Autoimmune Diseases Flashcards
1
Q
What cells are involved in innate immunity? What about in adaptive immunity?
A
Innate:
- Macrophages
- Dendritic cells
- Mast cells
- Neutrophils
- Complement
Adaptive:
- T cells
- B cells
2
Q
What is involved in innate immunity?
A
- Inflammation in target tissues
- No learning going on - no memory
- Cells recognise antigen (pattern recognition receptors)
- No amplification
- Little regulation
3
Q
What is speed of response of innate immunity? Duration?
A
Speed - fast response (hours - days)
Duration - short duration
4
Q
What is involved in adaptive immune response?
A
- Learned response in immune organs
- Highly specific (T and B cells receptors)
- Against a specific bacteria/virus etc (not broad classes of antigens like innate immunity) that cells have encountered in the past
- Strong memory and amplification component
- Many regulatory mechanisms
5
Q
What is speed of response of adaptive immunity? Duration?
A
- Speed: slow response (days to weeks for initial exposure)
- Responses may last months - years
6
Q
Are the innate and adaptive immune systems completely separate?
A
No - lots of crossover
7
Q
What do innate immune cells detect/attack?
A
Directly detect and attack antigenic targets (e.g. microbes) at sites of infection e.g. barrier organs (skin, gut)
8
Q
What mechanisms are involved in innate immunity?
A
- Phagocytosis
- Cytotoxicity (e.g. complement sticks to cell walls of microbes)
- Inflammatory mediators and chemokines to attract other cells
9
Q
How are inflammatory mediators released by the innate immune system involved in crosstalk with the adaptive immune system?
A
Inflammatory mediators and chemokines attract T cells/B cells
10
Q
How are dendritic cells involved in crosstalk with the adaptive immune system?
A
Dendritic cells are APCs –> digest antigen and present it to T cells (via MHC II)
11
Q
What is the result of dendritic cells presenting antigen to T cells and B cells? Where does this occur?
A
- Immune memory to determine specific learned responses
- Occurs in lymphoid tissues
12
Q
How can B cells and T cells then interact with the innate immune system? What do T cells active? What do B cells activate?
A
Adaptive immune cells activate innate immune cells, directing tissue inflammation to specific targets
- T cell cytokines activate monocytes, macrophages
- B cell antibodies activate complement
13
Q
What are the 5 main components of innate immune system inflammation?
A
- Phagocytic cells
- Histamine-producing cells
- Complement
- Cytokines
- Chemokines
14
Q
What are 3 examples of phagocytic cells? Functions?
A
- Neutrophils: eat and destroy pathogens
- Macrophages: also produce chemokines to attract other immune cells
- Dendritic cells: also present antigen to adaptive immune system
15
Q
Which phagocytic cells also produces chemokines to attract other immune cells?
A
Macrophages
16
Q
What are examples of APCs?
A
dendritic cells, macrophages, Langerhans cells and B cells.
17
Q
What are examples of histamine producing cells?
A
Mast cells, basophils, eosinophils: produce histamine and other chemokines and cytokines
18
Q
What is effect of histamine?
A
Vasodilatation, attract other immue cells
19
Q
What are histamine-producing cells involved in?
A
- Defence against parasites
- Wound healing
- BUT causes allergy and anaphylaxis
20
Q
What is the complement system?
A
A part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen’s cell membrane.
21
Q
How can the complement system be activated by the adaptive immune system?
A
Via antibodies
22
Q
Cytokines vs chemokines?
A
Cytokine is a general term used for all signalling molecules - signalling between different immune cells (e.g. innate to adaptive, adaptive to innate).
Chemokines are specific cytokines that functions by attracting cells to sites of infection/inflammation.
23
Q
APC goes to lymph node and presents antigen to Th cell. What change does Th cell then undergo? What is net result?
A
- Th cell then differentiates from a naive Th cell to a Th1 cell
OR
- Th cell then differentiates from a naive Th cell to a Th2 cell
Net result –> inflammation
24
Q
What cytokines does Th1 cell release?
A
Inflammatory cytokines:
- IL-2
- IL-12
- IFN-y
- TNF-a
25
What do Th2 cells then interact with? What do they release?
* Release IL-4, IL-5, IL-6, IL-10
* Crosstalk with B cells --\> turns B cells into memory B cells --\> plasma cells (these produce antibodies and autoantibodies)
26
What is autoimmunity? What are the main characteristics?
The adaptive immune system recognises and targets the body’s own molecules, cells and tissues (instead of infectious agents and malignant cells).
* T cells that recognise **self antigens**
* B cells and plasma cells that make **autoantibodies**
* Inflammation in target cells, tissues and organs is secondary to actions of T cells, B cells and autoantibodies
27
What is autoinflammation? What are the main characteristics? How is it different from autoimmunity?
* seemingly spontaneous attacks of systemic inflammation
* no demonstrable source of infection as precipitating cause
* absence of high-titre autoantibodies and antigen specific autoreactive T cells
* No evidence of auto-antigenic exposure
28
Autoinflammation vs autoimmunity:
1. Innate or adaptive?
2. Main cellular involvement?
3. Antibody involvement?
4. Clinical features?
5. Conceptual understanding?
6. Main genetic susceptibility?
7. Therapy?
8. Examples?
Autoimmunity:
1. Adaptive immunity
2. B and T cells
3. Autoantibodies present
4. Continuous progression
5. Breaking of self-tolerance
6. MHC class II associations and adaptive response genes
7. Anti-B and T cells
8. Monogenic ALPS and IPEX, Polygenic RA and SLE
Autoinflammation:
1. Innate immunity
2. Neutrophils, macrophages
3. Few or no autoantibodies
4. Recurrent, often seemingly unprovoked attacks
5. Tissue-specific factors/danger signals
6. Cytokine and bacterial sensing pathways
7. Anti-cytokine (IL-1, TNF, IL-6)
8. Monogenic hereditary periodic fevers, polygenic Crohn’s disease, spondylarthropathies
29
Autoimmunity vs autoimmune disease?
Autoimmunity is present in all individuals; however, autoimmune disease occurs only in those individuals in whom the breakdown of one or more of the basic mechanisms regulating immune tolerance results in self-reactivity that can cause tissue damage.
30
How is tolerance involved in autoimmunity?
* T cell selection in **thymus** and B cell selection in **bone marrow**
* ****Normally autoimmune ones are destroyed and ones that aren't autoimmune are positively selected
* Failure of this 'tolerance' in autoimmunity
31
How is genetic predisposition involved in autoimmunity?
* Certain **HLA (MHC)** types select for certain self-antigens
* Other genes that regulate immune functions
32
How are antigenic factors involved in autoimmunity?
* Infections that trigger autoimmune responses
* Environmental triggers: UV light, smoking
* Alterations in self-proteins that increase their immunogenicity
33
Combination of factors of autoimmune diseases:
1. Genes
1. Born with **genes** but not with **disease**
2. Immune regulation
1. The immune system has many regulatory functions to shut down immune functions – tolerance of self is a dynamic state
3. Environment
1. Not born with disease - must be environmental triggers
34
What is tolerance?
Tolerance is the prevention of an immune response against a particular antigen. The immune system is generally tolerant of self-antigens, so it does not usually attack the body's own cells, tissues, and organs.
35
Where does T-cell central tolerance occur? Peripheral?
Central: Thymus
Peripheral: spleen, lymph nodes
36
Explain central-T cell selection in thymus
* As T cells are randomly generated in the thymus, they are tested against self antigens
* If they react to self antigens --\> deletion
* Inbetween (e.g. recognises self antigen weakly) --\> turned into a **regulatory T cell**
* Tregs control the immune response to self and foreign antigens and help prevent autoimmune disease.
* If doesn't react --\> positive selection
* Positively selected T cells move out to the periphery
37
What genes are MHC class I and II encoded by?
HLA genes
38
Where is MHC I found? What is it recognised by?
* Found on all nucleated cells
* Presents antigen to **CD8+ T cells** (cytotoxic)
39
Where is MHC II found? What is it recognised by?
* Found on dedicated APCs
* Presents antigen to CD4+ T helper cells (Th1 or Th2)
40
What is the only way in which T cells can recognise antigens?
Is presented to them either via MHC I or II
41
How can class II MHC genes predispose to autoimmunity?
MHC type that presents a particular autoantigen a bit better --\> susceptibility
42
What are the other causative associations with autoimmunity?
* Sex (hormonal influence)
* Women \>\> men
* Age
* Autoimmunity more common in elderly
* Sequestered (hidden away) Antigens
* May be recognised as foreign by the immune system (e.g. cell nucleus, eye, testis)
* Environmental triggers
* Infection
* Trauma-tissue damage
* Smoking
43
What is molecular mimicry?
the theoretical possibility that **sequence similarities between foreign and self-peptides** are sufficient to result in the cross-activation of **autoreactive T or B cells** by pathogen-derived peptides.
44
How is molecular mimicry seen in rheumatic fever?
Antibodies against M protein of Streptococcus also react against the glycoproteins of the heart
45
What is citrulline? What is result of citrullination of proteins? What disease is this important in?
* Citrulline is an amino acid (not encoded in genome as not used to make protein)
* Citrullination is the conversion of the amino acid **arginine** in a protein into the amino acid **citrulline** (**post translational**)
* Citrullination of proteins make them look more **foreign** --\> makes them more **immunogenic**
* ****Important in **rheumatoid arthritis**
46
What can failure to clear apoptotic debris lead to? What disease is this seen in?
Increases the availability of sequestered antigens inside the cell --\> higher chance of autoimmunity eg. systemic lupus erythamatosus
47
What is a typical organ specific autoimmune disease?
Autoimmune thyroid disease
48
What is organ specific autoimmunity?
* Affect a single organ
* Autoimmunity restricted to **autoantigens of that organ**
* Overlap with other organ specific diseases
49
What is systemic autoimmunity?
* Affect several organs simultaneously
* Autoimmunity associated with **autoantigens found in most cells of body**
* Overlap with other non-organ specific diseases
50
What diseases are typical of systemic autoimmunity?
Connective tissue diseases
51
**_Case 1_**
_History_
A 28-year-old woman with recent **tiredness** and **difficulty concentrating** had experienced a **decline in memory** over the last several months. She also noted **decreased frequency of bowel movements** and an **increased tendency to gain weight**. She felt **chilled** without light sweater, even in warm weather.
_Examination_
She was 5'5" tall and weighed 125 lb. Her pulse rate was **58 beats** per minute and her blood pressure was **138/88**. She had a slightly **puffy face** and her **eyebrows were sparse**, especially at the lateral margins. The deep tendon reflexes were normally contractive, but showed **delayed relaxation**.
What is disease?
Hypothyroidism
52
What autoimmune disease can lead to hypothyroidism?
Hashimotos thyroiditis
53
How does Hashimotos thyroiditis lead to hypothyroidism?
* Destruction of thyroid follicles by autoimmune process
* Associated with **autoantibodies to thyroglobulin** and to **thyroid peroxidase******
* CD4 T cell recognise antigens found in thyroid
* Autoreactive B cells and CD8 T cells
54
**_Case 2_**
_History_
30 yrs old women presents with **anxiety, weight loss, diarrhea** and **palpitations.** Although it is winter she **hardly notices cold weather.** She finds it almost **impossible to sleep** but despite this she seems to have **abundance of energy**.
_Examination_
She had **swollen red eyes**, **rapid pulse** and **sweaty hands**. She has **rapid reflexes**.
What is the disease?
Hyperthyroidism
55
What autoimmune disease can cause hyperthyroidism?
Grave's disease
56
How can Grave's disease lead to hyperthyroidism?
Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody --\> leads to hyperthyrodism
Autoantibody binds to TSH receptor on thyroid cell --\> overactive
57
**_Case 3_**
_History_
58 yrs old man presents with **difficulty keeping his eyes open**, **speaking** and **swallowing**. His family have noticed he **hardly smiles any more.** He finds that his problems are worse as the day progresses.
What is disease?
Myasthenia gravis
58
How is Myasthenia gravis caused?
Autoantibodies **block** the ACh receptor --\> error in the transmission of nerve impulses to muscles.
59
What is Myasthenia gravis?
A long-term neuromuscular disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, drooping eyelids, trouble talking, and trouble walking
60
**_Case 4_**
_History_
A Caucasian woman of 61 yrs has had **increasing fatigue** for 3 months, and **tingling in her feet** for 2 weeks. She has **vitiligo** and **FH of hypothyrodism.**
* Hb very low
* WBCs and platelets quite low
* Mean cell volume very high
What is disease?
pernicious anemia
61
What is MCV test?
Mean corpuscular volume. There are three main types of corpuscles (blood cells) in your blood–red blood cells, white blood cells, and platelets. An MCV blood test measures the average size of your red blood cells, also known as erythrocytes.
62
MCV in pernicious anaemia?
The MCV is higher than normal when red blood cells are larger than normal. This is called macrocytic anemia. Macrocytic anemia can be caused by: Vitamin B-12 deficiency. Pernicious anemia is a type of macrocytic anemia due to the body not being able to absorb vitamin B-12.
63
Who is most prone to macrocytic anaemia?
Elderly, vegans, and alcoholics
64
MCV in iron deficiency anaemia?
Low (microcytic anaemia)
65
How can MCV determine type of anaemia?
Low --\> iron deficiency (microcytic)
High --\> B12 deficiency (macrocytic)
66
What is needed for the absorption of B12?
Intrinsic factor
67
What is intrinsic factor produced by? How are these cells targeted in autoimmune?
Parietal cells in stomach - autoantibody can target this cell so no intrinsic factor and no B12 absorption
68
How can pernicious anaemia be treated?
B12 injection
69
Symptoms of SLE?
* Butterfly rash on face (photosensitive malar rash)
* Hair loss
* Joint pain (and swelling)
* Severe fatigue
* Headaches
* Anaemia
* Mouth ulcers
* Roof of mouth
70
How can SLE manifest as pleural effusion?
SLE causes inflammation on lining of lungs --\> causes fluid build up around lungs --\> patient breathless
71
What does SLE stand for?
Systemic Lupus Erythematosus
72
Mechanism of SLE?
* **Antinuclear** antibodies --\> i.e. antibodies form against many different molecules in the cell nucleus:
* ddDNA
* dsDNA
* Ribosomes
* Histones
* Nuclear self-antigens are normally always intracellular, so shielded from the immune system – **sequestered antigens**
* In cell death by **apoptosis** nuclear material is digested and cleared
* In cell death by **necrosis** nuclear antigens may not be cleared and may then act as **antigens to the immune system**
* ****Some people have genetic defects in mechanisms to clear cell debris
73
Why is the sun bad for lupus patients?
Many people with lupus experience photosensitivity or unusual sensitivity to sunlight. This can trigger symptoms such as skin rashes, itching, and burning. Excess sun exposure can also cause flares in systemic lupus, triggering symptoms such as joint pain, weakness, and fatigue.
In people with lupus, the cells are much more sensitive to the damage caused by UV radiation --\> UV light causes DNA damage, and cell death
74
How are immune complexes involved in some autoimmune diseases?
* Antibodies against the antigens in the nucleus combine with their targets to form **IMMUNE COMPLEXES** in the circulation
* Immune complexes **deposit** in any organ (e.g. kidney) – activate **complement** and cause **inflammation**
75
Type II vs type III hypersensitivity reactions?
* Type II --\> involve IgG and IgM antibodies directed against cellular antigens
* Type III --\> involve the interactions of IgG, IgM, and, occasionally, IgA1 antibodies with antigen to form immune complexes.
76
How can immune complex deposition lead to renal failure (lupus nephritis)?
1. Immune complex deposition
2. Inflammation
3. Leaky glomerulus
4. Loss of renal function
5. Scarring (now it is irreversible)
6. Irreversible renal failure
77
Examples of overlapping 'connective tissue' diseases?
* Systemic lupus erythematosus
* Scleroderma
* Polymyositis
* Sjogrens syndrome
* Ubiquitous antigens (components of the cell nucleus) cause multisystem inflammation
