Immunology of autoimmune diseases Flashcards
What are the two types of immune cells haematopoetic stem cells can differentiate into?
Myeloid progenitor cells or Lymphoid progenitor cells
(Remember as the two classifications of leukemia)
What are the differences in maturation sites of myeloid and lymphoid progenitor cells?
Myeloid cells can mature within the bone marrow whereas lymphoid cells require maturation outside of the bone marrow.
What are the three cells types lymphoid progenitor cells are capable of differentiating into?
Natural killer cells
T lymphocytes
B lymphocytes
Where do T and B lymphocytes undergo maturation?
T lymphocytes: T for thymus
B lymphocytes: B for bone marrow
What are the four cell types myeloid progenitor cells are capable of maturing into?
Megakaryocyte
Erythrocyte
Mast cells
Myeloblast
What are the source of platelets?
Platelets also known as thrombocytes are made from large progenitor cells known as Megakaryocytes which release platelets once having undergone a series of complex maturation processes in the bone marrow.
What can myeloblasts further differentiate into?
Basophil
Neutrophil
Eosinophil
Monocyte (can further differentiate into macrophages)
Explain what is meant by immunological self-tolerance in the prevention of autoimmunity?
Immunological self-tolerance is the ability of white blood cells to distinguish between the self antigens presented on our healthy cells and foreign antigens and hence only initiate an appropriate immune response to foreign antigens.
In application to immunological self-tolerance, when does autoimmunity occur?
When an immune system loses it natural immunological tolerance meaning that our lymphocytes can no longer distinguish between self (autologous) and non-self antigens and begins to attack our healthy cells leading to tissue damage and loss of organ function (Type 1 DM).
Compare and contrast immunogen and a tolerogen?
Whilst both are foreign antigens;
Immunogens are antigens that induce the immune response whereas tolerogens are antigens that suppress the immune response (evokes tolerance).
Crucially an antigen can be both an immunogen and a tolerogen but its effects are dependent on how and where it is presented to the immune system.
What are the 3 methods of achieving self tolerance?
Immune privileged sites such as the eyes where B and T cells are unable to enter and hence respond to any antigen
Central tolerance
Peripheral tolerance
Define central tolerance.
Central tolerance is the selection process in the maturation of lymphocytes in which strongly reacting cells to self antigens are instructed to undergo apoptosis.
Define peripheral tolerance.
Peripheral tolerance is the monitoring of mature B and T cells in the periphery to ensure they are not initiating an immune response to self antigens in the periphery, either anergic or undergo deletion.
How is central tolerance incorporated into T cell maturation?
During maturation in the thymus, T cells undergo positive and negative selection. Positive and negative selection is a crucial aspect of achieving central tolerance.
Immature T lymphocytes during maturation are exposed to antigen presenting cells which present a self-antigen via their MHC-11 complex. Depending on how strongly the immature T lymphocyte reacts with the APC decides whether it undergoes positive or negative selection.
Explain the possible outcomes of an immature T lymphocyte having undergone positive or negative selection.
Strong reaction:
Negative selection, apoptosis
Intermediate reaction:
Becomes a T regulatory cell and enters the peripheral tissue
Weak reaction:
Positive selection
No reaction:
Apoptosis
How is central tolerance incorporated into B cell maturation?
An immature B lymphocyte is exposed to an APC presenting with an self antigen on its MHC-11 complex within the bone marrow. Similarly to T cells the dependence on the avidity IgG (the BCR) of the B lymphocyte reacting to an APC with the self antigen present decides whether the fate of the cell.
Explain the possible outcomes of an immature B lymphocyte having been exposed to a self antigen on an APC.
High avidity:
There is an opportunity for the B cell to undergo receptor chain editing where there can be alteration in the light chain sequence resulting in a new expression of the light chain which can affect the binding affinity of the BCR (IgG) to the self antigen.
If the B lymphocyte now demonstrates avidity below the threshold or has a low avidity to the self antigen initially, receptor expression can be reduced and the B cells becomes anergic meaning that it will be functionally unresponsive to the self antigen again.
Explain how peripheral tolerance of T cells is achieved?
When a mature T cell is exposed to a self antigen in the periphery it will either be:
Functionally unresponsive (anergic); the T cell will not become activated due to lack of co-stimulatory signals
Suppressed by T regs: Co-stimulatory signals is present but the activation of the T cell is prevented by T regulatory cells
Apoptosis: if the T cell does become activated it is then instructed to undergo apoptosis to prevent it becoming activated/reacting again with another self antigen
Explain the immunological response of a B cell reacting with a non-self antigen.
Foreign antigen binds to the BCR, the cell recognises it as a foreign complex presents it on the cell surface via an MHC-11 complex. B cell activation is not achieved until the cell presents the antigen to a Th2 cell to the TCR and then this T cell release cytokines which initiates differentiation of plasma cells producing antibodies in response to the foreign antigen.
Describe what happens when a B cell is exposed to a self antigen in the periphery?
Similar to the B cell response to a foreign antigen, the BCR binds to the self antigen and either distinguishes it as a self antigen itself or inhibited by the lack of T cell activation. This can be categorised as one of three outcomes as a result of exposure to a self antigen:
Anergy the B cell becomes functionally unresponsive to the self antigen without assistance from T cell inhibition
Regulated by inhibitory receptors
Apopotosis: instructed to undergo controlled cell death to prevent initiating an immune response to a cell antigen again in the future.
Discuss whether lack of T or B cell tolerance would be less impactful in the development of autoimmunity?
Lack of B cell tolerance- even if B cells were to loose immunological tolerance and their ability to distinguish between self and non-self antigen, their activation and synthesis of antibodies would be inhibited by lack of T cell activation which B cell activation is dependent upon.
Therefore maintaining T cell tolerance enforces B cell tolerance to the same antigens.
What are the six ‘layers’ of tolerance?
Central tolerance
Antigen segregation
Peripheral anergy
Regulatory cells
Cytokine deviation
Clonal deletion
How do regulatory T cells achieve self tolerance?
Regulatory T cells act in the secondary lymphoid tissue (Peyer’s patch for example)
What is the transcription factor that is expressed highly in T reg cells but not in other T cells?
FOXP3
What are the two types of T regs and what are their differences in roles?
Natural T regs are responsible for maintaining peripheral tolerance
Induced T regs which are derived from naive T cells are responsible for controlling inflammation
How are T regs able to maintain peripheral tolerance?
Produce anti-inflammatory cytokines such as IL-10 and TGF-B which prevent activation of other immune cells
Instruct cytolysis of self-reactive T cells in the periphery
How do T regs cause metabolic regulation and how does that help control inflammation?
T regs can consume large quanties of glucose and amino acids which are crucial for the proliferation of pro-inflammatory cells which drive inflammation.
What are the five processes in which T cells can help achieve immune tolerance and control inflammation?
- Anti-inflammatory cytokine production (IL-10 and TNF-B)
- Metabolic regulation
- Prevent activation of dendritic cells
- Direct killing of self reactive T cells
- Limiting an immune response to cancer cells
How does antigen segregation help to induce immune tolerance?
This is the physical barrier separation which prevents the exposure of self-antigens to the lymphoid system- preventing over exposure to possible self-reactive lymphocytes.
What is peripheral anergy?
It is when mature T and B cells are exposed to a self-antigen in the secondary lymphoid tissue and are functionally unresponsive (anergic) by weak signalling without co-stimulus
When do autoimmune conditions tend to occur?
When there is a breakdown of multiple layers of immunological tolerance, underlying genetic conditions which increase susceptibility to an auto-immune disease in addition to an environmental trigger (illness, infection, injury etc).
What would you expect to appear in a blood test for a patient that has an auto-immune condition?
High circulating levels of auto-antibodies
True or false.
When somebody has an auto-immune disease this increases their potential to develop additional auto-immune diseases.
True
Is it more common for males or females to have an auto-immune condition?
Females, it is believed to link to the estrogen levels which increases susceptibility
What are the UK statistics for auto-immunity prevalence?
Approximately one in ten have an auto-immune condition.
Roughly 13% of women and 7% of men
Describe the pathophysiology of how genetic susceptibility in addition to environmental factors leads to the development of auto-immune diseases.
A patient has underlying susceptible genes which leads to layers of self tolerance. When a patient has an intercurrent infection, illness or injury this leads to inflammation. As you would expect with any other inflammatory response there is an increase of antigen presenting cells, this leads to an increase in the recruitment of lymphocytes. However because of the underlying susceptible genes it results in self-reactive lymphocytes which become activated evoking an immune response not only to the foreign pathogens but the self-antigens leading to chronic inflammation, tissue injury and development of auto-immune conditions.
Why would developing gene therapy to target a faulty gene known to cause an auto-immune disease be ineffective?
Auto-immune diseases are polygenic meaning that there are multiple genes known to increase the susceptibility of/ development of auto-immune diseases. Individuals multiple genetic polymorphism that contribute to disease susceptibility. Therefore it would be ineffective to target one gene when the disease is known to be polygenic.
Which gene is particularly associated with auto-immune diseases?
MHC class 2
What is the relationship between infection and auto-immunity?
Infection can prevent some auto-immune diseases but often auto-immunity can occur as a result of infection which triggers an acute inflammatory response. Continuous underlying inflammation (chronic inflammation) can then precipitate into an autoimmune disease.
What are some examples of systemic auto-immune diseases?
Rheumatoid arthritis
Systemic lupus erythematosus
Systemic sclerosis
What are some examples of organ specific auto-immune diseases?
Myasthenia gravis
Grave’s disease
Autoimmune diabetes
What are the 5 immunologically privileged sites?
Eyes
Testes
Uterus
Brain
Hamster cheek pouch
Is the increased incidence of auto-immune diseases higher in monozygotic or dizygotic twins?
Monozygotic (identical) twins
What is the difference between induction of co-stimulators and molecular mimicry as mechanisms of causing auto-immune disease?
Induction of co-stimulators is simply the process of a microbe infecting a healthy cell that normally expresses self antigens. By the microbe infecting the cell this activates the antigen presenting cell leading to recruitment of T cells, but those with underlying auto-immunity result in the recruitment of self-reactive T cells leading to tissue damage.
Molecular mimicry is when a microbe infects a cell and instead of a self-antigen being presented a microbial antigen is presented which looks identical. A self-reactive lymphocyte is recruited and again initiates an immune response causing tissue damage.
What are some of the roles of auto-circulating antibodies?
Complement lysis
Interaction with the cell receptor
Formation of toxic immune complexes
Antibody dependent cytotoxicity
Penetration into living cells
How do T lymphocytes play a role in auto-immunity?
Cytokines cause the polarisation of CD4 cells toward Th1 responses
CD8 cells become activated inducing cytotoxic damage and cause cytolysis.
