Hello, maybe you have heard about severe combined immunodeficiency or maybe some of your relatives or friends have had this disease. You see this is the mind map which is covering most of the immune system disorders. Today we will deal with one of the six branches, the immunodeficiency one. You can see here that the severe combined immunodeficiency is part of a primary genetic inherited type.
What's the difference between primary and secondary? It's just that the secondary is acquired. and the primary is genetic, it's inherited.
The primary one can be further classified into those with the B-cell lymphocytic defects, those with T-cell lymphocytic defects, and we have in our case here the combined defect of both T and B lymphocytes. So if you look at this name and realize soon that if you have a defect in both T and B lymphocytes and also natural killer cells in some cases, then you will have an increased susceptibility to infection. And that would be severe. So it's fatal, it's death within one year. This boy named David Vetter in the 1970s had this disease.
His parents had a previous son who died from the same disease. And the doctors told these parents that they have to be very cautious with the next child, David, because this disease is inherited in the family. It's primary, as I said. So what they did was that David was born and he was directly put into chamber, a sterile environment where he could not be affected by any bacteria or any viruses.
The boy started to grow. It looked good. Everything looked good. You see in this picture, he's more than one year old.
and usually babies die within one year. The problem was that David wanted to go outside his chamber. He wanted to meet his mother. He wanted to show her love. He wanted to feel her love.
He wanted to associate and interact with people. So what they did was that they put him into a space suit where he could interact with people more easily. He was the first person, one of the first persons who were put into bone marrow transplantation treatment. Unfortunately, he died at the year of 12 years old. Why?
Because they didn't recognize an Epstein-Barr virus which caused his death. What do we have to learn from this? We have to immediately recognize this type of disease.
We have to check the family if they already had a child with this disease. So how can we do it? We have to diagnose the children. Pre-natally we can do it, by sequencing DNA.
Because if you sequence DNA, you find the mutations necessary to tell that this is a severe combined immune deficiency. You can see it in the newborn child also with the sequence, but you can also check levels of the thilumphocytes, the bilumphocytes, the natural killer cells and antibodies. So if you check these levels and you see that they are very very low for some reason, then you have to search for the reason.
These babies can appear healthy, so don't be confused. They can appear healthy until six months of age. Why? Because they still have the mother's antibodies in their body, but after six months this starts to be depleted and since they are not producing new antibodies, then they fail. The infection starts.
And what type of infections can we see? You see, these are the symptoms. You can see recurrent infections, which are resistant to antibiotics.
And what I've written here is that two months, if you see this for a longer period than two months, then it's an alarm. If you see it in the family, it's an alarm. If you see that the patient is not growing, so it's a failure of thrive. it's diarrhea, he has diaper rash, bronchitis, pneumonia, otitis media, liver abscess, morbilliform rash.
If you see any of these, you should think of an immune system disorder and then you can investigate if it's severe combined immunodeficiency. So what are the reasons? We see there's fungal infections, there are bacterial infections and viral infections.
You can see in the oral cavity that we have oral candidiasis, whitish black on the mouth. So if you turn to the failure of thrive in the x-axis you will have the the month so the age of the child and in the y-axis you will have the weight or the length and you will put these red dots or and mark at the specific month you will mark the the weight for example or the length and if you see that the curvature is not as it should be because these are standards averages these are like the most children are growing. So if it deviates then you know that the child is not really growing as it should.
That's one sign. Then you see the diaper rash. Then you see maybe bronchitis, this mucus plug which you can see.
You can also see that we have a alveolar filled with pus. So it's again pneumonia. and otitis media meaning that we have an inflammation of the middle ear cavity, bulging of the tympanic membrane, inflamed eustachian tubes, and loss of hearing of course therefore. And then we have a liver abscess where you see this pus-filled abscess in the liver. And we can also see a morbidly formed rash which is very similar to measles infection.
Google this and find more pictures of all these diseases. That was the symptoms. So what can we see in the microscope? What can we see morphologically?
We will see hypoplastic lymphoid tissues. Meaning that for example we have depleted zones of T and B lymphocytes. So where we usually have the T and B lymphocytes, like in the lymph nodes, there these areas will be depleted since we are not producing them. Or in the thymus we can have less lymphocytes and therefore the thymus will resemble the fetal thymus where we have lobules of undifferentiated epithelial cells.
And also the last one we can see in the chest x-ray that there's absence of thymic shadow. The last thing I have to mention is the Hassel's corpuscles, that there's absence of Hassel's corpuscles. So where can we find all these things? This is the thymus. This is the histology of the thymus.
You see a capsule. You see the trabeculae, the cortex, the medulla. And these are forming lobules. So these are the lobules now. You see the blue one is indicating cortex.
The green one indicating medulla. And in between them, we have corticomedullar junction. What we can find here...
is the thymocyte, which is maturing into T lymphocytes in this lobule. And we can also see the Husserl's corpuscles, but in this disease we will not have the same amount of thymocytes, T lymphocytes, mature ones especially, and we will not have Husserl's corpuscles, these ones, which are circulated epithelial type 6. cells. So we will not see these types of cells.
And in the x-ray we mentioned there will be absence of thymic shadow. In the left one we have absent and in the right one we can still see the thymic shadow. So what are the types of this disease? There's X-linked recessive one and there's autosomal recessive. Autosomal recessive have many many types and I've listed some of them here.
Most important adrenosin D aminase deficiency, which is the second most common. The most common is the X-linked recessive one. So if we turn to the X-linked one, we see that we have written a red T with a minus sign, and then we have written a B, a green one with a positive sign, and then again a red natural killer cell with a negative one.
So it's just meaning that we have lack of T cells and lack of natural killer cells. and we still have normal amount of B-lymphocytes in this case. As you see in the other cases, there are different types.
Adenosine deaminase deficiency, for example, have no cells. The same with the purine nucleoside phosphorylase gene mutation, no cells. And then some other types. If you look at this gene mutation, we'll have a gene mutation in the X-chromosome, Q13.1. You have to understand what it means.
If you look at the karyotype you will see that we have an X chromosome and then we have a short arm and a long arm. And when we are saying Q, we are referring to the long arm. When we are saying 13, we are actually saying 1 and 3. So region 1, band 3, and then subband 1. That's it.
So here you will see a mutation. And that will cause that the receptor will not work because the common gamma chain is not produced. It's not encoded.
since this gene mutation happened. So the interleukins will not be able to really bind to this receptor and cause its effect. And which are these interleukins?
2, 4, 7, 9, 11, 15 and 21. The 7 and 15 you see have specific defects. 7 T-cell deficiency, 15 natural ketocel deficiency. So if you remember here We said that we have a T cell defect and a natural killer cell defect.
And now you understand why. Because we didn't have interleukin 7 and interleukin 15, which could do its effect. Because the receptor is not functioning. Only because a small component called common gamma chain is not really encoded. If you look at the same picture we have YAK3 and YAK3, if you go down and look at the YAK3 intracellular kinase mutation, you will see that this is blocking the signal from the receptor.
And that will cause the same thing, that these interleukins, regardless of their binding or not, they will not cause their effect. What about adrenocyte and deaminase deficiency? We will see that it will have an elevated deoxyATP. which will inhibit something.
Let's look at it. Adenosine should become an inosine with this enzyme. And if you don't have the adenosine-DMNase enzyme, then the adenosine will be accumulated, and you will eventually accumulate deoxyATP, which will block ribonucleotide reductase.
If you block this enzyme, then the NDP, the ribonucleotides, cannot form deoxyribonucleotides and these are important for DNA synthesis. So just because of adenosine deaminase deficiency, we block DNA synthesis. And if you block DNA synthesis, then no cells are produced. No T-lumphocytes are produced.
That's it. You just kill that process. And the same with purine nucleoside phosphorylase, which usually is converting guanosine to guanine.
is blocked, it's not functioning, then duaneosine accumulate, DGTP accumulate, and that also blocks the ribonucleotide reductase. And the same happens. If you look at this picture, we have a bone marrow and the thymus.
In the bone marrow you will see the pluripotent stem cells, which give rise to myeloid stem cell and common lymphoid progenitor cells. These common lymphoid progenitor cells will give rise to the B cells, T cells. But we have an adenosine deaminase deficiency which blocked the DNA synthesis.
So we blocked the maturation of any cells. So here is another example where we have X-linked severe combined immunodeficiency. The X-linked type. This one is blocking it between the pro T cell and immature T cell. So the pro T cell matured, they reached into the thymus and then they stopped.
The same with the MHC class 2 deficiency. It's blocking at the immature T-cell becoming mature CD4 cells. So this was the big picture. Look at it. Adrenosyn deaminase deficiency we have elevated DGTP.
It's a mutation in the chromosome 20. Inhibit ribonucleotide reductase. reduced dMTP synthesis, reduced dDNA synthesis, and then reduced T-lymphocytes. Okay?
The purine nucleoside phosphorylase gene mutation elevated the DGTP, and then the same process as in the adenosine one, so it killed the T-lymphocyte maturation. Then we have something called Ohm-Memp syndrome, where you have a gene mutation in the RAG gene, and that will cause that the V... D, J recombination will not happen. So we will block maturation of lymphocytes again. And then there we have a bare lymphocyte syndrome.
And why is it called bare? Because we don't have any MHC2 receptors on these cells. And therefore the CD4 maturation is blocked.
That's it. We have to check now the treatment. How can we treat this patient? Bone marrow transplantation. gene therapy.
That's it. Bone marrow transplantation, you puncture, let's say, the pelvis, iliac crest, you take bone marrow from a healthy patient and you put that bone marrow into this patient of severe combined immunodeficiency. And this patient will be healed for more than one year sometimes and others one-fifth of them will eventually or maybe get acute T-cell leukemias.
Those with gene therapy are doing some other process. There, for example, when we have adenosine DMNAs deficiency, that other type, then we will take some stem cells from the bone marrow, these T-cell precursors, which are not functioning as they should. They have a mutated gene.
So What we do is we take a healthy gene, normal gene, put it into a virus, and then we put the virus into that T-cell precursor, and eventually this T-cell precursor will now produce normal genes and normal proteins. So then we take this and put it back into the patient. That's it. If you want to summarize now... We had a boy named David Vetter who had this disease.
If you don't have this bone marrow transplantation then you have a death within one year. Diagnosis early prenatally with sequencing DNA the same with newborns or you can have the levels of the lymphocytes checked. Remember that these babies will be healthy until about six months of age and then they will be depleted antibodies and then the symptom starts to appear.
which symptoms? Failure to thrive, diarrhea, diaper rash, bronchitis, pneumonia, otitis media, liver abscess and morbidly from rash, also oral candidiasis. The treatment were bone marrow transplantation and gene therapy.
We had the different types and we had morphology. Most important type, X-linked recessive. The second most is autosomal recessive one, the adenosine DMNAs.
What did we say about morphology? We could see that in the thymus there's lacking of lymphocytes. In the lymphoid organs we had depleted zones of T and B lymphocytes.
And we also saw that there's absence of these Husserl's corpuscles and the lobules are undifferentiated really when we have an absent thymic shadow on the x-ray. The types we had X-linked with no T and no natural chilo cells. the YAK3 with no T and no natural killer cells, and then we had adenosine deaminase deficiency and purine nucleoside phospholase which had no cells at all. The different, the important point we have to make here is that when I say that the X-linked recessive is having normal amount of B-lymphocytes, I'm not meaning that the function of the B-lymphocytes are good. since you have to understand one thing, T lymphocytes or T helper cells are usually activating B cells.
So if you have normal amount of B cells but there's no activation, then the function is not good. So remember this. And we can see here the steps which I've mentioned, increase dATP and dGTP, block ribonucleotide reductase. so blocked DNA synthesis, meaning blocked maturation of the T lymphocytes or B lymphocytes. And the other types in the thymus, we had the X-linked, which blocked between pro-T cell and immature T cell, and the MHC class 2 blocked between immature and mature T cells.
This was the big picture and we realized that this is a primary genetic deficiency, one of the branches. is the immunodeficiency and that's the whole picture. Thank you very much.