Immunology sheet # 11 - Suhaib 3ttiyeh

بسم الله الرحمن الرحيم
Today we will take about tolerance & autoimmunity.
*Tolerance:
Tolerance can be established centrally at the level of B & T-lymphocytes.
T-cells are introduced to self or non-self antigen but usually to self so during immunological maturity lymphocytes can be educated to recognize self.
B-lymphocytes are also susceptible to establish tolerance centrally but they differ from T-lymphocytes by the chance to change their receptor (receptor deleting).
Tolerance can be established at the peripheral level if central tolerance mechanism fails (B-cell tolerance).
• Mechanisms of peripheral tolerance:
1- lack of co-stimulatory molecule /signal or signal 2 :
B-cell tolerance can be broken so T-cell tolerance is more efficient than B-cell tolerance.
2- Activation induced cell death:
a- Not specific for antigen
b- Vast majority of activated calls die (active cells are removed) because space is needed & if they remain they cause damage
3- Immune deviation:
a- High dose & low affinity -------- TH2
b- Low dose & high affinity ---------TH1
And this is known as immune deviation were the activation deviates toward one of the cells depending on the amount of the dose & the affinity which means if antigen is introduced in high dose & low affinity this will result in activation of TH2 &thustolerance at the level of TH1 & vice versa.
Activation of TH1 in some diseases may lead to the cure in which activation of TH2 will lead to the progression & vice versa activation of TH2 may lead to the cure of some diseases in which activation of TH1 will lead to the progression of the disease so the type of T helper cell activated has the major effect on the disease so this is an important mechanism in avoiding self destruction.
4- CD8+ T-cells tolerance:
a- This tolerance is different from the central tolerance.
b- CD8 & anti-CD8 interaction can take place by cells known as veto cells for example if you have T-cell that can respond to certain antigen you can block this response by another T-cell known as veto or silencing T-cell so one is responding the other is blocking(regulatory)
Tolerance can be induced therapeutically in many cases as in organ transplantation & induction of tolerance means peripheral tolerance.
We should induce specific amount of the antigen (optimum dose) because induction of more or less (if wide deviation) will result in no response (no antibodies production).
There’s table in the slides shows what prefers induction of tolerance & what prefers induction of immune response. For example considering the differentiation state of cells; fully differentiated cells induce an immune response& undifferentiated cells will undergo tolerance (other examples are included in the slides).
Good example where it’s important to induce tolerance is in the cases of mother with RH- that has anew born with RH+ blood (RH antigen is composed of six subunits CcDdEe the most important is the D which can cause hemolytic disease in the new born & if we says it’s RH+ we mean D+ or D {capital}) so the mother may produce antibodies & as the RH are carried on IgG it crosses the maternal barrier & lead to hemolytic disease in the new born by destroying his RBCs. The antibodies are produced in the first pregnancy in process known as sensitization. In the second pregnancy these antibodies destroy the RBCs of the new born & kill him. One mechanism to inhibit this is to inject the mother by anti-RH (anti-D) antibodies early after delivery of the first new born & these antibodies can establish a state of tolerance.
Any individual loses the tolerance has increased risk of autoimmunity not necessarily disease but also autoimmune response.
So tolerance is specific acquired unresponsiveness that is subjected to go (it can fail).
• Sites & tissues of no responsiveness (tolerance):
1- Immunologically privilege sites: sites where no immunological response occur & these sites include brain because there’re no antigen presenting cells & also the presence of brain barrier, cornea, anterior chamber of the eye, the uterus & the testes.
2- Immunologically privilege tissues: tissues of no immune response & these include cornea (cornea is immunologically privilege site & tissue so in transplantation no immune suppression is needed), brain, bone (resist vascularization), cartilage, heart valves & the fetus.
The mechanisms by which this occur are lack of antidendritic cells, lack of antigen presenting cells, lack of lymphatic drainage, lack of MHC molecules, resistance to vascularization or presence of special barriers (blood brain barrier, blood testes barrier & placenta) so there’re many mechanisms & more than one may act together as in the case of pregnancy.
*Autoimmunity:
What was mentioned in the tolerance is the opposite here in the autoimmunity.
It’s defined as the state when the host responds to self antigen, the termination of the unresponsiveness to self (termination of tolerance) or specific adaptive immune response against self & this was called by Paul Erich as Horror Autotoxica.
Since tolerance isn’t genetically determined (acquired) it may fail although it’s not common but there’s a chance.
Both T & B-lymphocytes could exhibit autoimmunity.
Autoimmunity isn’t always associated with disease. There’s what is so called autoimmune response that is present in every individual. Actually autoimmune responses are essential, normal & acquired for the normal function of the immune system as in the interaction between T & B-lymphocytes in the antibodies production. But the autoimmune diseases are the abnormal & rare.
• The causes of autoimmunity:
1- Exposure to a hidden self antigen as in the cases of broken barrier (for example broken blood testes barrier led to formation of anti-sperms antibodies).
2- Death of cells & the release of nuclear antigens so we’re going to have anti-nuclear antibodies.
• So we have two types of autoimmunity:
1- Autoimmune response: the essential & the normal autoimmunity (presence of this autoimmunity doesn’t prevent the formation of tolerance) & also is not rare but should be in low titer (low concentration & low affinity).
2- Autoimmune disease: rare & abnormal autoimmunity.
a- Myasthenia gravis: Autoimmune disease that results from the formation of antibodies against muscle cells lead to extreme weakness. Mothers who have myasthenia gravis produce IgG antibodies with high affinity to Ach receptors & as they’re IgG they can cross the placenta to the fetus so the baby is born with the manifestations of myasthenia gravis however these antibodies have a half life & they decay with time (after six months all maternal antibodies are lost usually) so those infants born with myasthenia gravis improve after six months which is an evidence that these antibodies mediate the disease.
b- Rheumatoid arthritis.
c- Diabetes.
Autoimmune diseases are of significant (affect 2-3% of population) & should be distinguished from diseases caused by immune reaction like hypersensitivity (allergy for example is caused be hypersensitivity to an antigen (foreign antigen) & it’s not autoimmune disease (not due to self antigen)). Diseases caused by immune reaction are usually due to exaggerated response (response that deviates from normal where the normal response in normal people is enough to eliminate the foreign antigen) this exaggerated response leads to the destruction of the surrounding tissue.
We don’t know a single etiology of the autoimmune diseases because it’s multi factorial not single factor like infection, gene or exposure to external factor but more than one together. For example patient with genetic susceptibility to failure of self tolerance in the presence of environmental factors like infection or tissue injury will lead to autoimmune disease.
Immune suppression is very important in the autoimmune diseases because it stops the progression of the disease & controls it.
Autoimmune diseases vary greatly between the individuals it could be fatal to one individual & very benign in another and within the same individual there could be certain degree of variation once may lead to sever clinical involvement & a few months later it undergoes a non progressive course like those of multi sclerosis where patient may have a sever attack then years after that without an attack & also multi sclerosis differ in the course between different individuals.
• Mechanisms of autoimmunity:
1- Failure of tolerance which isn’t common.
2- Break down of peripheral tolerance.
3- Molecular mimicry which is an important mechanism (if there’s a present antigen (bacteria, virus…etc) that is similar to the host, the immune response that act against this antigen will also react with the self antigen & cause an autoimmune disease like rheumatoid arthritis).
4- TH1 & TH2 imbalance.
Others are written in the slides
There’s a figure in the slides shows that smoking damages lung cells which leads to the secretion of nuclear antigens followed by the formation of antibodies against self leading to an autoimmune disease that involve the basement membrane in the kidney & the lung.
Immunology lecture for Dr. Azme
At the date of 26/12/2010
Done by Suhaib mahmoud Attieh
“Good luck in the finals”