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Immunology > Autoimmunity > Flashcards

Autoimmunity Flashcards

1
Q

what is autoimmunity?

A

defined as presence of immune responses against self antigens

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2
Q

when does harmless response to self antigens become harmful?

A

well everyone has some sort of low titres of auto-antibodies or auto-reactive T cells and they are generally harmless. it’s harmful when there’s high levels of auto-antibodies or auto-reactive T cells as they cause significant tissue/organ damage and chronic inflammation

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3
Q

when is their huge potential for generation of autoreactive B or T cells?

A

in primary lymphoid tissue during normal lymphocytes development

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4
Q

what happens in normal B cell development?

A

receives 2 signals
1. to say it’s going to be a lymphcyte
2. to say it’s going to be a B cell
-> they then present IgM or IgD

stem cell -> lymphoid progenitors -> progenitor B cell -> mature B cell

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5
Q

what forms the IgM or IgD antibody?

A

2 variable regions (combine to form unique 3D shape)

  • heavy chain and light chain at top
    (the tops of both heavy chain & light chain form variable region) and the bottom part of heavy chain connected to plasma membrane is called the constant region
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6
Q

what is antibodies encoded by?

A

segmented genes

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7
Q

what is the Ig heavy chain locus segments?

A

variable sequence:
40 V segments at top (V for variable)
24 D segments at middle (D for diversity)
6 J segments at bottom bit that’s connected to constant region (J for joining)

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8
Q

what is Ig light chain locus segments?

A

variable sequence:
45 V segments
5 J segments

constant region:
either kappa or lambda

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9
Q

how are antibodies generated?

A

by production of heavy chain and light chain polypeptide that are synthesised from 2 seperate immunoglobulin (Ig) genes

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10
Q

what happens to gene segments in developing B cells?

A

random recombination of V, D & J segments in both lC and HC
= this gives each B cell it’s own unique antibody that binds to unique antigen which explains why human immune system is capable of generating millions of different antibodies

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11
Q

what happens to intervening genetic material in cell division?

A

it’s lost (not passed on to daughter cells)

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12
Q

in Ig HC gene transcription & translation, gene segment encoding for specific constant region is selected - what constant regions are selected for surface bound IgM and IgD ?

A

mu = IgM
delta = IgD

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13
Q

how is mature antibody molecules assembled?

A

Two HC proteins (with identical variable regions) and two light chain proteins (with identical variable regions) assemble to form mature antibody molecule

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14
Q

what makes up the antigen binding site?

A

the 3D structure of the interacting HC and LC variable regions
(2 antigen sites on each antibody molecule)

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15
Q

what happens if unsuccessful antigen receptor gene rearrangement?

A

no mature T or B cells

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16
Q

what is risk due to random nature of gene recombination?

A

means you risk make surface expression of functional self-reactive antigen-specific receptors

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17
Q

what are specific tolerance mechanisms used to do?

A

kill or inactivate auto-reactive lymphocytes

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18
Q

what are 2 specific tolerance mechanisms?

A
  1. Deletion of self-reactive lymphocytes in primary lymphoid tissues (central tolerance)
  2. Regulatory T cells (TREG cells) can help inactivate auto-reactive lymphocytes in peripheral tissues that escape central tolerance (peripheral tolerance)
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19
Q

what is Treg function?

A

to inactivate lymphocytes by secreting anti-inflammatory cytokines that prevent differentiation into effector ecells

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20
Q

what % of normal CD4+ T cell population do regulatory T cells make up?

A

5-10%

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21
Q

what are regulatory T cells crucial for?

A

suppressing hyper-reactive or auto-reactive T cells

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22
Q

what are monogenic disorders?

A

single gene defects causing autoimmune diseases

23
Q

what do most auto-immune diseases result from?

A

complex genetic interplay

24
Q

what is IPEX syndrome?

A

examples of monogenic disorder - rare genetic disorder of immune dysregulation

= affects regulatory T cells so they don’t make Treg which means they have lymphocytes that target self-antigens
= X-linked genetic disorder (more likely for males)

25
Q

when is IPEX syndrome presented?

A

presents in early childhood, characterized by stemic autoimmunity

26
Q

what are symptoms of IPEX syndrome?

A
  • severe infections
    -intractable diarrhoea
  • eczema
  • very early onset insulin dependant diabetes mellitus
  • autoimmune manifestations
27
Q

what is treatment of IPEX syndrome?

A

hemapoeitic stem cell transplant (HSCT)
supportive care = immmunosuppressive drugs plus total parental nutrition (IV nutrition)

28
Q

what is pathogenesis?

A

X-linked condition caused by mutation of FOXP3 gene

  • all nucleated cells express 6 class 1 molecules = HLA-A, HLA-B and HLA-C(3 maternally derived and 3 paternally derived)
    -specialised antigen-presenting molecule also present 6 class 2 molecules = HLA-DR, HLA-DQ and HLA-DP

The protein encoded by the FOXP3 gene is a key regulator of T cell tolerance and is crucially important for the development and function of specialised regulatory T cells

*all HLA are highly polymorphic (variable) -> they represent slightly different presentation of peptides

29
Q

what are HLA molecules?

A

HUman Leuocyte Antigen molecule
= another name for MHC molecule
(they present peptide antigens to T cells)

30
Q

are HLA alleles linked to autoimmunity?

A

certain HLA alleles have been linked to increased (or decreased) risk of developing autoimmunity
- most, if not all autoimmune conditions appearassociated with HLA region

31
Q

why is HLA functionally significant in terms of disease susceptibility & progression?

A

Products of different HLA alleles bind a different repertoire of peptides - this extensive polymorphism (variation) allows for differential binding of peptide

32
Q

what does wide range of peptides being able to be presented by MHC mean?

A

lots of different HLA alleles and huge polymorphism in genes encoding these proteins mean that a wide variety of peptides can be presented and means greater protection against a wide variety of pathogens

33
Q

how is there a clear sex bias in autoimmune disease?

A
  • sex hormones are known to influence lymphocyte function in males Vs females
  • alterations in disease severity for some autoimmune diseases are known to occur in pregnancy
34
Q

what environmental factors can trigger autoimmunity?

A
  • infections
  • cigarette smoking
  • hormone levels
  • tissue damage
35
Q

what are some mechanisms that help environment trigger autoimmunity in genetically predisposed individuals?

A
  • molecular mimicry (foreign & self molecules look similar)
  • alterations of self antigens
    -antigen sequestration (antigens behind physiological or anatomic barriers)
  • bacterial superantigens (protein toxins that bind to MHC class 2 and stimulate large numbers of T cells)
36
Q

what is an example of molecular mimicry leading to disease?

A

acute rheumatic fever after group A streptococcal infection
1. the streptococci cell wall stimulates antibody response
2. some antibodies cross-react with heart tissue (mistake cardiac tissue protein for strep M5 protein as structurally similar) and cause rheumatic fever

37
Q

what is an example of alteration of self antigen leading to disease?

A

drug induced haemolytic anemic
-> self antigens may become immunogenic if they’re altered in some way (chemically or physically)

in example = antibody is directed against neoantigen variably composed of drug & RBC membrane proteins

38
Q

what is example of antigen sequestration causing disease?

A

(reminder: antigen sequestration = antigens blocked by physiological or anatomical barriers)

Self-antigens normally sequestered from the immune system can become exposed and cause an autoimmune reaction during infections/trauma

39
Q

describe how bacterial superantigen can cause disease?

A

they can non-specifcally activate all lymphocytes, including auto-reactive T&B cells

40
Q

what are the classifications of autoimmune disease?

A
  1. clinical classification (organ specific disease OR non organ specific or multi-system autoimmune disease
  2. pathological classification (gel & coombs - hypersensitivity classification)
41
Q

what are auto immune diseases driven by type II hypersensivity for:
a) blood cells
b)Endocrine system
c)kidney/lung
d)nervous system
e)musculoskeletal system
f) skin

A

(cell bound antibody- antigen contact)
a)Blood cells - autoimmune haemolytic anaemia

b)Endocrine system - Graves disease

c)Kidney/Lung = Goodpasture’s syndrome

d)Nervous system = Guillan Barre syndrome

e)Musculoskeletal System = Myasthenia Gravis

f)Skin = Pemphigus Vulgaris

42
Q

what is graves disease?

A

example of endocrine autoimmune disease driven by type IIb hypersensitivity
= leading cause of hyperthyroidism
=auto-antibodies are generated that bind to the thyroid stimulating hormone receptor (TSHR)

mechanism - antibody binding to TSHR stimulates the receptor → increased T3 & T4 secretion

43
Q

what is good pasture’s syndrome?

A

An autoimmune disease driven by type II hypersensitivity that affects the lungs and kidneys

→pulmonary alveolar haemorrhage
→kidney disease (glomerulonephritis)

= Defined by the presence of autoreactive antibodies to the α3 chain of type IV collagen present in the basement membranes of alveoli and glomeruli

44
Q

what happens to in lung with goodpasture’s syndrome?

A

red blood cells (hemorrhage) filling the air sacs (alveoli) , bright green colour staining from immunofluorescence microscopy shows location of anti-GBM antibodies bound to capillaries in walls of air

45
Q

what occurs after B cells produce antibody directed against cell membrane protein?

A
  • antibody bound to cell surface antigen acts as an opsonin for phagocytes, leading to phagocytosis of antigen +ve cells
  • antibody bound to cell surface antigen results in NK cell & eosinophil activation -> antibody dependant cellular cytotoxicity (ADCC)
  • binding of antibody to cell surface antigen results in complement activation & osmotic lysis of the cell
46
Q

what is treatment of good pasture’s syndrome?

A
  • Immunosuppressive drugs
  • Anti-inflammatory drugs
  • Plasmapheresis
  • Stop smoking!
47
Q

what is good pasture’s syndrome thought to be caused by?

A

Thought to result from an environmental insult (smoking, infections, exposure to certain drugs) in a person with genetic susceptibility

48
Q

what are autoimmune diseases driven by type III hypersensitivity?

A

(reminder: type III = binding of antibodies to soluble antigens forming immune complexes)

  • Systemic lupus erythematosus (SLE)
  • Rheumatoid arthritis (secondary to disease driven by type IV reactions)
  • Glomerulonephritis (some types)
49
Q

what is systemic lupus erythermatosus (SLE)?

A
  • The prototypic multi-system autoimmune disease
  • Rare, type III hypersensitivity disease - skin rashes, nephritis, alveolitis
  • Peak age of onset: 2nd and 3rd decades
  • High female preponderance (90% cases)
  • Linked with increased risk of cardiovascular disease
  • Strong genetic predisposition

(auto-antibodies are generated against nuclear antigens)

50
Q

what happens in systemic lupus erythematosus?

A

environmental triggers & genetic factors -> immune dysregulation -> increased apoptosis & defective clearning of apoptotic material & immune complexes -> self antigens which bind to dendritic cells where naive T cells bind and differentiate to CD4+ T cells that help B cells produce auto-antibodies and still decreased clearance of immune complexes mean they’re deposited in small blood vessels where complement system & phagocytes are activated

51
Q

what environmental stimuli can trigger lupus flares?

A

UV radiation = increased cell death
infections = inflammation→neutrophil activation and degranulation →increased tissue damage and cell death

52
Q

what are autoimmune diseases driven by type IV hypersensitivity reactions in:
a) heart
b)pancreas
c)nervous system
d)musculoskeletal system

A

a)Heart - autoimmune myocarditis

b)Pancreas - diabetes mellitus type 1

c)Thyroid - Hashimoto’s thyroiditis

d)Nervous system - multiple sclerosis

e)Musculoskeletal system - rheumatoid arthritis

53
Q

what are most common symptoms of lupus?
a) systemic
b)psychological
c)mouth & nose
d) face
e)muscles
f) pleura
g) pericardium
h) joints
i) kidneys
j) fingers & toes

A

a) systemic = low grade fever & photosensitivity
b)psychological = fatigue & loss of appetite
c)mouth & nose = ulcers
d) face = butterfly rash
e)muscles = aches
f) pleura = inflammation
g) pericardium = inflammation
h) joints = arthritis
i) kidneys = inflammation
j) fingers & toes = poor circulation

Immunology (6 decks)

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