Immune deficiencies and Cancer
Welcome back to the podcast.
This is the next episode of immunology 101 where we are breaking down our complex immune system. Teaching you about how your body works and misbehave so that you can feel empowered. We are becoming immune confident together.
Immune Deficiency Disorders
Today we are going to jump back into some of those instances where our immune system is misbehaving. And in particular today, we're going to talk about conditions that are near and dear to my heart. In particular, those are folks living with immune deficiencies or immune systems that are not able to recognize and/or fight off infection as well as they should.
There are a group of over 450 different conditions known as primary immune deficiency disorders. These are very variable conditions, but they all resolve in the immune system not functioning correctly. They also can be known as "inborn errors of immunity." Most of these conditions are characterized by an increased susceptibility to infections, but this can look different in different people. Some folks will have more repeat or recurrent infections, other folks will have infections that won't improve as you would expect when you're treating them. Sometimes, people will have more severe infections or they may be infected with bugs that are really rare and normally wouldn't cause infection in humans.
So why is it that this group of 450 different conditions are grouped together? In large part, it's because on their own, they are extremely rare. But when we group them together and we think of them together because they do have a lot of similarities, we realize that they are actually quite common and affect upwards of 1 in every 1200 people.
What else happens when folks have primary immune deficiency disorders? These folks typically experience, like I said, increased number or severity or types of infections. But they also very often will experience inappropriate inflammation or autoimmune conditions along with their immune deficiency. This is the really obnoxious thing about the immune system when it misbehaves: it tends to do so in multiple ways.
Genetics of Immune System Disorders
Many of these immune system disorders we know have a genetic predisposition. In some of these primary immune deficiency disorders, there's very apparent familial connection. A couple of those where this is very much the case is X-linked agammaglobulinemia and another condition called chronic granulomatous disease or CGD. Both of these particular conditions tend to occur in boys because the genes that are specifically responsible for them occurring, fall on the X chromosome () the female sex chromosome), so boys only have one copy of this chromosome, so there is really a 1 in 2 chance that they would then have this condition if their mother had a gene that coded for it.
In other primary immune deficiency diseases, there's a genetic predisposition, there's something in the code, and then over the course of our lives, we're exposed to certain things that will turn on and turn off our genes. These are our epigenetic changes that we've talked so much about. It's some of these life experiences or things that we encounter that then may result in a primary immune deficiency presenting little bit later in life and then being diagnosed thereafter.
Challenges in Diagnosis of Primary Immunodeficiency
The real problem with primary immune deficiencies, because they're rare because they're typically invisible is there are significant delays in diagnosis. It's really common ranging anywhere from 9 to 15 years for a patient to be recognized as immune deficient. And immune deficiencies can occur in people of all ages, all races, all genders. It's really important to consider this on our list of possible diagnoses for anyone who is experiencing an increased number in or severity of infections.
One of the real problems I see where this comes up is so often if we have a, bad sinus infection or an ear infection, a lot of times our care is disjointed. We end up at the minute clinic or the urgent care because that's what's open when it has an opening to see us when we had these infections. But if you are going to the urgent care every month, every couple months needing antibiotics that are really considerably helping you in treating your sinus infection, your ear infection, your primary care doctor or one point person isn't necessarily aware of all of these infections and won't know over the course of time that this is abnormal and this should be evaluated for. And reasons for those recurrent infections should be should be considered.
Overview of Immunodeficiency Disorders
What are some of these primary immune deficiencies and how does this all relate to what we've been talking about over the last several weeks? As an immune system physician, I am commonly asked to evaluate patients for a weakened or a deficient immune system. I want to share a little bit of light into how I think about that and how that evaluation occurs and also how that plays into sometimes us thinking about the role of malignancy or cancers. That will segue into our discussion about them and system and its role in cancer detection.
So, when we think about our immune system and our defense mechanisms, there are all different types of cells, all different types of proteins, and structures that have particular purpose and protect us from certain types of infections or bugs.
Identifying Deficient Immune Systems
The first thing I'm going to do when I talk with a patient who has a suspected immune system problem is ask them what types of infections they've experienced. What is their infection history? Going back to when they were a child, were they that kid that was getting sick, frequently needed antibiotics often? Did they have ear tubes placed? Did they need multiple sets of ear tubes, were they hospitalized, were they born premature, did they have any problems with their lungs? All of these are really helpful questions and answers for me to take into account as I'm thinking about this person's immune system health.
How have things been in the last several years? Has there been a dramatic change in health? Are you on particular medications? There are certain medications that can weaken the immune system and can weaken the immune system's ability to fight off infection in various ways. So I want to know where are the infections, how often are they occurring, what have you needed to do to get better from them and have you had any lasting problems related to those infections? Is there any family history of immune system not functioning correctly? That also can be really helpful as I'm thinking through all the possibilities of what might be going on.
I'm also taking into account the patient's age, the patient's gender, background, because those are certain characteristics that may increase or decrease the likelihood of particular types of primary immune deficiency disorders. Based on that information I get, say the person is suffering from more bacterial infections and those bacterial infections are sinus infections, ear infections, a couple of pneumonias. That really helps me then narrow in what I'm thinking about maybe going wrong or not working correctly. If a patient says, "Hey, I tend to get recurrent yeast infections," and when I got this plea utter word, it wasn't just one word. It was a ton of words that's going to bring my brain in a different direction.
Once I have that information then I'm going to start thinking about, okay, what do I need to look for on my examination of the patient? What do I need to have my eyes and ears open for? Are there any variations in there in your teeth, in your nails, especially your cuticles? Is there any change in the appearance of the fingertips? How do the lungs sound, does it sound like there are maybe signs or symptoms or signs that there's been lung damage from prior pneumonias? Are there any scars or similar findings? Are there any particular birthmarks or other skin findings that may be associated with particular immune system disorders?
There's a tendency for immune system disorders to go along with other problems with our connective tissues as well. So that is why we're keeping an ear and an eye out for changes in kind of bone structure, teeth, hair, skin, all of those sorts of things.
Screening and Laboratory Testing
After that, I start thinking about, okay, what labs will be helpful? I want to see are the parts of the immune system present and accounted for. So that's a quantitative like "how much?" Are the pieces there? I also want to know qualitatively, "how are things doing?" How good are things functioning? Are the pieces of the puzzle there and do they fit together?
There are different lab tests that help determine that based on the part of the immune system that you are suspicious. Is the problem or causing the problem if I'm worried about bacterial infections, especially what we call Sino-pulmonary infection, so sinus, ears, lungs. I'm thinking about problems with our humoral immune system, the antibody part of our immune system. So I'm likely going to say," Hey, let's check a blood count with a differential, a CBC with differential." That's going to just make sure your white blood cells are there and accounted for. It's a pretty, routine blood test, patient may have already had it. See if we have those results.
IgG, IgA, IgM Tests
I'm also going to say, "Hey, let's see. Do you have antibodies? Do you have immunoglobulins?" Those are the same thing. " Do you have the right number of them?" And "do you have memory to infections and or vaccines that you should have, or would have been exposed to?" and "how do those look?" So, a humoral immune workup typically will be a CBC with differential. It will be quantitative immunoglobulins, the numbers of your IgG, your IgA, your IgM. It also will usually include vaccine titers, the IgG levels specific for your technic shot, maybe your diptheria is shot, and then likely your pneumonia vaccine as well. We'll look to see, "how did it look?" Does it look consistent with what we would expect, or does it look like maybe some aspects to that are missing or low or not really demonstrating that you've kept good memory to things you should have been exposed to?
Now many folks, especially folks, my age, have not received a pneumonia vaccine. I would not expect that I would have great memory to the types of bacteria that are in the pneumonia vaccine, because I haven't seen it. I've only seen the specific strains that I maybe have fought off. So in that instance, if those titers are low and a patient has not had that vaccine, or it's been several years since they've had it, often we'll recommend giving that vaccine, knowing that it's helpful and can help provide protection from a lot of common causes of ear infections, sinus infections, and pneumonias.
Then we'll repeat those titers about four to six weeks after that vaccine knowing that it takes that long for the immune system to make memory IgG antibodies to that vaccine. Then we'll see, "did the immune system respond as it should or was it slacking?" That can be really helpful information to help us decide and determine what's your risk of infection and what should we think about doing or what are the options we should do moving forward.
The other situation I mentioned about is if someone is experiencing frequent viral and or fungal infections like yeast infections. In this case, we're more worried about the cellular component of our immune system, those T cells. More often in that case, we'll not only get that CBC with differential, that blood count with the types of white blood cells, but often we will also check something called immunophenotyping. It's called flow cytometry. It seems like everything has two names in medicine.
But this is a very specialized test that is like looking at your white blood cells in high definition. It's going to tell us how many T cells, how many specific, like those helper T cells, those killer T cells. How many B cells are there? How many natural killer cells are there? It really breaks down those specific types of white blood cells to a greater degree and give us more granularity in the quantity of those particular types of cells. So again, this is more of a quantitative test that tells us, "are the pieces there?"
Mitogen Stimulation and Antigen Stimulation Tests
And then we have different tests that tell us if those pieces are functioning. So for looking for a T cell function studies, we are going to send studies off called mitogen stimulation test and antigen stimulation test. These essentially are tests where they take your T cells, your white blood cells, these specific ones, and they mix them with particular stimuli that should get them really excited, all jazzed up and making more of them. They see if that works or not and if that works according to plan, and those cells get jazzed up, as you would expect, then we say those are normal. If they don't, then we say, okay it looks like perhaps you do have a problem with your T cell function. Then that can lead us down a whole nother road of testing.
Complement Deficiencies Workup
The last common test that we will check for, and this will come up a little more often and folks who maybe have a history of lupus or other significant autoimmune disease, something called compliment deficiency. So compliment again is one of the sets of proteins. It works in a cascade like function that is very elegant but complicated and essentially pokes holes in bacterial cell walls in order to kill them. If you're missing one of the components of this compliment cascade, the cascade can't progress, it can't poke that hole. So we typically are able to check if you have the pieces and if they're functioning all in one particular test called a CH50. And this is concerning if that level would be low.
So we've walked through what a typical immunodeficiency workup may consist of. Whatever we discover and decide is the diagnosis will guide our treatment. In many instances we'll be left having conversations with patients discussing risks versus benefits. Thinking through what all those potential options are. Those are really going to be personalized based on the cause of the primary immune deficiency disorder and how severe that is, what are the treatments available, and what is most consistent or most inline with what that patient and family.
Antibiotics and Prophylaxis
Some more common treatment options include putting people on antibiotics and a preventative way called prophylaxis.
Immunoglobulin Infusions (IVIG or subcutaneous IgG)
Another strategy that is helpful for, in particular, if IgG levels are low or immunoglobulin infusions, these are sometimes called IVIG or subcutaneous IgG infusions.
Then there are little bit more rare treatment options for very specific immune deficiencies which include things like interferon injections.
Transplants (thymus or bone marrow)
Last, but not least there are even in more severe and complicated situations. We have the ability for some folks to undergo a transplant of thymus, which is one of the immune system organs and bone marrow transplant.
There also are types of gene therapies that are also now used for particular immune deficiency disorders.
The Immune Systems Role in Cancer
One of the frustrating aspects of primary immune deficiencies are that with that deficiency the immune system many times does not do as good of a job, not only recognizing infections, but also potential cancers. So that's a nice segue into discussing the immune system's role in cancer.
Cancer is uncontrolled or unchecked growth and multiplication of our own cells that shouldn't be occurring. It's unchecked tissue growth and that can occur in all types of our cells and based on where those cells come from or what types of cells those are, that's where the name of the cancer is drived from.
The immune system is able to, and should be able to generally speaking, identify when our own cells go rogue. In part, because when these changes occur in a cell and the cell goes rogue, they start producing typically certain proteins or other receptors, other substances that are not normal.
So, in a perfect world, the immune system recognizes that something is not right, that this is not a normal self and then works to identify and attack those rogue cells. Unfortunately, what happens in many instances, is that cancers or tumors will evolve strategies to evade the immune system's response.
There are certain things that will be looked for when someone undergoes a biopsy for particular cancer diagnosis and workup. A biopsy is when we use either a needle or a surgical technique to get a piece of the cancer tissue or the tissue that we suspect is cancerous and to look at it under the microscope. Also many times now run very specialized immune system based testing, staining type techniques, to see what is going on in that tissue to see, is there blood vessel growth, what types of markers are present, and what types of immune system responses are occurring or are not occurring.
For instance, in certain tumors, if you see lymphocytes, this T and B cells around some tumors and see enlargement in lymph nodes or those factors where the speed dating is going on, that may indicate a better prognosis; the immune system is recognizing that cancer and is doing something about it. This has impart also really spurred on some phenomenal and exciting work in how we treat cancer.
Cancer Treaments: Radiation Surgery and Chemotherapy
So often, in years past, cancer was really treated in two main ways: one was to cut it out and the other was to either cut it out or burn it out, surgery radiation or to use chemotherapy, which are strong medications that are aimed at tissues that are growing fast and work to prevent those cells from growing and/or kill them. Now though we're looking at ways to stimulate our immune system in many cases, stimulate or turn our immune system back on so that our immune system can also help fight off the cancer.
PD-1 Inhibitors or CTLA-4 Inhibitors
This is where a lot of really great advances have come in the last several years. In particular, you will come across treatments known as PD-1 inhibitors or CTLA-4 inhibitors. Essentially, this is blocking an inhibitory response, it's blocking a blocker, and it's turning on the immune system again, in particular, it's turning on. T-cells.
Another common strategy that is used both in the treatment of cancer, but also sometimes autoimmune disease is passive immunotherapy with monoclonal antibodies. Monoclonal antibodies are proteins that are created outside of us. Specific and directed to particular receptors that are on certain cell types of interest. The one that I'm thinking of that is a great example is CD-20, a marker that is found on B cells. So there are anti CD-20 medications, rituxan is a very common one, that are used to treat B-cell tumors and B-cell disorders. B-cells are typically the factories for our antibodies. If we deplete CD-20 cells by sending out antibodies that are specific for them, that then decreases the production of antibodies that may be causing our autoimmune disease and/or if you have a B cell cancer that will take out those cancerous cells as well.
Now, of course, these medications are not without their downsides. I will tend to see patients sometimes many years after the fact, if those B cells, the healthy B cells, don't repopulate and if those folks end up needing immune system medications like IVIg to replace antibodies that have not repopulated.
CAR T-cell Therapy
Another strategy that has been used in essentially retraining the immune system is CAR-T, C-A-R-T. This is really new and exciting treatment where T-cells are taken from the patient, they're taken back to the lab and they are mixed with special ingredients gone through special processes, but essentially, they are retrained then to attack the tumor and specifically attack the tumor. They are then transferred back into the patient and essentially provide the patient with customized tumor fighting immune system cells.
This is another strategy that I'm hopeful will be looked at for more autoimmune treatment as well. It's been looked at a little bit for a lupus and showed some promising results. So I am excited to continue to follow the potential and the availability of these treatments as they continue to be refined and understood a lot more.
What's really challenging is the immune system is incredibly complex there are so many variables at play and slight variations in some of these variables can create extraordinary immune system responses. So with some of these different immunotherapies that we have for particular cancers, often we will see that some folks will have significant side effects that are related to the immune system being activated.
High fever, low blood pressure, tissue swelling, not being able to think, becoming delirious, and sometimes multiorgan failure and those are some of the issues that continuing to be worked through and hopefully we'll be able to, as we learn more and gain more experience using these treatments, understand better how to prevent those so that we have targeted effective and safe therapies available.
Coming Up Next Week: Dysbiosis and Alterations in our Metabolism
All right, that was a lot of immunology for one day. I think we will spend a little time next week talking about the role of dysbiosis and alterations in our metabolism and how those affect our immune system responses. I will share some of the information from the recent New England Journal article on incorporating that into the paradigm of inflammation.
Then we're going to jump in to talking to a few of my allergy colleagues and getting back to talking with other colleagues, all with the purpose of helping you become immune confident. My goal with this resource, this podcast, is that you are able to learn more about your body, how it functions, how it may malfunction.
I want you to be able to navigate our healthcare and wellness industries with confidence and with greater ease, because it can be incredibly overwhelming even for an immunologist.
I hope you enjoyed this new episode and if you did please consider leaving us a review over on apple podcasts and share this episode with others who may be interested in all things allergy autoimmunity, anti-inflammatory living, and really becoming immune confident.
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