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MD4001 Week 11 > 2. Immunology: the immune response, auto-immunity, white blood cells > Flashcards

2. Immunology: the immune response, auto-immunity, white blood cells Flashcards

1
Q

What is the tissue response to injury?

A

Tissue damage + cell death
–>
Acute inflammation. This leads to one of the followingL
1. Cells repopulate –> Tissue regeneration –> Restoration of normal function
2. Cells cannot repopulate –> Healing by repair –> Scar formation and loss of specialised function
3. Damage or agent persists–> Chronic inflammation –> Damage or agent is overcome? If yes the repair by healing. If no then chronic inflammation continues.

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2
Q

What is the mechanism for exudate formation in acute inflammation?

A
  1. Transient constriction – lasting for a few minutes after injury
  2. Followed by widespread vasodilation (10 - 15 min after injury)
  3. Up to 10-fold increase in blood flow-rate
  4. Slowing of blood flow-rate to normal
  5. Stasis – due to increased viscosity in microcirculation caused by loss of fluid 6. White cells line up on walls of vessels ( ‘margination’)
  6. Movement of cells into extravascular compartment ( ‘emigration’)
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3
Q

What are the 3 types of response that lead to increased vascular permeability?

A
  1. Immediate Transitory Response
    Caused by chemical mediators, primarily histamine
    Occurs within 15 – 30 mins
    Protein-rich exudate leaves blood vessels at site of injury Leakage occurs through ‘gaps’ between endothelial cells of venules
  2. Immediate Persistant Response
    Severe injury such as a burn – causing direct damage to endothelial cells Leakage peaks at around 1h after injury
  3. Delayed Persistant Response
    Leakage from venules and capillaries occurs at times up to 24hrs
    Aggregates of platelets and endothelial cells seen in some capillaries e.g. Sun-burn
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4
Q

What are the cell derived chemical mediators for inflammation?

A

• Histamine is the main pre-formed mediator (released from mast cells, basophils
and platelets)
• Other mediators are actively synthesized in various cell types: prostaglandins,
leukotrienes, platelet-activating factor, cytokines (e.g. IL-1, IL-8, tumour necrosisfactor-TNF,nitricoxide)

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5
Q

What are the plasma derived mediators for inflammation?

A

• Gain access to damaged area via exudate
• Activated by proteolytic enzymes – short half-lives in tissue (broken down)
e.g. bradykinin (activated Hageman factor), plasmin, complement C3a, C3b, C345, C5a (activated by Ab-Ag reaction)

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6
Q

Where are mediators derived from?

A

Cells or plasma

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7
Q

signs of acute inflammation?

A

Causes redness, swelling, heating, and pain

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8
Q

Main 3 effects of chemical mediators?

A

vascular permeability, chemotaxis and induce fever

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9
Q

Role of neutrophil in acute inflammation? Where? Produce?

A

Neutrophil accumulation in the extracellular space is the diagnostic feature of acute inflammation. Have short life-span once activated

Role:
Kill invading organisms
Degrade necrotic tissueIngest offending agents

Produce:
Produce chemical mediators
Produce toxic oxygen radicals Produce tissue damaging enzymes

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10
Q

Role of endothelial cells in acute inflammation?

A

Once activated they
synthesize and secrete numerous regulatory molecules
• Endothelial cells of local vessels are activated by products of tissue damage
and by cytokines (e.g. IL-1 and TNF)
• This induces expression of cell surface adhesion molecules which interact with complementary molecules in neutrophil cell membrane

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11
Q

Neutrophils are recruited to the damaged region of tissue via endothelium of local vessels. This involves several steps:

A
  • Margination
  • Adhesion
  • Emigration
  • Chemotaxis
  • Phagocytosis
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12
Q

What is involved in the emigration step of tissue damage response?

A
  • Leukocytes (neutrophils, basophils, eosinophils, macrophages, and lymphocytes) can escape from venules (less often from capillaries)
  • Emigration occurs by amoeboid movement (between 2 – 9 min) to pass through vessel wall
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13
Q

What is involved in the chemotaxis step of tissue damage response?

A
  • Cells attracted to chemotactic agents e.g. prostaglandins, leukotreines (products of arachadonic acid metabolism), and complement C5a
  • Chemotactic agent binds to specific surface receptors on leukocyte membrane • Causes increased ionised calcium within the cytoplasm which promotes construction of contractile elements (actin and myosin) responsible for cell movement
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14
Q

What is involved in the phagocytosis step of tissue damage response?

A

• Once arrived at damage site, neutrophils and later macrophages
injest bacteria and debris – process called ‘phagocytosis’
• Bacteria are coated with plasma proteins called Opsonins-promote adhesion between the bacterium and phagocyte cell membrane

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15
Q

Role of E-selection?

Aka Endothelial leukocyte adhesion molecule 1 (ELAM-1)

A

Binds to a complex carbohydrate celled ‘SialyLewisX’ present on neutrophils and monocytes (about 2-4h after stimulation and
expressed for 24h)

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16
Q

Different types of opsonin?

A

3 types of opsonin:
• Specific antibodies of IgG class
• Activated complement C3b and its inactive form C3bi
• Plasma fibronectin

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17
Q

Name 4 examples of chronic inflammation?

A
  1. Extension of acute inflammation:
    Ulcer or abcess
  2. Persistent injury:
    Embedded bullet, splinter etc. (resistant to phagocytosis and lysosomal enzymes)
  3. Recurrent injury:
    Inhalation of smoke, asbestos, silica causing lung damage
  4. Persistant infection:
    - May occur from bacterial or fungal pathogens e.g. Mycobacterium tuberculosis (bacterium causing TB)
    - Some may evade immune defence as intracellular pathogens e.g. Mycobacterium leprae (leprosy)
    - Conditions associated with poor nutrition, poor circulation, cancer or some immunosuppressive drugs
  5. Recurrent antigen exposure:
    May lead to hypersensitivity and autoimmunity e.g. asthma, sarcoidosis (epithelial granulomas), rheumatoid arthritis
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18
Q

Role of macrophages in chronic inflammation?

A

Derived from monocytes

During chronic inflammation there is continued recruitment from circulation, due to expression of adhesion molecules on endothelial cell membranes in response to cytokines (e.g. IL-1)
Macrophages become ‘activated’ (due to interferon-γ) and enlarge

Multinucleate giant cells may fuse further macrophages and develop into giant Langhan’s cells

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19
Q

Cells involved in chronic inflammation?

A 
T lymphocytes
Plasma cells
Neutrophils
Eosinophils 
Fibroblasts
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20
Q

Role of t cells in chronic inflammation

A

Secrete cytokines that are chemotactic for monocytes, activate macrophages and fibroblasts, provide cell mediated immunity

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21
Q

Role of plasma cells in chronic inflammation

A

(derived from B-lymphocytes) produce large amounts of immunoglobulin

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22
Q

Role of neutrophils cells in chronic inflammation

A

may be present in large numbers, esp. in response to recurrent or continuing infections

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23
Q

Role of eosinophils cells in chronic inflammation

A

esp. in parasitic infections. Secrete major basic protein that is toxic to parasite but can cause local tissue destruction

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24
Q

Role of fibroblasts cells in chronic inflammation

A

Present during ‘repair’of damaged tissue produce collagen fibres – leads to ‘scar’ formation

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25
Q

What is present in the histology of TB?

A

Caseous necrosis containing tubercle bacilli
Epithelioid macrophages
Langhan’s giant cells

26
Q

Name examples of chronic inflammatory disorders?

A

TB: caused by inhaled bacilli of Mycobacterium tuberculosis

Syphilis: Caused by the spirochaete Treponema pallidum

Leprosy: Primary chronic inflammatory disorder. Limbs damaged due to insensitivity

27
Q

Progression of syphilis

A

• Primary lesion is genital ‘chancre’ (a reddened nodule due to high
concentration of plasma cells and lymphocytes)
• Progresses in stages via widespread secondary rash to tertiary disease
and formation of ‘gumma’ (foci of infection in other organs)

28
Q

Cause of leprosy?

A

Bacillus mycobacterium

29
Q

Examples of the different forms of arthritis?

A

Ankylosing spondylitis, antiphospholipid syndrome, Bechet’s syndrome, carpal tunnel syndrome, fibromyalgia, lupus, osteoarthritis, osteomalacia (rickets), osteoporosis, Paget’s disease, psoriasis, reactive arthritis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, vasculitis. out all this l

30
Q

What is rheumatoid arthritis?

A

Chronic, systemic autoimmune disease

Characterized by: Inflammation of the lining, or synovium, of the joints.

Leads to –> long-term joint damage
–> chronic pain, loss of function, and disability

31
Q

Epidemiology of rheumatoid arthritis?

A

Affects over 350,000 people in UK

More women x 3

30-50yrs

32
Q

Rheumatoid arthritis symptoms?

A

•Inflamed joints that are warm, tender, swollen, often red and painful, and
difficult to move
•Fatigue
•Loss of appetite, weight loss, flu-like symptoms, depression, anemia
•Vasculitis
•Sjogren’s syndrome: Disorder of immune system, often presents as dry mouth and eyes
•Inflammation surrounding heart and lungs

33
Q 
Effect of RA on:
Foot/ankle/knee?
Hip?
Hands and wrists?
Elbow?
Shoulders?
A

Foot and Ankle, Knee: Effusions and synovial thickening of the knee usually are detected easily.

Hip: involvement is common in RA, but early manifestations are not apparent.

Hands and Wrists: affected in virtually all people with RA.

Elbow: Effusion difficult to detect on physical exam. Only objective finding is loss of motion.

Shoulders: Neck stiffness and general loss of motion

34
Q

Impact of RA on blood?

A

Hypochromatic-microcytic anaemia with low ferritin low/normal iron-binding capacity

35
Q

Effect of RA on nerves?

A

Results from cervical spine instability, peripheral nerve entrapment and vasculitis
–> Mononeuritis multiplex

36
Q

Effect of RA on the heart?

A

Pericardial effusion in 50% of patients

37
Q

Effect of RA on the lungs?

A

Interstitial lung disease common, but may be asymptomatic

38
Q

Effect of RA on the lungs?

A

Keratoconjunctivitis sicca, episcleritis, scleritis

39
Q

Effect of RA on the skin?

A

Rheumatoid nodules in 50% of RA patients; dermal vasculitic lesions

40
Q

Mechanism of antigen recognition by t cells?

A

Major histocompatibilty complex (MHC): are membrane glycoproteins on the cell surface that display peptide antigens to T cells

41
Q

What is MHC II?

A

•MHC II: bind peptides from extracellular sources that have been internalised into intracellular vesicles
(DC, macrophage or phagocytic cells and B cells)
– Class II MHC presents peptides to CD4+ T-helper (TH) Cells

42
Q

Difference between Th1 and Th2 products?

Note these are both types of CD4 T cells

A

Th1 cytokines produce cell mediated immunity by producing macrophage activating cytokines

Th2 produce antibody responses by producing b-cell activating cytokines

43
Q

What is the relationship between genetics, RA and the immune system?

A

•Specific human leukocyte antigen (HLA)-DR genes have been found to be associated with RA
–HLA-DR4 (two-thirds of Caucasians with RA)

HLA-DR4 reside int he MHC and participate in antigen presentation –> Higher risk of severity of disease and increased homozygosity

44
Q

What are the potential roles of HLA-DR genes?

A

–Binds to arthritogenic peptides

–Serves as a target for autoreactive T cells –Closely linked to other genes in the MHC

45
Q

Mechanism of auto immunity?

A

= Immune-mediated destruction of self-tissues

–Occurs via specific recognition of self-antigens
–Specific activation of self- reactive lymphocytes by
self-antigens
–Regulatory T (Treg) cells
help mediate autoimmunity
by suppressing autoreactive T cells by secreting inhibitory cytokines such as IL-10 and TGF-Beta

46
Q

Examples of autoimmune diseases?

A 
T1DM
Goodpasture's syndrome
MS
Grave's disease
Hastimoto's thyroiditis
Autoimmune pernicious anaemia
Autoimmune addison's disease
Vitiligo
Myasthenia gravis
47
Q

What is “tolerance”?

A

The process that keeps the immune system from attacking self

2 forms: Deletional (recessive) and regulatory (dominant)

48
Q

What is deletional tolerance?

A

Recessive form

Self reactive T cells are delated in the thymus. Occasional self-reative t cells may escape deletion
In the periphery such escaped self-reactive T cells can cause tissue damage

49
Q

What is regulatory tolerance?

A

Dominant form

T cell specific for self-antigen becomes a regulatory t cell (T reg)
Cytokines (IL10 and TGF-beta) produced by T reg inhibit other self-reactive T cells

50
Q

What are cytokines?

A

Proteins made by cells that impact other cell behaviour (i.e. interleukins)

51
Q

What are chemokines?

A

Small chemoattractant proteins that sitmulate the migration and activation of cells

52
Q

Role of synovial fibroblasts in RA?

A 
Synovial fibroblasts (activated by IL-1 and TNF-alpha) invade cartilage and bones.
Here they regulate monocyte differentiation into osteoclasts
53
Q

What lab tests are used in RA?

A

•Lab tests
–Imaging studies – Erythrocyte Sedimation Rate –Blood tests – C-reactive Protein (CRP) –Rheumatoid factor – Antinuclear Antibodies (ANA)

54
Q

What are the treatments focuses for RA?

A

–relieving pain
–reducing inflammation
–stopping or slowing joint damage
–improving functioning and sense of well-being

55
Q

What are the different RA meds:

  • Symptomatic?
  • Disease modifying?
  • Biological modifiers?
A

•Symptomatic Medications
–Nonsteroidal anti-inflammatory drugs (NSAIDs)
–Analgesics
–Corticosteroids

•Disease Modifying Drugs 
–Methotrexate
–Sulfasalazine– Azathioprine –Cyclosporine 
– Hydroxychloroquine 
–Minocycline

•Biologic Modifiers
–Infliximab (anti-TNF) - Rituximab (anti-CD20) •Combination DMARD Therapy

56
Q

What is ankylosing spondylitis (AS)?

Epidemiology?

A

Chronic inflammatory arthritis
predominantly affecting the joints of the spine
Affects males more than females (3:1), ie reverse of usual higher incidence of autoimmune conditions affecting females.

57
Q

AS treatment?

A
  1. NSAID. Aspirin, ibuprofen,
    indomethacin,
    Diclofenac, ketoprofen (COX-2 inhibitors, but many withdrawn)
  2. Anti-TNF mAb (infliximab) has proved very effective.
58
Q

HLA-B26 linked to…

A

Ank Spond
+
ReA (reactive arthritis)

59
Q

Triggers for Reactive arthritis?

A

Bacterial infection usually of the gut or urinary tract e.g. (salmonella, camplyobactera, chlamydia)

60
Q

Theory behind HLA-B27 and Ankylosing spondylitis link>

A
  • Peptides- a peptide from a bacteria is presented by B27. This peptide looks like a host peptide in the spine. Autoreactive T cells target this joint. (however in the animal model you can remove the CD8 T cells and still get disease)
  • B27 misfolds insides cells and causes cells to be stressed and secrete cytokines. Or misfolded B27 at cell surface is recognised incorrectly by Natural Killer cells.
61
Q

Genetic links of Ra and AS?

A

RA= HLA-DR4

AS= HLA-B27

62
Q 
What is coeliacs disease?
Presentation?
Onset?
Cause?
Management?
A

Coeliac disease =gut condition where small intestines become inflamed

Presentation:
Diarrhoea, abdominal pain, bloating (complications include osteoporosis, iron-, vitamin B12-, folate-deficiency anaemia, bowel cancer)

Onset:
• Incidence around 1 in 100 in UK. 2-3 x higher in females.
• Onset – within first year (diagnosis may take longer).
Adulthood 40-60 years.

Cause?
• Driven by autoimmune reaction to gluten (wheat, barley, rye)

Management?
• No cure – gluten free diet (first degree relatives should also be tested)

MD4001 Week 11 (7 decks)

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