Genetic Factors in Cytokine Storm Syndrome Susceptibility and Pathophysiology

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• Genetic Susceptibility Threshold Model
• Perforin Pathway Cytotoxic Dysfunction
• Prolonged Immune Engagement & Cytokine Production
• Secondary Forms of Cytokine Storm
• Multiple Pathways & Immunodeficiency Overlap
• Clinical Triggers & Threshold Crossing
• Full Transcript

Genetic Susceptibility Threshold Model

Dr. Randy Cron, MD, explains the complex genetics of cytokine storm syndrome using a threshold model. This model helps explain why secondary forms of cytokine storm appear later in childhood or adulthood. Dr. Cron, MD, states that individuals carry partial genetic defects all along, but they are not severe enough to cause disease on their own. A combination of these genetic factors and a significant inflammatory trigger can push the immune system past a critical tolerance threshold.

Perforin Pathway Cytotoxic Dysfunction

The best-studied genes associated with cytokine storm susceptibility are involved in the perforin pathway. Dr. Randy Cron, MD, describes this pathway as critical for natural killer (NK) cells and cytotoxic CD8+ T cells to kill infected target cells. Key genes in this pathway include perforin itself, which punches a hole in the target cell, and others like Rab27a, Munc13-4, and STX11 that are involved in trafficking and docking the killing machinery. Homozygous mutations in these genes cause a rare, severe condition known as familial hemophagocytic lymphohistiocytosis (HLH), which has an incidence of approximately 1 in 50,000 live births.

Prolonged Immune Engagement & Cytokine Production

Dr. Cron's research focuses on how heterozygous mutations can partially disrupt immune cell function. Laboratory studies show that immune cells with these mutations cannot kill infected target cells as quickly or efficiently. Dr. Randy Cron, MD, explains that this results in a prolonged interaction between the killer cell and its target. Instead of a quick kill and moving on, the cells remain engaged for up to five times longer than normal. This prolonged engagement leads to excessive activation and the overproduction of pro-inflammatory cytokines, most notably interferon-gamma.

Secondary Forms of Cytokine Storm

These partial genetic defects are a major contributor to secondary forms of cytokine storm syndrome. Dr. Randy Cron, MD, emphasizes that the high levels of pro-inflammatory cytokines, while necessary for fighting infection, become pathological when they exceed a certain threshold. This cytokine excess is a direct driver of the multi-organ failure characteristic of a full-blown cytokine storm. The interview with Dr. Anton Titov, MD, highlights how this mechanism moves beyond rare genetic syndromes to more common, acquired conditions.

Multiple Pathways & Immunodeficiency Overlap

Genetic susceptibility to cytokine storm is not limited to the perforin pathway. Dr. Randy Cron, MD, notes there are hundreds of primary immunodeficiency disorders that can impair viral clearance through other mechanisms. Metabolic disorders can also affect immune system function and contribute to a hyperinflammatory state. Dr. Cron, MD, references colleague Dr. Scott Canna's description of these various routes as "highways to hell," underscoring the frequently fatal outcome of cytokine storm syndrome and the multiple potential genetic pathways that can lead to it.

Clinical Triggers & Threshold Crossing

The final step into cytokine storm often requires a clinical trigger in a genetically susceptible individual. Dr. Randy Cron, MD, explains that most people tolerate a single copy of a mutated gene throughout life. However, a significant insult like SARS-CoV-2, a virulent influenza strain, or dengue fever can provide the necessary trigger. This risk is compounded if the individual also has an underlying inflammatory state from conditions like systemic lupus erythematosus, Still's disease, or active leukemia. The combination of genetic predisposition, chronic inflammation, and an acute trigger can overwhelm the immune system's regulatory capacity.

Full Transcript

Dr. Anton Titov, MD: You also published some work on the genetics of macrophage activation syndrome, of cytokine storm syndrome. So, for example, some genes involved in impaired viral control, dysregulated inflammasome activity, and other immune defects. Could you comment on the genetics of cytokine syndrome susceptibility? You've already mentioned some of that in the context of earlier questions.

It's fascinating to me, and it's still controversial. There are some people who believe—myself and others who push this concept—others not so much. And it's because it's not necessarily the low-hanging fruit of having two mutated genes that give you whatever disease. It may be that it requires both genes to be mutated.

Now, it wasn't low-hanging fruit before those were identified. But once you identify those diseases and you find those mutations, it's pretty straightforward. These are much more complicated.

Dr. Randy Cron, MD: As humans, we're not perfect; no one has the perfect genome. And so we use something called a threshold model to explain some of these secondary forms of cytokine storms that show up after infancy, for example, or later childhood or adulthood.

Clearly, if these mutations are contributing, you've had them all along. It's just that they're not severe as a single mutation. But if there's a threshold over which your immune system can no longer tolerate the degree of inflammation that's been created by whatever trigger it may be—whether it's a virus, or just having a flare of your lupus, or Still's disease, for example, or your leukemia is active—the combination of that and having a partial defect in your immune response, and then maybe an additional trigger on top of that, or maybe not, but maybe a virus helps kind of put you over the threshold to the point where your immune system can no longer tolerate the amount of inflammation that is there, and the cytokine storm is much more apparent.

And so the genes that we know best to look for, that have been studied the best, and we know the pathophysiology the most about, are again these ones that lead to this rare familial HLH or hemophagocytic lymphohistiocytosis. And there, there's a slew of genes because it's a pathway.

So inside of two of your white blood cell types—one called natural killer cells and another one called your cytotoxic, or killing CD8+ (that's a marker on these T cells)—those two cell types share this common pathway by which they recognize, for example, an infected cell. We call it an antigen-presenting cell because that infected cell will take a piece of the virus that they cut up and put it out onto the surface of the cell so that they can be recognized by the cytotoxic CD8+ T cells, for example.

And then those cells will kill them, or lyse them, through this peripheral pathway. And so perforin is one of the genes in that pathway. It actually punches a hole in the target cell so it can deliver a killing message through these proteins called granzymes.

Dr. Randy Cron, MD: But there are a whole bunch of other proteins that are important for getting perforin to do what it does, to make that actually traffic from inside the cell to outside the cell. And they come in these vesicles, and trafficking of those vesicles and fusing them to the membrane, and docking them at the membrane—all these various processes are done by other proteins, and they all have these funny names: Rab27a, Munc13-4, STX11, for example.

And if you're homozygous-deficient in any of those genes, you will get this rare one in 50,000 live birth, familial HLH. But my lab and other labs posit that even having one bad mutation, if, for example, it changes an amino acid in one of those proteins, it can disrupt that pathway partially.

So that the cells, whether it's the natural killer cell or the CD8+ T cells, don't kill quite as well. And you can study that in the lab. You can study them directly in the patient, or you can actually study—in my lab alone, what we do a lot of is we take those mutations and we introduce them into a natural killer cell that we have grown in the lab. And then we can say, does having that mutation make the killer cell not function quite as well?

And what happens? This has been shown now by about three groups that I'm aware of.

Dr. Anton Titov, MD: When you don't kill as well, so this white blood cell that's trying to kill this infected antigen-presenting cell, for example, instead of killing it, they remain engaged and are talking to each other approximately five times longer than they normally would. Normally it would kill the cell and move on, go do its job somewhere else.

Dr. Randy Cron, MD: But what happens here is they can't kill the cell because there's a defect in the perforin. And if it's homozygous, if it's one copy or a heterozygous mutation, then they kill the cell; they just don't kill it quite as quickly. And so that is a prolonged interaction of those two cells. They're talking to each other, and they're spewing proteins and having signals through proteins on their surface to each other.

That activates them to make these pro-inflammatory cytokines, for example, interferon-gamma. Those levels become higher than you would normally see in infection. You need those pro-inflammatory cytokines to fight the infection, but the levels get too high, then this can contribute to the multi-organ failure that we see in cytokine storm.

So that's one group of genes that we've been looking at in some of these secondary forms of cytokine storm. And like you said, there are also some rare gene disorders called primary immunodeficiencies. And it's just every year we learn more and more of these; there are hundreds of them now.

And if you have a defect in these genes and have trouble clearing viruses by even mechanisms beyond this perforin pathway, then again, the virus may overly activate your immune system if it's not being cleared. And so even having partial defects again in them may contribute to cytokine storm.

There are even metabolic disorders. And metabolism is an important aspect of the immune system. We don't again know exactly how these work as well as we do the different pathways. So there are multiple different pathways.

Dr. Anton Titov, MD: What we called—Dr. Scott W. Canna called—"highways to hell," because cytokine storm syndrome is frequently fatal.

Dr. Randy Cron, MD: But there are multiple ways to get there, and sometimes even overlap in ways that an individual patient may get there. But because most of us are humans, again, most of us aren't having both copies of that particular gene mutated, but maybe just one copy. And again, we can probably tolerate that throughout our life until we get the wrong insult—whether it's SARS-CoV-2 or a bad strain of influenza, or dengue fever, or whatever it may be—and we are in an inflammatory state because maybe we have underlying lupus, or Still's disease, or leukemia. And that combination of those things gets us over a threshold at which our immune system can no longer control itself.