days with eyes watering (as they are now while writing this) and red and swollen, sneezing, and needing to reach for tissues to blow my nose throughout the day. I remember my father suffered the same thing in South Africa when we were growing up, and I had it to a slight degree in South Africa too, but it has been far worse than since we moved to the UK, and sadly does not seem to be improving much as the years pass by, as I hoped it might. I also am allergic to bees and swell up when stung, though thankfully had not had such a misfortune for a few years. Clinicians reading this would quickly diagnose me as having a hypersensitive immune system, and I am sure there are quite a few out there that suffer similarly to me from such allergies on a seasonal basis. A cousin in the family has suffered from ulcerative colitis since adolescence, an inflammatory bowel disorder, whose basis is also an auto-immune dysfunction, and he has had it for many years, with it chronically affecting his lifestyle, choice of foods, and what he can do as part of his daily life, since it first flared up. My wonderful wife Kate, who has been my life-partner for more than twenty years now, also has had issues with immune system dysfunction, though of a far greater order of magnitude than my issue with allergies, and perhaps even ulcerative colitis. When she was fourteen, she developed symptoms of a fever and malaise, and initially her parents were not concerned and thought she was simply getting an infection. But she felt worse, and was taken to the local hospital, and it was noted she had no pulses in her legs, and after a battery of tests, was diagnosed with Takayasu’s arteritis, an auto-immune disorder whereby immune system related inflammation destroys the aorta, the main artery emanating from the heart, and potentially the pulmonary artery too. She was treated first with anti-immune function drugs and eventually needed a stent replacement of her entire abdominal aorta (basically the insertion of a plastic tube in place of the aorta, which was too damaged to continue functioning), and fortunately survived the ordeal and disorder, and is well and happy today. The immune system is supposed to be protective, yet here are three examples, with many others, where our own immune system appears to have ‘turned against’ ourselves, and caused physical harm, instead of protecting us folk from external threats. In this article thus we will examine the immune system and attempt to understand how it can go so badly wrong.
As described above, the immune system is an incredibly complex network of interconnecting biological molecular systems which protects each of us from external pathogens that potentially can harm us and cause disease. The first line of protection we have is the physical barriers that exist between our bodies and the environment – skin cells on the outside, and protective layers of cells in all the bodies internal structures which come into contact with the external environment, such as the respiratory system, gastrointestinal system, and reproductive and urinary excretion systems. If this protective lining is breached, the immune system then springs into action. Firstly the innate (generic) immune system is activated by an array of signalling molecules, and white blood cells principally are released which both destroy the invading pathogen, be it a virus, bacteria, foreign body or cancer cell, and stimulate a general body response which helps to remove and repair the damaged tissue and destroyed invading pathogen, such as increasing body temperature, and increasing blood flow to the damaged area, which causes the redness and swelling in the area around the damaged tissue, and is a sign of the body trying to first destroy then heal the damaged / invaded area. There is no cellular ‘memory’ to this response, and it occurs similarly to each attempt a pathogen makes to invade, damage, or devour us. A second ‘adaptive’ immune response occurs, after a lag period of time after the initial infection and response, during which, via very complex cellular and blood born signalling mechanisms, a ‘learned response’ to the specific virus, or bacteria, or whatever has damaged and / or entered the body occurs, which further targets the specific pathogen, but perhaps more importantly, is maintained as an ‘immunological memory’, so if the same pathogen ‘attacks’ us again at a later stage, it is remembered and a far faster specific response occurs to the infecting agent, and the period of ‘illness’ and inflammation associated with the ‘pathogen killing process’ is less. The immune system has become a very hot topic for research, and more is being found out about its incredibly complex pathways and methods of action, and it is perhaps beyond the scope of this article to describe each of these processes and pathways, some of which have magnificent names such as natural killer cells, macrophages, neutrophils, and others suchlike, which recognise their ‘foes’ using ‘pattern recognition receptors’ and ‘toll-like’ receptors, which recognise ‘pathogen-associated molecular patterns’ and ‘damage-associated molecular patterns’ and tailor-make specific responses which both destroy the infective agents and leave an ‘immunological memory’ using methods that are still being worked out and are currently not completely understood, and involve the development of antibodies associated with ‘multiple histocompatibility complex molecules’ against ‘antigens’ (pieces of the external agent which cause an immune response) expressed by the invading pathogens, which when complete travel around the body in the blood plasma or lymph systems and bind to pathogens expressing these ‘antigens’ and mark them for destruction by white blood cell structures or other immune system generated molecules.
In an ideal world, if this superb protective system did its job perfectly, the immune system would destroy all external agents, first using the generic response, and then using the second wave of more specific, targeted response which is ‘remembered’, so that if the same external agent ‘attacks’ us again, there would a quicker and more focussed response, which destroys the external agent – bacteria, virus, or whatever, in a speedy manner and with less general immune response. However, unfortunately the system is prone to errors, from a hypersensitivity response where the immune system response is so severe as to damage the body systems or organs, and is not attenuated with time, creating an allergy or allergic reaction to some external agent, be it pollen, bee-stings, or peanut allergy (which can be very severe), to a horrendous situation where the immune system stops recognising the ‘self’ as opposed to the ‘non-self’ / external agents, and ‘attacks’ its own body systems and organs, for reasons that are still almost completely unknown to us. There are also in some folk with genetic disorders, an absence of immune function maturation, leaving the individual with no possible protective response to any external agent or infection, or a situation where external agents actively target the immune system, such as HIV infection, and ‘wear out’ the immune system, leaving it again predisposed to a lack of ability to have any immune response and thus chronic infections (and, interestingly, unusual types of cancer generation), but these hypo-immune challenges are outside the scope of this article.
Hypersensitivity reactions are divided into different types according to which components of the immune system generates the response, and the speed of response. A very fast ‘anaphylactic’ immune response to infective agents or food types – think peanut allergies or acute asthma in which there is extreme reaction of the respiratory tract to external triggers – is usually associated with more ‘humoral’ (blood borne) immune responses such as degranulation of mast cells and basophils and the release of IgE into the blood, causing vasoconstriction, bronchoconstriction and thus difficulty breathing which can lead to death if not treated quickly. A longer type of hypersensitivity reaction – such as contact dermatitis where there are red, inflamed reactions or ‘wheals’ in the skin as a result of touching an unusual substance that causes a hypersensitivity response is caused by T cells, monocytes and macrophages, and takes a few days to evolve and then subside. These extreme hypersensitivity immune responses need prompt treatment with immunosuppressive and anti-inflammatory drugs, either topical, inhaled, oral or intravenous, depending on the seriousness of the hyper-immune response, and are not to be taken ‘lightly’ by folks who witness someone having such a hyper-immune / anaphylactic response, with prompt emergency management and hospitalization often being needed, and one should rather err on the side of caution when witnessing or treating such patients and sufferers.
The most challenging ‘error’ response of the immune system is autoimmunity, when the immune system fails to recognise ‘self’ from ‘non-self’ and attacks its own cells and organs. As described above, there is an incredibly complex system of recognition and destruction of external agents or infections which threaten the body and a human’s existence (all creatures have a similar immune system and responses). How or why this happens is unclear, and normally in the bone marrow and thymus, young lymphocytes are presented with ‘self-antigens’ so that they recognise ‘self’ from ‘non-self’ and eliminate cells which appear to no longer recognise ‘self’ cells as such. For some reason, perhaps genetic, perhaps environmental factors, perhaps related to toxins or specific infective agents which ‘hijack’ the self-recognizing system, the immune system ‘turns against’ itself and starts destroying its own cellular structures, organs, or body parts. In the late 19th century Paul Ehrlich recognized this ‘self’ destructive capacity of the immune system and perhaps appropriately proposed to call it ‘horror autotoxicus’. While the initial symptoms for most of these autoimmune disorders are the generic ones of the immune system responding to an external target, such as low grade fever, fatigue, malaise (generally feeling unwell), muscle aches and joint pain and skin rashes, the specific autoimmune disorder being ‘created’ by the attack on ‘self’ structures gradually become apparent, such as the joints in the hands in Rheumatoid Arthritis, to the digestive system wall being damaged in Crohn’s disease, to the vascular system in Takayasu’s Arteritis. An astonishing array of disorders are linked to this lack identity of the ‘self’ by autoimmune system, including diabetes mellitus type 1 disease (damage to the insulin-secreting beta cells of the pancreas), systemic lupus erythematosus (systemic damage to many body parts, including joints and soft tissue), multiple sclerosis (nerve damage), alopecia areata (general body hair loss), psoriasis (dry, itchy skin disorder), Graves’ disease (predominantly thyroid gland disorder), myocarditis (heart muscle damage), Addison’s disease (predominantly adrenal gland disorders), aplastic anaemia (failure to make new blood cells), and many others. The severity of symptoms and longevity of these disorders vary, with their re-appearance being called a ‘flare-up’, and can result in mild to severe damage to organ tissue and function, with no obvious pattern to these variations and all usually with significant morbidity to those suffering from them (it has been suggested that up to 7% of the human population suffers from either a hypersensitivity or autoimmune disorder). Diagnosis is related to the specific symptoms related to each of these pathologies described above, as well as non-specific anti-inflammatory markers of infection, or cellular damage. Treatment is either generic, such as rest, vitamin D ingestion (some autoimmune disorders such as multiple sclerosis appear to have a relationship to vitamin D deficiency), physical therapy of affected joints or organs involved, surgical treatment where possible, non-steroidal anti-inflammatories to reduce inflammation along with glucocorticoids and anti-rheumatic drugs, and new immune system targeting drugs, though of course all of these, if used for too long or at too higher doses, cause side-effects which can be challenging themself. Specialist care is needed, as well as psychological support, as often these autoimmune disorders can last a long time, or are terminal, and are often extremely debilitating to the sufferers.
If there is an upside to the autoimmune disorders, or to our increasing knowledge of the immune system and its function, it has been in the adjuvant use of its function for treatments of other pathologies and disorders. For example, the antigen-antibody recognition functions and pathways have been the basis of the development of vaccines, where components (antigens) of for example a dangerous virus such as the polio virus are given to individuals in order to create a mild response to the vaccine, which thus creates a ‘memory’ of the virus which is / would be protective for the person if they were actually infected by a ‘live’ virus later in time. Furthermore, it has also been shown that there are strong links between the function of the immune system and cancer development and treatment, and some treatments aimed at the immune systems have shown to have positive effects in some cancers, and a lot of research work is examining the relationship between changes in recognition patterns and pathways in the immune system and the development of cancer, which in many ways can be thought of ‘self’ cells becoming ‘non-self’ cells that then actively work to damage ‘self’ cells. While there are a lot of possible areas for future breakthroughs in the treatment of cancer, this is currently thought to be a fertile one, and laboratories around the world are working at the relationship between the immune system and cancer development and propagation.
While each of the different autoimmune disorders have their own specific symptoms and physical damage associated with each (and why this is the case, is interesting in itself), where there is cause for hope, is that many of them ‘wax and wane’, some appear for a short period of time, or once or twice then do not appear again (such as multiple sclerosis, but of course, this disorder can also progress quickly and become severe). Furthermore, with contemporary treatment, many of the autoimmune disorders can be well controlled, and a small but significant percentage of them go into remission. Folks suffering from most autoimmune disorders can live as long a life as healthy folk, if taking the required treatment of their specific disorder, although some of the disorders, such as rheumatoid arthritis, cause folk to die ‘on average’ a few years earlier than healthy folk. While these autoimmune disorders can be severely debilitating, clinicians often need to work in the business of hope, and folks suffering from many of these autoimmune disorders can be counselled that they will in all likelihood be able to live a long life, and may go into remission, and should never forget this in the tough days when the symptoms of their specific autoimmune disorder are challenging to them, and they worry about their future.
Understanding what ‘is’ and what ‘is not’ part of us, however, becomes even more problematic given that the human body hosts millions of microbes which – bacteria, fungi, viruses – called the human microbiome, which live ‘in harmony’ with the human being, are often suggested to be needed for synergistic function in the gut for example, and whose presence does not initiate an immune response. It has been suggested there are perhaps more microbes in the human tissues and biofluids than cells – in the gut, respiratory tract, oral cavity, uterus and vagina, skin and other places. Why these do not result in an immune response, while auto-immune response to one’s own body happens as described above, creates another order of mystery to both the function of the immune system and the pathophysiology of how and why it goes wrong when it attacks its own cells.
Who are we, and who are we not, and how we recognise what is, and what is not, seems to be the basic issue inherent in both the successful functioning of the immune system, and the development of autoimmune disorders, where the immune system ‘turns against’ itself and destroys its own systems and structures, in a way that is usually devastating to those individual who are unfortunate to suffer from its deprivations. The immune system, with its capacity to recognise ‘self’ from ‘non-self’, and to turn against its the living organism / human of which it is part, makes it one of the most fascinating human conditions to research and attempt to understand, but is surely one of the most horrendous types of diseases one can suffer from, as Ehrlich was aware of when he described the disorder as ‘horror autotoxicus’. In cancer cells ‘go rogue’ and turn against the body of which it was once past, but in autoimmune system diseases, the body’s natural defensive mechanism itself turns against its own body and self. It is astonishing that a system so needed to keep the human safe from foreign pathogens, can itself be so harmful and toxic to its own self, and that this happens in a fairly large percentage of people, usually with extremely debilitating symptoms and negative effects on those affected life and lifestyle. I know that I am me. You know you are you. Why sometimes in some folk who me and you are gets forgotten is one of life’s biggest mysteries, and one of medical researchers’ biggest challenges to solve. Crippled and bent hands. Loss of insulin function. Arteries damaged. Nerves damaged. Heart damaged. Gut function impaired with chronic bowel abnormalities. Horror autotoxicus. Horror, caused by our body’s basic protective mechanisms going rogue and mutineering against themselves. Self-destructive perfidy, of seemingly the most foolish type possible, and for no obvious rhyme or reason.