Lecture 18 (10B) - Autoimmunity Flashcards
Autoimmunity
when we start making T cell or antibody responses against self antigens
• a breakdown in self tolerance
• we are all autoimmune
• autoantibodies do not mean autoimmune disease
• although detectable, autoantibody levels are low
• frequency of autoantibodies increase with age
Autoimmunity is caused by
hypersensitivity
T cell clonal deletion of self-reactive cells is not completely efficient
between “receptor binds self-peptide weakly” and “receptor binds self-peptides strongly” is a gray area that makes autoreactive T cells
• in the thymic cortex millions of T cells are made every day
• many recognize self-peptides strongly and so have to be deleted (clonal deltion)
• many do not recognize anything and die (neglect)
• a few recognize self-peptides weakly and are allowed to mature and leave the thymus (positive selection)
• autoreactive caught by regulatory T cells
B cells develop from
stem cells in the bone marrow
• B cells which meet self antigen in the marrow are anergized, alive but unresponse
- B cells - receptor editing
- B cells out into body with potential to make autoantibodies
Recombination produces
B cells with surface receptors (antibodies) for self antigens
• not killed when they develop
• they are tolerized - anergic
The process of T and B selection is not perfect
• we all have self-reactive T and B cells in our bodies
• but only a few of us get autoimmune ddisease
1. how do we control these autoreactive cells
2. what triggers can allow these autoreactive cells to mature and become effector cells against our own cells and tissues
Assume we al have autoreactive T and B cells
1970s-80s = suppressor cells
1990s - 2013 = regulatory cells and cytokines
All of us have a population of regulator cells in our blood
- small percent of CD25+ CD4+ cells
- IL-2 receptors = CD25
- CD25+ don’t divide, down-regulate immune response
Regulatory T cells
help suppress autoreactivity
in the thymus, make self reactive T cells, nearly all deleted but a few reach the periphery
• CD4+, C25+ Foxp3+ Treg
–> suppression of TGFβ (an immune suppressor)
• children who do not have Foxp3 develop autoimmunity, especially to endocrine and exocrine glands
TGFβ
an endogenous inhibitor of T cells
• made by fibroblasts, epithelial cells, Treg cells
• knock it out in mice, animal dies of generalizeed T cell-mediated autoimmune disease in early life
(autoimmune T cells ont he attack)
T reg cells come from the thymus
just after birth
• thymectomize 2 days of age
–> allow to grow up = autoimmune gastritis
• thymectomize 2 days of age, then inject with CD25+ Cd4 cells (regulatory cells) = healthy mouse
Costimulatory molecules with positive and negative effects on T cell activation
APC CD80 + Tcell CD28 = positive signal
APC CD86 + Tcell CTLA-4 = negative (dampening) signal
• there’s a balance between positive and negative
Make CTLA-4 knockout mouse
animal dies of autoimmune diseases early in life (the dampening signal)
In the absence of costimulation,
T cells are not triggered
• affinity of receptor weak - doesn’t activate
• need stimulation or become anergic
Costimulatory molecules and their receptors
control autoreactivity