autoimmune diseases

what is autoimmunity

an immune response against self (autologous) antigens

what are autologous antigens

antigens we produce ourselves in our body

what does autoimmunity result from

some failure of the host’s immune system to distinguish self from non-self

what does the adaptive immune system do 

mounts specific/targeted response to foreign antigens without harming self 

what is an immunogen

a substance capable of eliciting an immune response

what is a tolerogen

antigens that induce tolerance rather than immune reactivity

can a compound be an immunogen and tolerogen

• yes

• depending on how and where it is presented to the immune system 

how do we achieve self tolerance

• segregation of antigens 

• central tolerance

• peripheral tolerance 

segregation of antigens

physical barriers and immune privileged sites i.e. eyes 

central tolerance

• limits the development of auto reactive B and T cells 

• undergoes selection process so it doesn’t attack self

peripheral tolerance

regulates auto reactive cells in circulation 

why do we have both central and peripheral tolerance

• not all self antigens are expressed in central lymphoid organs where the negative selection occurs

• there is a threshold requirement for affinity to self antigens before deletion os triggered- some weakly self reactive survive

immature T lymphocytes in the thymus

• immature lymphocyte which interacts strongly with self antigen displayed as peptide bound to a self MHC molecules —> negative selection- cell undergoes apoptosis 

• some immature T cells that recognise self antigens with high affinity develop into regulatory T cells and enter peripheral tissues

immature B lymphocytes in the bone marrow

• immature B lymphocyte that recognise self antigen with high acidity undergo receptor editing- express genes to make new light chain of antibody so that no longer specific for self antigen 

• if editing fails0 negative selection- apoptosis 

• if low avidity- antigen receptor expression is reduced and cell becomes anergia (functionally unresponsive)

definition of anergy

functional unresponsiveness, without the necessary costimulatory signals 

what is suppression

block in activation by regulatory T cells

what is deletion

apoptosis

mature T lymphocytes

• anergy- costimulation or cell death

• sensitive to suppression by regulatory T cells 

mature B lymphocytes

• if recognises a self antigen without T cell help os functionally inactivated and becomes incapable of responding to that antigen (anergy) or dies by apoptosis, or its activation is suppressed by engagement of inhibitory receptors 

why should T cell tolerance be maintained

• enforces B cell tolerance to the same antigens

• without activation of T cells B cells won’t be able to become fully active 

central tolerance summary

deletion of lymphocytes specific for self antigens present in generative organs

peripheral tolerance summary

deletion or anergy of lymphocytes that recognise self antigens in peripheral tissues

what is the mechanism and site of action for central tolerance

• deletion editing

• thymus, bone marrow 

what is the mechanism and site of action for antigen segregation

• physical barrier to self-antigen access to lymphoid systems 

• peripheral organs e.g. thyroid, pancreas

what is the mechanism and site of action for peripheral anergy 

• cellular inactivation by weak signalling without co-stimulus

• secondary lymphoid tissue 

what is the mechanism and site of action of regulatory cells 

• suppression by cytokines, intercellular signals 

• secondary lymphoid tissue and sites of inflammation

what is the mechanism and site of action of cytokine deviation

• differentiation to Th2 cells, limiting inflammatory secretion 

• secondary lymphoid tissue and sites of inflammation

what is the mechanism and site of action of clonal deletion

• apoptosis post-activation

• secondary lymphoid tissue and sites of inflammation

when do autoimmune diseases develop

when multiple layers of self tolerance are dysfunctional 

what is the response to in an autoimmune disease

• response to endogenous self antigen

• since the antigen cannot be eliminated, response Is sustained

what does an autoimmune disease result from

results from a combination of genetic susceptibility, breakdown of natural tolerance mechanism and environmental triggers

what is the immune system designed normally to do

destroy invaders presenting antigens that are ‘non-self’

what do sufferers have a high circulating level of

auto-antibodies

which gender is more frequent with autoimmune diseases

• women

• possibly oestrogen in females influences immune system to predispose to autoimmune diseases

what does the presence of one autoimmune disease increase the chances of 

for developing another simultaneous autoimmune disease

what is there a strong component in autoimmune disease 

strong genetic component 

what incidences increase automminue diseases 

• twins

• more in monozygotic than in dizygotic twins 

what are most autoimmune diseases

• polygenic 

• affected individuals inherit multiple genetic polymorphism that contribute to disease susceptibility 

what do autoimmune diseases have a strong association with 

MHC class II genes with disease 

what are the challenges of genetics of autoimmunity 

identified disease-associated polymorphisms have small effects, therefore little predictive value 

how can autoimmunity develop

develop after infection is eradicated (e.g. autoimmune disease is precipitated by infection but is not directly caused by the infection)

how are some autoimmune diseases prevented

prevented by infections (type 1 diabetes, multiple sclerosis) mechanism unknown- similar protection suggested for asthma —> the hygiene hypothesis

mechanisms of autoimmune damage

• circulating autoantibodies 

• T lymphocytes

• non-specific 

circulating autoantibodies 

• complement lysis (as in haemolytic diseases)

• interaction with cell receptors (as in myasthenia graves, thyrotoxicosis)

• toxic immune complexes (as in systemic lupus erythematosus) 

• antibody dependent cellular cytotoxicity (possibly in organ specific autoimmune diseases)

• penetration in living cells 

T lymphocytes mechanism of autoimmune damage

• CD4 cells polarised toward Th1 responses via cytokines (as in rheumatoid arthritis, multiple scleorsis, type 1 diabetes)

• CD8 cells activated to become cytotoxic T cells ab cause direct cytolysis 

non-specific mechanism of autoimmune damage

• recruitment of inflammatory leucocytes into autoimmune lesions (as in synovitis)