Autoimmunity

Autoimmunity is the failure of an organism to recognize its own constituent parts (down to the sub-molecular levels) as "Self", which results in 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. Paul 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. Autoimmunity should not be confused with alloimmunity.

Immunological tolerance
Pioneering work by Rose and Witebsky in New York, and Roitt and Doniach at University College London provided clear evidence that autoimmune diseases are a result of loss of tolerance. An essential prerequisite for the pathogenesis of autoimmune diseases is indeed 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 lymphoid 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, scientists such as H. McDevitt, G. Nepom, J. Bell and J. Todd have also provided strong evidence that 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-dependent 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. Scientists such as NA Mitchison, SJ Ono and J Klein have also investigated whether correlations exist between polymorphisms within class II MHC promoters and autoimmune disease.

Gender
Gender 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 spondylitis 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.

It has also been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity. This would tip the sex balance in the direction of the female.

Environmental Factors
An interesting inverse relationship exists between infectious diseases and autoimmune diseases. In areas where several infectious diseases are rampant, autoimmune diseases are quite rarely seen. The reverse, to some extent, seems to hold true. Whilst such an observation has been variously termed as spurious and ineffective, a paradoxical observation has been the strong association of certain microbial organisms with autoimmune diseases.

For example, Klebsiella pneumoniae and coxsackievirus B have been strongly correlated with ankylosing spondylitis and IDDM respectively. This has been explained by the tendency of the infecting organism to produce super-antigens which are capable of polyclonal activation of B-lymphocytes, and production of large amounts of antibodies of varying specifities, some of which may be self-reactive (see below).

Certain chemical agents and drugs can also be associated with the genesis of autoimmune conditions, or conditions which simulate autoimmune diseases. The most striking of these is the drug-induced lupus erythematosus. Usually, withdrawal of the offending drug cures the symptoms in a patient.

Pathogenesis of autoimmunity
Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation. It is beyond the scope of this article to discuss each of these mechanisms exhaustively, but a summary of some of the important mechanisms have been described:
 * T-Cell Bypass - A normal immune system requires the activation of B-cells by T-cells before the former can produce antibodies in large quantities. This requirement of a T-cell can be by-passed in rare instances, such as infection by organisms producing super-antigens, which are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to β-subunit of T-cell receptor in a non-specific fashion.
 *  Molecular Mimicry - An exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens and amplify the immune response. The most striking form of molecular mimicry is observed in Group A haemolytic streptococci, which shares antigens with human myocardium, and is responsible for the cardiac manifestations of Rheumatic Fever.
 * Idiotype Cross-Reaction - Idiotypes are antigenic epitopes found in the antigen-binding portion (Fab) of the immunoglobulin molecule. Plotz and Oldstone presented evidence that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody and a host cell receptor for the virus in question. In this case, the host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells.
 * Cytokine Dysregulation - Cytokines have been recently divided into two groups according to the population of cells, whose functions they promote: Helper T-cells type 1 or type 2. The second category of cytokines, which include IL-4, IL-10 and TGF-β, seem to have a role in prevention of exaggeration of certain immune responses.

The role of certain specific suppressor lymphocytes, and the special γδ T-cells in the genesis of autoimmunity are under investigation.

Classification
Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease.
 * Systemic syndromes include SLE, Sjögren's syndrome, Scleroderma, Rheumatoid Arthritis and polymyositis.
 * Local syndromes may be endocrinologic (diabetes, Hashimoto's thyroiditis, Addison's disease etc.), dermatologic (Pemphigus vulgaris), haematologic (autoimmune haemolytic anaemia), neural (multiple sclerosis) or can involve virtually any circumscribed mass of body tissue.

Diagnosis
Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein). In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens.

Alternative theory
Some researchers have theorized that the autoimmune diseases are in essence diseases of endorphin deficiency. Proponents of this theory claim that successful treatment options include low-dose naltrexone (LDN), and opioid medication. 

There is some in vitro data that indirectly suggest the potential benefits of LDN therapy. Anecdotal accounts and case reports have also been cited in favor of LDN therapy. Some of the conditions where LDN has been reported as beneficial include multiple sclerosis, Crohn's disease, HIV/AIDS, chronic fatigue syndrome, fibromyalgia, AD in children (Elchaar GM, et al. 2006) and cancer. Several clinical trials have been planned.