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Autoimmunity- from horror autotoxicus to miracle cure



Dr Lindsay Nicholson University of Bristol




1. INTRODUCTION

The immune system is a tour de force of the human body. Discretely disseminated around the body as a distributive network to deal with ingress from any site, it is in total about the same size as the heart. It provides a sophisticated defence against toxins and infective agents, for example, bacteria and parasites, that seek to feed on, damage or otherwise detrimentally alter the human condition. 

In the natural world, immune systems are not restricted to humans, nor exclusively to animals generally, but variants of the same system operate effectively in most organisms including trees and bacteria. The first vestiges of knowledge about the immune system were developed by investigations into rabies infections by Louis Pasteur (1822-1895), and later, by German bacteriologist and immunologist, Paul Ehrlich (1854-1915)- see Fig 1.



Fig. 1 Paul Ehrlich (1854-1915) was a Nobel prize-winning German physician and scientist who worked in the fields of hematology, immunology and antimicrobial chemotherapy





In fact, Ehrlich, a Nobel laureate (1908 Physiology or Medicine) declared that the immune system was so potent that it was impossible for it to turn against the body it was protecting, the so-called Horror Autotoxicus, literally, the horror of self-toxicity, a term to describe the body's innate aversion to immunological self-destruction. This bold declaration and its acceptance by most scientists precluded an analysis to the contrary, stymieing, for five decades, research of what later turned out to be autoimmune diseases. Time has consequently demonstrated that a denial of Horror Autotoxicus was incorrect. The immune system can compromise functions of the body, but also provides opportunities to re-programme the natural defences to fight those cancers that can successfully slip under the coverage provided by immune surveillance.

To discuss autoimmunity, its challenges and potential, Science Cafe welcomed Lindsay Nicholson of the University of Bristol, who specialises in autoimmune responses in the eye, most particularly non-infective uveitis (inflammation of the iris, ciliary body and choroid).

2. THE IMMUNE SYSTEM

Commonly known structures of the immune system include the lymph nodes, spleen, bone marrow and thymus gland (see Fig. 2) together with many types of cell working together as a close team to mediate the immune response. The most significant of these include monocytes, neutrophils, basophils, eosinophils, antigen-presenting cells and lymphocytes, to name but a few. It is an expensive system for the body to maintain but a highly effective way to ensure survival.





Fig. 2 Components of the immune system




The immune system provides two layers of defence:

Innate immune system: an immediate, non-specific response by leukocytes;

Adaptive immune system: an accommodative response to improve recognition of an invading pathogen. It is mediated mainly by T-cells and B-cells, provides a stronger response to invaders and retains a ‘memory’ of past antigens.

Critically important amongst immune cells are lymphocytes. They recognise unwanted invaders and set up a swift, targeted response. They are two main varieties, B-cells, which produce antibodies and the highly versatile T-cells, the revolutionary guards of the immune system (see Fig. 3). Both originate in the bone marrow. T-cells are further maturated in the thymus gland and released when capable of responding to an antigen. 

T-cells are of several types. Helper T-cells assist other immune cells, including B-cells in producing antibodies to attack invaders. Killer T-cells eliminate pathogen infected and dysfunctional cells and Memory T-cells retain a memory of earlier antigens, permitting a swift response to a repeat invasion.





Fig. 3 Process of T-cell activation. Some T-cells will differentiate into Memory T-cells







A distinctive biochemical characteristic of antigens (and of life in general) are proteins, which themselves are composed of amino acid chains.  These possess a regularity in their arrangement which allows them to be identified and recorded (or bar coded) by the immune system for reference.

This process is carried out by the MHC (Major Histocompatibility Complex)- (see Fig.4), a set of genes that code for MHC cell surface molecules. Antigen-presenting cells (which include dendritic cells, macrophages, Langerhans cells and B-cells) ingest and destroy pathogens, select peptide fragments derived from the pathogen and display them on the cell surface within MHC molecules for recognition by appropriate T-cells. These become activated against the displayed peptide fragments and are able to make an immediate, targeted response. The MHC also determines compatibility of donors for organ transplant, as well as susceptibility to autoimmune diseases. 

Within this system, Regulatory T-cells introduce a critical mechanism of tolerance to distinguish self from invader. It is these cells which are frequently co-opted by cancer cells to dial down an immune response allowing a tumour to develop unopposed.




Fig. 4 MHC and antigen presentation






Two MHC properties make it difficult for pathogens to evade the immune response. Firstly, the MHC is polygenetic, containing different MHC class genes, so that every individual possesses a set of MHC molecules with different ranges of peptide-binding specificities. Secondly, the MHC is highly polymorphic with multiple variants of each gene. Both these features contribute to the ability of the immune system to respond to a multitude of different and rapidly evolving.


3. KEY CHALLENGES FOR THE IMMUNE SYSTEM

The immune system therefore has several major challenges, namely discriminating self from non-self, initiating an appropriate, targeted response in a timely manner, managing infection and retaining a memory of invaders which can be used against recurrent insurgents. 

A key vulnerability is when organisms lack genetical diversity. Witness Dutch Elm Disease which gained a hold because of the genetic similarity of Elm trees. Likewise, Tasmanian Devils, a small population of antipodean carnivorous marsupials, demonstrate reduced MHC diversity with a consequent susceptibility to Devil Facial Tumour Disease (DFTD) which has detrimentally affected the species.

Protecting the body from intruders is an unremitting task. Assaults often come from invaders that have never been seen before, a new flu virus, for example. In all cases, an appropriate response is required and the range of challenges is potentially infinite. Taking into account the number of inspections made by the immune system throughout the body, the error rate response is very low. Amazingly, in dealing with these challenges, the immune system makes more decisions in its complex realm of oversight than any other bodily organ except the brain. 

Operational conflicts can occur which need to be resolved. Not every invader is bad. Many, such as gut bacteria, are beneficial. Also, some of the body’s own cells will inevitably become ‘rogue’ (cancerous) and need to be killed. Whilst identifying antigens is generally effective, if the difference between infection and self is small, there is a risk of generating dangerous T-cells capable of attacking the body they are protecting.


4. AUTOIMMUNITY

Autoimmune disease occurs when an immune response attacks our own tissues (see Fig. 5). In contrast to infection, the antigens that immune cells recognise are processed from proteins within a target organ and this drives a chronic inflammatory process that disrupts the normal function of the tissue. Like all adaptive immune responses, it is focused on specific antigens by T- and B-cells.

Self-reactive cells are usually removed prior to becoming active within the immune system. One mechanism takes place through a negative selection process within the thymus during T-cell maturation. Another is removal by regulatory cells. If any one of these mechanisms fails, a reservoir of self-reactive cells becomes functional within the immune system. 



Fig. 5 The immune response in autoimmune disease recapitulates that of responses directed against infection, except that self-antigens are, or become, the target of the adaptive immune system





These occasional, misdirected autoimmune responses can inflict considerable suffering (e.g. rheumatoid arthritis, multiple sclerosis, lupus, Crohn’s disease). 5% of the population have an autoimmune disease of some type, and the proportion of the population affected is increasing. There are 50 (or 80, depending on source consulted) recognized autoimmune diseases. Bill Bryson, in his recent book, The Body, a Guide for Occupants, notes that autoimmune diseases are grossly sexist with 80% of all such diseases being incurred by women. It is likely that female hormones are in some way responsible for this discrepancy.

5. ALLERGIES 

Allergies are a category of immune disorder where an inappropriate response to an often harmless invader is displayed. Surprisingly, allergy rates (10-40%) positively mirror economic performance. One theory is that inappropriate use of antibiotics or pollutants might be the cause. A commonly espoused explanation for increasing rates of allergy affliction is the so-called ‘Hygiene Hypothesis’. This has been shifted to one side in recent years by the ‘Old Friends Hypothesis’

The Hygiene Hypothesis was first proposed in 1989 by Dr David Strachan, who noted that children in bigger households had less susceptibility to allergies. He concluded that children with a large number of siblings are more exposed to germs. Strachan also observed that reduced infections in the sanitised western world ran hand-in-hand with an increase in autoimmune diseases. This was supported in the 1990’s by Dr Erika von Mutius who demonstrated that children raised in the dirtier East Germany had less allergy affliction than those raised in the cleaner, neighbouring West Germany. The implication was that children growing up in richer economies are exposed to cleaner environments and their immune systems don’t have the opportunity during that early window of immune development, to habituate to infections. Dr Karl Kruszelnicki, a well-known medical doctor and Australian science commentator (‘Dr Karl’), has, at his children’s naming ceremonies, invited guests to gently rest a forefinger in the baby’s mouth to encourage the ingestion of new antigens. 

Often taken as given, the problem with the Hygiene Hypothesis is that whilst we have been clean for many decades, the rise in allergies has been prevalent only for the last three or four decades. A new version, the Old Friends Hypothesis, suggests that throughout our evolution, mankind has co-evolved with various microbes. Ingestion of these particular microbes assists in developing our immune systems and fighting infection. Attempts to limit our risk of infection has deprived individuals of exposure to these ‘old friends’ with a consequent loss of immune effectiveness.

6. IMMUNOTHERAPY

Blocking the immune response can be effective in managing autoimmune disease, but is accompanied by adverse effects due to immunosuppression. This can enable  the reactivation of latent infections and reduce immunosurveillance. Therefore, a different approach, antigen-specific immune therapy, targeted at a specific immune response, rather than general therapies aimed at the whole immune system, remains a critical goal for the treatment of these chronic, debilitating diseases.

There are currently two immunological approaches to eliminating cancer:

IMMUNE CHECKPOINT THERAPY- cancers have learnt to exploit the immune response by sending stop signals to prevent the immune system mounting an attack. Checkpoint therapy overrides these signals, working fantastically well with some cancers and at other times, inexplicably, not working at all. This is clearly work-in-progress at the present time.

CAR (Chimeric Antigen Receptor) T-cell therapy- a patient’s T-cells are removed and genetically modified to include special receptors (Chimeric Antigen Receptors). These are returned to patient’s blood stream to attack cancer cells. It is vastly expensive, works well, especially with some leukaemias; in other cases, as well as killing the cancer, there is a scorched-earth effect affecting many essential, healthy cells, leaving the body very vulnerable to infection.

7. CONCLUSION

The immune system is a major, under-rated, player in maintaining the health of the body. Current understanding of the system allows a whole range of autoimmune diseases to be competently managed. However, areas of ignorance remain, such as the rising incidence of autoimmune diseases. Research also points the way to a range of new therapies which are currently being trialled and promise a more effective way to attack cancers, as naturally as possible, using the bodies own defences. An exciting, new era of treating cancer is possibly already underway.  

REFERENCES

Bryson, Bill (2019), ‘The Body, a Guide for Occupants’, Doubleday, ISBN: 9780857522405

Nicholson, L. ‘Autoimmunity: Introduction’, available @  https://www.immunology.org/public-information/bitesized-immunology/immune-dysfunction/autoimmunity-introduction



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