What mechanisms work to prevent autoimmunity
Central tolerance in the bone marrow and thymus: immature cells. Peripheral tolerance: abrogates activity of auto-reactive cells that snuck through the bone marrow or thymus that causes them to undergo anergy, apoptosis or suppression by regulatory T cells.
When are B cells most tolerizable?
1st they develop in the bone marrow and then move to the lymph node. In the lymph node once they develop into an immature B cell with IgM on the surface, but not yet IgD, they are most tolerizable. This means that if they encounter antigen at this stage they are shut (anergized).
How does central T cell tolerance develop?
1st they develop in the bone marrow and then move to the thymus. There they trickle down the stroma of the thymus, coming into contact with cortical epithelial cells, dendritic cells, medullary epithelial cells. Only 5% of the T cells that entered will leave the thymus to seed secondary lymphoid organs.
Positive and negative selection that occurs in the thymus?
If a T-cell's alpha and beta subunit of the TCR tightly binds to a dendritic cell in the thymus it dies (negative selection). If binding is moderate then it lives (positive selection).
What causes a T-cell to become anergic in the periphery?
T-cells are activated by 2 signals 1) TCR binds CD3 on APC 2) CD28 binds B7 on APC (note that B7 is only expressed on APCs if the APC is activated after phagocytosis of a pathogen). If only one of these signals is presents the T cell becomes anergic.
What causes a T-cell to undergo apoptosis in the periphery?
If the T-cell recognizes self antigen, it induces pro-apoptotic proteins and expresses FasL that binds to Fas and induces apoptosis.
Pathogenesis of autoimmune lymphoproliferative syndrome?
ALPS is a result of defective FasL expression by T-cells after they recognize self antigen.
What causes T-cell suppression in the periphery?
Recognition of self antigen by a T-cell results in induction of regulatory T-cells that inhibit T-cell activation and T-cell effector functions.
Pathogenesis of immune dysregulation polyendocrinopathy enteropathy X-linked disease?
IPEX is a result of absence of FOXP3 transcription factors in regulatory T-cells that suppress T-cells that react with self antigen.
Important factors in triggering autoimmunity
1) Failure of tolerance mechanisms 2) Genetic factors 3) Infection 4) Environmental exposure
What genetic alleles make transplantation so difficult?
HLA alleles determine the antigenic variation seen in MHC I and MHC II surface proteins. Note that both maternal and paternal alleles are expressed which results in high variability and difficulty finding a match for transplantation.
Ankylosing spondylitis and acute anterior uveitis HLA allele
Goodpasture's and multiple sclerosis HLA allele
Grave's disease HLA allele
What is the mechanism by which infection can trigger sympathetic ophthalmia?
Tissue barrier disruption -> Sequestered self-antigen released -> Non-tolerized cells activated because they never saw that antigen during development.
What is the mechanism by which infection can trigger rheumatic fever, reactive arthritis or lyme arthritis?
Molecular mimicry: infection results in production of T-cells and antibodies that cross-react with host tissue.
2 ways we can classify autoimmune diseases
Organ-specific and systemic.
Pathogenesis of Grave's disease
Anti-TSH receptor antibody production mimics TSH and causes hyperthyroidism.
Pathogenesis of Systemic Lupus Erythematosus?
Circulating IgG antibody against cell surfaces, cytoplasm and nucleic acids forms complexes and deposits in tissues all around the body.
Pathogenesis of Rheumatoid arthritis?
80% of patients make IgM, IgG and IgA antibody against the Fc region of human IgG (called rheumatoid factor).
Self to self (skin from your own leg to your own arm)
Between genetically identical
Between genetically different individuals in the same species
Between individuals of different species
1st set rejection
Rejection of allograft ~10 days afterwards because it is the individuals 1st sensitization
2nd set rejection
Rejection of allograft ~3 days afterwards because the individual was previously sensitized (memory response)
2 major diseases associated with allograft rejection. How do you determine if one of these is going on?
1) Healthy host mounts T-cell response against allograft (host-versus-graft disease) 2) Allograft attacks the recipients tissues (graft-versus-host disease). This is tested with the mixed lymphocyte reaction (MLR): cells from the donor and recipient are mixed and the proliferation of T-cells is measured radioactively. Note that T-cell proliferation is dependent on MCH II differences and CTL proliferation is dependent on MCH I differences.
Preexisting alloantibodies cause immediate rejection
Effector T cells attack allograft due to HLA differences between donor and recipient. This is because despite having an MHC surface protein, the host T-cells recognize it as a self MHC with a foreign peptide, causing them to proliferate and attack.
May involve specific alloreactivity or non-immune injury like atherosclerosis or ischemia.
What have we done to minimize the incidence of graft-versus-host disease in people receiving bone marrow transplants?
Removing of mature and memory T cells from the donor marrow. This prevents donor T cells from interacting with host dendritic cells, proliferating and entering host tissues to cause damage.