The Blood and Body Defences

Question 1

Give examples of three major forms of myeloproliferative neoplasms

Answer 1

Polycythemia Vera = an excess of red blood cells in circulation

Essential Thrombocythemia = an excess of platelets

Idiopathic Myelofibrosis = Too few RBC, too many platelets and WBCs

Question 2

What is Polycythemia?

Answer 2

An excess of RBC in circulation.

Clinical Signs: Breathing difficulties, dizziness, excessive bleeding, splenomegaly, headache, itchiness, red coloring (especially face), shortness of breath, symptoms of phlebitis

Question 3

What is Primary Polycythemia?

Answer 3

Primarily familial and congenital polycythemia: due to enhanced responsiveness to EPO due to mutations in EPOR.

JACK2V617F

Question 4

What is Polycythemia Rubra Vera (PV)?

Answer 4

Most commonly associated with JAK2V617F mutation; increased RBC, white blood cells & platelet production; may lead to myelofibrosis and acute leukemia.

Question 5

What is Secondary Polycythemia?

Answer 5

Occurs due to conditions that promote RBC development:

1. Hypoxia (due to COPD, kidney transplant - kidneys being a major source of EPO)
2. EPO secreting tumours e.g. renal cell carcinoma, hepatocellular carcinoma
3. Neonatal Polycythemia - seen in 1-5% of neonates, due to maternal DBC transfusion after intrauterine hypoxia.

Question 6

What is Relative Polycythemia?

Answer 6

RBCs normal but reduced plasma volume; this is due to dehydration, severe vomiting.

Question 7

What are the clinical signs of essential thrombocythemia?

Answer 7

• Frequently asymptomatic; hemorrhage or thrombosis; occasional progression to MF and leukemia.

Question 8

What are the clinical signs of Idiopathic Myelofibrosis?

Answer 8

leukoerythroblastic blood picture, splenomegaly and bone marrow fibrosis, anaemia, thrombocythemia or thrombocytopenia and variable white cell counts; unusual progression to acte leukemia.

Question 9

What is the JAK2 gene?

Answer 9

The JAK2 gene is a member of a family of four Janus Kinases, 1 2 and 3 and tyrosine kinase 2.

These are non-receptor kinases.

Question 10

What does the V617F mutation do?

Answer 10

Mutation of the auto-inhibitory domain makes JAK2 constitutively active in the absence of ligand binding.

Question 11

Describe Type I Hypersensitivity

Answer 11

Question 12

Type 1 = basically allergies.

Can be minor (like hay fever) or major (anaphylaxis).

Fc receptors on mast cells can be detected by the IgE antibody. Mast cells have a lot of Fc receptors that recognise IgE molecules.

So when IgE binds to Fc receptor, it can cross link with other molecules. If this happen, binding is stronger, causing degranulation of mast cell.

But if this happens too much - in multiple cells, in multiple organs, resulting in the production of histamine and other inflammatory mediators, it can be life threatening. This is called a type 1 hypersensitivity response.

These massive allergic responses occur not first time of exposure but second time. Because second time round, your body has made very strong IgE responses against these molecules.

Individuals predisposed to genetically produce more IgE than required are termed atopic individuals.

Question 13

What are the pathological consequences of mast cell degranulation?

Answer 13

GI tract - increased fluid secretion, increased peristalsis = explosion of gastrointestinal tract contents.

Airways - decreased diameter, increased mucus secretion = explosion of airway contents (phlegm, coughing)

Blood Vessels = increased blood flow = increased permeability = edema, inflammation, increased lymph flow and carriage of antigen to lymph nodes.

Question 14

What is Type II Hypersensitivity?

Answer 14

Type II Hypersensitivity is antibody and complement dependent mechanism of killing.

Uses IgG, complement, targeting cell surfaces.

1. Antibody binds antigens on the surface of target cells.
2. Fc receptors on NK cells recognise bound antibody.
3. Crosslinking of Fc receptors signals the NK cell to kill the target cell.

Question 15

What is Type III Hypersensitivity?

Answer 15

• Also IgG.
• Also involves complement and phagocytes.
• Soluble molecules are target of the antibodies.
• Another word for Type III Hypersensitivity = immune complex disease.

Question 16

Explain the mechanism of Type III hypersensitivity

Answer 16

Mechanism

1. Locally injected antigen to immune individual with IgG antibody.
2. Local immune-complex
3. Activation of complement releases inflammatory mediators, C5a, C3a and C4a. C5a also induces mast-cell degranulation.
4. Local inflammation, movement of fluid and protein into tissue and blood vessel occlusion.

Question 17

Explain Type III immune complex-mediated diseases (T3 hypersensitivity)

Answer 17

1) You have an environment with excess antigens and antibodies.
2) Formation of immune complexes with slight antigen excess.
3) Complement is activated by the immune complexes via the classical pathway. This causes basophils to degranulate, releasing mediators that increase vascular permeability
4) Complexes circulate and are trapped in the basement membrane of small blood vessels.
5) Activated complement attracts neutrophils and causes them to degranulate.
6) Neutrophils release enzymes for much of the tissue damage.

E.g. lupus, eczema

Question 18

Explain Type IV (delayed) Hypersensitivity

Answer 18

1. Antigen is introduced into subcutaneous into subcutaneous tissue and processed by local antigen-presenting cells.
2. A th1 effector cell recognises antigen and released cytokines which act on vascular endothelium
3. Recruitment of T cells, phagocytes, fluid and protein to site of antigen injection causes visible lesion

24-72 hours

Question 19

In the context of chronic ganulomatous disease, explain primary immunodeficiency

Answer 19

• Basically its a primary phagocytic disease.
• Chronic granulomatous disease - x linked - mutations affecting phagocyte oxidase systems

Histopathology: presence of granulomas

Clincal Signs: impetigo, skin and rectal absecces,

Question 20

What is chronic granulomatous disease

Answer 20

Question 21

What drugs can be used to target immunity in therapeutic applications?

Answer 21

Question 22

What is the phagocyte NADPH oxidase?

Answer 22

Under normal circumstances, the complex is latent in neutrophils and is activated to assemble in the membranes during respiratory burst.

NADPH oxidase generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling these to molecular oxygen to produce superoxide anion, a reactive free-radical.

Superoxide can be produced in phagosomes, which contain ingested bacteria and fungi, or it can be produced outside of the cell. In a phagosome, superoxide can spontaneously form hydrogen peroxide that will undergo further reactions to generate reactive oxygen species (ROS).

Question 23

What is the impact of HIV associated immunodeficiency?

Answer 23

Question 24

How can naieve T cells differentiate?

Answer 24

Question 25

What can too much / too little of a B/T cell response result in?

Answer 25

**Too much:** Acute lymphoblastic Leukemia of B or T cells **Too Little:** Insufficient T or B cell response to recognise and kill the tumour cells.

Question 26

What is autoinflammation/autoimmunity?

Answer 26

**Autoinflammation =** when phagocytes do what they do long after acute inflammation. **Autoimmunity -** where we just have too much recognition by the acquired immune response.

Question 27

What are the therapeutic interventions in autoimmune and autoinflammatory diseases?

Answer 27

Question 28

Give some examples of autoinflammation:

Answer 28

Question 29

What is molecular mimicry?

Answer 29

- Aberrant immune activation against self antigen triggered by the presence of a foreign antigen that shares molecular or antigenic properties with self. Tolerance is a fundamental property of the immune system. Tolerance involves non-self discrimination which is the ability of the normal immune system to recognize and respond to foreign antigens, but not self antigens. Autoimmunity is evoked when this tolerance to self antigen is broken. Tolerance within an individual is normally evoked as a fetus. This is known as maternal-fetal tolerance where B cells expressing receptors specific for a particular antigen enter the circulation of the developing fetus via the placenta. After pre-B cells leave the bone marrow where they are synthesized, they are moved to the bone marrow where the maturation of B cells occurs. It is here where the first wave of B cell tolerance arises. Within the bone marrow, pre-B cells will encounter various self and foreign antigens present in the thymus that enter the thymus from peripheral sites via the circulatory system. Within the thymus, pre-T cells undergo a selection process where they must be positively selected and should avoid negative selection. B cells that bind with low avidity to self-MHC receptors are positively selected for maturation, those that do not die by apoptosis. Cells that survive positive selection, but bind strongly to self-antigens are negatively selected also by active induction of apoptosis. This negative selection is known as clonal deletion, one of the mechanisms for B cell tolerance. Approximately 99 percent of pre-B cells within the thymus are negatively selected. Only approximately 1 percent are positively selected for maturity.

Question 30

What is bystander activation?

Answer 30

i.e. the stimulation of unrelated (heterologous) T cells by cytokines during an Ag-specific T cell response, specific to CD8 cells

Question 31

What are protein changes, cryptic antigens?

Answer 31

They are a source of autoimmunity. Self epitopes, which are found in high concentration on the surface of antigen-presenting cells (APC's) in association with its major histocompatibility complex (MHC) are known as dominant epitopes. These are stimulants of negative selection mechanisms to remove potentially self destructing autoreactive T cells. Their "self" antigens are displayed to a developing T-cell and signal those "self-reactive" T-cells to die via programmed cell death (apoptosis) and thereby deletion from the T cell repertoire, preventing autoimmunity. However, self epitopes which appear in very low concentration on APC are termed cryptic in the sense that they do not delete autoreactive T-cells which will then join the peripheral adult T cell repertoire. This causes autoimmunity in the body.