5. Tolerance and Autoimmunity

IS loses its tolerance to self-antigens and produces autoantibodies or autoreactive T cells that attack the body’s own components.

T&B cells activated against self-antigen

Chronic inflammatory diseases damaging own organs and tissues

Mechanism that prevents IS to react on self structures

1. Central Tolerance

   • thymus and bone marrow

   • Mechanismus: autoreaktive Zellen werden erkannt und eliminiert (Apoptose)

   • Bei B-Zellen zusätzlich: Rezeptor-Editing (Neuanordnung der Rezeptorgene)

   • Ziel: keine stark autoreaktiven Zellen verlassen die Primärorgane.

     
     

2. Peripheral Tolerance

   • peripherial organs & secondary lymphoid tissue

   • anergie, supression, deletion/apoptose

• regulatory Tcells

  • supression by cytokines, intercellular signals

• Immunological ignorance

  • Mechanismus: autoreaktive Zellen existieren, aber sehen das Antigen nicht oder binden zu schwach, um aktiviert zu werden.

  • Ziel: Ruhe durch Nicht-Begegnung.

• Immonologically privileged sites

  • differntiation of regualtory T cells that limit inflammatory cytokine secretion

  • local immunsupressive factors

• antigen segregation

  • Mechanismus: manche Selbstantigene sind physisch getrennt vom Immunsystem (z. B. Gehirn, Auge, Hoden, Plazenta)

  • Ziel: autoreaktive Zellen sehen diese Antigene nie.

• peripheral anergy

  • Mechanismus: autoreaktive Zelle erkennt Antigen ohne Kostimulation → wird funktionell inaktiviert (anergisch)

  • Ziel: keine Aktivierung ohne „Gefahrensignal“.

• functional deviation

  • Mechanismus: potenziell schädliche T-Zellen werden in nicht-entzündliche Typen „umprogrammiert“ (z. B. Th1 → Th2 oder Treg-ähnlich unter Einfluss von IL-10, TGF-β)

  • Ziel: Entzündung in harmlose Reaktion umlenken.

• activation-induced cell death

  • Mechanismus: wiederholte Aktivierung → Expression von Fas/FasL → Apoptose

  • Ziel: verhindert Überreaktionen und Autoimmunität bei Dauerstimulation.

natural regualtory Tcell:

• tcell specific for self antigen recognized in tyhmus becomes nTreg

induced regualtory Tcell:

• tcell specific for self or commensal microbiota antigen recognized in presence of TGF-b becomes an iTreg

-> cytokines produced by treg cell inhibit other self reactive T cells

1. Activation: by recognizing self-antigen on APC via MHC II (antigen-specific).

2. Where: in peripheral tissues (e.g., gut, skin, thyroid).

3. How: release IL-10, TGF-β, use CTLA-4, consume IL-2 → suppress nearby T-cells.

4. Note: once activated, can also inhibit bystander T-cells in same tissue. (activated only through same Ag specifity)

By infection or tissue damage → APC activation → ↑antigen + costimulation (CD80/86, cytokines) → low-affinity self-reactive T-cells get activated → autoimmunity.

Self-DNA or RNA from dying cells forms immune complexes → bind autoreactive BCR → internalized → activate endosomal TLR9 (DNA) or TLR7 (RNA) inside the same B-cell.This provides a T-independent second signal, activating the B-cell to produce anti-DNA or anti-RNP autoantibodies(as in SLE).

Normally, self-reactive B-cells bind self-antigen too weakly to activate.But when self-antigens form immune complexes (e.g. bound by IgG during tissue damage or inflammation), they become multivalent and can cross-link many BCRs at once.This generates a strong activation signal that breaks ignorance and induces autoantibody production, especially if TLR or T-cell help is also present.

An infection triggers immune responses to microbial antigens that resemble self-antigens,causing cross-reactive T- or B-cells to attack host tissues → autoimmunity.🧩 Example: Streptococcal infection → antibodies attack heart (rheumatic fever).

Damage or inflammation releases hidden self-antigens from immune privileged sites → they drain to secondary lymphoid organs, where APCs present them → activation of self-reactive T/B cells → autoimmunity (e.g., sympathetic ophthalmia).

1. organ specific autoimmune disease

   • autoantigen dervied from that organ

   • response againt autoAg in that organ

   • type1 diabetes mellitus, mulitple sclerosis, Hashimoto

2. systemiy autoimmune diseases

   • autoantigen is generic and present in multi organs

   • response against autoAg in mulitple organ

   • rheuma

• targeting self protein

• accumulation of immune complexes

• response against self peptides

• damage direct or via recruitment of innate cells

development of immune responses to endogenous epitopes secondary to the release of self antigens during a chronic autoimmune or imflammatory response

• release of new self Ag

• priming of new self reactive T and B cells

Eine Immunreaktion, die gegen ein bestimmtes Epitop (ein kleines Stück eines Antigens) gerichtet war,breitet sich auf andere Epitope desselben oder anderer körpereigener Proteine aus.

Exposure of one self-antigen activates autoreactive cells → tissue damage releases more hidden self-antigens → APCs present new epitopes → new autoreactive T/B-cells activate → expanding autoimmune cascade.

• Anitbody is pathogenics

• Abs on surface of red blood cells recognized by macrophages & RBC is phagocytosed, either by

  • FcR recognition

  • complement fixation (can also lead to direct lysis by membrane attack complex

• b cells / AB

• ABs act as an agonist (activation)

• results in excessive receptor activation

• ab / B cells

• ab act as an antagonist

• results in receptor blockade

• agonist

• antagonist

• Abs on surface lead to phagocytose

• abs on aurface of cells can induce ADCC (cytotoxic)

1. direct killing

2. cytokine production & activation of innate mechanisms or direct tissue injury

3. help bcells for the production of AB

By autoreactive CD8+ T cells to insulin antigens

• Th17 & 1 enter CNS

• they become reactive

• Cytokines recruit & activate innate cells causing tissue damage > demyelination

• but also direct on neurons

• anti-myelin AB is induced

1. presence CD4 & CD8 T cells in brain lession

2. T cell associated cytokines present in cerebropsinal fluid

3. Drugs to treat MS often target T cells or reduce their activity

-> most of what we know comes from animal models/mice (EAE)

• manipulation of genes in T cells that impair development

T cell infilitrate thr synovium

• genetics

• environment

• life style

AI are very sex spec

• SNP around gene (autosomal recessive / X linked)

  • can be correlated with multiple diseases

• specific HLA alleles

  • typ 1 diaetes HLA DQ2 and DQ8