The Molecular Basis for Autoimmune Diseases Dr. Adel Almogren Dept of Pathology, Immunology unit

2. The Molecular Basis for Autoimmune Diseases Dr. Adel Almogren Dept of Pathology, Immunology unit Email: almogren@ksu.edu.sa Office: 467-1843

3. Autoimmunity Immune system has evolved to discriminate between self and nonself or safe and dangerous signals Ability developed during fetal life Tolerance, a form of censorship of the immune system, is acquired by • Deletion (clonal deletion) • OR • B) Functional inactivation (clonalanergy) • of developing lymphocytes that possess antigenic receptors with high affinity for self-antigens.

4. (Absence of Co-stimulation) Central and Peripheral Tolerance

5. Peripheral Tolerance of T Lymphocytes

6. Peripheral B cell Tolerance Mechanisms

7. Autoimmune Diseases Self-reactive lymphocytes (the forbidden clones) should be eliminated from the immunological repertoire. Diseases involving an immunological response to normal tissue – termed autoimmunity or autoimmune diseases. Original concept – the receptors of lymphocytes with specificity for foreign antigens underwent mutation – results in a new class of receptors with specificity for self-antigens.

8. Autoimmune Diseases in Humans

9. Pathology of Autoimmune Diseases Most of the autoimmune diseases attributed to autoantibodies. Other autoimmune diseases have an autoreactive T cell component. Disease processes and tissue damage are due to Type IIType III and Type IV hypersensitivity reactions.

10. Type II Hypersensitivity Autoimmunity

11. Autoimmune Diseases due to Type II Hypersensitivity

12. Type III Hypersensitivity Autoimmunity

13. Autoimmune Diseases due to Type III Hypersensitivity

14. Type IV Hypersensitivity

15. Autoimmune Diseases due to Type IV Hypersensitivity

16. Organ specific AI diseases: • (mediated by direct cellular damage) • Hashimoto thyroiditis: Autoabs & T DTH • Autoimmune Anaemia: Pernicious A, A hemolytic A, Drug—induced A. • Goodpasture’s syndrome • Insulin dep. DM (IDDM) • the second category is: • (mediated by stimulating or blocking autoantibodies) • Graves’ disease • Myasthenia gravis

17. Grave’s Disease • Production of thyroid hormones is regulated by thyroid-stimulating hormones (TSH) • The binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of two thyroid hormones: thyroxine and triiodothyronine • A person with Grave’s Disease makes auto-antibodies to the receptor for TSH. The binding of these auto-antibodies to the receptor mimics the normal action of TSH, without the regulation, leading to overstimulation of the thyroid • The auto-antibodies are called long-acting thyroid stimulating hormones

18. Myasthenia gravis Motor end-plates of muscles

19. Systemic AI diseases : • SLE • SLE patient

20. Multiple sclerosis: affects CNS. autoreactive T cells– myelin sheath of nerve fibers Individuals with the DR2&DR3 variant of MHC genes are most susceptible to the disease.

21. RA Rheumatoid arthritis (RA) affects peripheral joints and may cause destruction of both cartilage and bone. The disease affects mainly individuals carrying the DR4 variant of MHC genes. This fact can lead to better prognoses and in aiding efforts to change immune reactions that involve the DR4 variant while leaving other reactions intact.

22. Proposed Mechanisms of Autoimmunity

23. Release of Sequestered Antigens Induction of tolerance in self-reactive T cells occurs through the exposure of immature T cells to self-antigens in the thymus. The elimination/silencing of all self-reactive T cells requires that all self-antigens be presented within the thymic environment. Some self-antigens are sequestered in specialized tissues and may not be expressed in the thymus. These are not seen by the developing immune system – will not induce self-tolerance. Exposure of T cells to these normally sequestered/tissue-specific self-antigens in the periphery results in their activation.

24. Examples of Sequestered Antigens Myelin basic protein (MBP), associated with MS. Sperm-associated antigens in some individuals following vasectomy. Lens and corneal proteins of the eye following infection or trauma. Heart muscle antigens following myocardial infarction.

26. Cross-reacting Antigens (Molecular Mimicry) Viruses and bacteria possess antigenic determinants that are very similar, or even identical, to normal host cell components. This phenomenon, known as molecular mimicry, occurs in a wide variety of organisms. Molecular mimicry may be the initiating step in a variety of autoimmune diseases.

27. Examples of Molecular Mimicry

28. Inappropriate Expression of Class II MHC Molecules The elimination of self-reactive T cells involves contact with APC presenting self-peptides within the thymic environment. Results in deletion or functional inactivation. Highly tissue specific proteins not expressed within the thymus, do not induce clonal deletion or tolerance. T cells will not respond in the periphery if the tissue expressing these specific proteins does not express class II MHC molecules. Class II MHC ordinarily expressed on antigen presenting cells, such as macrophages, dendritic cells and B cells. The aberrant expression of MHC determinants allows the recognition of these autoantigens by self-reactive T cells. Results from the local production of IFN-, which is known to increase class II MHC expression on a variety of cells. The inducer of IFN- under these circumstances could be a viral infection.

29. Type I Diabetes: Pancreatic β cells express abnormally high levels of MHC I and MHC II (?) MHC II – APC only! This may hypersensitize TH cells to β cell peptides. Normal Pancreas Pancreas with Insulitis

30. Polyclonal B Cell Activation Viruses and bacteria can induce nonspecific polyclonal B cell activation, including: Certain gram negative bacteria Herpes simplex virus. Cytomegalovirus Epstein Barr Virus Human immunodeficiency virus (HIV) Induce the proliferation of numerous clones of B cells to secrete IgM in the absence of a requirement for CD4 T cell help. Polyclonal activation leads to the activation of self-reactive B cells and autoantibody production. Patients with mononucleosis (caused by EBV) and AIDS (HIV) have a variety of autoantibodies.