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Neural Biology 1 > Autoimmunity and autoimmune disease > Flashcards

Autoimmunity and autoimmune disease Flashcards

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1
Q

how does the body avoid autoimmunity?

A
  • the body has developed self-tolerance mechanisms to distinguish between self and non-self to avoid autoimmunity
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2
Q

how does the self-tolerance mechanisms break down?

A
  • sometimes self-tolerance mechanisms break down with the production of autoantibodies and autoreactive T-cells
  • B-cells attack your cells
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3
Q

what does autoimmune mechanisms underlie?

A
  • autoimmune mechanisms underlie many diseases
  • some are organ-specific and others are systemic
  • more than one auto-immune disease may co-exist
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4
Q

what is autoimmune disrases?

A

B-cells and T-cells start attacking your body

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5
Q

what are the types of autoimmune disease?

A
  • organ specific- autoimmune disease will only attack one particular cell type that is if found in one specific organ
    e. g. Hashimoto’s thyroiditis -in this disease only your thyroid gland is targeted by the immune system
  • non-organ specific
    e. g. systemic lupus erythematosus (SLE)
  • this is a systemic autoimmune disease
  • this disease attacks antigens from within your nucleus
  • proteins from nucleus are recognised as foreign by your immune system and therefore any nucleated cell in your body can get attacked by your immune system
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6
Q

what is multiple sclerosis?

A
  • not sure if its an autoimmune disease
  • not organ -specific as it attacks CNS
  • its also not systemic
  • targets all of the myelin in your body
  • all of the myelin is stripped of neurons in your CNS
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7
Q

what type of autoimmune disease is type 1 diabetes?

A
  • Type 1 diabetes - systemic effect because it effects the blood glucose levels through out the body
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8
Q

what is the prevalence of autoimmune disease?

A
  • Grave’s disease and Rheumatoid arthritis affect 1% if population ( 1 in 100 )
  • type 1 diabetes which affects ( 1 in 500)
  • sjogren syndrome which affects the hydration of external parts of the body such as skin, eyes ( causes dry eye)- very high prevalence in the population
  • there is a higher prevalence of autoimmune diseases in females - this may be due to males having testosterone which can suppress the immune system
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9
Q

what are the mechanisms of autoimmune disease ?

A
  • in organ-specific diseases type II and type IV reactions are most important
  • in non organ-specific autoimmune disorders e.g. SLE type III reactions ( immune complex mediated ) predominate
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10
Q

what is type 5 autoimmune disease ?

A

specialised version of type 3 where antibodies are actually autoantibodies - so they don’t bind to cell receptor and induce cell to be eaten
- what they actually do is bind to a receptor and stimulate that receptor to get an overproduction of metabolism - they overstimulate that cells

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11
Q

what is the damage caused by autoimmune disease reaction?

A

1- complement activation by autoantibodies - antibodies can recognise cell surface proteins on cell
- they can trigger complement to create a membrane attack complex

  1. autoantibody recognition of self antigens - antibody forming immune complexes

3- autoreactive T-cell recognition of self antigens

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12
Q

what genetic factors play role in the development of autoimmunity

A
  • inheritance of HLA
  • in autoimmune diseases , the genetic factors normally correlate to specific genotypes of the human leukocyte antigen (HLA)
  • we don’t have a specific gene mutation causing an autoimmune disease
  • we’ve got genetic variance of these HLA - which risk autoimmune disease
    e. g. if you have gene produce from this coding DR3/4 then you have 20 times the increased risk of developing type 1 diabetes
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13
Q

what is HLA ?

A
  • HLA = human leukocyte antigen

- HLA is the human version of the major histocompatibility complex (MHC)

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14
Q

what is the major histocompatibility complex (MHC) ?

A
  • ( MHC ) is a gene locus that codes for histocompatibility antigens
  • histocompatibility antigens are cell surface glycoproteins that play important roles in interactions amongst immune cells- they are integral membrane
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15
Q

what is function of MHC?

A
  • sample what’s going on inside a cell and present it to the T-cells
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16
Q

what MHC/HLA class 1 gene products?

A
  • class 1 gene products found on all nucleated cells and participate in antigen presentation to cytotoxic T cells ( CD8+ve)
  • also found in platelets
  • sample all of the cytoplasmic proteins, they present to outside of cell in a binding pocket
  • then T-cell decides if that cell is self or not self
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17
Q

what are MHC/HLA class 2 gene products?

A

class II products found on antigen presenting cells and participate in antigen presentation to T helper cells ( CD4+ve)

e. g macrophages , dendritic cells and some B cells
- they present what they phagocytosed e.g bacteria
- then present on cell membrane
- T-cell decides what to do

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18
Q

where is HLA in humans?

A
  • In human the MHC locus is designated the human leukocyte antigen ( HLA ) locus
  • HLA in humans is found on the short arm of chromosome 6
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19
Q

what does class I region of HLA have ?

A
  • the class I region consists of HLA, A, B and C loci
  • class I sample what is inside of the cytoplasm and then present it in a binding picket for the T-cell to have a look at
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20
Q

what does class II region of HLA have?

A
  • the class II region is divided into HLA-DP, DQ and DR sub regions
  • they have two letters because they’re formed from two proteins that come together in cell membrane
  • they pick up what is inside the lysosome and then when it fuses back with the plasma membrane it will be on the outside showing the external environment
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21
Q

what is property of HLA antigen ?

A
  • HLA antigens are highly polymorphic with multiple allelic forms which differ from one person to another
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22
Q

what is function of HLA ?

A
  • HLA are important for the ability of T cells to differentiate between self and non-self
  • this why they are often found in autoimmune disease
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23
Q

what is HLA B27?

A

its a variant of HLA

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24
Q

how is the HLA B27 variant involved with immune disease ?

A
  • 70-80% of people that have this variant (HLA B27) antigen have no clinical phenotype
    -however the remaining 20% have a clinical phenotype which is associated with many diseases
  • isolate acute anterior uveitis
  • the spondyloarthropathies
  • ankylosing spondylitis
  • Reiter’s disease and reactive arthritis
  • undifferentiated spondyloarthropathies
  • IBS
  • YOU DO NOT HAVE TO HAVE HLA B27 TO DEVELOP THESE DISEASES
    e.g. ankylosing spondylitis - 90% of people with AS have the HLA B27 antigen
    uveitis - 19-88% of people who have acute anterior uveitis have the HLA B27 antigen
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25
Q

why do we have receptors on lymphocytes?

A
  • lymphocytes become immunocompetent before they meet the antigen they will later attack
  • therefore we have receptors on the lymphocytes that can interact with MHCs and determine if cell is self or non-self
26
Q

what is the function of our genes?

A
  • our genes determine which specific foreign substances our immune system will be able to recognise and neutralise
  • NOT THE ANTIGENS THEY ENCOUNTER
27
Q

how does the body determine self and non-self cells?

A
  • the body produces millions of variance in our body
  • the body produces protein antigen receptor complexes that will recognise billions of different types of protein combination
  • the antigens merely determine which T cell responds and proliferates to mount the attack against it
  • this means that most of the immune cell receptors our lymphocytes produce will never recognise anything and those T cells will never be activated to attack
  • mostly idle - as they will never react with a protein they recognise
28
Q

how many antigen receptors do lymphocytes make ?

A
  • lymphocytes make 1 billion different antigen receptors

- which are specified by genes

29
Q

how many genes do we have for every protein in the body?

A
  • we have 20,000 genes to code for every protein of the body

-

30
Q

how are antigen receptors coded ?

A

they are coded by segments of genes: few hundred genetic blocks

31
Q

how can we create a billion different variants of an antigen receptor from 20,000 genes?

A
  • when it comes to creating these antigen receptors , you have building blocks ( little parts of genes ) clustered together in your genetic code, the building blacks are taken out and put together and then you can create a protein with billion of possible antigen combination by taking out little pieces of information and putting them together
  • this is known as somatic recombination
  • then the antigen receptors are expressed on B and T cell membranes
32
Q

what is an example of somatic recombination?

A
  • small sections of genetic-line alpha-chain DNA are put together
  • only those few combinations are transcribed into mRNA
  • then that goes through RNA splicing
  • that put it together to make messenger RNA and that is used to make proteins
  • you can take different variants and get completely different proteins made
33
Q

what is the problem with this method of creating random receptors ?

A
  • the probability that some of those random receptors will actually recognise self proteins - this means that immune system will attack it self
  • these must be removed before release into circulation, otherwise the immune system would attack the cells its their to defend
34
Q

what happens in thymus where T cells mature?

A
  • epithelial cells in your thymus , which express self peptides and also have the MHC class 1
  • continuously sampling their own cytoplasm
  • they are giving your maturing T-lymphocytes exposure to all of the possible self antigens
35
Q

what are the two processes that T-lymphocytes in the maturation phase go through ?

A
  • positive and negative selection
36
Q

what is positive selection?

A

T-cells must recognise self MHC

37
Q

what is negative selction?

A
  • binding too tightly to self MHC lead to apoptosis

- recognising self antigens leads to apoptosis

38
Q

what is the process of self-tolerance by clonal deletion?

A
  • the immature T-cell comes into your thymus
  • this stats of by going to the cortex of the thymus
  • we have to positively select all of those T cells which will interact with MHC class I , because if they can’t interact with MHC class I then they will not be able to go around and talk to the cells of your body ( this positive selection)
  • if your T cell doesn’t bind to the MHCs then those cells are induced to go through apoptosis
  • now you go through a phase of negative selection
  • this is where you select that ones that are binding incorrectly
  • in the cortex of the thymus if the T-cell receptor binds to the MHC too tightly , they are also taken out of the system and induced to go through apoptosis
  • T-cell is now migrating to the medulla of thymus , now if it binds and recognises one of those self-antigens , then that maturing T-lymphocyte will undergo apoptosis
  • you are left with only the T-lymphocytes that recognise self MHCs but don’t bind too tightly , and those with the antigen receptor that will bind but doesn’t recognise proteins that are self as foreign
  • leave and go through self circulation
39
Q

what happens in B-cell maturation?

A
  • similar selection process to defend against self reactivity takes place
  • only B cells that recognise foreign proteins are released into two to system
40
Q

what can result in autoimmunity ?

A
  • a breakdown in these selection processes ( either in B or T cell maturation) that allow self reactive lymphocytes to mature and be released will result in your immune system attacking self cells and chronic inflammation
  • another way is you get infection in your bone marrow or infection in thymus , then it is possible that the bacteria that gets in there is an environment during maturation phase of these lymphocytes
  • this means that during that selection process, they may recognise one of the foreign proteins as self and release into systemic circulation- this results in immunodeficiency
41
Q

when can you get immunodeficiency ?

A

when lymphocytes have matured to think that foreign peptide is self , therefore it won’t attack it

42
Q

what is rheumatoid arthritis ?

A
  • women affected more 3:!
  • prevalence 1-3% of population
  • onset usually 4th - 5th decade of life
  • genetic risk association
  • MHC class ii complexes - HLA - DR1
    HLA -DR4
    both increase risk
43
Q

what does rheumatoid arthritis affect?

A
  • joints are affected mainly
44
Q

what does lesion developed in rheumatoid arthritis involve?

A
  • the development of lesion in rheumatoid arthritis involves both cell-mediated and antibody response
  • T-helper cells respond and activate B lymphocytes
45
Q

what causes rheumatoid arthritis?

A
  • cytokines secretion by activated T-cells leads to an inflamed synovium and the formation of pannus ( inflammatory granulation tissue)
  • the major cell types in the granulation tissue is T-lymphocytes and macrophages
  • as the granulation tissue forms - all those immune cells (macrophages )that come in start to secrete substances designed to break down connective tissue
  • you break cartilage , bones as result of wound healing process that is out of control
46
Q

what do B lymphocytes do in RA (rheumatoid arthritis)?

A
  • B-lymphocytes are responding and produce an autoantibody called Rheumatoid factor
  • this autoantibody binds to Fc portion of other immunoglobulin
  • RF+IgG can lead to complement activation which can trigger inflammatory system
47
Q

what are the ocular conditions caused due to RA?

A 
1- (KSC)- keratoconjunctivits sicca 
-most common 15-25% 
-caused due to lymphocyte migration of lacrimal gland 
-reduced water content in tear film resulting in dry eye
2. episcleritis 
- inflammation of episclera 
-common ish 
3. scleritis 
inflammation of sclera 
rare
  1. peripheral ulcerative keratitis
    - epithelial cells of cornea die
    - very rare
48
Q

what is keratoconjunctivits sicca ‘dry eye’?

A
  • symptoms: redness ( vasodilation ), dryness, gritty or foreign body sensation , burning and photophobia
  • get worse in windy or dry condition
  • signs
  • decreased TBUT ( tear break up time)
  • positive rose bengal stain
  • mucous strands attached
    to cornea and/or inferior fornix
49
Q

what RA treatment?

A

1 - strong immunosuppression
by the use of steroids
2. anti malarials (chloroquine ) are sometimes used to treat RA- delay and alleviate RA symptoms
the mode of action is unknown but it is believed to interfere with antigen presentation

50
Q

what are side effects of using steroids?

A
  • steroid induced glaucoma
  • increased risk of infection
  • delayed wound healing response
  • posterior subcapsular cataract
  • osteoporosis - target bones
51
Q

what are the side effects of chloroquine ?

A
  • chloroquine retinopathy associated with chloroquine
  • binds to RPE and can inhibit function and lead to necrosis of RPE cells
  • results in neuronal loss of neuronal retina with long term use
52
Q

what is graves disease?

A
  • is a common cause of hyperthyroidism ( over production of thyroid hormone)
  • associated with enlargement of thyroid ( goitre ), exophthalmos heat intolerance and anxiety
53
Q

what is the pathogenesis of graves disease?

A
  • B-cells which produce auto anitbody which stimulates receptors on your follicular cells in your thyroid gland
  • when auto antibody binds to the receptor it induces the follicular cells in thyroid to secrete the hormone thyroxine
  • the hyperthyroidism and goitre of graves disease are caused by stimulation of the thyroid by thyroid stimulating hormone ( TSH) receptor auto antibodies
    so type II mediated hypersensitivity , but also classified as type V as the autoantibodies bind to receptors
  • production of these antibodies is primarily within the thyroid gland it self
54
Q

what causes an ocular phenotype of graves disease?

A
  • you have autoantibodies produced which are also recognised by receptors in connective tissue and muscle in back of eye and stimulate that receptors which induces those connective tissues to proliferate and enlarge and pushes eye forward in eye socket - this puts tension in optic nerve
55
Q

what is the cotton wool spot?

A
  • associated with autoimmune diseases and ischemic disease if you have occlusion of blood vessel in the eye , you can induce cotton wool spot
  • little opaque patches through retina
  • may be isolated
  • may be surrounded by haemorrhage
  • may be seen in regions of retina oedema and infraction
  • strong link between lupus retinopathy and renal nephropathy
56
Q

what is cotton wool spots caused by?

A
  • caused by defective axoplasmic flow in retinal ganglion cells
  • ganglion cell sits in the retina and sends an axon all the way back through your optic nerve back into your brain
  • if you have something which is stopping the flow of the cytoplasm in that bit of the axon then it will go opaque
57
Q

what are cotton wool spots associated with?

A
  • often associated with systemic autoimmune diseases
  • diabetes type I
  • SLE
58
Q

which HLA is associated with autoimmune diseases in the eye?

A

HLA B27

59
Q

where can ocular autoimmunity occur?

A
  • ocular autoimmunity can occur in the presence or absence of systemic autoimmune disease
60
Q

what is an example of ocular autoimmune disease that occurs in the absence of systemic involvement ?

A
  • sympathetic ophthalmia which can occur after a penetrating wound to the eye
  • what is inside your eye is normally not exposed to your immune system
  • lymphocytes are never normally exposed to the proteins that are produced by the cells in your retina or in the vitreous
  • so if lymphocytes are exposed to proteins just a little bit they may start to recognise it as foreign after you have a penetrating object which disrupts the barrier between your blood supply and retina
  • some proteins get out and can be identified by T-cells
  • those T-cells can be auto-reactive as they have not been exposed to that type of protein
  • macrophages can take it in and present it via HLA II to T-lymphocytes which recognise it
  • if T-lymphocytes fail to recognise it , you get auto reactive T-cells which can the attack healthy eye

Neural Biology 1 (58 decks)

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