autoimmune disease

see also:

• adaptive immunity
• immunology

• most autoimmune diseases are due to cell-type selective cell destruction due to antibodies produced from B cells binding those cells and making them a target for T cell mediated destruction
  • these often arise due to structural similarities of cell antigenic targets to pathogen antigenic targets or to cell components (eg. XIST RNPs) when repeated cell deaths occurs in a permissive genetic background with repeated tissue injury
• autoimmune diseases are the third most prevalent chronic disease category, outpaced only by cancer and heart disease
• there are more than 100 auto-immune diseases that in aggregate, comprise one of the top ten leading causes of death for women in the Western world under the age of 65
• their prevalence appears to be increasing
• there are few targeted therapies for autoimmune diseases available, the most common therapies involve B cell depletion but are not always effective

• it was thought that viruses induce production of proteins which are immunologically similar to human proteins which then get targetted, however, a 2024 study suggests this is incorrect and instead, the trigger is virus-induced mutations in 'rogue clone' B cells ¹⁾
• many autoimmune diseases result from over-activity of TH2 T lymphocytes and under-activity or dysregulation of TH1 T lymphocytes
• autoimmune diseases disproportionately affect females more than males due to immune sexual dimorphism:
  • some examples auto-immune condition with sex differences:
    • in systemic lupus erythematosus (SLE), the ratio of patient sex is 9:1 females to males; the ratio in Sjögren’s disease is 19:1 female to male patients
    • patients with Klinefelter syndrome (XXY) are phenotypically males, have male hormonal pattern, but have an elevated risk of autoimmune disease equivalent to females
  • the gene Malat1 is a critical player in regulating immune responses in female TH2 cells, but not in males.
    • Malat1 regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL-2. Malat1 is required for appropriate cytokine expression (especially IL-10 but also IL4 and IL-13) in female but not male T helper 2 (Th2) cells in mice. ²⁾
  • epigenetically silencing of one of the two X chromosomes in females
    • to make the gene expression output roughly equivalent between females and males, every cell in a female’s body epigenetically silences one of two X chromosomes via the action of the long non-coding RNA (lncRNA) Xist
    • Xist is an ∼17-kb lncRNA (19 kb in human) that is transcribed only from the inactive X chromosome and thus not expressed in males
    • Xist is critical for the establishment of X chromosome inactivation (XCI) spreading from the X-inactivation center and coating the entire inactive X in association with its protein partners
    • when a female cell dies due to tissue injury, XIST RNPs will invariably be exposed to the immune system
    • in a genetically autoimmune-resistant background, a low level of XIST, even in the presence of tissue injury, leads to only changes in T cell subsets and chromatin states but not to frank organ pathology.
    • epigenetic changes in accessibility are then subsequently reflected in the gene expression programs upregulating autoreactivity and downregulating immune modulation and in the context of a permissive genetic background and repeated tissue injury, the presence of XIST RNP exacerbates full-blown end organ pathology and activation of multiple immune cell types resulting in atypical age-associated B cells (which expand with increased TLR7 signalling) as a population of immune cells that accumulates as a consequence of this Xist RNP expression
    • atypical B cells appear as the immunological nexus of two potential consequences of mammalian XX dosage compensation—autoreactivity to Xist RNP and escape from XCI — and suggest that these consequences may synergize to promote female-biased immunity
    • thus this sex-biased autoimmunity is primarily driven by the Xist ribonucleoprotein complex containing various autoantigenic components. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. ³⁾
  • fetal-maternal microchimerism:
    • fetuses transfer cells (“FMc”) to their mother from 4th week of gestation until delivery and while most of the cells in the blood stream are eliminated by maternal immune cells in the puerperium, many persist for decades in various tissues of the body and their presence may be a factor in many immune related conditions
    • FMc could differentiate into active T lymphocytes, developing an autoimmune response against the maternal tissues (graft-versus-host reaction)

• systemic lupus erythematosus (SLE)
• Sjögren's syndrome (SS)
• scleroderma
• rheumatoid arthritis
• diabetes mellitus - type 1
• vasculitis