Auto-inflammation and autoimmune inflammation Flashcards
What is autoinflammation
abnormal immune response due to dysregulated secretion of pro-inflammatory cytokines that leads to chronic inflammation
characteristics of auto inflammatory disease
characterised by unprovoked fever and inflammation
• Known as periodic fever syndromes
• Involve abnormal activation of innate immune system
○ Trigger fever and inflammation to fight infection
• Then kicks-start adaptive immunity
• Do not produce autoantibodies or effector T cells
symptoms of auto inflammatory disease
• Recurrent fever
• Sores
• inflammation of eyes, muslces, joints, skin, GI tract, internal organs
○ Repeated inflammation lead to amyloidosis (澱粉樣變)
• Caused by build-up of amyloid protein in organs and tissues and make organs and tissues hard to work properly
What is the cause of familial mediterranean fever
abnormality in a gene called MEFV encoding for protein - pyrin
pyrin is a PRR found in macrophages and is produced by leukocytes and keep inflammation under control. IT monitors function of the Rho GTPases.
• Members of GTPases are common targets of bacterial exotoxins and blocking Rho activity can interfere with macrophage migration and phagocytosis
§ When Rho GTPase function is shut down
□ Pyrin is activated and kicks in
• Pyrin assembles the molecular complex -> inflammasome
what is inflammasome
- Intracellular multiprotein oligomer
- Promotes the maturation and secretion of pro-inflammatory cytokines
- Responsible for activation of inflammatory responses
- Responsible for activation of caspase 1 and 5 leading to the processing and secretion of pro-inflammatory cytokines IL-1B
- Composed of NALP1 and adaptor protein ASC
- When activated form activate caspase 1 and caspase 5
- Enzyme proteases that cleave inactive proIL-1B to the active pro-inflammatory cytokine IL-1b
- When activated form activate caspase 1 and caspase 5
mutated porin protein produce lead to inappropriate activation of inflammasome and release of pro-inflammatory cytokine IL-1B through activation of caspase 1 and 5
Treatment of auto inflammatory disease
- Low doses of colchicine reduced symptoms in at least 95% of patients
* Inhibit multiple proinflammatory mechanisms- Anakinra, rilonacept, canakinumab
- Monoclonal antibodies that target IL-1B
- Anakinra, rilonacept, canakinumab
What is self- antigen and non self antigen
Self antigen Normal component of the body to which the immune system would react if there were not mechanisms in place designed to destroy dangerously reactive B and T cells
Non-self antigen • An antigen which is not part of our body and is thus not something our immune system has developed tolerance for, some can be come tolerated = tolerogens
• An antigen that leads to an immune response
What is self-tolerance
ability of immune system to recognize self-antigens as safe while remaining able to recognise and mount immune response to foreign substances
Action of self-tolerance
- Removal of self-reactive lymphocytes that have receptors bind strongly to self-antigens
- Autoreactive cells are removed by apoptosis, termed clonal deletion or by induction of anergy (state when cells can no longer respond to antigen)
What is anergy
- State of long term hypo-responsiveness in T cells
- Happens when T cells are presented antigens in the absence of co-stimulation (CD80/CD86)
- Characterised by active expression of TCR signalling (CTLA4) and IL-2 expression
What are the two kinds of tolerance
- Central tolerance
• Takes place in thymus (T cells) and bone marrow (B cells)
• Make new developing lymphocytes tolerant to self-antigens
• Mechanism : clonal deletion
• When immature BCR/TCR recongise self- antigens with very high affinity or strong BCR signalling : preventive measure can occur through three mechanisms
1. Killed by apoptotic mehcniams by programmed cell death
2. Suppresed or go to anergy where BCR are down regulated
3. Immature BCR re-edit BCR so no longer show high affinity with self-antigen
4. Some CD4+ T cells receive signals to differentiate into natural T regs which express FoxP3 TF and suppress immune response- Peripheral tolerance
• Occurs outside the organ of maturation, at site of antigen recognition
• Where lymphocytes begin to elicit an immune response (circulation, lymph nodes, lymph organs)
• Ensure that affinity maturation and somatic hypermutation to BCR do not produce self-reactive antibodies and autoreactive B cells would die
• Can occur through one of three mechanisms :
1. Induction of anergy
• Eg. If DCs are not appropriately activated and present self-antigen to T cells without signals 2 and 3, they will produce T cells that are tolerant or anergic to that self antigen
2. Deletion of autoreactive T cells via Apoptosis
3. Development of ‘induced’ regulatory T cells
• T cells exposed to cytokine TGF-b can differentiate into induced Treg
- Peripheral tolerance
What is positive selection
- Process by which T cells are tested for the expression of receptors that recognise on one of the self-MHC molecules expressed by a thymic epithelial cell
- Testing T cells for MHC restriction- If the T cell’s TCR do not recognise the Self-MHC, then the cell will die by apoptosis
What is negative selection
- If Immature T cells recongise and bind self-peptide with very strong affinity -> apoptosis
* The intracellular signalling is so strong might lead to formation of self-reactive T cells capable of inducing autoimmune disease- Eliminates T cells that may contribute to auto-immunity
what is autoimmune disease
abnormal immune response against self-antigens occurs when tolerance breaks down and tissues are attacked by their own immune response
Mechanisms of autoimmune diseases
- Environmental modulation
• Eg. Typical western diet - rich in saturated fat and salt - impact on local and systemic immune response- Molecular mimicry
• Structural similarities of exogenous antigen to host antigens
• Antibody produced against antigen that mimics self antigen can bind to host and initiate immune response - Epitope modification
• Result from exposure of unseen carbohydrate motifs of glycoproteins on non-haematopoietic cells (eg.stromal cells)
• Activates one or more innate immune cell receptors to induce a chronic sterile inflammatory state - Epitope spreading or epitope drift
• immune reaction changes from targeting the primary epitope to also targeting other epitopes with similar structure. - Idiotype cross reaction
• Idiotypes - groups of antibodies with similar sequences around the antigen-binding site (Fab region) of the immunoglobulin molecule
• Binding between the idiotype of an antibody an host protein - Cytokine deregulation
• Overexpressed cytokine so propagating the pathogenesis of disease - T-cell bypass
• Infection can initiate polyclonal activation of B cells in non-specific fashion
• Super antigen can crosslink a TCR to MHC, allowing T cell signalling without antigen specificity
Over-produce autoreactive antibody propagates autoimmune responses
- Molecular mimicry
