Ritu's Biology Hub

Continued from Part 1

Causes

1. Release of Sequestered Antigens

• Induction of self-tolerance in T-cells occurs by exposing the immature thymocytes to self-antigens at the time of maturation in thymus followed by deletion of those that are self-reactive
• Tissue antigens sequestered from circulation and thus, not presented during T-cell maturation does not induce self-tolerance. Therefore, exposure to such antigens later in life results in T-cell activation
• Situations that release normally sequestered antigen into circulation:
  • Trauma to tissues after accident or viral or bacterial infections
  • Vasectomy that may release sperm antigens
  • Eye damage releasing lens proteins
  • Myocardial infarction releasing heart muscle antigens
• Injection of sequestered antigens into thymus prevents development of autoimmune antibodies

2. Molecular Mimicry

• Many viruses and bacteria have antigens similar/identical to host proteins in conformation or primary sequence. This is known as molecular mimicry
• Post-rabies encephalitis – Earlier rabies vaccine was used to be prepared in rabbit brain-cell culture and vaccine preparations used to contain some brain antigens. Injecting the vaccine would initiate a cross reaction with the brain antigens in humans causing encephalitis
• Rheumatic fever caused by infection with Streptococcus pyogenes. Antibodies formed against streptococcal antigens cross react with heart muscle antigens damaging the heart in humans

3. Inappropriate expression of Class II MHC molecules

• Pancreatic beta cells from individuals with IDDM and thyroid acinar cells from people suffering from Grave’s disease express high levels of MHC class I and II molecules on their surface
• Inappropriate expression results in expression of antigens derived from those cells thereby sensitizing T_H 1 cells and activation of B and T_C cells
• Studies have revealed that high levels of IFN-ϒ can induce expression of MHC II molecules in variety of somatic cells. Therefore it is hypothesized that viral infections or tissue injuries set up an inflammatory response increasing concentrations of IFN-ϒ

4. Polyclonal B-cell activation

• Several bacteria and viruses generate polyclonally activated B-cells e.g., Gram negative bacteria, CMV EBV etc. If B-cells specific to self-antigens arise, it would give rise to autoimmune disorders
• In infectious mononucleosis caused by EBV, autoantibodies are produced specific to T and B-cells, rheumatoid factors and antinuclear antibodies
• SLE patients show the presence of IgM antibodies suggesting polyclonal activation
• Many AIDS patients show autoantibodies to platelets and RBCs which could be due to coinfection with EBV or CMV that are known to induce B cells

Treatment

Current therapies are aimed at alleviating symptoms. Treatments provide nonspecific suppression of the immune system and therefore not being able to distinguish between an autoimmune response and protective immune response. Immunosuppressive drugs slow down lymphocyte proliferation. The immune suppressed patients become greater predisposed to cancer and other opportunistic infections. Cyclosporin A (FK506) blocks signal transduction by TCR thus, inhibiting only activated T-cells. Thymectomy controls symptoms in myasthenia gravis. Plasmapheresis is beneficial to disease which involve formation of immune complexes such as Myasthenia gravis, Grave’s disease, SLE or rheumatoid arthritis (RA).

1. T-cell Vaccination

• Mice studies have shown that injection of cloned T-cells for MBP (myelin basic protein), they did not develop EAE. Instead they became resistant to the development of EAE when later challenged with a lethal dose of MBP with adjuvant or activated MBP specific T cells
• Efficacy of Cloned T-cells could be enhanced by crosslinking cell-membrane components with glutaraldehyde or formaldehyde leading to permanent remission of symptoms of EAE
• These cross linked T-cells perhaps evoke T regulatory cells that suppress the autoimmune T-cells

2. Blocking of MHC molecules with Peptide

• Experiments show that synthetic peptides differing by only one amino acid from their MBP counterparts are capable of binding to MHC molecules with same affinity
• Co-injecting the two in a mice blocks the development of EAE. This is presumably due to the synthetic peptide being a competitive inhibitor to the MBP protein
• Other studies have revealed that blocking peptides complexed with soluble Class II MHC molecules actually reverse the clinical progression of EAE in mice. It has been assumed that this is because of induction of a clonal anergy state in autoimmune T-cells

3. Monoclonal Antibodies

• Anti-CD4 monoclonal antibodies can block or deplete TH cells and are prospective candidates for immune therapy. However, they can threaten the overall immune system
• One strategy to curb this effect is to block only antigen activated T_H This can be accomplished by synthesizing mAbs to the α-subunit of IL-2 receptor which is expressed only by activated T_H cells. Blocking the subunit would consequently block its activity
• V_β2 mAb specific to V_β 8.2 TCR has been found to reverse the symptoms of EAE in mice
• mAbs to MHC molecules might retard the development of autoimmunity

4. Oral Antigens

• When antigens are administered orally they tend to induce tolerance. Mice fed with MBP do not develop EAE after subsequent administration of MBP
• Clinical trials in humans have not been found to be promising probably due to ineffective dosage or inappropriate antigens

Points to be noted

• Mice studies indicate the involvement of CD4⁺ T_H1 cells. T-cell recognition of antigen requires presentation of antigens by MHC molecules. This implies that individuals susceptible to autoimmune disease possess MHC molecules and TCRs that can bind self-antigens.
• It has been found in a number of studies that while T_H1 cells are implicated in the development of autoimmune disorders, T_H2 cells not only protect against the induction of the disease but also prevent progression of the established ones.