Sterile inflammation, autoimmunity, and treatment strategies Flashcards
What is inflammation?
Inflammation is a localized physical condition in which part of the body becomes reddened, swollen, hot, and often painful, especially as a recognition to injury or infection.
It is normally a protective response to infection, injury, an loss of tissue homeostasis. It is induced when homeostatic capacity is overwhelmed. It absolutely and categorically depends on the recruitment of leukocytes.
The pathway consists of 4 universal components:
1. Inducers - infection, tissue damage
2. Sensors - PRRs on innate cells; macrophage, dendritic cells, mast cells, neutrophils
3. Mediators - cytokines (TNF, IL-6, etc), chemokines (CCL-2 CXCL8, etc), autacoids (histamine, eicosanoids, etc)
4. Effectors - T and B cells, plasma cells, neutrophils, activated fibroblasts, macrophages
It is normally followed by a resolution phase to retune to homeostasis. The response operates at a cost to incompatible (or competing) lower priority functions. And, it can cause pathology when it is excessive inappropriately induced, or due to collateral damage.
What is sterile inflammation?
Sterile inflammation is an inflammation that occurs in response to tissue injury and in the absence of microorganisms.
What can trigger sterile inflammation?
Triggers of sterile inflammation is when there are trauma to the cells resulting in constitutively expressed DAMPs or LAMPs (life associated molecular patterns; endogenous/exogenous). This activates the pattern recognition receptors on different cells (often macrophages/DCs), which results in an inflammatory mediator release with an feedforward loop including signal amplification with inducible DAMPs.
What role play cell death in the induction of sterile inflammation?
Dying cells are capable of activating the innate immune system and induce a sterile inflammation response. There are two types of cell death related to sterile inflammation:
Accidental cell death (ACD) - triggered by unexpected attack an injury that overwhelms any possible control mechanisms (Ex: necrosis); and regulated cell death (RCD) - involved in precise signalling cascades, is executed by a set of defined effector molecules, and has unique biochemical, functional, and immunological consequences (Ex: NETosis, immunogenic cell death, autophagy-dependent cell death).
Explain the induction and propagation of sterile inflammation.
Induction:
1: cellular damage and necrosis - when cells are damaged due to physical injury, toxins, or other non-infectious causes, they may undergo necrosis.
2: release of DAMPs (also called alarmins) are molecules released by stressed, damaged, or dying cells. Common DAMPs include high mobility group box 1 (HMGB1), heat shock proteins (HSPs), ATP, and DNA fragments. These molecules are normally intracellular and only become immunogenic when released into the extracellular space due to cell damage.
3: recognition by PRRs - DAMPs are recognised by PRRs on immune cells (macrophages and DCs). Key PRRs involved in sterile inflammation include TLRs and RAGE. The interaction between DAMPs and PRRs activates intrinsic signaling pathways that lead to the production of pro-inflammatory cytokines and chemokines.
Propagation:
1: cytokine and chemokine release - activated immune cells release various cytokines (ex: IL-1beta, TNF-alpha, IL6) and chemokines (CXCL1 and CXCL2 => chemotaxis gradient) that further amplify the inflammatory response. These mediators recruit additional immune cells, like neutrophils and monocytes to the site of injury.
2: infiltration of immune cells - recruited immune cells infiltrate the damaged tissue, where they can phagocytose debris, secrete more inflammatory mediators, and potentially cause further tissue damage. This influx of immune cells not only helps clear damaged cells and repair tissue but also perpetuates/sustain the inflammatory response.
3: resolution phase - ideally, once the initial cause of damage is mitigated, the inflammatory response resolves. Mechanisms of resolution include the secretion of anti-inflammatory cytokines (ex: IL-10, TGF-beta) and the production of specialized pro-resolving mediators (SPMs). Failure to resolve sterile inflammation can lead to chronic inflammation, which is associated with various pathological conditions.
What characterize potential DAMPs?
The DAMPs criteria are: rapidly released in response to infection/injury; have effects on antigen-presenting cells that modulate immune activity; active as a purified molecule at concentrations in pathophysiological situations; selective eliminations of inactivation should inhibit biological activity; have a separate biological role in non-inflammatory states.
They can be either endogenous (constitutive DAMPs - passively released from necrotic cells or exposed on the surface of stressed cells; or inducible DAMPs - actively secreted by activated cells) or exogenous - entering the host cell from the outside.
Explain how the release of DAMPs can lead to more released DAMPs.
The release of DAMPs can initiate a self-propagating cycle of inflammation that leads to the release of more DAMPs, exacerbating the inflammatory response.
1: Sterile inflammation is triggered by a first signal by DAMPs that can act on receptors such as TLRs, RAGE, and P2X7.
2: DAMPs often act on several receptors at the same time: Activating signaling by TLRs initiate a cascade that translocate NF-kappaB to the nucleus and stimulates pro-IL1beta and pro-IL18 expression. Whereas, activation to RAGE also activates NF-kappaB, although by a different signaling pathway (the MAPK pathway)
3: A second signal stimulates inflammasome assembly from NLR (ASC and pro-caspase-1).
4: Pro-caspase-1 is cleaved, and activated within the complex.
5: The active caspase-1 further activates IL-1beta and IL-18, and Gasdermin-D.
6: Gasdermin-N is responsible for the pore-formation and an initiation of Pyroptosis.
7: IL-1beta and IL-18 are released from the cell through these pores, and this initiate a self-perpetrating loop of sterile inflammation
What is the link between sterile inflammation and autoimmunity?
“although sterile inflammation plays an essential role in tissue repair and regeneration, unresolved chronic inflammation is detrimental to the host and can lead to sterile inflammatory diseases, including metabolic disorders, neuro-degenerative diseases, autoimmune diseases, and cancer”.
What is immunity?
Immunity is the state of being resistant to a particular infectious disease or pathogen.
Define autoimmunity.
Autoimmunity is a self-damaging immune effector response manifested in various autoimmune diseases.
It is when there is an immune response leading to reaction with self-antigen. Self-reactivity arise either through the triggering of receptors directly by autoantigen or by virtue of cross-reaction between foreign and self-antigens.
It occurs when having a the loss of control of self-reactive T lymphocytes. Thus, having a breakage of the central tolerance.
What is the difference between autoinflammation and autoimmunity?
Autoimmunity refers to an aberration in the body’s normal development such as the immune system mounts an attack against its own cells. This involves the adaptive immune system; especially the B lymphocytes making autoantibodies/self-peptides. And thus, having an autoimmune disease originate from a dysfunctional adaptive immune system (ex: RA, Type-1 diabetes, SLE) .
Autoinflammation refers to a dysfunctional innate immune system, that causes sporadic inflammation throughout the body (when having a systemic autoinflammatory disease - ex: Crohn’s disease). Caused by hyperactivation of innate immune cells (macrophages stimulated by DAMPs) by constant release of IL-1beta and TNF-alpha (pro-inflammatory cytokines).
Which cells are involved in tissue damage in autoimmune diseases?
T cells:
- CD4+ T cells (helper T cells) - play a crucial role in orchestrating the immune response by producing cytokines that activate the other immune cells. In autoimmune diseases, they can help drive the inflammatory process by promoting the activation of macrophages, B cells, an cytotoxic T cells.
- CD8+ T cells (cytotoxic T cells) - directly attack and destroy body cells that they mistakenly recognise as foreign or infected. In autoimmune diseases, they can target and kill the body’s own cells, contributing to tissue damage.
NK cells - contributes to tissue damage if they become activated against self-cells.
B cells:
- Antibody production - B cells produce antibodies that are specific to antigens. In autoimmune diseases, they generate autoantibodies that target the body’s own tissue. These autoantibodies can form immune complexes that deposit in tissue, leading to inflammation and damage.
- Antigen presentation - they can also present antigens to T cells, further promoting T cell activation and the autoimmune response.
Macrophages:
- Phagocytosis and inflammation - they engulf and digest cellular debris and pathogens. Here, they can also ingest healthy tissue due to mistaken identity. They are potent producers of pro-inflammatory cytokines (TNF-alpha and IL-1beta) which contributes to inflammation and tissue damage.
- Tissue remodelling - they are involved in tissue remodelling and can secrete enzymes that degrade extracellular matrix (matrix metalloproteinases, MMPs) potentially leading to further tissue damage in the context of chronic inflammation
Dendritic cells
- Antigen presentation - DCs are key antigen-presenting cells (APCs) that activate T cells. Here, they can present self-antigens to T cells, initiating or perpetuating an autoimmune response.
- Cytokine production - produce cytokines that modulate the activity of other immune cells, influencing the inflammatory environment.
Neutrophils
- Acute inflammation - they are often the first responders to inflammation, and can release enzymes and ROS that (while intended to kill pathogens) can damage surrounding tissues.
NETosis - they release neutrophil extracellular traps (NETs) that trap pathogens. NETs can also cause tissue damage and promote autoimmunity by exposing self-antigens and stimulating immune responses.
How can genes and the environment influence the development of autoimmune?
Genetic factors:
1: genetic predisposition - certain genes are strongly associated with an increased risk of developing autoimmune disease. Ex: human leukocyte antigen (HLA) gene complex, which plays a critical role in immune system function and has been linked to many autoimmune conditions (T1D, RA, MS). Mutations or polymorphisms in genes that regulate immune responses can lead to dysregulation of immune tolerance and thus promote autoimmunity.
2: familial aggregation - these diseases often occur more frequently within families, suggesting a hereditary component relatives of individuals with autoimmune diseases may have a higher risk of developing the same or a different autoimmune condition.
Environmental factors:
1: infections - molecular mimicry; some infections trigging autoimmune responses where the microbial antigens resemble self-antigens, leading to cross-reactivity and autoimmunity. Infections can also cause bystander activation, where the inflammatory response to an infection activates autoreactive immune cells.
2: diet and gut microbiota - nutritional factors can influence gut health and immune function. Ex: vitamin D deficiency has been associated with increased risk of MS. The gut microbiome plays a crucial role in the development and regulation of the immune system. Dysbiosis has been linked to several autoimmune disease (ex: bowel disease).
3: chemicals and drugs - certain chemical, pollutants, and drugs can contribute to the development of autoimmune diseases. Ex: exposure to silica dust and smoking => RA, while certain medications can induce lupus-like symptoms.
4: stress and hormones - physiological stress can affect immune function and may trigger or exacerbate autoimmune responses. Hormonal changes, particularly those related to sex hormones (estrogen and progesterone) can influence the course of autoimmune diseases. This is evidenced by the higher prevalence of many autoimmune diseases in women.
Describe the pathogenesis of SLE. What is the hallmark?
Systemic lupus erythematosus (SLE) pathogenesis involves:
1: genetic susceptibility - SLE has a strong genetic component with multiple genes implicated in its development, including those involved in the immune system (ex: HLA genes, complement components, and genes regulating cytokine production).
2: environmental triggers - various environmental factors can trigger SLE including UV light exposure, infections, and certain drugs. These factors are through to initiate inflammatory processes or directly stimulate the immune system.
3: immune system dysregulation - abnormal B cell activation leads to the production of a wide array of autoantibodies (antinuclear antibodies (ANAs). These autoantibodies form immune complexes with their corresponding antigens. Altered T cell function (CD4+ and CD8+ T cells) contributes to the loss of immune tolerance and supports ongoing B cell activation and autoantibody production.
4: formation of immune complexes - the autoantibodies produced bind to self-antigens forming immune complexes. These complexes can deposit in various tissues (kidneys, joints, skin, and blood vessels).
5: inflammation and tissue damage - the deposition of immune complexes triggers a series of inflammatory responses, activating complement and recruiting inflammatory cells. Leading to tissue damage through direct injury and inflammation.
6: impaired clearance of apoptotic cells - it is associated with defects in the clearance of apoptotic cells. Accumulation of apoptotic debris may provide a continuous source of autoantigens, perpetuating the autoimmune response.
Hallmarks: the presence of antinuclear antibodies (ANAs)! These autoantibodies are directed against components of the cell nucleus, including DNA, histones, and other nuclear proteins. They are highly sensitive for SLE, but can be present in healthy individuals, so their specificity for SLE is not absolute.
Describe the pathogenesis of MS. What is the hallmarks?
Multiple sclerosis (MS) pathogenesis involves:
1: genetic susceptibility - it has a genetic component with several genes associated with increased risk (HLA system, and other genes related to immune function).
2: environmental factors - examples vitamin D deficiency and viral infections (Epstein-Barr virus).
3: immune system dysregulation - CD4+ Th cells activated in the peripheral blood. These cells cross the blood-brain barrier into the CNS, where they recognise myelin antigens and initiate inflammatory response. B cells become activated and contribute to the disease process by producing autoantibodies, presenting antigens, and secreting pro-inflammatory cytokines. The activation of T and B cells leads to the recruitment of additional immune cells (macrophages, microglia) contributing to myelin destruction and axonal damage.
4: demyelination and neurodegeneration - the immune response against myelin leads to demyelination disrupting nerve signal transmission. Over time, the chronic inflammation also leads to axonal loss and neurodegeneration => accumulation to neurological disability.
Hallmarks: demyelination, inflammation, neurological symptoms (visual disturbance, muscle weakness, coordination and balance problems, etc.), relapsing-remitting course over time (good and bad periods).
