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
2 ways to think about autoimmune T cells
active suppression
Treg cell –> self-reactive T cell + APC
== active suppression
Overcoming weak affinity
self-reactive T cell + APC increase MHC, costimulation
==costimulation starts to divide
So all healthy people have
self-reactive T and B cells
• but most people keep them under control
Theory of autoimmmunity
• infections can cause autoimmunity
eg EBV
EBV –> anergic B cell –(polyclonal activationo f lots of B cells)–> transformed B cell –> autoantibodies –> disease?
Theory of autoimmmunity
• infections can cause autoimmunity
eg Rheumatic fever
infection –> polyclonal antigen-specific response –> antibody against the infection, but also binds to self-antigen (x-reactive), autoimmunity-Rheumatic fever
Rheumatic fever
• auto streptococcus antibodies but something on heart looks similar –> attack heart (need heart transplant) (x-reactive)
Molecular mimicry
sequence similarities between self and infectious antigens
Molecular mimicry
sequence similarities between self and infectious antigens
• measles virus and myelin basic protein have sequence similarity
• papilloma virus and insilun receptor have sequence similarity
• so when B cell recognizes one, the antibodies made by the plasma cell recognize the one that looks similar also
Lots of autoimmune diseases are associated with
HLA
• this suggests that presentation of self-peptides to autoreactive T cells is important
• HLA controls immune response
• T cell only recognizes angiten in presence of HLA
• HLA B27 presents self-peptide to T cells
Some theories of autoimmunity
- defects in regulatory T cells
- molecular mimicry between pathogens and self-peptides (antibody against streptococci x-react with heart muscle)
- polyclonal activation of B cells during immune responses or infection (EBV) inevitably leads to some which recognize self antigens
- sequestered antigen not seen by developing T and B cells o really just seen like a foreign antigen (sperm)
(sperm is neoantigen - immune system hasn’t seen it before) - during affinity maturation in germinal centers, somatic hypermutation leads to self-reactive specificities
Autoimmune diseases are classified as
• organ specific
• non-organ specific
depending on the tissue distribution and autoantibodies
Hashimoto’s thyroiditis
- hypothyroidism
- inflammation (goitre)
- antibdoies and T cells recognize thyroglobulin
Graves’ disease
- hyperthyroidism
- stimulating auto-antibodies (Graves’ disease)
- regulated production of thyroid hormones
- negative feedback control
- pituitary gland stimulates hormone synthesis
- -> unregulated overproduction of thyroid hormones
Hypothyroidism
vs
hyperthyroidism
hypothyroidism
CD4 T cell –> autoreactive (B cell and CD8 T cell) –> apoptosis, necrosis/apoptosis
==> hypothyroidism
hyperthyroidism
CD4 T cell helps TSH-reactive B cell –> TSI (of antibody) –> thyroid cell survival
Multiple sclerosis
the myelin sheath which is a single cell whose membrane wraps around the axon is destroyed with inflammationa nd scanning
• activated autoreactive T cell induces microglial cell to make toxic cytokines (TNFα, IFNγ)
Information from animal models
experimental autoimmune encephalitis (EAE) model of MS
• immunize mice with bovine myelin basic protein in adjuvant (Th1)
• T cells enter brain see mous MBP, pertussis toxin opens BB barrier
• T cell makes IFN, TNF in draining node and periphery
Myasthenia gravis
blocking auto-antibodies • acetylcholine for muscle contraction • antibody against receptor • transmissable mother to child --> muscles become weak
Hemolytic anemia
antibody-complement mediated lysis
• intravascular
• extravascular
antibodies against RBC - type II hypersensitivity
Systemic lupus erythematosis
systemic autoimmune disease
• antibodies to DNA, red cells, platelets, histones
• patients have problems with their kidneys
• immune complex disease - form deposits in the kidneys
It’s probable that there’s no single pathway to autoimmunity
- to recognize foreign antigens we have to know self, so there’s a fine balance between immunity, autoimmunity, hypersensitivity
- the evolutionary selective pressures for the immune system assumed we would all have procreated by 25-30 years of age
- so largely our own fault for living longer
