Autoimmunity

Autoimmunity is the failure of an organism to recognise its own constituent parts (down to the sub-molecular levels) as "self", as a result of which it attempts to mount an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease, the prominent examples being Systemic Lupus Erythematosus (SLE), Sjögren's syndrome and Rheumatoid Arthritis (RA).

The illusory misconception that an individual's immune system is totally incapable of recognising "self" antigens is not new. Ehrlich, at the beginning of the twentieth century, proposed the concept of horror autotoxicus, wherein a 'normal' body does not mount an immune response against its own tissues. Any autoimmune response thus was perceived to be abnormal and postulated to be connected with human disease. Now, it is accepted that autoimmune responses are vital to the development and functioning of vertebrate immune system, and central to the development of immunological tolerance to self-antigens. The latter concept has been somewhat prematurely termed natural autoimmunity.

Immunological Tolerance

An essential prerequisite for the pathogenesis of autoimmune diseases is the breakage of immunological tolerance, which refers to the ability of an individual to differentiate 'self' from 'non-self', and mounting an effective and specific immune response to the latter. The exact genesis of immunological tolerance is still elusive, but several theories have been proposed since the mid-twentieth century to explain its origin.

Three hypotheses have gained widespread attention among immunologists:

• Clonal Deletion theory, proposed by Burnet, according to which self-reactive lympoid cells are destroyed during the development of immune system in an individual.
• Clonal Anergy theory, proposed by Nossal, suggests that self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.
• Idiotype Network theory, proposed by the Nobel laureate Jerne, wherein a network of antibodies capable of neutralising self-reactive antibodies exists naturally within the body.

In addition, two other theories are under intense investigation - the so-called "Clonal Ignorance" theory, according to which host immune system becomes primed to ignore self-antigens, and the "Suppressor population" theory, according to which specific CD8+ T-lymphocytes function to suppress exaggerated immune responses.

Tolerance can also be differentiated into 'Central' and 'Peripheral' tolerance, on whether or not the above checking mechanisms operate in the central lymphoid organs (Thymus and Bone Marrow) or the peripheral lymphoid organs (lymph node, spleen etc., where self-reactive B-cells may be destroyed).

It must be emphasised that none of these theories are mutually exclusive, and evidence has been mounting which suggests that all of these mechanisms may actively contribute to the putative vertebrate immunological tolerance.

Genetic Factors

It is now well established that certain individuals are genetically susceptible to the development of autoimmune diseases. However, this susceptibility is not inherited in a simple Mendelian segregation, but usually tends to be polygenic. That even individuals with genetic predisposition always do not develop autoimmune diseases could only mean that the pathogenesis of such disorders must also be multifactorial.

The main genetic loci involved in the body's immune system include the genes for immunoglobulins and T-cell receptors, both of which are involved in the recognition of antigens, and the major histocompatibility complex (MHC) antigen system. Of these, the first two are inherently variable and susceptible to recombination, and sporadic variations may give rise to lymphoid cells which are capable of self-reaction.

However, certain MHC class II genotypes are strongly correlated with specific autoimmune diseases:

• HLA DR2 is strongly correlated with SLE, Multiple Sclerosis, and negatively correlated with insulin-dependant diabetes mellitus (IDDM).
• HLA DR3 is correlated strongly with Sjögren's, Myasthenia gravis, SLE and IDDM.
• HLA DR4 is correlated with the genesis of RA, IDDM and Pemphigus vulgaris.

Fewer correlations exist with MHC class I molecules, the most notable and consistent being the association between HLA B27 and ankylosing spondylitis.

Sex

Sex also seems to have a major role in the development of autoimmunity; most of the known autoimmune diseases tend to show a female preponderance, the most important exception being ankylosing spondylosis which has a male preponderance. The reasons for this are unclear. Apart from inherent genetic susceptibility, several animal models suggest a role for sex steroids.