Autoimmunity Flashcards
what is autoimmunity?
defined as presence of immune responses against self antigens
when does harmless response to self antigens become harmful?
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
when is their huge potential for generation of autoreactive B or T cells?
in primary lymphoid tissue during normal lymphocytes development
what happens in normal B cell development?
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
what forms the IgM or IgD antibody?
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
what is antibodies encoded by?
segmented genes
what is the Ig heavy chain locus segments?
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)
what is Ig light chain locus segments?
variable sequence:
45 V segments
5 J segments
constant region:
either kappa or lambda
how are antibodies generated?
by production of heavy chain and light chain polypeptide that are synthesised from 2 seperate immunoglobulin (Ig) genes
what happens to gene segments in developing B cells?
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
what happens to intervening genetic material in cell division?
it’s lost (not passed on to daughter cells)
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 ?
mu = IgM
delta = IgD
how is mature antibody molecules assembled?
Two HC proteins (with identical variable regions) and two light chain proteins (with identical variable regions) assemble to form mature antibody molecule
what makes up the antigen binding site?
the 3D structure of the interacting HC and LC variable regions
(2 antigen sites on each antibody molecule)
what happens if unsuccessful antigen receptor gene rearrangement?
no mature T or B cells
what is risk due to random nature of gene recombination?
means you risk make surface expression of functional self-reactive antigen-specific receptors
what are specific tolerance mechanisms used to do?
kill or inactivate auto-reactive lymphocytes
what are 2 specific tolerance mechanisms?
- Deletion of self-reactive lymphocytes in primary lymphoid tissues (central tolerance)
- Regulatory T cells (TREG cells) can help inactivate auto-reactive lymphocytes in peripheral tissues that escape central tolerance (peripheral tolerance)
what is Treg function?
to inactivate lymphocytes by secreting anti-inflammatory cytokines that prevent differentiation into effector ecells
what % of normal CD4+ T cell population do regulatory T cells make up?
5-10%
what are regulatory T cells crucial for?
suppressing hyper-reactive or auto-reactive T cells
what are monogenic disorders?
single gene defects causing autoimmune diseases
what do most auto-immune diseases result from?
complex genetic interplay
what is IPEX syndrome?
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)
when is IPEX syndrome presented?
presents in early childhood, characterized by stemic autoimmunity
what are symptoms of IPEX syndrome?
- severe infections
-intractable diarrhoea - eczema
- very early onset insulin dependant diabetes mellitus
- autoimmune manifestations
what is treatment of IPEX syndrome?
hemapoeitic stem cell transplant (HSCT)
supportive care = immmunosuppressive drugs plus total parental nutrition (IV nutrition)
what is pathogenesis?
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
what are HLA molecules?
HUman Leuocyte Antigen molecule
= another name for MHC molecule
(they present peptide antigens to T cells)
are HLA alleles linked to autoimmunity?
certain HLA alleles have been linked to increased (or decreased) risk of developing autoimmunity
- most, if not all autoimmune conditions appearassociated with HLA region
why is HLA functionally significant in terms of disease susceptibility & progression?
Products of different HLA alleles bind a different repertoire of peptides - this extensive polymorphism (variation) allows for differential binding of peptide
what does wide range of peptides being able to be presented by MHC mean?
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
how is there a clear sex bias in autoimmune disease?
- 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
what environmental factors can trigger autoimmunity?
- infections
- cigarette smoking
- hormone levels
- tissue damage
what are some mechanisms that help environment trigger autoimmunity in genetically predisposed individuals?
- 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)
what is an example of molecular mimicry leading to disease?
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
what is an example of alteration of self antigen leading to disease?
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
what is example of antigen sequestration causing disease?
(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
describe how bacterial superantigen can cause disease?
they can non-specifcally activate all lymphocytes, including auto-reactive T&B cells
what are the classifications of autoimmune disease?
- clinical classification (organ specific disease OR non organ specific or multi-system autoimmune disease
- pathological classification (gel & coombs - hypersensitivity classification)
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
(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
what is graves disease?
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
what is good pasture’s syndrome?
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
what happens to in lung with goodpasture’s syndrome?
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
what occurs after B cells produce antibody directed against cell membrane protein?
- 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
what is treatment of good pasture’s syndrome?
- Immunosuppressive drugs
- Anti-inflammatory drugs
- Plasmapheresis
- Stop smoking!
what is good pasture’s syndrome thought to be caused by?
Thought to result from an environmental insult (smoking, infections, exposure to certain drugs) in a person with genetic susceptibility
what are autoimmune diseases driven by type III hypersensitivity?
(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)
what is systemic lupus erythermatosus (SLE)?
- 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)
what happens in systemic lupus erythematosus?
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
what environmental stimuli can trigger lupus flares?
UV radiation = increased cell death
infections = inflammation→neutrophil activation and degranulation →increased tissue damage and cell death
what are autoimmune diseases driven by type IV hypersensitivity reactions in:
a) heart
b)pancreas
c)nervous system
d)musculoskeletal system
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
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) 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
