The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 61

75. What other diseases and disorders are commonly associated with mast cell disease?

I often joke that it would be easier to list what conditions are not commonly associated with mast cell disease because so many conditions occur alongside it. However, there are some conditions that you see a lot in the mast cell population relative to others. In every instance, mast cell disease has the potential to irritate the other condition and vice verse.

Clonal hematologic disorders. Systemic mastocytosis is so frequently accompanied by other blood disorders that it has a diagnosis specifically for this phenomenon: systemic mastocytosis with associated hematologic disorder (SM-AHD). It is estimated that up to 40% of patients with SM eventually develop another clonal hematologic disorder. A clonal hematologic disorder is a condition in which your bone marrow makes too many blood cells. Examples include chronic myelogenous leukemia, acute myeloid leukemia, polycythemia vera, myelofibrosis, and essential thrombocythemia.

Unlike mastocytosis, MCAS can occur secondarily to lots of conditions. In some instances, it’s not clear if the MCAS is secondary to a condition or the condition is secondary to MCAS or neither.

Heritable connective tissue diseases. Ehlers Danlos Syndrome (EDS), is the most common connective tissue disease in the mast cell population. There are multiple types of EDS. While hypermobility type EDS (formerly called Type III) is the most common in MCAS patients, other forms occur also. Other connective tissue diseases seen in mast cell patients include Marfan Syndrome and Loeys-Dietz Syndrome.

Dysautonomia. Dysautonomia is a condition in which your body’s autonomic nervous system doesn’t regulate essential bodily functions correctly. POTS is the most common form of dysautonomia found in mast cell patients but other forms occur, too.

Mast cell patients commonly have MCAS, EDS and POTS together. They cooccur so commonly that some experts think that that this presentation is actually one overarching disease rather than three separate ones affecting mast cell patients.

Eosinophilic GI disease. Mast cells are closely related to eosinophils. They activate eosinophils and eosinophils activate them. Mast cell patients sometimes have eosinophil GI disease where eosinophils activate to lots of triggers and damage the GI tract.

Immunodeficiency. Conditions that specifically impair a person’s immunity, especially those that affect T or B cells, like SCID or CVID, are not unusual in mast cell patients.

Gastrointestinal disease. Mast cells normally live in the GI tract so they are very sensitive to GI inflammation. MCAS can occur secondarily to lots of GI diseases. Crohn’s, ulcerative colitis, inflammatory bowel disease, and irritable bowel syndrome are examples. GI disorders that specifically affect motility are also seen in mast cell disease, like gastroparesis and chronic intestinal pseudoobstruction.

Allergies. Some mast cell patients have true IgE allergies or other allergic disorders like atopic dermatitis.

Autoimmune disease. Autoimmune disease is more common in MCAS patients than in SM patients. The specific disorder could be virtually any autoimmune condition, including rheumatoid arthritis, lupus, Hashimoto’s thyroiditis, autoimmune urticaria, and many others.

Adrenal insufficiency. The body’s mechanisms for produce stress hormones like cortisol can become dysregulated in mast cell patients. This results in a situation in which the body does not make enough steroids of its own to take care of the body during periods of stress. Patients with adrenal insufficiency are dependent upon daily steroids to stay safe.

Chiari malformation. This condition affects the space around a person’s brainstem, causing a wide array of symptoms. Some patients have surgery for this condition.

Asthma. It is difficult to draw an exact line where mast cell disease ends and asthma begins in mast cell patients as the symptoms can be virtually identical.

This list is not exhaustive. Many other conditions sometimes occur in mast cell patients.

For additional reading, please visit the following posts:
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 31
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 32

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 60

74. Is mast cell activation the cause of many other diseases?

No, but it is involved in many other diseases.

I write a lot about mast cells and the way they are involved in various other conditions. Mast cells live throughout the body in many tissues. Because they are in so many tissues, their role in many diseases is well researched.

Mast cell activation is not the same as mast cell activation syndrome. I have written about this here. Basically, there are tons of things in the body that cause mast cell activation. These are conditions where we want or need mast cells to become activated because then the mast cells help keep our body working the way it is supposed to. For example, during a woman’s menstrual cycle, if mast cells could not become activated the way they normally do, a woman’s period could become very irregular. This in turn could affect the amounts and types of hormones in a person’s body, causing symptoms and problems.

Situations where mast cells normally become activated include labor and delivery, during any type of infection, during situations where the GI tract is inflamed, when your body is growing new blood vessels, any time your body is healing, and when you have cancer or a tumor. In these situations, the mast cells activate to send signals to other cells in the body to help regulate what is happening. Mast cell activation is not always bad. It is, in fact, a normal and necessary process that happens in the body of everyone every day. Mast cell activation is necessary to stay alive.

Now let’s look at the role of mast cells in diseases that are not mast cell diseases.

When I was little, I was a Girl Scout for three weeks before I got kicked out. (This is true and not related to mast cell activation.) There was a game that we used to play called “Telephone.” During this game, everyone would sit in a big circle. One person would think up a short sentence and whisper it into the ear of the person next to her, who would in turn whisper into the ear of the person next to them, and so on. Often, people misheard the sentence and so it was completely wrong by the time it got back to the person who started it.

Diseases in the human body are like a very complex game of Telephone. In every disease, many cells that did not cause the disease can cause symptoms even though they are not the cause. The way to know if a disease is a true mast cell disease is to know which cell first messed up the sentence in the game of Telephone.

Here’s what this sounds like in people:

Lisa says to Pari: Puff the magic dragon

Pari says to Dana: Puff the magic dragon

Dana says to Celeste: Puff’s magic is dragging

Celeste says to Lisa: Puff’s magic is dragging

So in this situation, Dana changed the sentence. Because she changed it, Celeste also had the sentence wrong. So Dana caused the problem. Celeste did not. (In real life, Dana is lovely and not a problem.)

When your body has a disease, the symptoms and damage are caused by cells giving or receiving messages incorrectly. Instead of using words to talk to each other, cells use molecules. Even though they use molecules to talk to each other, it is very much like a language. If the message is “said” wrong in this cell language, then all the cells after the mistake are doing things that are unhelpful or dangerous. However, they are NOT the cause of the disease because they are not the one that changed the message.

Now let’s look at this with cells in the human body during a disease. I’m going to use a very simplified explanation of rheumatoid arthritis as an example.

T cell says to B cell: I think our body is dangerous to us!

B cell says to T cell: Oh, snap! Let’s get the word out!

B cell needs to tell the body about this danger. It makes a message that says, “Danger right here! Danger!”

B cell says to mast cell: WE ARE IN GRAVE DANGER! ATTACK! ATTACK!

Mast cell to other cells: KILL THIS INVADER KILL IT TO DEATH

Except there is no invader. It is just your regular joints being regular and not dangerous.

Other cells: *trying to kill your joints*

Joints: Uh, guys, I’m actually supposed to be here –

Mast cell: I CAN’T HEAR YOU OVER THIS SCREAMING B CELL

Let’s recap.

T cell gives the B cell bad information. This causes B cell to alert other cells of “danger.” But this wasn’t the B cell’s fault. It was the fault of the T cell which gave the B cell bad information. And that means that everything that comes after the T cell giving the B cell the bad information makes the problem worse but is not really the cause of the problem.

I used rheumatoid arthritis as an example because a lot of treatment of rheumatoid arthritis revolves around blocking those danger signals from mast cells. But is the mast cell the cause of the rheumatoid arthritis? No, it is not. It is not the cause because mast cells have to respond to commands from B cells in order to help protect us against infection and do other helpful things. The mast cell did not decide the joints were dangerous. The B cell told the mast cell this so the mast cell is working with bad information that it doesn’t realize is bad.

If the mast cell isn’t the cause of the rheumatoid arthritis, why do we bother blocking mast cell signals instead of telling the T cell and B cell to be quiet? Because quieting the mast cell signal will help with symptoms and we know how to quiet the mast cell signal and we don’t always know how to quiet the other signals. Stopping the mast cell signal can make symptoms much better but it does NOT cure rheumatoid arthritis. Why? Because mast cells do not cause rheumatoid arthritis.

So mast cells are involved in many diseases without causing most of them. The way you can tell they are not the cause is that they did not start the wrong “message” that caused the symptoms and damage.

Now, I would like to address the fact that there are some diseases that have some research to suggest that they may genuinely be a form of mast cell activation disease. Fibromyalgia is one of these diseases. However, at this time, there is not enough evidence for it to be classified as a mast cell disease.

I tried to be as clear as possible about a very complicated topic. If I didn’t do it well, tell me and I’ll have another go at it.

(Author’s note: This is a SUPER simplified version of rheumatoid arthritis. RA is an autoimmune disease and it is still not clear exactly how the T cells and B cells start sending the wrong messages in an autoimmune disease. I just simplified it here to make it easier to see my point.)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 38

45. Is mast cell disease autoimmune?

An autoimmune disease is the result of a patient’s immune system specifically targeting a normal, healthy part of their body. How particularly and precisely the immune system identifies part of the body to attack is very important to understanding my answer to this question.

Let’s look at some autoimmune diseases as examples.

Autoimmune thyroiditis (also called Hashimoto’s thyroiditis) is a prevalent autoimmune disease that targets the thyroid. The thyroid’s job is to make hormones that tell your body to do other things. These hormones are called thyroid hormones. When you have autoimmune thyroiditis, your immune system makes antibodies that target the thyroid and thyroid hormones. These are called autoantibodies. They target a normal part of body. There is no reason for the body to make these autoantibodies. They do not perform any healthy function for the body. The only function they serve is to attack part of the body.

When you have autoimmune thyroiditis, the immune system makes antibodies to things that are only found in the thyroid or made by the thyroid. (I’m being very general here.) Other autoimmune diseases target parts of the body that are found throughout the body so that the effects of the disease are more widespread. However, those diseases still target specific things.

Lupus is an autoimmune disease that affects many places in the body by precisely attacking things found throughout the body. The cells in your body all have DNA inside of them. This DNA has the genes to make proteins and other things your body needs. If the cell can’t use the DNA inside it correctly, it makes your body sick. This is exactly what happens in lupus. Lupus makes autoantibodies and attacks things inside your cells that your body needs to use the DNA. Because all of the cells in your body need to use their DNA, the things lupus attacks are found all over the body, not just one organ. But even though lupus attacks many organs and places throughout your body, it is still targeted to harm specific pieces of the body.

In autoimmune disease, the body makes specific things for the explicit purpose of damaging specific things.

Now let’s talk about mast cell disease.

Currently, mast cell diseases are not considered to be autoimmune by most – but not all – experts. (I’ll circle back to this.) When a person has mast cell disease, the fundamental issue is that they release tons of mast cell mediators at times when they shouldn’t, causing symptoms and damage to the body. But even though those chemicals can cause all kinds of problems, they are not targeted to attack specific structures. This is where the distinction is from autoimmune diseases. Mast cells release tons of histamine, but that histamine isn’t targeted to find a specific molecule inside of a liver cell. They release prostaglandin D2, but that PGD2 isn’t made for the particular purpose of attacking one particular thing inside of your thyroid.

Instead, the molecules released incorrectly by mast cells affect whatever cells are in its path. This is one of the reasons why there is such variability in symptoms and disease effects for mast cell patients. What parts of the body are affected the most is dependent upon a million things happening in the patient’s body. This is because the chemicals mast cells release are not targeted to any one place. They are just released by the mast cell and they go wherever they can before the body breaks them down.

I mentioned above that most experts did not consider mast cell diseases to be autoimmune, but not all of them. So let’s go back to that. Mastocytosis is not considered autoimmune but anyone as far as I am aware. There is absolutely no evidence that mastocytosis is autoimmune after decades of research. But MCAS is a newer entity and so there is less information on it due to less time spent researching it. There are still a lot of questions around MCAS and some experts think that whether or not it is autoimmune is one of them.

We know that at the very least that there is a connection between MCAS and autoimmune disease. Many MCAS patients have autoimmune disease, often more than one. We think MCAS occurs secondarily to the autoimmune disease in these patients. There’s also the fact that many MCAS patients are positive for ANA (antinuclear antibody), an autoantibody linked to lupus, even though they don’t have a diagnosed autoimmune disease that would cause that to be positive. Some people think that maybe MCAS is the autoimmune disease in that situation and that ANA is a marker indicating that MCAS is autoimmune. I have mentioned elsewhere that while we consider MCAS to usually be a secondary disease, there are some patients for whom we can’t find a primary disease. It is possible that MCAS is a primary condition in those people and that it is autoimmune.

You still need to keep in mind that even if we say that maybe the positive ANA shows that MCAS is autoimmune, there is still no evidence of any kind that indicates that mast cell mediators target a specific part of the body – a defining characteristic of autoimmune disease. That doesn’t mean there isn’t an autoantibody or some other mechanism for targeting precise structures in the body, just that we have no evidence of one existing right now.

Let’s recap: currently, most experts believe that mast cell diseases are not autoimmune because they do not target specific normal, healthy structures in the body. Mastocytosis is roundly agreed to not be autoimmune. There are some experts who feel that at least some cases of MCAS might be autoimmune. They feel this way because of the clear link between MCAS and other autoimmune diseases, as well as the fact that many MCAS patients are positive for an autoimmune marker, ANA, without evidence of an autoimmune disease that would explain that.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 11

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

19. How do other conditions affect mast cell disease?
Mast cell activity can affect literally every system in the body.
• Mast cells are found throughout the body and live in many tissues and organs in significant numbers.
• There are essentially three types of damaging mast cell activity:
Normal mast cells are getting bad signals from other cells and they do bad things. This is not mast cell disease because these mast cells are not broken. They are getting signals from other broken cells.
Abnormal mast cells do bad things and tell other nearby cells to do bad things. This is mast cell disease, specifically mast cell activation syndrome and sometimes monoclonal mast cell activation syndrome.
You make way too many mast cells, they are abnormal, they do bad things, and they tell other nearby cells to do bad things. This is mast cell disease, specifically all forms of mastocytosis (systemic, cutaneous, and mast cell leukemia), sometimes monoclonal mast cell activation syndrome and mast cell tumors (mastocytoma and mast cell sarcoma).
• Generally speaking, if you have mast cell disease, any other condition you have will irritate your mast cell disease. This can also work the other way around and mast cell disease can irritate your other conditions.
• Many conditions naturally trigger higher level mast cell activation.
• Any disease that causes your body to make a lot of cells very quickly is likely to trigger to mast cell activation. Cancers are mast cell activating. Non cancerous diseases where you make too many blood cells at once, like polycythemia vera or essential thrombocythemia, are are mast cell activating.
• Mast cells are usually found very close to tumors. Sometimes, they are found inside tumors. Mast cells are important for tumors to survive because they can make blood vessels to bring tumors the blood they need.
Diseases affecting the immune system are triggering to mast cells. In fact, many patients have mast cell activation syndrome caused by the immune disease irritating their mast cells so much. Many mast cell patients have autoimmune diseases like lupus or rheumatoid arthritis. Many patients also have deficiencies in their immune system. Because mast cells are immune cells, they are very responsive to signals from other immune cells. Mast cells think those cells need help from them to fight an infection or disease so they respond strongly to “help”.
Diseases that cause inflammation also trigger mast cells. This can happen whether the inflammation is local or not. Systemic inflammation is more irritating to mast cells since that kind of inflammation can find more mast cells throughout the body. Local inflammation can irritate mast cells nearby. It can also call mast cells from other parts of the body to that location.
• Mast cells are actively involved in fighting infections from viruses, bacteria, fungi, and parasites. This is the reason many mast cell patients find they are more reactive when they have even a minor illness, like a cold.
Any type of physical stress can activate mast cells. This can be something as simple as exercise or something more traumatic such as a car accident, a surgery, or childbirth. Even things that should be easy to recover from can activate mast cells, like a small cut, dehydration, or getting overheated. This also includes stress caused by another disease.
Emotional stress can activate mast cells, even if the big emotion is joy.
For more detailed reading, please visit this page:

Symptoms and effects of mast cell disease

 

Rare disease month, day 2: CVID (Common variable immunodeficiency)

Common variable immunodeficiency (CVID) is a primary disease of the immune system characterized by inability of B cells to generate an appropriate antibody response. CVID patients demonstrate low levels of serum IgG alongside other deficiency of IgM, IgA, or both. Diagnosis is based upon both serum immunoglobulin levels; decreased vaccine response; and exclusion of any other condition that could explain these inadequacies.

As the result of an inherent inability to properly defend against infection, CVID patients results in recurrent respiratory infections, both upper and lower. Specifically, encapsulated bacteria such as S. pneumoniae and K. pneumoniae are the most frequent pathogens. Atypical organisms like Mycoplasma spp. are known to cause infections in this population. Recurrent respiratory infection can cause chronic inflammation, leading to chronic sinusitis, hearing loss, bronchiectasis, and structural damage to the lungs.

CVID patients are at increased risk of complications beyond infections. Approximately 15% of patients develop cancer. 20-25% of patients report autoimmune disease. A significant amount of CVID patients with autoimmune disease have low blood counts as a result.

CVID can lead to known complications affecting the lymphatic system. 10-25% of CVID patients develop granulomatous lymphocytic interstitial lung disease. Enlarged lymph nodes occur in approximately 20% of CVID patients. Infiltration by lymphoid cells can be found in multiple organs, including kidney and liver.

Gastrointestinal manifestations are not unusual for CVID patients and can affect any portion of the tract. Inflammatory bowel disease is common. Of note, small bowel enteropathy is well documented in this population and may resemble inflammation seen in celiac disease. CVID patients may also demonstrate nodular lymphoid hyperplasia upon biopsy.

Treatment for CVID is based upon replacing the missing antibodies through administration of intravenous or subcutaneous gammaglobulin. While gammaglobulin replacement can help significantly with immune defense, CVID patients are still at risk for progression of organ damage. Specifically, obstructive or restrictive lung disease, along with bronchiectasis, may be stemmed by gammaglobulin replacement.

For more information, please visit the Immune Deficiency Foundation.

Reference:

Tam JS, Routes JM. (2013) Common variable immunodeficiency. Am J Rhinol Allergy, 27(4), 260-265.

Take home points: November 2015

Immunoglobulin free light chains: A possible link between autoimmune disease and mast cell activation

  • Light chains are part of antibodies that fight infections and responds to allergens
  • Free light chains are pieces of antibodies that broke off and do not work as antibodies
  • Elevation of immunoglobulin free light chains has been linked to many diseases, including lupus, rheumatoid arthritis, inflammatory bowel disease and food allergy
  • Free light chains correlate with symptom severity and flares in some conditions
  • Free light chains may be able to activate mast cells without IgE involvement
  • Free light chains may be the link between mast cell activation and autoimmune disease

Explain the tests: Complete blood count (CB) with differential and platelets (Part One)

  • A complete blood count (CBC) counts white blood cells, red blood cells and platelets in blood
  • It also looks at the shape, size and variation in size of cells

Explain the tests: Complete blood count (CBC) – Low red cell count (Part two)

  • Mature red blood cells live in the blood for 100-120 days
  • Hemolysis is when red blood cells burst and a little bit of hemolysis is normal
  • Red blood cells transport oxygen from lungs to tissues
  • Red blood cells have hemoglobin inside them
  • Hemoglobin is a protein with iron in the middle and it carries oxygen
  • Low red blood cell count or hemoglobin is called anemia
  • Red blood cell count can be low for several reasons, including nutritional deficiency and production dysregulation in bone marrow
  • Mast cell patients often suffer from anemia of chronic inflammation, which can cause low red count
  • Patients with inflammatory bowel disease can have low red count due to bleeding
  • Swelling of spleen can cause low red count

Patient questions: Is mast cell disease autoimmune?

Autoimmune disease is when your body has an abnormal immune response to something that is a normal part of the body. There are more than eighty currently identified autoimmune diseases and they affect a significant population worldwide. At least 2% of women are estimated to have at least one autoimmune condition. Multiple sclerosis, rheumatoid arthritis and lupus are examples of autoimmune disease. Autoimmune diseases can affect small areas or multiple organs or targets throughout the body.

There are a number of possible causes of autoimmune disease. Some well supported theories include:
1. Molecular mimicry. This occurs when the body is exposed to an external danger and direct antibodies and immune defense against this danger. However, once the danger has been resolved, the antibodies and immune defense are directed toward damaging some normal part of the body that by happenstance looks like the dangerous thing. A classic example of this is development of rheumatic fever, PANDAS and other complications after a Streptococcus infection. The body makes antibodies to fight Strep, the Strep is killed and infection resolved, but the antibodies then attack things in the body that look like strep to the antibodies.
2. Genetic predisposition. Mutations and improper expression of genes that mediate tolerance, like HLA genes, can result in autoimmune disease. In these patients, these anomalies cause the body to fail to recognize itself as “safe”.
3. Cryptic determinants. This refers to the situation in which a hidden part of a normal structure in the body is not usually “seen” by the rest of the body. When that hidden part is exposed to the rest of the body, the immune system does not recognize it and attacks it, thinking it is dangerous. I imagine this as a waterway in a year of drought. A river has many small black rocks on the bottom. When the water is high, like most years, you cannot see these rocks. In a year of drought, the water level drops and you can the black rocks on the bottom. They were always a natural part of the riverbed, and they were always there, you just couldn’t see them. This can happen inside the body too. Sometimes your immune system sees things that were always there but not seen by it before.

The key feature unifying autoimmune diseases is that the immune system directly targets a part of the body that is normal and healthy. In lupus, the body makes antibodies that target the DNA inside our cells, which is not just normal but critically important to survival. It doesn’t target defective DNA, it targets regular old, keeps us alive, DNA.

Mast cell diseases are not autoimmune diseases. Mast cell diseases are not directly their attacks to a normal, healthy part of the body. In mast cell disease, mast cells are dysregulated and behave inappropriately. While this can damage parts of the body, this damage occurs due to the general inflammatory environment rather than because mast cells specifically targeted those parts of the body. Aberrant mast cells aren’t saying, “Quick, there’s an intruder in the liver! Let’s go get them!” when it’s just your regular liver hanging out. They are just so activated that mediator release could damage some cells in the liver, and in other places at the same time. The mast cell activation does not specifically target the liver in this scenario.

A confusing aspect of mast cell disease is that MCAS can occur secondary to autoimmune disease and many MCAS patients have autoimmune disease. In this patient population, the MCAS is probably induced by the inflammation caused by the autoimmune disease. Even still, while the primary autoimmune disease targets specific parts of the body, MCAS does not target specific parts of the body to attempt to destroy them.

Immunoglobulin free light chains: A possible link between autoimmune disease and mast cell activation

An antibody (also called an immunoglobulin) is shaped like a Y.  The base of the Y is called the Fc region.  The arms of the Y are made of pieces called light chains and heavy chains.  Light chains (described as K or λ) have variable sequences that allow the complete antibody to stick to specific things, like bacteria or allergens.  Light chains are part of how your body fights infections and responds to allergens.  Importantly, free light chains do not work as antibodies.  They are not able to stick to the target the way the total antibody can.

Antibodies are made by white blood cells called plasma cells, which are B cells that circulate and release antibodies as needed.  When producing antibodies, B cells normally make more light chains than heavy chains.  Only about 60% of the light chains made are needed to produce antibodies.  The rest of the light chains are released into plasma and are present there for 2-6 hours, until they are cleared by kidneys.  Light chains that are released into plasma are called immunoglobulin free light chains, shortened as Ig-fLCs.

Another way Ig-fLCs are formed is when they antibody is bound and degraded by a cell.  Antibodies bind things like allergens.  Once they bind allergens (or something else), the antibodies can then bind to receptors on the outside of cells to tell the cells what they found.  Once the antibody is bound to the receptor, it can be partially broken down.  However, light chains are not damaged in this process, and they may be released back into serum.

Ig-fLCs are the subject of ongoing research in various disease models.  Ig-fLC elevation has been linked to a number of inflammatory conditions, including autoimmune diseases.  Systemic lupus erythematosus (SLE) patients demonstrate a significant elevation of Ig-fLCs in urine 4-8 weeks prior to a symptomatic flare.  SLE is an antibody driven disease and the extra Ig-fLCs may be produced as a byproduct of making more autoantibodies in advance of a flare.  In this capacity, it would demonstrate hyperactivity of the B cells that make the autoantibodies.

Ig-fLCs were also found to be elevated in 1/3 patients with rheumatoid arthritis and 1/5 patients with systemic sclerosis.  A number of cancers also induce elevation of Ig-fLCs.

Ig-fLCs are involved in a number of allergic processes.  In allergic asthma animal models, Ig-fLCs have been found to induce bronchoconstriction and acute mast cell degranulation.  Using an experimental light chain antagonist can prevent this reaction.  Κ light chains are elevated in serum of asthmatics, regardless of whether or not the asthma is atopic is nature. λ light chains are not elevated in this population.

Ig-fLCs are also involved in other allergic mouse models, including contact dermatitis, food allergy and inflammatory bowel disease.  In these models, the Ig-fLCs can sensitize mast cells to allergens so that exposure to the allergen causes mast cell activation and degranulation.

Ig-fLCs have also been implicated in mast cell dependent colitis and inflammatory bowel diseases such as ulcerative colitis and Crohn’s.  It is believed that antigen specific Ig-fLC sensitizes mast cells to cause activation and degranulation.  This is especially important because it describes a mechanism that occurs in the absence of IgE.  Serum κ and λ light chains are elevated in Crohn’s models and using an experimental blocker prevents these bowel symptoms.  Research has indicated that the IgE, IgG and paired Ig-like receptor A receptors are not involved in binding Ig-fLCs in these models.

Many mast cell patients have a primary inflammatory condition, such as IBD or autoimmune disease.  Mast cell activation via Ig-fLCs is, to me, the most plausible explanation for this relationship.  Currently, mast cell activation by Ig-fLCs has not been demonstrated in humans, though present in many animal models.  However, Ig-fLC correlation to autoimmune diseases such as lupus has been shown in humans.

References:

Kraneveld A, et al. Elicitation of allergic asthma by immunoglobulin free light chains. PNA 2005: 102(5); 1578-1583.

Thio M, et al. Antigen binding characteristics of immunoglobulin free light chains: crosslinking by antigen is essential to induce allergic inflammation. PLoS One 7(7): e40986.

Rijnierse A, et al. Ig-free light chains play a crucial role in murine mast cell-dependent colitis and are associated with human inflammatory bowel diseases. J Immunol 2010; 185:653-659.

Gottenberg JE, et al. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren’s syndrome. Ann Rheum Dis 2007; 66:23-27.

Aggarwal R, et al. Serum free light chains as biomarkers for systemic lupus erythematosus disease activity. Arthritis Care and Research 2011: 63(6): 891-898.

Privilege

My body is changing. I am tired but do not sleep for twenty hours at a time. Bones and angles emerge as my swelling wanes. I exercise. I eat real food. I sleep at night.

At the same time, I am carefully engineering to encourage these continued changes. I still take a ton of medication. I still need IV fluids every day. I still need IV meds. I still need to manage my pain. I still need to be careful. This nethervoid I currently inhabit might never be mistaken for healthy, but it is healthy for me. It is stable at least, predictable. It is good for me.

Last week was composed of the oppressive, sticky summer days that Boston is known for. Heat, humidity and sunlight form my own personal triad of doom. I got halfway through my short walk between stations and started reacting badly. I went into a Starbucks and promptly threw up while hives appeared on my neck. All of my exposed skin was bright red. I took some Benadryl and drank some cold water and waited for things to calm down. They did. I continued on my way to work.

It is hard for me to gauge how bad I look on any given day, as I was for many years in a persistent reactive state. My only indication is that initial surprise when people look at me, that flash of concern as their eyes widen, a brief moment before they recover. I knew as soon as I got to work that I must look terrible.

We have a cold room at work that is essentially an enormous refrigerator. “Girl, you need to go stand in there,” one of my coworkers said with a supportive nod. So I did. It helped. When I emerged, multiple people told me they were worried I would anaphylax and to please take a cab home. I am so fortunate to work with this group of caring, wonderful people that understand my disease and want me to be safe.

I did end up taking a cab home. I didn’t want to, but I did. It’s hard for me to articulate why I didn’t want to, when I knew it was safer and easier, in a way that doesn’t make me sound crazy. Getting in that cab made me sad in this nebulous but palpable way.

Taking the train to work is a privilege. Going to work, cleaning your house, paying your bills, food shopping, making dinner, eating solids, crunching lettuce as you watch television, being part of the world. These are privileges. These are the things you miss when you are hospitalized or so tired that your whole body feels heavy or riding that knife’s edge of anaphylaxis because your body is fighting you on something you need to do.

All of the days you spend fighting – this is what it is for. You fight for these privileges. You fight to be in the world. These are the things you will miss. All you can ever hope for is to wake each day to a world full of mundane privileges.

Some days I want to take the train even if there is a chance I will get sick. Because there is a chance that I won’t. Once that was impossible. Maybe it will be again. Maybe tomorrow it will be impossible, but not today.

I am still sick. I am still in pain. I still have a poorly functioning GI tract. I still carry two Epipens and a backpack full of meds everywhere I go. I am still nauseous. After all of the effort put forth in the last three months, I did not get cured. I got to walk to work sometimes. I got to eat salad. I got to feel the sunlight on my skin. That’s what I got. And it’s enough, and even more than it’s enough, it’s amazing. All of this is amazing. I am alive this summer and I am alive in the heat and I am alive when I’m too hot and I’m alive in the sun.

You cannot always decide what you do, but you can always decide who you are. I cannot always walk in the summer sun, but I am always a person who wants to.

I choose to live in the world and to enjoy it and be alive. I choose this even when it might hurt me. I choose this even when it might kill me. It is where I want to be.

It is a privilege to participate in this world. It is a privilege to be alive.

Angioedema: Part 4

Deficiencies of an early component of the classical complement pathway (C1q, C1r, C1s, C2, C4) have been associated with lupus like autoimmune conditions. The reason for this is that these proteins help to clean up large groups of molecules called immune complexes before they can cause inflammation. Dead cells are also removed by these complement molecules. Without these proteins, immune complexes and dead cells are not removed and cause local irritation.

In HAE types I and II, complement proteins C2 and C4 are low. However, HAE patients have been shown to have a normal level of immune complexes. For this reason, it is still unclear whether or not low C2 and C4 may contribute to overall inflammation and pain profile for these patients. Despite this fact, it is still possible that deficiency in C2 and C4 may predispose HAE patients to autoimmune diseases.

A number of studies have assessed the prevalence of autoimmune conditions in HAE patients. One study looked specifically for two thyroid antibodies and found that 13.2% HAE patients had autoantibodies to the thyroid.

When expanding the autoimmune profile to include “lupus-like” conditions such as those often associated with complement deficiencies, a much higher prevalence of autoantibodies was found in HAE patients. Three other studies measured the frequency of ANA (anti-nuclear antibody, a generic marker found in many autoimmune conditions); RF (Rheumatoid Factor, associated with rheumatoid arthritis); anti-thyroglobulin(autoimmune thyroiditis); TPO (thyroid peroxidase, autoimmune thyroiditis); and thyroid antibodies along with some or all of the following antibodies: anti-dsDNA (anti double stranded DNA, systemic lupus erythematosus); ENA (extractable nuclear antigens, a panel of six tests that can identify mixed connective tissue disease, systemic lupus erythematosus, Sjogren’s, Scleroderma and dermatomyositis); TMA (microsomal antibodies, autoimmune thyroiditis); AMA (antimitochondrial antibodies, drug-induced or systemic lupus erythematosus, Sjogren’s, autoimmune hemolytic anemia, autoimmune liver disease); ANCA (antineutrophil cytoplasmic antibodies); anti-cardiolipin (systemic lupus erythematosus, Behcet’s, antiphospholipid syndrome); anti-b2GPI (b2-glycoprotein I, systemic lupus erythematosus, Behcet’s, antiphospholipid syndrome); anti-C1q (urticarial vasculitis); anti-P ribosomal (systemic lupus erythmatosis); EMA (anti-endomysial antibodies, Celiac disease); tTG (anti-tissue transglutaminase antibodies, dermatitis herpetiformis); and ASCA (anti-saccharomyces cerevisiae antibodies, Behcet’s, Celiac disease, Crohn’s disease, ulcerative colitis). The three studies found that 47.5-48% HAE patients had at least one of these autoantibodies. In comparison, the average for healthy controls was 10%.

Other studies looked at prevalence of autoimmune disease rather than autoantibodies. One study found that 12% of HAE patients had at one of the following autoimmune conditions: glomerulonephritis, Sjogren’s syndrome, irritable bowel disease, thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, drug induced lupus, pernicious anemia, juvenile RA with IgA deficiency, or sicca syndrome.

Other studies found that 3.4% HAE patients had lupus rash or glomerulonephritis; that 0.9% had RA or Sjogren’s; that 11.5% had Crohn’s, Celiac, Hashimoto’s thyroiditis, discoid lupus erythematosus, chronic lymphocytic leukemia, MGUS, or IgA deficiency; that 11.4% had systemic lupus erythematosus, Celiac, multiple sclerosis-like syndrome, systemic sclerosis, or mixed connective tissue disease; that 4.2% had lupus like syndrome, psoriatic arthritis, mixed connective tissue disease or antiphospholipid syndrome; that 0.4-0.9% had lupus-like or unspecific cutaneous lupus or subacute lupus.

An interesting feature of HAE is the frequent complaint of decreased sense of smell. Facial edema and chronic rhinosinusitis were not found to be the cause. However, systemic lupus erythematosus and Sjogren’s syndrome can also cause impairment of smell. Despite the frequency of lupus in HAE patients, it usually affected the mucocutaneous regions of the body and was generally mild.

In addition to the frequent prevalence of autoantibodies and autoimmune disease, HAE patients have increased B cell activation and autoreactive B cells. This can also contribute to an inflammatory and autoimmune profile.

 

References:

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

Kaplan AP, et al. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010 Aug; 47(13):2161-9.

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Csuka, Dorottya, et al. Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. J Allergy Clin Immunol 134 (6) 1388-1393.e3.

Triggianese, Paola, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmunity Reviews 2015 (ahead of press).