- Name some common allergens associated with extrinsic allergic alveolitis and the disease that they cause.
A table to show common allergens associated with extrinsic allergic alveolitis, including
the disease and the source (micro-organisms).
A table to show common allergens associated with extrinsic allergic alveolitis, including
the disease and the source (animal antigens).
There are also other causes of extrinsic allergic alveolitis which are by chemicals used in paint and fungicide, these antigens cause paint sprayer’s lung and vineyard sprayer’s lung.
- Are you more or less likely to get extrinsic allergic alveolitis if you smoke? Explain your answer.
Smoking has been inversely related to extrinsic allergic alveolitis. If you smoke the risk of developing extrinsic allergic alveolitis has been shown to be lower than that of a non-smoker. The precipitating antibodies of extrinsic allergic alveolitis are less common in smokers than non smokers. It is unknown to why this is; it is possibly down to the physical impairment of alveolar macrophage phagocytosis and antigen presentation common in smokers.
Case study 2. Severe Combined Immunodeficiency (SCID).
- SCID has many known genetic causes. Describe the 5 most common conditions including the functional defect, pathogenesis and inheritance.
The defining pathological feature of SCID is a defect in the white blood cells (B- and T-lymphocytes) that defend us from infection by viruses, bacteria and fungi. Due to a compromised immune system SCID patients are susceptible to recurrent infections such as pneumonia, meningitis and chicken pox. As a result of these recurrent infections patients can die before the first year of life. There are many different causes of SCID and all of them are inherited either by X linked inheritance or autosomal recessive inheritance.
X linked cause of SCID.
The main and most common cause of this disorder is the X linked form known as SCID – X1. This is caused from mutations in one of the genes on the X chromosome known as the IL2RG. It is this gene which is responsible for creating the component of the receptor which lies on the surface of a lymphocyte that transmit information to the lymphocytes to mature and fight infection activated by chemical messengers called cytokines. The area of the lymphocyte receptor that has the defect is in the "common" gamma chain (γ). This is an important component for the mobilisation of the immune systems defences for the fight against infection. The γ chain is a component of the lymphocyte receptors for several cytokines and the interleukin-2 (IL-2) receptor. Defects in the γ chain of the IL-2 receptors result in an absence of the T- and natural killer cell maturation; although the B- lymphocyte count may be normal, despite this there function is very poor. This may give evidence that suggest the γ chain also plays a role in the development of the B-cell.
SCID – X1 affects only males and the overall incidence of SCID is higher in males than in females. This is due to females having two X chromosomes so if there is a defect or mutation that defects the IL2RG on one of the X chromosomes the other X chromosome has a spare normal gene that can compensate for the mutation. This would result in the female having a normal functioning immune system.
However, since males have only one X chromosome and one Y chromosome, they do not have a spare IL2RG gene. If the male has the defective IL2RG gene the γ chain of the receptor will be defective and the receptors will be unable to respond to any immune response and SCID sets in.
Deficiency of Janus Kinase 3 (Jak3).
Similar to SCID – X1 is the deficiency of the Janus Kinase 3 (Jak3). However as this is an autosomal recessive trait both male and female can be affected. This form of SCID accounts for less than 10% of all cases of the disorder. It caused by a mutation in a gene on chromosome 19. This gene encodes for the Jak3 enzyme which is necessary for the function of the γ chain. Sufferers of this form have the same T- cell, B-cell and NK lymphocyte counts as SCID-X1.
Deficiency in Adenosine Deaminase ADA SCID.
Caused by a mutation on a gene that encodes for the enzyme adenosine deaminase (ADA) which is an essential enzyme for a variety of body cells to produce new DNA and metabolic function. The ADA also breaks down toxic metabolites which are harmful to T- lymphocytes. If there is an absence of this enzyme the toxic products accumulate within the lymphocyte and cause them to die. This affects approximately 20% of all cases of SCID and babies with this form of SCID have the lowest lymphocyte count with T- cell, B-cell and NK lymphocyte all being very low. This form of SCID is also an autosomal recessive trait. Babies affected with this form of SCID often have to take antibiotics and infusions of antibodies to help them protect themselves against serious infections. Treatment of this can also involve adenosine deaminase injections given once or twice a week. Similar to the ADA deficiency is a deficiency in Purine nucleoside phosphorylase (PNP). The mechanics of this deficiency are similar to that of the ADA deficiency; however this causes an accumulation of deoxyguanosine triphosphate which in turn exerts a lymphotoxic effect in the body. In both deficiencies it is the function of the T- cell that is most severely affected.
Deficiency if the alpha chain (α) of the IL-7 receptor.
Another autosomal recessive trait with the mutation in a gene on chromosome 5. This gene encodes the alpha chain of the IL-7 receptor (IL-7Rα). With this form of SCID there are B- cells and NK lymphocytes but there are no T- cells. The function of the B- cells is affected due to there being no T- cells. This form accounts for approximately 5% of SCID cases.
Recombinase activating gene abnormality.
B- cell and T- cell maturation involve recombination. This is when various combinations of these variable genes assemble to form unique and specific new antigen receptors. Mutations in the genes that encode for the Recombinase activating genes 1 and 2 (RAG1/RAG2) on chromosome 11 necessary for the development of antigen receptors on the T- and B- cells, result in a combined absence of T- and B- cells but have NK lymphocytes. This form of SCID is an autosomal recessive trait.
- Chris had X- linked T- B + SCID as shown by IL-2 receptor deficiency (γ chain). Describe the structure and function of the IL-2 receptor.
The IL-2 receptor is made up of three chains the α, β, and the γ chains. In cases of resting T- cells a form of this receptor composed of just the β and γ chains is expressed which will bind to IL-2 with moderate affinity. This allows the resting T-cells to respond to very high concentrations of IL-2. When the form of the receptor is expressed associated with the α, β, and γ gamma chains the receptor has a much higher affinity for the IL-2. This causes the IL-2 receptor to respond to much lower concentrations of IL-2. It is when binding to the high affinity receptor the progression through the rest of the cycle is triggered. The function of the IL-2 receptor is to attract the IL-2 to the T- cell to activate the cell to divide rapidly to produce armed effector T-cells.
Fig. 2. Shows the high affinity IL-2 receptor with all three chains produced on an activated T-cell with the IL-2 binding to the cell.
- Describe the treatment of T- B + SCID- X1.
The first approach would be to treat and control any current infections by placing the patient in a sterile environment. One way this is done is by using an isolator crib”bubble”. The child would be kept free from any possible infections but as the child grew the bubble would have to grow. However the most effective treatment would be a bone marrow transplant with a compatible donor. The stem cells in the bone marrow live for a long period as they can renew themselves when they are needed to and they produce a continuous supply of healthy immune cells. Transplants that are performed in within the first three months of life have the highest success rate.
Barry Hollinshead.
References.
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Warren. C. P. “Extrinsic allergic alveolitis: a disease commoner in non-smokers”. Thorax, Vol 32, 567-569. 1977.
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Anon. “Severe Combined Immunodeficiency”. IDF patient/family handbook. .
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Anon. The SCID homepage. “Missing body defense systems” . visited 24/03/2006.