autoimmune disease

Every second of our lifetime, we are exposed to a large variety of microorganisms in the environment, which are capable of causing fatal diseases. However, normal individuals rarely succumb to such infections and, even if they do, it is usually for a short duration and with limited damage. This is because of an efficient immune system that destroys these organisms and other foreign substances.

An immune response is brought about by two components of the immune system, namely the innate immunity and the acquired or specific immunity, acting in conjunction with each other and with other molecules. Acquired immunity involves the production of antibodies, each specifically designed to combat a particular antigen — a component of the invading substance or organism. For its normal function of defence, five features of the acquired immune system are essential. These are: (i) specificity for distinct antigens; (ii) diversity; (iii) memory; (iv) self-limitation; and (v) discrimination of self from non-self.

It is the last two features which raise the possibility of Dr Jekyll turning into Mr Hyde. Loss of self-limitation or the failure to maintain self-tolerance can actually turn the immune system from playing a defensive role to causing debilitating diseases. A pathological condition arising from uncontrolled or aberrant immune responses is defined as a hypersensitivity reaction, or allergy. Diseases that are caused due to the immune system acting against self-antigens are called ‘autoimmune diseases’, a situation which has been melodramatically described as ‘horror autotoxicus’ by the famous biologist Paul Erlich.

A wide range of diseases have now been classified as having autoimmune causes. At one end of the spectrum of such diseases are conditions like Hashimoto's thyroiditis, where the antibodies are directed against one specific organ (in this case the thyroid gland). At the other end of the spectrum are diseases such as systemic lupus erythematosus (SLE), where the antibodies are directed against the nucleus of the cells, thereby affecting the whole body; in most instances, specific antibodies can be detected circulating in the blood. In another disease condition, known as Goodpasture's syndrome, the autoantibodies bind to components of the membrane that separates air from blood in the alveoli of the lungs and of the glomerular capillaries of kidneys, where filtration occurs. This causes a localized immune reaction and leads to lung haemorrhages and glomerulonephritis. Similarly, in autoimmune haemolytic anaemia antibodies are directed against red blood cells, enhancing breakdown and phagocytosis of the cells.

In certain cases, however, the autoantibodies do not cause cell damage, but instead alter the normal physiological functions by mimicking normal signalling molecules. For example, in Grave's disease (thyrotoxicosis) autoantibodies bind to the receptors for the thyroid stimulating hormone (TSH) from the pituitary gland and mimic its functions, leading to excessive thyroid hormone production. In another disease, known as myasthenia gravis, autoantibodies bind to the receptors on muscle cells for the neurotransmitter, acetylcholine, and thereby inhibit nerve-to-muscle conduction; over a period of time these receptors are endocytosed (taken up inside the cells) and degraded, causing progressive muscle paralysis.

Sometimes, autoimmune diseases may arise because antibodies, which are produced against foreign antigens, cross-react with the body's own proteins (‘self-proteins’). Thus in acute rheumatic fever, which can develop following a throat infection, antibodies against a cell wall protein of streptococcus bacteria may cross-react with an antigen in the person's own cardiac muscle cells. This leads to myocarditis and damage to the valves of the heart. It is also associated with inflammation of the joints and destruction of the joint cartilage brought about by immune responses.

The immune response involves not only the production of antibodies which circulate in the blood, but also the multiple activities of ‘T-cells’, the lymphocytes which have been ‘programmed’ in the thymus gland to recognize specific antigens, and which mediate the ‘cellular’ component of the immune response. In certain autoimmune diseases, it is the T-cells which become auto-reactive. This occurs in some patients with insulin-dependent diabetes mellitus. In these patients, activated lymphocytes and macrophages destroy the insulin-producing cells in the pancreas, which leads to the disorders of metabolism characteristic of this condition. Some types of anaemia are thought to be due to antibodies being generated against factors required for absorption from the gut of vitamin B₁₂, which is essential for maturation of red blood cells.

Besides the examples described, numerous other pathological conditions have also been classified as autoimmune diseases. Extensive research has been conducted to elucidate the mechanisms by which the immune system discriminates between self and non-self, and the transformation from protector to aggressor in certain pathological conditions of autoimmunity.

One of the cardinal features of immunity is the ability to maintain self-tolerance against self-antigens. Its is an actively acquired process, where self-reactive antibodies are prevented from becoming functionally capable of reacting with self-antigens. A negative selection process plays a major role, whereby immature T-cells, specific for self-antigens, are deleted in the thymus. In certain conditions, the clones may survive but are unable to respond to self-antigens. This is known as clonal ignorance. All these mechanisms lead to the capability of the immune system to discriminate between self and non-self.

Despite these several mechanisms for inducing self-tolerance, autoimmunity remains a significant cause of disease in humans. Multiple factors are implicated in the breakdown of self-tolerance. These factors range from genetic predisposition to microbial infections. Autoimmunity can also arise from abnormalities in lymphocytes following failure of the selection process in the thymus. It is proposed that an individual's ‘major histocompatibility’ genes, which determine their ‘HLA type’ (classification based on human lymphocyte antigens, used in determining tissue compatibility for organ transplants), influence thymic selection, implying a genetic role in autoimmunity. Studies of a particular strain of mice, which develops an accelerated, severe form of systemic autoimmunity, revealed a genetic predisposition. Indeed, autoimmune diseases are often said to ‘run in the family’. HLA typing has shown that some individuals have 90 to 100 times the average predisposition to developing the autoimmune condition called ankylosing spondylosis. This may possibly be due to the controlling of T-cell selection and activation by the gene products which determine the HLA type.

Some autoimmune diseases are caused when antibodies or T-cells, stimulated to act against a foreign antigen, recognize a similar molecular component on a self-protein. This ‘molecular mimicry’ is often a cause for autoimmunity, as described earlier in the case of rheumatic fever.

A plethora of causal factors are thus implicated in leading to autoimmunity. Recent advances have also been made in elucidating the mechanisms involved in self-tolerance and generation of autoimmunity; these hold promise for development of effective strategies for management of these debilitating conditions.

— Shiladitya Sengupta, Tai-Ping Fan

See also immune system.