Autoimmunity

Autoimmunity

Immune Tolerance
1. Tolerance Definition: A type of specific unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen, but response to other antigens normally
  1. Tolerogens Definition: Antigens that induce tolerence
    1. Normal individuals are tolerant of their own antigens (self-antigens) --> self-tolerance
      1. Foreign antigens may be administered in ways that preferentialy inhibit immune response by inducing tolerance in specific lymphocytes- antigen induction
2. During neonatal stage of life, or when immune system is developing, all antigens present are recognised as self
3. Tolerence is achieved by clonal deletion - cells which come across self-Ag undergo apoptosis
4. Tolerance is antigen specific and results from recognition of antigens by specific lymphocytes
5. Mechanisms of Immune Tolerance
  1. central tolerance
    1. in the central lymphoid organs as consequences of immature self-reactive lymphocytes recognising ubiquitous self-antigens
      1. clonal deletion (apoptotic cell death
        During maturation of lymphocytes in the thymus (T-cell) or bone marrow (B-cell), immature lymphocytes that recognise ubiquitous self-antigen with high affinity are deleted by negative selection
  2. peripheral tolerance
    1. induced in peripheral organs as aresult of mature self-reactive lymphocytes encountering tissue-specific self antigens under particular conditions
      1. Clonal anergy
        functional inactivation without cell death: lack of co-stimulatory signal
Autoimmunity
1. An autoimmune response against a self-antigen(s)
  1. autoimmune disease is tissue damage or disturbed physiological function due to an autoimmune response
    1. The burden of autoimmune diseases is considerable in western society
      1. around 3% of the population have an autoimmune disease
        many of the major chronic disabling diseases affecting people of a working age are considered to be autoimmune
        These include MS, RA Type 1 diabetes
        autoimmune diseases are rare in childhood; the peak years between puberty and retirement (except childhood type 1 diabetes
        almost all autoimmune disease are more common in women
        the prevalence of autoimmunity is higher in westernised, industrialised societies and seems to increase progressively as this pattern and social and economic organisation develops
        autoimmune diseases also show evidence of clustering within families
2. layers of self tolerance
  1. central tolerance - deletion, editiong - thymus, bone marrow
    1. antigen segregation - physical barrier to self-antigen access to lymphoid system
      1. peripheral anergy - cellular inactivation by weak signalling without costimulous - 2ndary lymphoid tissue
        regulatory cells - suppression by cytokines, intercellular signals - 2ndary lymphoid tissue & site on inflammation
        cytokine deviation - differentiation to Th2 cells, limiting inflammatory cytokine secretion - 2ndary lymphoid tissue & sites of inflammation
        clonal exhaustion - apoptosis post- activation - 2nary lymphoid tissue & sites of inflammation
3. autoimmune diseases are either:
  1. systemic
    1. RA, scleroderma, SLE, sjoren's syndrome, polymyositis
  2. organ-specific
    1. type 1 diabetes, goodpastures syndrome, MS, graves disease
      1. hashimotos thyroiditis, autoimmune pernicious anaemia, autoimmune addisons disase, vitiligo, myasthenia gravis
Molecular Mimicry
1. structural similarity between self proteins and those from microorganisms may trigger an immune response
  1. a self peptide in low concentration and with no access to appropriate antigen presenting cells may cross react with a structurally similar microbial peptide
    1. In a systemic infection, this cross reactivity will cause expansion of the responsiveness of T-cell population, which may then recognise the self peptide (MM)
      1. Once tolerance has broken down to a particular peptide the resulting process of inflammation may allow presentation of further peptides
        immune system broadens and local tissue damage accelerates
        this domino effect is called epitope spreading
        e.g. immunising with a single peptide from a nerve sheath (MBP-myelin basic protein) -> CNS inflammation -> immune response against MBP and other CNS protein peptides
        local inflammation, particularly in the presence of a pathogen that has some structural similarity to a self antigen present at the sire of inflammation -> induce a self-sustaining autoreactive pathogenic process
        While transient autoimmune responses occur commonly after infection or other forms of tissue damage, the development of sustained immunity is relatively rare
Genetic Factors
1. The use of twin and family studies has confirmed a genetic contribution in all autoimmune diseases studied
  1. multiple autoimmune diseases may cluster within the same family; subclinical autoimmunity is more common among family members than overt disease
    1. The genetic contribution to autoimmune disease is complex and involves multiple genes
      1. There are a number of single gene defects in bot humans and animals that can lead to immunity
        some single gene defects involve defects in apoptosis or breakdown of self anergy and are compatible with the mechanisms for peripheral tolerance and its breakdown
        many of the strongest and best characterised associations between genes and autoimmunity involve different varients or alleles of the MHC, which are in T-cell function and antigen presentation
        the MHC molecules expressed in humans as Human Leucocyte antigens (HLA) and associations between these antigens and disease were initially described in terms of one or another HLA allele
        RA is associated with the HLA antigens DR1 and DR4, likewise, type 1 diabetes is associated with DR3 and DR4
Environmental Factors
1. Environmental factors identified as possible triggers in autoimmunity including hormones, infection, and therapeutic drugs and miscellaneous other agents such as UV
Hormones
1. The mechanisms underlying this relationship is unclear but evidence suggest that oestrogens can stimulate certain types of immune response
  1. Removal of the ovaries inhibits the onset of spontaneous autoimmunity in animal models, and the administration of oestrogen accelerates the onset of disease
    1. Most autoimmune diseases have their peak age of onset within the reproductive years and much experimental and some clinical evidence exists to implicate oestrogens as triggering factors
      1. Hormonal factors appear to play a major role in the increased prevalence of autoimmunity in females
  2. The pituitary hormone prolactin also has immuno- stimulatory actions, particular on T-cells
    1. Prolactin levels surge after pregnancy, and this may be linked with the tendency of some autoimmune diseases such as RA being present at this time
Infection
1. The relationship between infection and autoimmunity is clearest in the situation of molecular mimicry
  1. Infection of the target organ may play a key role in the regulation of co-stimulatory molecules and also in inducing altered pattern of antigen breakdown and presentation -> autoimmunity molecular mimicry
    1. infections have been sought for a link to RA and MS in particular
      1. Autoimmune diseases tend to be less common in parts of the world that have a high burden of parasitic disease and other infections
        some animal studies have shown autoimmunity to be inhibited in a high infection environment
        Germfree environments promoted autoimmunity in these animals
Drugs
1. Drugs may induce a variety of pathological immune responses, and it is important to distinguish between an immunological response to drug, either in its native form or "complexed" with a host molecule, and a true autoimmune process induced by the drug
  1. The former mechanism of drug hypersensitivity is usually reversible on drug withdrawal, whereas the second process may progress independently of drug treatment and require some form of immunosuppressive treatment
    1. The distinction in comparable to that between autoimmune are poorly understood, but may involve mechanisms comparible to molecular mimicry, whereby the drug or a drug-self molecule complex have a structural similarity to self, and hence allow bypass of peripheral.
      1. some drugs such as penacillamine have the ability to bind directly to the peptide containing groove in the MHC molecules
        This mechanism is largely genetically determined
        genetic variation within the MHC would potentially influence recognition of drugs-self complexes by T-cells, or may directly influence drug binding to the MHC
        eg. HLA DR2 is associated with penicillamine induced myasthesia gravis, whereas DR3 is associated with nephritis
Other physical agents
1. Exposure to UV is a well defined trigger for skin inflammation and sometimes systemic involvement in SLE
  1. It is most likely that this acts merely to cause flares in a pre-existing autoimmune response, rather than being a true aetiological factor
    1. UV can cause free radical mediated structural modification to self-antigens, thus enhancing their immunogenicit
      1. It can also lead to apoptopic death of cells of the skin. this process is associated with cell surface expression of lupus autoantigens which are associated with photosensitivity usually only found within a cells
        These autoantigens are then able to bind appropriate autoantibodies and trigger tissue damage

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	Created by Sami-Jaine almost 11 years ago

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