Block E Lecture 3: Chronic Inflammation and Autoimmunity Flashcards
What happens if the inflammatory response persists even after clearing the antigen?
Chronic inflammation and systemic effects
(Slide 3)
What is chronic inflammation?
A pathological condition (disease or disorder) involving persistent, increased expression of inflammatory cytokines
(Slide 4)
What is an example of chronic inflammation?
Type II diabetes
(Slide 4)
What 4 conditions does Type II diabetes exacerbate (make worse)?
Heart disease
Alzheimer’s
Autoimmunity
Cancer
(Slide 4)
What 2 categories can causes of chronic inflammation be divided into?
Infectious and non-infectious causes
(Slide 4)
What is an infectious cause of chronic inflammation?
Chronic infections - pathogens not being cleared hiding or evading the immune system, continuously triggering inflammation
(Slide 5)
What is an example of a non-infectious cause of chronic inflmmation?
Obesity - visceral fat cells can be stimulated to produce inflammatory cytokines
(Slide 5)
What 4 factors do the consequences of chronic inflammation vary depending on?
Tissue of origin
Sex
Age
Health status
(Slide 6)
What 3 cytokines show increased levels in chronic inflammation?
IL-1, IL-6and TNF-α
(Slide 6)
What can inflammatory cytokines IL-1, IL-6 and TNF-α contribute to?
Insulin resistance (Causing Type II diabetes)
(Slide 6)
What 4 things can inflammatory cytokines IL-1, IL-4 and TNF-α induce in chronic inflammation?
Scar tissue
Organ dysfunction
Cell proliferation
Angiogenesis (the formation of new blood cells)
(Slide 6)
What is self-tolerance?
The process of defining ourselves from foreign cells / antigens / allergens
(Slide 8)
What antigens other than self are tolerated by the body?
Benign and beneficial ones
(Slide 8)
What does the immune system do on top of ignoring self-antigens?
Recognises and protects self-components and beneficial commensals (microbes)
(Slide 9)
What were T-regulatory cells (Tregs) formally known as?
Suppressor T-cells - useful to know for old papers
(Slide 9)
Where does central tolerance occur?
Primary lymphoid organs - Thymus for T-cells, bone marrow for B-cells
(Slide 10)
Where are Tregs formed?
The thymus
(Slide 11)
Do surviving T cells from central tolerance recognise self-antigens?
No
(Slide 11)
Do surviving regulatory T cells (Tregs) from central tolerance recognise self-antigens?
Yes
(Slide 11)
What is positive selection of T cells?
T-cells undergo selection in the thymus to ensure they can recognise and respond to antigens presented by MHC receptors. T cells that cannot interact with self-MHC molecules undergo apoptosis and those that interact successfully receive signals for survival
(Slide 11)
What is negative selection of T cells?
The elimination or inactivation of T cells that strongly recognise MHC receptors, preventing autoimmunity from self-reactive T cells
(Slide 12)
What is clonal selection?
The activation and differentiation of effector lymphocytes that recognise the foreign antigen
(Slide 12)
What 3 expression are Tregs identified by?
FOXP3, CTLA-4 and CD25
(Slide 13)
What do Tregs do?
Suppress or “regulate” autoimmune responses to self-antigens in the periphery
(Slide 13)
Are the majority of Tregs CD8+ or CD4+?
CD4+
(Slide 13)
What is one way used by Treg cells to inhibit APCs?
Their CTLA-4 physically interacts with CD80/CD86 (B7-1/B7-2), preventing the interaction between these co-stimulatory molecules and CD28 on conventional T cells. This inhibits the activation of effector T cells
(Slide 14)
How can activation of indoleamine 2,3-dioxygenase (IDO) by Treg cells create an immune-inhibitory environment?
As they convert tryptophan to kynurenine
(Slide 14)
What does IL-2 do?
It stimulates proliferation and growth of helper and cytotoxic T cells
(Slide 14)
How do Tregs absorb local IL-2?
Via CD25
(Slide 14)
What kind of cytokines do Tregs make?
Inhibitory cytokines
(Slide 14)
What 3 ways can auto-immune diseases be mediated?
Anti-body mediated, Cell-mediated or a mix of both
(Slide 16)
What causes auto-immune diseases?
The destruction of self-proteins, cell and organs
(Slide 16)
What are the 2 categories of auto-immune disease?
Organ-specific or systemic
(Slide 16)
How do genetics play a role in autoimmunity?
Particular class I and II MHC alleles or mutations are associated with auto-immune diseases
(Slide 17)
What do people with MHC class I and II alleles and mutations associated with particular immune events still need on top of this to develop the auto-immunedisease?
A trigger event from the environment
(Slide 17)
Is auto-immunity more prevalent in males or females?
Females
(Slide 17)
Name 3 examples of auto-immune diseases with genetic associations.
Type 1 Diabetes
Rheumatoid arthritis
Multiple Sclerosis
Crohn’s disease
Systemic lupus erythematous
(Slide 17)
What are 3 factors that may account for females being more susceptible to auto-immune diseases than males?
Hormonal differences
Conception and pregnancy
Gut microflora after puberty
(Slide 18)
What 5 factors are believed to cause autoimmunity?
Diet
Obesity
Smoking
Infection
Mucosal flora
(Slide 19)
How can infection result in auto-immunity developing?
Tissue pathology following infection may result in the release of sequestered (hidden) antigens the immune system hasn’t encountered before, which can be presented by APCs in a way that promotes immune activation.
The molecular components of certain microbial antigens may share strong similarities to self-antigens resulting in cross-reactive responses
(Slide 20)
Is Hashimoto thyroiditis organ specific or systemic ?
Organ-specific
(Slide 22)
What is Hashimoto thyroiditis?
Production of auto-antibodies and sensitised Th1 cells specific for thyroid antigens thyroglobulin and thyroid peroxidase - with binding to this proteins interfering with iodine uptake
(Slide 22)
What does Hashimoto thyroiditis result in?
Hypothyroidism (underactive thyroid)
(Slide 22)
What are 3 symptoms of Hashimoto thyroiditis?
Fatigue
Lethargy (lack of energy)
Unexplained weight gain
(Slide 23)
What does therapy for Hashimoto thyroiditis involve?
Daily administration of the lost thyroid hormone thyroxine
(Slide 23)
What is Myasthenia?
Production of auto-antibodies against the acetylcholine receptors (AChRs) on the motor end plates of muscles, blocking the normal binding of acetylcholine and inducing complement-mediated lysis of the cells
(Slide 24)
What are the 2 symptoms of the progressive weakening of the skeletal muscles due to Myasthenia?
Drooping eyelids
Inability to retract the corners of the mouth
(Slide 25)
What 3 things does the treatment of Myasthenia involve?
Increasing acetylcholine levels
Decreasing antibody production via immuno-suppressants
Removing antibodies via the removal and exchange of blood plasma
(Slide 25)
What occurs in systemic auto-immune diseases?
Auto-reactive cells recognise a target antigen or antigens found in multiple tissues or organs resulting in inflammation and physiological disruptions at multiple locations within the body
(Slide 26)
What tissue damage occurs in systemic autoimmune diseases?
Wide-spread tissue damage
(Slide 26)
What 4 things can the wide-spread tissue damage as a result of systemic auto-immune diseases driven (Controlled) by?
Cell-mediated immune activity, auto-antibodies, accumulation of immune complexes or a combination of these
(Slide 26)
What is the typical age range where systemic lupus erythematous onsets?
20 - 40 years old
(Slide 27)
Does systemic lupus erythematous have a genetic link?
Yes
(Slide 27)
What 2 cells are auto-antibodies generated against in systemic lupus erythematous and what can this lead to?
Red blood cells and platelets leading to complement-mediated lysis of the cells
(Slide 28)
What does systemic lupus erythematous cause?
Haemolytic anaemia and then thrombocytopenia
(Slide 28)
What is haemolytic anaemia?
A disorder in which red blood cells are produced faster than they can be made
(Slide 28)
What is thrombocytopenia?
Deficiency of platelets in the blood
(Slide 28)
What do immune complexes do in systemic lupus erythematous do and what type of hypersensitivity is it?
Type III hypersensitivity - immune complexes of auto-antibodies and nuclear antigens are deposited along the walls of small blood vessels
(Slide 28)
What do immune complexes deposited alone walls of small blood vessels activate in systemic lupus erythematous?
The complement cascade and generation of membrane attack complexes (MAC)
(Slide 28)
What can occur in severe cases of systemic lupus erythematous?
Excessive complement activation produces elevated serum levels of complement fragments - leading to neutrophil aggregation and attachment to vascular endothelium
(Slide 28)
What are 5 signs / symptoms of systemic lupus erythematous?
Fever
Weakness
Arthritis
Kidney disfunction
Skin rashes
(Slide 29)
Does rheumatoid arthritis have a genetic susceptibility element?
Yes
(Slide 31)
What is the typical age range in which rheumatoid arthritis onset occurs?
Between 40 and 60 years old
(Slide 31)
Is rheumatoid arthritis an antibody or cell-mediated disease?
It’s both
(Slide 31)
What 2 things do auto-antibodies target in rheumatoid arthritis?
Citrullinated proteins and rheumatoid factor (RF)
(Slide 31)
What type of hypersensitivity reaction is rheumatoid arthritis?
Type III
(Slide 33)
What 5 immune cells are involved in rheumatoid arthritis?
Macrophages
Dendritic cells
Neutrophils
Natural Killer cells
T-cells
(Slide 34)
What 3 pro-inflammatory cytokines do CD4+ T helper 1 (Th1) cells induce and what does this lead to in rheumatoid arthritis?
IFN-gamma, TNF-α, IL-2 leading to cartilage destruction and bone erosion
(Slide 35)
What are Th17 cells?
A large subset of CD4+ Th cells which can provide large numbers of cytokines such as IL-17A and IL-17F
(Slide 35)
What diseases are Th17 cells thought to play an important role in developing?
Immune-mediated diseases
(Slide 36)
How does Th17 play a part in the development of rheumatoid arthritis?
IL-17 they secrete triggers changes in the synovium that lead to synovitis and maintain inflammation in the joint
(Slide 36)
What are 4 symptoms of rheumatoid arthritis?
Answers include:
Pain or arching in more than 1 joint
Stiffness in more than 1 joint
Tenderness and swelling in more than 1 joint
The same symptoms in both sides of the body (i.e in both hands or both knees)
Weight Loss
Fever
Fatigue or tiredness
Weakness
(Slide 37)
What are 4 immunotherapies for systemic auto-immune diseases?
General immune suppression - with immuno-suppressants
Immunosuppression of specific cells/pathways
Drugs to block co-stimulation
Re-establishing tolerance
(Slide 38)
