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 Disease, Part 23

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

  1. Is mast cell activation the same as mast cell activation syndrome?
  • No.
  • This is the single most important clarification I make as an educator. It is crucial to understand that they aren’t the same thing, especially if you research mast cell activation syndrome online.
  • Mast cell activation is a normal and healthy process. Mast cell activation mostly means that they are ready to release chemicals in response to signals from inside the mast cell or from other cells. It is one of the major ways mast cells carry out their normal functions, like fighting infections, healing the body post trauma, and regulating the menstrual cycle.
  • Many things activate mast cells to tell mast cells to act in their normal functions. Bacteria, viruses, fungi, cancer cells, diarrhea, pain, surgery, physical or emotional stress, and many other things all activate mast cells normally. It is not surprising that these things activate mast cells because they should activate them.
  • Sometimes mast cells overreact to signals to activate, like in allergies and anaphylaxis.
  • The reason mast cell activation is a problem in mast cell disease is because mast cells respond way too strongly to activation signals. They release too many chemicals too often.
  • The other reason mast cell activation is also a problem in mast cell disease is because they become too easily activated.
  • Think of mast cells like houses. Like any house, they have doors. In healthy people, you need a lot of people knocking on the doors and windows at the same time to get the mast cell to open the doors and release chemicals. In mast cell patients, one person can knock a few times and all the doors open and release chemicals at once.

For more information, please visit this post:

The Provider Primer Series: Introduction to Mast Cells

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

 

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 5

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

10. How is mast cell disease diagnosed?
• There are several tests you need to definitively determine if you have mast cell disease and what kind you have.
The most well known test for mast cell disease is serum tryptase. This is a blood test. This is the test doctors are most likely to have heard of. Doctors may think that you can’t have mast cell disease if tryptase is normal. This is not true.
• If a patient has a tryptase over 20 ng/mL, the next step is usually a bone marrow biopsy. A tryptase over 20 ng/mL increases the likelihood that a patient has systemic mastocytosis. SM is most commonly confirmed by a bone marrow biopsy.
• You need a special stain in order to see mast cells in any biopsy. Stains that show mast cells include Giemsa Wright stain and toluidine blue. Your doctor should specify these stains.
• Several tests must be run on the bone marrow biopsy to look for clonal mast cell disease. Remember that in clonal diseases, the body makes too many broken cells.
• The shape of the mast cells in the biopsy is very important. If the mast cells are not shaped right, this can be a sign of mast cell disease.
• The number of mast cells grouped together in the body is also important. If 15 or more mast cells are all stuck together, this is called a cluster. When mast cells are clustered together like this, they can punch holes in the tissue and damage it a lot. This prevents the tissue from working right.
• Immunohistochemistry (IHC) is a way to find specific proteins that allow us to know what cells we are looking at in the biopsy. Often, these proteins are on the outside of the cells. Think of these are flags that a cell can wave. IHC can look for the specific flags a cell is waving so that we know for sure which cell is which. For mast cell disease, they want to look for CD117, CD25, and CD2. The CD117 flag is flown normally by all mast cells. CD25 and CD2 are special flags flown by mast cells if you have clonal mast cell disease.
• PCR is a way to look for genetic mutations. They need to look for a mutation in the mast cells in the bone marrow. The mutation is found at a specific place in the CKIT gene. This mutation is found in 80-90% of patients with systemic mastocytosis. It may also be found if patients have monoclonal mast cell activation syndrome.
• If a patient does not have a tryptase over 20 ng/mL, a bone marrow biopsy is often not ordered. There are other tests that can indicate mast cell disease.
• Urine collected over 24 hours can be tested for specific chemicals. In the case of mast cell disease, they are looking for chemicals that can be high if you have mast cell disease. These chemicals have very long, complicated names. I will explain in a later post exactly what they are and what they do. The most common ones are called n-methylhistamine, prostaglandin D2, 9a,11b-prostaglandin F2, and leukotriene E4. Anti-heparin Xa and chromogranin A are sometimes tested. They are much less reliable as indicators of mast cell disease than the others mentioned here.
• If a patient is suspected to have cutaneous mastocytosis, a skin biopsy is needed to confirm. As with bone marrow biopsies, your doctor should specify that they need to use toluidine blue or Giemsa Wright stain to be sure they see the mast cells.
• The skin biopsy should also receive the other tests I described above for bone marrow biopsy: the counting of mast cells and looking at the shape; looking for CD117, CD2, and CD25; and looking for the same mutation with PCR.
11. What kind of doctor diagnoses mast cell disease? Can any doctor order these tests?
Doctors from all different specialties may diagnose and manage mast cell disease. It depends upon the individual provider and where you are located. It could be a dermatologist, allergist, hematologist, pulmonologist, gastroenterologist, or another specialist.
• The serum tryptase is the easier to order and the most well known test. Many labs can run this test.
• The 24 hour urine tests are specialized. Some of them are run in only a few places and samples are usually shipped there. Most often, these samples are run at the Mayo Clinic. Many outpatient labs have no way to run those tests. You will need to speak with your doctor about how to get these tests. It is often easiest if they are run by a hospital lab but again, this depends upon the hospital.
• The PCR genetic test for this specific gene is run in more places than the urine tests but is still not very common. Again, it is often easiest if they are run by a hospital lab.
• A bone marrow biopsy is usually ordered by a hematologist or by another specialist that works commonly with hematologists. They are usually performed by hematology providers. Some testing can usually be performed in house (the counting of the cells and looking at the shape) while others may need to be sent out (the IHC testing).
• A skin biopsy is usually ordered by a dermatologist. Some testing can usually be performed in house (the counting of the cells and looking at the shape) while others may need to be sent out (the IHC testing).
For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The Provider Primers Series: Introduction to Mast Cells

Mast cells : Introduction

  • Mast cells are bone marrow derived. They migrate to tissues before maturity and remain tissue bound.[i]
  • Mast cell development in tissues is regulated by a number of molecules, most significantly stem cell factor (SCF) which binds at the CKIT (CD117) receptor. A number of other molecules, including IL-3, IL-4 and IL-10, also participate in this process.[ii]
  • Mast cells are long lived, with some living for years in tissue.[ii]
  • Mast cells are versatile actors. Their functions and granule contents are tailored to the needs of the local microenvironment.[iii]
  • Mast cells perform a number of critical roles, including immune defense against microbes and larger parasites; clotting; wound repair; tissue remodeling; angiogenesis; regulation of reproductive cycle; digestion and GI motility; pain response; participation in stress response via interaction with HPA axis; inflammatory response; and regulation of sleep and some aspects of cognition.[iv]
  • Mast cells produce a multitude of mediators which are stored in granules or produced de novo. Stored mediators of consequence include histamine; tryptase; heparin; bradykinin; serotonin; and substance P. De novo mediators include prostaglandin D2; leukotrienes C4, D4, and E4; platelet activating factor; tumor necrosis factor; interferons; and a number of interleukins, including IL-1a, IL-1b and IL-6, among many others. [iii]

Mast cell involvement in disease

  • Mast cells are involved in the pathology of many conditions, including asthma[iv]; autoimmune diseases[iv]; GI dysmotility, including post-operative ileus[v]; cardiovascular events[iv], such as myocardial infarction, rupture of atherosclerotic plaques or aneurysms, and coronary syndromes, including Kounis syndrome[vi]; cardiovascular disease; malignant and neoplastic [iv]; chronic kidney disease[iv]; cutaneous conditions[iv], including many forms of urticaria; depression and anxiety; and chronic pain[vii].
  • Mast cells are effectors in all mast cell diseases.
  • Most famously, mast cells are involved in allergy and anaphylaxis.[viii]

Mechanisms of mast cell activation

  • Mast cells are primarily activated via IgE crosslinking at the FcεRI receptor. This is the mechanism for the classic allergy model in which specific IgE binds the target allergen and crosslinks at the FcεRI receptor on the surface of mast cells and basophils. In this traditional model, crosslinking causes immediate degranulation of stored mediators and late phase release of mediators produced de novo upon activation[viii].
  • There are several other mechanisms for direct mast cell activation that are independent of IgE.
  • A number of inflammatory molecules can directly activate mast cells by binding surface receptors including corticotropin releasing hormone; substance P; histamine; cysteinyl leukotrienes; adenosine; stem cell factor; IL-3; IL-4; IL-9; and IL-33, among others[ix].
  • Substances associated with immune defense and infection can directly activate mast cells. Products derived from pathogens can activate via toll like receptors (TLR2 and TLR4), Dectin-1 or CD48. Host production of β-defensins and complement C3a and C5a can also provoke mast cell activation[ix].
  • IgG can bind at FcγR receptors on mast cell surfaces. Immunoglobulin free light chains have triggered degranulation in murine models but this has not yet been demonstrated in humans[ix].

Definition of anaphylaxis

  • The definition of anaphylaxis continues to be disputed. The 2006 NIAID/FAAN criteria detailed below have been validated and are widely used.[x]
  • Anaphylaxis is likely when any one of the following three criteria is met:
  • Criterion 1: Acute onset of illness with skin and mucosal issue involvement (hives, itching, flushing, swelling of lips/tongue/uvula) with at least one of the following: compromised airway (difficulty breathing, wheezing, low blood oxygenation); or reduced blood pressure or symptoms thereof (fainting, incontinence.)
  • Criterion 2: Two or more of the following occurring after exposure to a likely allergen: skin or mucosal tissue involvement (hives, itching, flushing, swollen lips/tongue/uvula), compromised airway (difficulty breathing, wheezing, low blood oxygenation); reduced blood pressure or symptoms thereof (fainting, incontinence); or persistent GI symptoms (cramping, abdominal pain, vomiting).
  • Criterion 3: Reduced blood pressure after exposure to known allergen.  For adults, this is <90 mm Hg systolic, or at least 30% decrease from baseline.  For children under 1 year of age, this is <70 mm Hg systolic; ages 11-17, <90 mm Hg systolic.  For children 1-10 years of age, this is <(70 mm Hg + (2x age)).  So for a child who is 8 years old, this would be <(70 + (2 x 8)) = <86 mm Hg.

References:

[i] Dahlin JS, Hallgren J. (2015). Mast cell progenitors: origin, development and migration to tissues. Molecular Immunology 63, 9-17.

[ii] Amin K. (2012). The role of mast cells in allergic inflammation. Respiratory Medicine, 106, 9-14.

[iii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[iv] Rao KN, Brown MA. (2008). Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann NY Acad Sci, 1143, 83-104.

[v] De Winter, BY. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta, 1822, 66-73.

[vi] Kounis NG. (2016). Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[vii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1), 38-44.

[viii] Galli SJ, Tsai M. (2013). IgE and mast cells in allergic disease. Nat Med, 18(5), 693-704.

[ix] Yu Y, et al. (2016). Non-IgE mediated mast cell activation. European Journal of Pharmacology 778, 33-43.

[x] Sampson HA, et al. (2006). Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol, 117(2), 391-397.

Mast cell mediator release mechanisms

There are many ways for mast cells to be activated.  Each of them involves a sequence of events involving several molecules.  These molecules change the next molecule in line in a way that causes it to perform a specific action.  It is hard to visualize and one of the harder concepts to understand about molecular biology.

I think of it like carrying the Olympic Torch to the Olympic Games. Before the Olympic Games, the Olympic Torch is lit in Greece.  Then a series of different people from all over the world carry the torch part of the way before giving it to another person.  Many, many people are involved, and the environment changes, but the torch always stays lit.  Finally, the very last person carries the torch into the stadium to light the Olympic Flame to open the Olympics.  Even though the people and environment changed, it’s still the same flame.

In the body, pathways are just like passing this Olympic torch. Instead of people carrying the flame and keeping it lit, molecules carry a message that they tell to the next molecule, and so on until the pathway ends.  The best known mast cell activation pathway is IgE activation.  IgE binds to a receptor on the outside of the mast cell.  The receptor knows that this means it has to degranulate.  It passes this message to a molecule, which passes the message down the line, just like the torch, until the mast cell degranulates.

Mast cells are well known for having many large granules that hold mediators until there is a signal to release. Granules are like pockets and mast cells stuff them full of premade mediators like histamine and tryptase. Mast cells actually sort mediators so that the granules are organized and mediators aren’t distributed randomly. The way mediators are stored together greatly affects the action of these molecules once they are released.

Large scale degranulation (sometimes called complete or anaphylactic degranulation) is the best known mast cell mediator release mechanism. In this kind of degranulation, granules swell and then lots of granules actually clump together to make a very large pocket. Then, this super pocket goes to the edge of the mast cell, the cell membrane, and pokes a hole to the outside.  The mediators in the super pocket are then released at once.  The granules and membrane have holes in them that will eventually be repaired. Following large scale degranulation, it takes about two days for normal mast cells to regranulate.

There is another kind of degranulation called piecemeal degranulation. This involves release of some mediators in a granule.  There is still a lot we don’t know about this process, but the general idea is that a regular granule puts some of its mediators into a tiny little bubble.  The little bubble then goes to the edge of the mast cell and slowly releases these mediators.  In piecemeal degranulation, the granules do not clump together to make one large granule, and there is no hole made in the membrane.  It is believed that some molecules help to push the mediators out of the cell but we don’t know what they are.

A number of mast cell mediators are not stored in granules and are instead made upon signals from specific pathways. Because these molecules aren’t stored in granules, it takes some time for them to be produced and released after mast cell activation. Lipid mediators, like prostaglandins and leukotrienes, are packed together and then transported across the membrane to the outside by other molecules.  Cytokines and chemokines are also produced on demand and then stored in small bubbles.  These small bubbles are then actively pushed out of the cell in a process called exocytosis.

References:

Moon TC, et al. Mast cell mediators: their differential release and the secretory pathways involved. Front Immunol 2014: 5:569.

Wernersson S, Pejler G. Mast cell secretory granules: armed for battle. Nat Rev Immunol 2014: 14(7), 478-494.

 

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.