- Briefly describe autoimmunity
- Autoimmunity is an immune response against self (autologous) antigens which results in autoimmune disease.
- Disturbances in immune tolerance results in autoimmune disease.
- They affect 2-5% of the population in developed countries. Autoimmune diseases may be organ-specific (affecting only one or a few organs) or systemic (with widespread tissue injury and clinical manifestations).
- Tissue injury in autoimmune disease is caused by Antibody or T cell reactions to self-antigens (autoantibodies and self-reactive T-cells)
- What are the risk factors for autoimmunity
- Inheritance of susceptibility genes
- Genes that interfere with self-tolerance, causing self reactive B and T-cells to persist
- Environmental triggers
- Infections causing tissue injury and inflammation, activates self-reactive lymphocytes and release of autoantibodies
- Inheritance of susceptibility genes
- Describe how genetic factors contribute towards autoimmunity
- Polymorphisms in HLA genes
- The incidence of particular autoimmune disease is often greater among individuals who inherit a particular HLA allele
- Polymorphism in Non-HLA genes
- IL-2R a-chain (CD25): contributes to self-tolerance and abnormal activation of lymphocytes
- IL-23R: promotes development of proinflammatory Th17
- CTLA-4; Key inhibitory (checkpoint) receptor in T-cells that removes B7 on APCs
- PTPN22: Protein Tyrosine Phosphatase N22 mutations (gain of function) lead to uncontrolled activation of B and T cells, associated with RA, SLE and T1DM
- NOD-2: reduces its resistance to intestinal microbes, associated with Crohn’s dz
- C2, C4 complements: Causes defective clearance of immune complexes and B-cell tolerance, associated with SLE
- Genes with high penetrance (via mendelian inheritance)
- AIRE: Autoimmune polyendocrine syndrome, reduced expression of peripheral tissue antigens in the thymus leading to defective elimination of self-reactive T-cells
- FOXP3: IPEX syndrome, causes deficiency of Treg, IPEX = Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked
- FAS: causes defective apoptosis of peripheral self-reactive T and B cells
- CTLA4: causes impaired inhibitory checkpoint, and Treg function
- Polymorphisms in HLA genes
- Describe how environmental triggers contribute towards autoimmunity
- Molecular mimicry
- Environmental antigens mimic a component of the body causing cross-reactivity against the body component
- Example: M-protein of GAS in RF, LOS of Campylobacter Jejuni in Guillain Barre
- Release of sequestered antigens from immunoprivileged sites
- Antigen from seminiferous tubules, CNS, lens, and uveal tract elicit both a humoral and cellular response.
- Examples: DNA, Histones, Mitochondria by infections, radiation and chemicals (This is why UV exacerbates skin rash in SLE), RA: Acute and chronic inflammation results in conversion of arginines to citrullines in self-proteins causing their recognition as non-self and autoreactivity
- Failure of Treg
- Mutations in FOXP3 cause defective suppression of self-reactive T-cells
- Induction of co-stimulation on APCs
- Production of co-stimulators and cytokines by tissues during inflammation causes APCs to stimulate self-reactive T-cells that encounter self-antigens in tissue
- Infections break tolerance and cause self-reactivity
- Epitope spreading
- Autoimmune reactions initiated against self antigens cause release of additional self-epitopes that cause another secondary autoimmune reaction, resulting in a cascading reaction
- Molecular mimicry
