Immunology of Autoimmunity Flashcards
when do autoimmune diseases occur
when components of the human immune system become perturbed
- some factors involved in this are known
how do biologics used to treat autoimmune diseases work
- work by interacting and modulating with components of the innate and adaptive immune system
- so autoimmune diseases can be treated by either dampening down these adaptive immune responses (mostly auto reactive B and T cells)
- or innate responses (mostly proinflammatory cytokines) - based on antibodies- work by blocking receptors or binding to and inactivating their ligands
what do many autoimmune diseases manifest as
chronic inflammatory diseases
what are the characteristics of innate immunity
- present at all times
- reacts immediately
- activates the adaptive system
what are the characteristics of adaptive immunity
- develops in response to infection and is protective against specific pathogens
- leverages components of the innate response and develops memory
- both innate and adaptive are required for normal function
what is inflammation
the reaction of vascularised living tissue to local injury
- it is a series of vascular and cellular reactions, aiming to protect the body against the injurious agent
what are the cardinal signs of inflammation
- heat
- redness
- swelling
- pain
- loss of function
what are the types of inflammation
- acute- sudden onset and short duration
- chronic- gradual onset and long duration
give examples of innate immune cells
- neutrophils
- macrophages
- dendritic cells
- natural killer cells
where are monocytes derived
derived from hematopoietic stem cells in bone marrow
- blood= 1-6% leukocyte
what is the function of monocytes
- migrate into tissues and differentiate into macrophages
- they phagocytose microorganisms and present antigens to T cells
what does the name of monocyte derived cells depend on
depends on the tissue they reside in:
1. liver= Kupffer cells
2. lung- alveolar Mf
3. CNS- microglial cells
4. bone- osteoclasts
where are polymorphonuclear neutrophils derived
- 50-70% of circulating white blood cells
- infection activates cytokines that stimulate the bone marrow to produce neutrophils
what is the function of neutrophils
- they are active phagocytic cells
- they circulate in peripheral blood for 7-10 hours and migrate by extravasation into tissues, where they have a lifespan of a few days
- they are attracted to tissues by chemotactic factors
give examples of soluble mediators
cytokines and chemokines
how does the balance and level of cytokines and chemokines secreted affect the outcome of the response
- alert to infection
- recruit cells to site
- activate further immune response
what effect do cytokines have on endothelial cells
change the morphology, adhesive properties and permeability of endothelial cells
give examples of cytokines
IL1, IL6, TNFa
describe the permeability of post endothelial cells
impermeable to cells and plasma
what is autoimmunity
the responses to self antigens or antigens associated with the microbiota that leads to tissue damage and disease
when does autoimmunity occur
when adaptive cells break self tolerance
-host cells recognised as foreign and adaptive immune cells target them for destruction
how is auto inflammation caused
when innate immune cells become activated
- due to dysregulated secretion of pro inflammatory cytokines and consequent damage to host tissues
what is the critical function of the immune system
to discriminate self from non self
what do autoimmune responses resemble
resemble normal immune responses to pathogens, in that T and B lymphocytes are activated by antigens (autoantigens)
describe the result of the effects of autoantigens
- gives rise to auto reactive effector (T) cells and autoantibodies (from B cells) against the self antigen
- regulatory T cells may also fail to do their job of keeping the immune system in line
- such dysregulated immune responses to self tissues lead to chronic syndromes
- autoimmune diseases
what is CD4 lineage
antigen presenting cells see antigen which present it as peptides with MHC II to naive CD4+ T helper cells, which become effector T cells of 4 basic types
where does CD4 lineage occur
in the adaptive immune system
how does a lymphocyte distinguish between self and non self
- there are mechanisms that prevent autoimmunity like checkpoints
- each partially effective in preventing anti self responses
- together, acts synergistically to prevent autoimmunity without ablating protection against pathogens - ultimate aim is immunological tolerance
what is immunological tolerance
mechanisms hat prevent an immune response being mounted against the bodys own tissues
- this is manifested by immunological non reactivity of B and T cells to self antigens
what are the 2 major groups of checkpoints
- central tolerance mechanisms in thymus and bone marrow
- peripheral tolerance mechanisms in secondary lymphoid tissue/sites of inflammation
what are the functions of T regulatory cells
- protectors against autoimmunity
- express a transcription factor which alters the expression of many genes
- when activated, Tregs express large quantities of the cytokines TGFB and IL10
- these are immunosuppressants that inhibit activity of NK cells and CD8 cells - Tregs also have powerful destructive effects on APCs such as dendritic cells
- the antigenic peptides recognised by the TCRs of Tregs tend to be self peptides (autoantigens)
- so major function is to inhibit CD4+ Tn1, Tn2, Tn17, CD8 and CTLs from mounting an immune attack against self components to protect the body against autoimmunity
what occurs when there is a lack of Tregs
severe autoimmune conditions arise
what does inflammation due to hashimotos disease lead to
leads to underactive thyroid gland
what is the diagnostic sign of Hashimotos disease
enlarged thyroid
what are symptoms of Hashimotos disease
- enlarged thyroid
- front of neck looks swollen
- may make swallowing difficult
- weight gain
- fatigue
- paleness/puffiness in face
- joint/muscle pain
- constipation
- hair loss or thinning
- slowed heart rate
what is the treatment of HD
daily use of synthetic thyroid hormone
- levothyroxine
what does RA show characteristics of
both autoimmune and auto inflammatory disease
describe the autoinflammatory responses in RA
- once RA is triggered, immune cells migrate into joints where they produce large quantities of immune mediators (cytokines/chemokines), leading to activation and recruitment of more immune cells into the tissue
what do mutations in cells of the innate immune system lead to
- leads to elevated levels of proinflammatory cytokines, creating a positive feedback loop of exacerbating inflammation
- by blocking these secreted cytokines, the systemic inflammatory symptoms are alleviated
why were immunotherapies developed and what do they do
- were developed to decrease the amount of circulating TNFa, IL6 and IL1B
- these drugs (tocilizumab, etanercept) are able to bind to and sequester these cytokines or their receptors
what is the mode of action of TNFa, IL1 and IL6
binding of an inflammatory cytokine to its receptor leads to the production of inflammatory effector molecules
what is TNFa involved in
involved in systemic inflammation
- as TNF promotes the proinflammatory response, amplified and dysregulated production of TNF if associated with autoimmune disorders such as RA, ankylosing spondylitis, IBS and psoriasis
- these disorders can be treated using a TNF inhibitor
what is TNFa secreted by
macrophages
what is the role of IL6
- regulates many pathways that could contribute to its effect on inflammatory disease progression
- during CD4 T cell differentiation, IL6 promotes IL17 and IL21 production and suppresses Treg cell function
- IL6 promotes neutrophil and macrophage recruitment and survival through induction of IL17 production
- also acts on non immune cells, altering the function of fibroblasts and osteoclasts
- this all leads to deposition of matrix, antibody complexes and proteases in the targeted tissue, leading to tissue destruction
