Autoimmunity, Biology tutorial

Introduction:

Autoimmunity and autoimmune diseases are the effects of immunological destruction of the tissues of body following the loss of recognition through lymphoid organs of the self-cells as self. Throughout differentiation and speciation of lymphoid stem cells in prime organs, most of the cells which are capable of causing autoimmunity are deleted. Yet, the body includes large numbers of lymphocytes which are self-reacting.

Causes of Autoimmunity:  

The controlling factors which restrain the growth of autoimmune responses comprise Ts cells, cytokines and products of macrophages. Though, such regulatory methods might be evaded through:

1) Discharge of generally sequestered auto-antigen that is then taken up through antigen presenting cells and therefore stimulation of TH cells.

2) Unsuitable expression of MHC class II and incapability of auto-reactive TH cell to identify potential Autoantigens on cells that generally don't express MHC class II genes.

3) Defects in the generation of Ts cells having hyperactivity of TH. This might over stimulate B-cells for extreme production of antibody which might comprise auto-reactive ones. In thyroxicosis, antibody to thyroid stimulating the hormone TSH receptors joins by TSH receptors as if it is TSH, thus auto antibodies to hormone receptors mimic the job of the normal hormone concerned.

4) Deletion of the self-antigen recognizing T- and B-lymphocytes throughout maturation procedure. In pernicious anaemia, autoantibody is made against intrinsic factor. This autoantibody joins with the intrinsic factor to disrupt the uptake of Vitamin B12. This is transported across the intestinal mucosa if it joins by the intrinsic factor. In systemic lupus erythematosus, immune complexes having auto-antigens and auto antibodies are deposited in the kidney to cause the hypersensitivity, glomerulonephritis and proteinuria.

Low Level Autoimmunity:                                                       

Since a high level of autoimmunity is unhealthy, a low level of autoimmunity might in reality be beneficial. First, low-level autoimmunity might help in the recognition of neoplastic cells through CD8+ T cells, and therefore decrease the incidence of cancer.

Second, autoimmunity might play a role in allowing the quick immune response in the early phases of an infection if the availability of foreign antigens limits the response (that is, if there are some pathogens present). In their study, Stefanova et al. (2002) injected an anti-MHC Class II antibody into the mice expressing a single kind of MHC Class II molecule (H-2b) to temporarily prevent CD4+ T cell-MHC interaction.

Naive CD4+ T cells (such that have not encountered any antigens before) recovered from such mice 36 hours post-anti-MHC administration showed reduced responsiveness to the antigen pigeon cytochrome C peptide, as found out by Zap-70 phosphorylation, proliferation and Interleukin-2 production. Therefore Stefanova et al. (2002) explained that self-MHC recognition (that, if too strong might contribute to autoimmune disease) sustains the responsiveness of CD4+ T cells if foreign antigens are absent. This idea of autoimmunity is theoretically identical to play-fighting. The play-fighting of young cubs (TCR and self-MHC) might outcome in a few scratches or scars (that is, low-level-autoimmunity), however is advantageous in the long-term as it primes the young cub for the proper fights in the future.

Immunological Tolerance:

Pioneering work through Noel Rose and Witebsky in New York, and Roitt and Doniach at University College London provided clear proof that, at least in terms of antibody-producing B lymphocytes, diseases like rheumatoid arthritis and thyrotoxicosis are related by loss of immunological tolerance that is the capability of an individual to overlook 'self', whereas reacting to 'non-self'. This breakage leads to the immune system's mounting an efficient and specific immune response against the self determinants. The precise genesis of immunological tolerance is still subtle; however some theories have been introduced since the mid-twentieth century to describe its origin.

There are three hypotheses which have gained widespread attention among the immunologists:

1) Clonal Deletion theory, introduced by Burnet, according to which self-reactive lymphoid cells are destroyed throughout the growth of the immune system in an individual. For their work Peter B. Medawar and Frank M. Burnet were awarded the Nobel Prize in the year 1960 in Physiology or Medicine 'for the discovery of acquired immunological tolerance'.

2) Clonal Anergy theory, introduced by Nossal, in which self-reactive T- or B-cells become inactivated in the normal individual and can't amplify the immune response. 

3) Idiotype Network theory, introduced by Jerne, in which a network of antibodies capable of neutralizing self-reactive antibodies exists naturally in the body. 

Genetic Factors:

Some individuals are genetically susceptible to developing the autoimmune diseases. This susceptibility is related by multiple genes plus other risk factors. Genetically predisposed individuals don't for all time build up autoimmune diseases.

The three main sets of genes are suspected in numerous autoimmune diseases. Such genes are associated to: 

a) Immunoglobulin

b) T-cell receptors

c) The main histocompatibility complexes (MHC).

The primary two, which are comprised in the recognition of antigens, are innately variable and susceptible to the recombination. Such variations facilitate the immune system to respond to a much broad variety of invaders, however might as well give rise to lymphocytes capable of self-reactivity.

Scientists like H. McDevitt, G. Nepom, J. Bell and J. Todd have as well given strong evidence to propose that some MHC class II allotypes are strongly interrelated with:

a) HLA DR2 is strongly positively associated by Systemic Lupus Erythematosus, narcolepsy and multiple sclerosis and negatively associated by DM Type 1.

b) HLA DR3 is associated strongly by Sjogren's syndrome, myasthenia gravis, SLE and DM Type 1.

c) HLA DR4 is associated by the genesis of rheumatoid arthritis, Type 1 diabetes mellitus and pemphigus vulgaris. 

Some correlations exist by MHC class I molecules. The most notable and consistent is the relationship between HLA B27 and ankylosing spondylitis. Correlations might exist among polymorphisms in class II MHC promoters and autoimmune disease.

Sex:

Sex of a person as well seems to have certain role in the growth of autoimmunity, categorizing most of the autoimmune diseases as sex-related diseases. Almost 75% of the more than 23.5 million Americans who suffer from the autoimmune disease are women; however it is less-often acknowledged that millions of men as well suffer from such diseases.

Environmental Factors:

A fascinating inverse relationship exists among infectious diseases and autoimmune diseases. In regions where multiple infectious diseases are endemic, autoimmune diseases are quite seldom seen. The reverse, to certain extent, seems to hold true. The hygiene hypothesis features such correlations to the immune manipulating plans of pathogens. Whilst this observation has been variously named as spurious and ineffective, according to some studies, parasite infection is related by decreased activity of the autoimmune disease. 

The putative method is that the parasite attenuates the host immune response in order to protect itself. This might give serendipitous advantages to a host which as well suffers from autoimmune disease. The description of parasite immune modulation is not yet known, however might comprise secretion of the anti-inflammatory agents or interference by the host immune signaling method.

A paradoxical examination has been the strong relationship of some microbial organisms with the autoimmune diseases.

Some of the chemical agents and drugs can as well be related by the genesis of autoimmune conditions or conditions which simulate the autoimmune diseases. The most striking of such is the drug-induced lupus erythematosus. Generally, withdrawal of the offending drug treats the symptoms in a patient.

Smoking cigarette is now established as a main risk factor for both incidence and sternness of the rheumatoid arthritis. This might relate to abnormal citrullination of proteins, as the consequences of smoking correlate by the presence of antibodies to the citrullinated peptides.

Pathogenesis of Autoimmunity:

Some of the pathological methods have been introduced to describe the growth of autoimmune conditions. Aside from the roles participated by genetic and ecological factors, a few of the major pathological methods introduced are explained below:

1) T-cell bypass:

Generally, B cells are activated through T cells prior to B cells can generate antibodies in big quantities. Though, when the T cells are bypassed and the antigen directly stimulates the B cells, the immune response might be modified.

2) T-cell and B-cell discordance:

Healthy and fit immune responses need B and T cell reactions to the similar antigen. Though, scientists Rosnek and Lanzavecchia exhibited how B cells that identify IgGFc can recruit help from any T cell stimulated through an antigen which has been co-endocytosed through a B cell. In celiac disease, for illustration, it seems B cells that identify transglutamine are helped through T cells which identify gliadin.

3) Aberrant B cell receptor-mediated feedback:

Modified B cell receptor-mediated feedback might give augment to spontaneous autoimmunity. Whenever an antibody binds to some antigen, it might cause aberrant signals to be fed back to B cells via ligands bound to the membrane, like the B cell receptor, IgGFc receptors, CD21 and toll-like receptors 9 and 7. This makes the basis of the idea which self-perpetuating self reactive B cells can exist.

4) Molecular mimicry:

The structural similarities shared among an exogenous antigen and some specific self antigens might outcome in any antibody generated against the exogenous antigen as well binding to the host antigen to flag it up for attack through the immune system. This is assumed to be the underlying cause of rheumatic fever; however the exogenous antigen has not yet been properly recognized.

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