Lecture 18 (10B) - Autoimmunity Flashcards Preview

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Flashcards in Lecture 18 (10B) - Autoimmunity Deck (34):
1

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

2

Autoimmunity is caused by

hypersensitivity

3

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

4

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

5

Recombination produces

B cells with surface receptors (antibodies) for self antigens
• not killed when they develop
• they are tolerized - anergic

6

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

7

Assume we al have autoreactive T and B cells

1970s-80s = suppressor cells
1990s - 2013 = regulatory cells and cytokines

8

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

9

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

10

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)

11

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

12

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

13

Make CTLA-4 knockout mouse

animal dies of autoimmune diseases early in life (the dampening signal)

14

In the absence of costimulation,

T cells are not triggered
• affinity of receptor weak - doesn't activate
• need stimulation or become anergic

15

Costimulatory molecules and their receptors

control autoreactivity

16

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

17

So all healthy people have

self-reactive T and B cells
• but most people keep them under control

18

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?

19

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

20

Rheumatic fever

• auto streptococcus antibodies but something on heart looks similar --> attack heart (need heart transplant) (x-reactive)

21

Molecular mimicry

sequence similarities between self and infectious antigens

22

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

23

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

24

Some theories of autoimmunity

1. defects in regulatory T cells
2. molecular mimicry between pathogens and self-peptides (antibody against streptococci x-react with heart muscle)
3. polyclonal activation of B cells during immune responses or infection (EBV) inevitably leads to some which recognize self antigens
4. 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)
5. during affinity maturation in germinal centers, somatic hypermutation leads to self-reactive specificities

25

Autoimmune diseases are classified as

• organ specific
• non-organ specific
depending on the tissue distribution and autoantibodies

26

Hashimoto's thyroiditis

• hypothyroidism
• inflammation (goitre)
• antibdoies and T cells recognize thyroglobulin

27

Graves' disease

• hyperthyroidism
• stimulating auto-antibodies (Graves' disease)

1. regulated production of thyroid hormones
2. negative feedback control
3. pituitary gland stimulates hormone synthesis
--> unregulated overproduction of thyroid hormones

28

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

29

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)

30

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

31

Myasthenia gravis

blocking auto-antibodies
• acetylcholine for muscle contraction
• antibody against receptor
• transmissable mother to child
--> muscles become weak

32

Hemolytic anemia

antibody-complement mediated lysis
• intravascular
• extravascular

antibodies against RBC - type II hypersensitivity

33

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

34

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