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Autoimmunity
 

Autoimmunity

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    Autoimmunity Autoimmunity Document Transcript

    • Autoimmune disease arises when tolerance is lost and immune responses against self ensue • Autoimmune responses – Generation of immune complexes (Ag:Ab) Autoimmunity complement activated – Activation of CD4 helper T cells – generation of pro-inflammatory cytokines – Activation of PMN and macrophages – Activation of CD8 cytotoxic T cells • ie regular immune response but self-directed Tolerance Tolerance arises from • Deletion • Specific immunological unresponsiveness - • Clonal anergy no reaction to an antigen with an otherwise • Sequestration normal immune system Clonal anergy DELETION • Clonal anergy occurs outside the thymus • Self reactive T cells are deleted during and involves the functional inactivation of thymic education in embryonic life - and the the T cells. Inappropriate presentation of cells die by apoptosis (programmed cell antigen leading to failure of IL-2 production death) (no 2nd signal) – the reason why T cells become tolerant more – Other co-stimulatory signals may not be readily than B cells produced
    • T cell regulation • Cell mediated or humoral mediated immunity controlled by Th1 and Th2 helper cells respectively. • Tolerance is dominated by Th2 cytokines - downregulating B7 (present only on APC’s) • Tolerance in B cells arises more from clonal • Th2 also stimulates a population of CD8 anergy than deletion cells that potentiate this effect. • Can also have down regulation of IgM expression and hence no 1st signal. Development of tolerance or Sequestration immunological response • Immunological maturity • Sequestration of antigen in inaccessible • Structure and dose of antigen sites - so called ‘immunologically – Simple molecules induce tolerance more readily than a privileged’ sites complex one – Brain – High or low doses can result in tolerance – Anterior chamber of the eye • Immunosuppressive drugs enhance tolerance – Ovary • Administration of a cross reacting antigen tends to – Testes terminate tolerance – Pregnant uterus, placenta • Tolerance is maintained best if the antigen remains present T cell autoreactivity Autoimmunity arises when tolerance is lost and immune responses against self ensue • Autoimmune disease can result from T or B cell autoreactivity • A microbe may be capable of triggering an auto reactive T cell which a self protein was unable to stimulate
    • Diminished suppressor T cell T cell autoreactivity Function • Non- self antigens - from bacteria, viruses and drugs are implicated as a source of • If suppressor T cell functions decrease, cross reacting antigens that trigger the antibodies to self antigens may arise activation of autoreactive T cells • eg antibody to normal IgG Rheumatoid • eg rheumatic fever and S. pyogenes factor (IgM specific for normal IgG) • SLE and procainamide deposited in joints • Mammalian hsp 65 (heat shock protein) has > 50% homology with hsp60 from bacterial and parasitic pathogens. B cell auto-reactivity Autoimmunity arising by way of molecular mimicry - Factors contributing to evidence for RA and IDDM autoimmunity • Genetic associations • Sex influences • Environmental influences – Microbial – non- microbial Auto-reactive B cells could be stimulated directly by LPS or certain viruses. MHC system Genetic associations • Peptide binding region which binds peptides between 9 and 11 • 70% concordance rate for IDDM in aa residues in lengthfor MHC I and 10-30 aa residues for MHC II monozygotic twins with Dr3/Dr4 and a • Immunoglobulin like region lower rate for dizygotics - therefore genetic • transmembrane region component is strong but still 50% • cytoplasmic region unaccounted for. • In SLE concordance rate of only 25%
    • HLA and autoimmune disease associations MHC Disease HLA allele Relative risk • MHC I present on all nucleated cells RA DR4 6 • MHC II on expressed on macrophages, dendritic IDDM DR3 5 cells and B cells DR3/DR4 20 • In humans the MHC is the HLA (human leucocyte Pemphigus DR4 24 antigens) vulgaris Sjogrens DR3 10 • MHC I syndrome – HLA-A, HLA-B and HLA-C Coeliac disease DR3 12 • MHC II Ankylosing B27 90 spondylitis – DP, DQ and DR. Relative risk is the chance of an individual with a particular HLA of developing a disease compared with individuals lacking that allele Sex influences Non- microbial triggers • Autoimmune diseases are more commin in • Fish oils females than males • Females of child- bearoing age are at a higher risk • sunlight of developong autoimmune diseases. • organic solvents • Have maximal production of oestrogens and progesterone • Castration would normalise the incidence between males and females • Incedence evens out in later years Spectrum of Auto-immune Microbial triggers diseases • Strep. pyogenes • Organ Specific • M. paratuberculosis – e.g. Hashimoto’s thyroiditis • Chlamydia sp • Yersinia sp • Helminths • Systemic • Plasmodium spp – e.g. SLE
    • Disease Oral manifestation Hashimoto’s thyroiditis Primary myxoedema Pernicious anaemia Atrophic glossitis Autoimmune gastritis Addison’s disease Mucosal hyperpigmentation Myasthenia gravis Weak masticators Diabetes Periodontal disease Goodpastures syndrome Disease Oral manifestation Pemphigus vulgaris Mucosal vesicles/ blisters Sympathetic opthalmia Multiple sclerosis ?? Auto immune haemolytic anaemia Primary biliary cirrhosis Hyperthyroidism Ulcerative colitis Ulcers, pustules Autoantibodies stained with immunofluorescent label in Coeliac disease Hashimoto’s thyroiditis Sjogrens syndrome Hyposalivation/ glossitis Hypothyroidism Disease Oral manifestation Rheumatoid arthritis TMJ swelling / pain Scleroderma Wegeners granulomatosis Dermatomyositis Lichenoid mucosal lesions Amyloidosis Macroglossia (50%) Bechets disease Oral ulceration Discoid lupus erythematosis Ulceration / discoid lesions Systemic lupus erythematosis Ulceration / discoid lesions
    • % positive reactions for antibodies to: Disease Thyroid Stomach Nuclei V V V IgG@ Hashimotos 99 32 8 2 Pernicious 55 89 11 anaemia Sjogrens 45 14 56 75 RA 11 16 50 75 SLE 2 2 99 35 Controls 0-15 1-16 0-19 2-11 VImmunofluorescence @Rheumatoid factor test test