AUTOIMMUNITY 3: COMPONENTS, MECHANISM OF INDUCTION AND TREATMENT

IMMUNE COMPONENTS INVOLVED IN AUTOIMMUNITY

• the autoimmune diseases can involve both the humoural and CMI branch of immune system.
• Out of these, CD4+ T cell has been detected as the primary mediator of autoimmune diseases in a lot of experiments.  It has been shown that diseases can be prevented by administering the animals with anti-CD4+ antibodies.
• As we know, T cell recognition of antigen involves a trimolecular complex of the T-cell receptor , an MHC molecule and an antigenic peptide. So, an individual susceptible to autoimmunity must possess MHC molecules and T cell receptors capable of binding self-antigens.
• In most cases of organ specific autoimmune diseases, ratio of T-helper 1 and T-helper 2 cells was seen unbalanced resulting in the development of autoimmunity.
• T-helper 1 has been seen to contribute to the development of disease.;whereas T-helper 2 cells don't only protect against the induction of disease but also against the progression of an already established one.
• Expts. in case of EAE(experimental autoimmune encephalitis) with mouse have proved that when mice were injected with IL-4 at the time of immunization with MBP(meyelin basic protein ) and adjuvant; then the development of EAE was inhibited;  whereas injecting IL-12 had opposite effect because IL-4 promotes he development of T-helper (2) cells and IL-12 promotes the development of T-helper (1) cells.
• similarly, association has been detected between a particular type of MHC allele and an autoimmune disease. e.g. HLA-B27 have a 90 times higher likelihood of developing ankylosing spondylitis than individuals with a different HLA-B allele.
• Adding to this, presence of TCRs containing a particular V-alpha and V-beta domains has been linked to a number of disease including EAE and multiple sclerosisand myasthenia gravis.

MECHANISMS FOR INDUCTION OF AUTOIMMUNITY:

There are a variety of mechanisms responsible for the generation of autoimmunity. Autoimmunity doesn't develop from a single event but from anumber of different events. adding to this, susceptibility to autoimmune diseases also differ among different sexes.

reasons for induction of autoimmunity:

1)release of sequestered antigens,
2)role of molecular mimicry
3)sensitization of autoreactive T cells
4)activation of polyclonal B cells.

1) Release of sequestered antigens. :-

• any tissue antigens that are sequestered from the circulation are not seen by the developing T cells in the thymus and so won't induce tolerance.
• exposure of mature T cells to such an antigen later might result in autoimmunity because they are foreign to the immune system.
• Trauma to tissues following either an accident or a viral or bacterial infection might release sequestered antigens in to the circulation. e.g. sperm arise late in development and are sequestered from the circulation. However, after a vasectomy, some sperm antigens are released into the circulation and can induce auto-antibody formation in some males.
• Similarly, the release of lens proteins after eye damage or of heart muscle antigen after myocardial infarction has been seen to form auto-antibodies.
• It has also been seen that injection of normally sequestered antigens directly into the thymus can reverse the development of  tissue-specific autoimmune disease in animals.

2)Role of molecular mimicry:

• A large number of bacteria and viruses possess antigenic determinants that are identical or similar to normal host cell components.
• if immune system has already encountered the similar antigens during maturation; then antibodies are not produced in such cases and this helps microbes to escape the immune response. whereas, if they are similar to sequestered antigens; then auto-antibodies can be formed due to this similarity leading to autoimmunity.e.g- post-rabies encephalitis:- in the past, rabies virus was cultured in rabbit brain cell cultures and vaccine thus prepared included antigens derived from the rabbit brian cells. In a vaccinated person, antibodies against the rabbit brian cell antigen is made which can cross react with recepient's own brian cells leading to encephalitis.

Activation of polyclonal B cells-

many bacteria and viruses induce nonspecific polyclonal B cell activation.This can lead to production of B cells reactive to self antigens.

TREATMENT:

• Treating autoimmune diseases is a very difficult deal; because care has to be taken that we are not hampering the whole immune system by targetting  just a single disease..
• Besides, current therapies that have been developed so far, target more the symptoms than the disease.
• Immunosuppressive drugs like corticosteroides, azathioprine, and cyclophosphamide are given and they intent to slow down proliferation of lymhocytes. this ,although, reduce the severeity of autoimmune symptoms, but put the patient at a greater risk of infections and cancer.
• Another  major limitation is the stage at which disease is identified.earlier the disease is identified, more susceptible it is to the treatment. But, unfortunately, n humans, a disease is diagnosed only after appearence of the symptoms.
• Another problem is the use of animal models; as many treatments have been a succes with animal models but failure in humans.
• so, treatments should be more specific ; the one which can distinguish between a pathologic autoimmune response and a protective immune response. an example is use of cyclosporin or FK506 which block signal transduction mediated by the T cell receptor and so inhibit only antigen activated T cells and spare the nonactivated ones.

practising plasmapheresis:

• it has proven beneficial to patients with autoimmune diseases that involve Ag-Ab complexes. Actually, plasma is removed from patient's blood by continuous flow centrifugation. The blood cells are then resuspended in a suitable medium and returned to the patient. This removes the Ag-Ab complexes present in the patient's blood and give temporary relief. e.g. myasthenia gravis, grave's disease, systemic lupus erythematosus, rheumatoid arthritis.

Targetting inflammation:

• inflammation is a symptoms in many autoimmune diseases and thus, automatically becomes a target.many drugs like humira,remicade, enbrel are products that target TNF-alpha and are used for rheumatoid arthritis, psoriasis etc.
• Antibodies against IL-1R, IL-6R, and IL-15 are being used. Anti-IL-1R is even approved for treatment of rheumatoid arthritis.

use of monoclonal antibody;

• initially, monoclonal antibody directed against CD4 has been used but this deplete all T-helper cells and bring more discomfort than cure. So, not a good idea. ( it was a success in mice to treat multiple sclerosis and arthritis bu a failure in humans.)
• similarly, use of  Mab against alpha subunit of IL-2R or CD25 might preferentially block autoreactive T cells.
• as we know, that certain TCR chain components are specifically involved in autoimmune diseases. Targetting them by administering Mab against them might be therapeutic . Same goes with certain allelles of MHC that are specifically associated with certain autoimmune diseases.

Use of oral antigens:

•  Different antigens associated with different autoimmune diseases can be administered as vaccines orally preferentially  to induce tolerance so that later interaction in any way won't result in autoimmunity.