Mystery Rays from Outer Space

TcR interacting with artificial membrane1

Why does autoimmune disease (sometimes) follow viral infection?²

It’s a pretty well-known phenomenon, but a definite answer isn’t yet known — and of course there may not be a single answer, there may be multiple causes. We know that many autoimmune diseases seem to be triggered by some sort of infection or inflammation. A classic example is Guillan-Barre syndrome, which is a little more common (though still very rare) in people who have received certain influenza vaccines, but there are plenty of other examples.³ It’s not believed that the infection actually “causes” the disease, but rather that someone who already has a genetic predisposition to the autoimmune disease needs to have some kind of environmental trigger to have the disease actually kick in; and, very rarely, a viral or other infection will provide that trigger.

(The genetic predisposition is clear because, among other points, identical twins are much more likely to both get autoimmune disease than are fraternal twins; whereas the need for an environmental trigger is clear because even if your identical twin gets an autoimmune disease, you’re usually less than 50% likely to get it yourself. Note that I’m lumping together hundreds of different diseases into the “autoimmune” package, and the specific odds and so on differ for each one.)

OK, so if you have a genetic predisposition to autoimmunity — and let’s get more specific, the paper I’m looking at deals with multiple sclerosis (MS) — there’s a small chance that a viral infection will trigger that disease. One of the most popular models for this is “molecular mimicry”. Simplified: This is the notion that a viral protein looks, to a T cell, a little bit like a self protein. The viral protein appears in the context of infection, with its concomitant inflammation and tissue damage and so on, and the T cell is activated to it. The T cell wouldn’t be activated by the self protein because it hasn’t been seen in the context of inflammation before, but once over the activation hurdle the T cell is now able to attack the self protein, and this is autoimmunity.

T cell receptor (top) interacting with MHC

Molecular mimicry is an attractive model, but there’s not a lot of direct evidence for it.  Another possibility has been proposed for a while: Dual TcRs. Normally, T cells can only recognize a single target. This is by “design”;⁴ if the T cell can see two targets, it could get activated by one, and then attack the other, even if the second target was never present during inflammation. This sort of dual target recognition is obviously dangerous, and there are safeguards that mostly prevent it; but some T cells do sneak through with at least the theoretical potential for dual recognition. So what could happen here is that one TcR could be directed against the pathogen, and activate the T cell; then the other TcR, recognizing self, could run amok because it’s now on an activated T cell.

T cells with dual specificity do exist, at a fairly significant frequency (1-8%; at least one source claims as high as 33%, which seems much too high to me), but whether they actually do anything in autoimmunity is up in the air. This idea has been around for a while, but I don’t think there’s been much evidence for it happening naturally. In at least one case, where it was tested in an artificial system, dual TcRs did not seem to be responsible for an automimmune disease. ⁵

The most recent paper offers evidence that (in quite an artificial system) dual-specificity T cells are responsible for multiple sclerosis: ⁶

Our results demonstrate the importance of dual TCR–expressing T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected people, as suggested by the etiology of multiple sclerosis.

It’s an interesting and solid paper as far as it goes, but we’re left with the issue of this being a highly artificial system — mice with manipulated TcRs and manipulated autoimmune disease. Is this a real issue in natural autoimmunity and natural infections? This paper doesn’t really address that, but it does support the notion that it’s something to look more closely at.  (And again, different autoimmune diseases, or even different people with the same disease, may have altogether different triggers.  Maybe some people have molecular mimicry as the trigger while others have dual TcRs and other have who knows what.)

1. By Raghuveer Parthasarath, then in the Groves lab[↩]
2. Also, why are so many of my keyboard keys sticking together? An altogether easier question quickly answered by pointing to my kids “helping” me with my work while holding popsicles[↩]
3. For a review:
   Fujinami, R. (2001). Can Virus Infections Trigger Autoimmune Disease? Journal of Autoimmunity, 16 (3), 229-234 DOI: 10.1006/jaut.2000.0484[↩]
4. I.e. evolution.[↩]
5. McGargill MA, Mayerova D, Stefanski HE, Koehn B, Parke EA, Jameson SC, Panoskaltsis-Mortari A, & Hogquist KA (2002). A spontaneous CD8 T cell-dependent autoimmune disease to an antigen expressed under the human keratin 14 promoter. Journal of immunology (Baltimore, Md. : 1950), 169 (4), 2141-7 PMID: 12165543 [↩]
6. Ji, Q., Perchellet, A., & Goverman, J. (2010). Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs Nature Immunology, 11 (7), 628-634 DOI: 10.1038/ni.1888[↩]

A truly amazing paper in today’s Nature¹ shows 2-photon microscopy videos of T cells entering the brain in search of their target antigen.  The title of this post is taken from the commentary,² also in Nature.

Disease-causing T cells first adhere to the inner walls of the pial vessels and then crawl in continuous contact with activated endothelial cells, most often in the opposite direction to the blood flow. …  After crossing the blood-vessel wall, the lymphocytes move along the outer surface of the vessel, encountering an array of antigens displayed by antigen-presenting cells, including macrophages. …  Last, the cells detach from the outer surface of the blood vessel and enter the spinal cord, travelling most often alongside penetrating vessels. In the spinal cord, they initiate tissue injury.²

There are a myriad of stunning videos and images.  Here’s just one video of the many, showing T cells (in green) exiting a blood vessel in the brain, and (in part 1) swimming off into the brain tissue to spread devastation and destruction (since these are autoimmune, self-reactive T cells):

1. Bartholomäus, I., Kawakami, N., Odoardi, F., Schläger, C., Miljkovic, D., Ellwart, J., Klinkert, W., Flügel-Koch, C., Issekutz, T., Wekerle, H., & Flügel, A. (2009). Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions Nature, 462 (7269), 94-98 DOI: 10.1038/nature08478[↩][↩]
2. Ransohoff, R. (2009). Immunology: In the beginning Nature, 462 (7269), 41-42 DOI: 10.1038/462041a[↩][↩]

After the “suppressor T cell” debacle of the 1980s, there was an embarrassed pause for a few years before people dipped their toes back into the suppressor T cell water; but the underlying phenomenon itself is a very strong and important one, and by the late 1990s and early 2000s researchers were again studying the cells, renaming them “regulatory T cells” (TRegs) in the process. Since the phenomenon is so strong, the field quickly exploded (from two papers mentioning TRegs in 2000, to 780 this year). We now know where TRegs are made and, mostly, how they’re made; we know what they look like and which cells they talk with; we know of various ways to make them in the lab; we know diseases where they’re overactive, and diseases where they’re underactive.  I’ve talked about these things quite a bit here.  

We didn’t know, though, how they actually work. Do they act directly on their target T cells, or via intermediaries? Do they have to contact their targets, or can they act at a distance? What molecules deliver their “regulatory” signals, and what molecules receive the signal? Well, we still don’t really know the answers to most of those questions, but a paper last month¹ brought the answers a lot closer with evidence that CTLA4 is essential for TRegs to have their regulatory effect.

TRegs in normal skin

This isn’t a new idea; it was first put forward in one of the very early TReg papers, way back in 2000². The difference is that the earlier papers couldn’t cleanly distinguish TReg-specific effects of CTLA4 from its myriad other effects. CTLA4 is a very broad-acting molecule with lots of immunosuppressive (or if you prefer, immunoregulatory) activities. In the present paper, Wing et al managed to eliminate CTLA4 specifically from TReg cells, leaving its other activities intact. These TReg-specific knockouts still developed the horrible, fatal autoimmune diseases characteristic of TReg deficiencies.

So CTLA4 is essential for TReg function. This is especially interesting because there’s a lot of clinical interest in CTLA4; for example, blocking CTLA4 has been effective in generating (or regenerating) immunity to cancers, at least in experimental models. The rationale for this has been because signaling through CTLA4 on “conventional” (that is, effector, as opposed to regulatory) T cells reduces or blocks their activity;³ but now this is directly linked to TReg activity as well.

The link between TRegs, CTLA4, and tumor immunity was really emphasized in the Wing et al paper. In one experiment, they demonstrated that mice with normal TRegs were not able to reject a tumor (“All recipients of FIC splenocytes died of tumor progression within a month“), whereas mice with the knockout TRegs (that is, TRegs lacking CTLA4) were able to control it (“In contrast, recipients of CKO splenocytes halted the tumor growth, with the majority surviving the 6-week observation period, during which 60% of them completely rejected the tumor“).

Obviously, you don’t want to eliminate TReg function willy-nilly even in cancer patients; remember that these mice died of autoimmune disease when they were a couple of months old. But if there’s a way of localizing CTLA4 blockade so that the tumor-specific TRegs alone are affected, this could be very interesting.

1. K. Wing, Y. Onishi, P. Prieto-Martin, T. Yamaguchi, M. Miyara, Z. Fehervari, T. Nomura, S. Sakaguchi (2008). CTLA-4 Control over Foxp3+ Regulatory T Cell Function Science, 322 (5899), 271-275 DOI: 10.1126/science.1160062

   Also see the commentary by Ethan Shevach:
   E. M. Shevach (2008). IMMUNOLOGY: Regulating Suppression Science, 322 (5899), 202-203 DOI: 10.1126/science.1164872[↩]

2. Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25⁺Cd4⁺ Regulatory Cells That Control Intestinal Inflammation.  S. Read, V. Malmstrom, F. Powrie, J. Exp. Med. 192, 295 (2000).[↩]
3. For a review, see:
   Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Karl S Peggs, Sergio A Quezada, Alan J Korman and James P Allison Curr Opin Immunol. 2006 Apr;18(2):206-13. doi:10.1016/j.coi.2006.01.011[↩]

Our bodies are crammed with millions of tiny time bombs: lymphocytes that could begin to attack our own bodies, causing lethal autoimmune disease. Traditionally, it was said that these self-reactive lymphocytes were rare, because they were eliminated during their development and were never allowed to reach maturity. But it’s been known for quite a few years now that that’s not entirely true. The vast majority of self-reactive T cells may, indeed, be destroyed in the thymus, but by no means all. (Something like a couple million T cells leave a happy, functioning thymus every day. If central tolerance is 99.999% perfect, then 10 self-reactive T cells will enter the system every single day — and it only takes a couple of T cells to initiate a lethal disease.)

Why don’t we all die as infants of autoimmune attack, if circulating self-reactive T cells are so (relatively) common? As with just about everything in our body, there are redundant systems. For autoimmunity, the next line of defense is the regulatory T cell (TReg).

TRegs were identified as a phenomenon long ago, in the 1960s and 1970s; but the concept abruptly fell out of favor in 1984 (for fascinating and rather embarrassing reasons I talked about here), and it wasn’t until the new millennium that immunologists really returned to the field (first firmly changing the name from “suppressor T cells” to “TRegs” to keep their feet out of the muck), and the field really exploded 5 or 6 years ago.

TRegs have proved more important and powerful than just about anybody would have believed ten years ago. Even very powerful immune responses can be controlled by TRegs; strong TReg responses can actually allow a complete “take” of an organ transplant, for example (I mentioned some examples here).

Regulatory t cells infiltrate tumor tissue

As well as transplants, being able to turn on TRegs has potential for lots of other diseases. Autoimmunity, obviously, could be controlled this way; but also, less obviously, it’s possible that some virus diseases might benefit from a TReg response. HIV infection, for example, is exacerbated when T cells are activated, and monkeys with SIV are resistant to disease when their T cells are less reactive (see here and here); could a controlled TReg response reduce the harmful activation associated with HIV? It may seem counterintuitive to try to treat a viral disease by reducing immunity, but there is some precedent. Rodents infected with hantaviruses develop a TReg response and don’t have much disease (see here), while humans react with a more conventional immune response and have severe disease. And recently, it was shown that elite suppressors of HIV may have an exceptionally strong TReg response.¹

Conversely, there are lots of instances where we’d like to turn off TRegs, in a controlled way. Tumors are often associated with TRegs, which very likely prevent a cleansing immune response to the tumor (discussed here). And the well-known observation that the elderly often have poor immunity against various pathogens is at least partly because TRegs build up over time.

This is a very fast-moving field, and there are a several recent papers that show exciting advances. One is a huge basic step forward, and I’ll talk about that later. The others² are technical advances, developing new techniques (that are much less cumbersome and finicky than some of the previous approaches) to generate large numbers of TRegs in a controlled way. The obvious use for this is in transplants:

The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants.³

Controlled TRegs have been a holy grail of transplant biology for years, and it’s exciting to see that we may finally be entering an era when TRegs can be produced and used as tools.

1. Preservation of FoxP3+ regulatory T cells in the peripheral blood of human immunodeficiency virus type 1-infected elite suppressors correlates with low CD4+ T-cell activation.
   Chase AJ, Yang HC, Zhang H, Blankson JN, Siliciano RF
   J Virol 2008 Sep 82(17):8307-15[↩]
2. Including, but not limited to:
   W. Tu, Y.-L. Lau, J. Zheng, Y. Liu, P.-L. Chan, H. Mao, K. Dionis, P. Schneider, D. B. Lewis (2008). Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells Blood, 112 (6), 2554-2562 DOI: 10.1182/blood-2008-04-152041

   In Vitro Expanded Human CD4+CD25+ Regulatory T Cells are Potent Suppressors of T-Cell-Mediated Xenogeneic Responses. Wu, Jingjing; Yi, Shounan; Ouyang, Li; Jimenez, Elvira; Simond, Denbigh; Wang, Wei; Wang, Yiping; Hawthorne, Wayne J.; O’Connell, Philip J. Transplantation Volume 85(12), 27 June 2008, pp 1841-1848.

   Jorieke H. Peters, Luuk B. Hilbrands, Hans J. P. M. Koenen, Irma Joosten (2008). Ex Vivo Generation of Human Alloantigen-Specific Regulatory T Cells from CD4posCD25high T Cells for Immunotherapy PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002233

   and a review in Piotr Trzonkowski, Magdalena Szary?ska, Jolanta My?liwska, Andrzej My?liwski (2008). Ex vivo expansion of CD4+CD25+ T regulatory cells for immunosuppressive therapy
   Cytometry Part A, 9999A DOI: 10.1002/cyto.a.20659 [↩]

3. Jorieke H. Peters, Luuk B. Hilbrands, Hans J. P. M. Koenen, Irma Joosten (2008). Ex Vivo Generation of Human Alloantigen-Specific Regulatory T Cells from CD4posCD25high T Cells for Immunotherapy PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002233[↩]

Melanoma blood vessel

Designing tumor vaccines presents a bunch of problems that anti-pathogen vaccines don’t. One of those problems is identifying an appropriate antigen. There’s been a lot of interest in finding tumor antigens that cytotoxic T lymphocytes will recognize, and in fact hundreds have been identified. The database of tumor antigens at Cancer Immunity lists some 750 of them, divided into various categories:

• Unique antigens result from point mutations in genes that are expressed ubiquitously. They are unique to the tumor of an individual patient or restricted to very few patients;
• Shared tumor-specific antigens are expressed in many tumors but not in normal tissues;
• Differentiation antigens are also expressed in the normal tissue of origin of the malignancy;
• Overexpressed antigens are expressed in a wide variety of normal tissues and overexpressed in tumors

Overall, shared tumor-specific antigens may be the ideal target. Because they’re found in multiple tumors, a vaccine can be pre-designed and go through a time-consuming optimization and validation process; because they’re only found in tumors, there’s less concern about safety. That is, the risk of the vaccine precipitating an autoimmune reaction to normal cells is low.

MHC expression in eye before and after vaccination

The problem with this class is that there just aren’t all that many tumor-specific antigens. The database lists 20-odd such antigens, and many of them are only found in a limited subsets of tumors (mostly melanomas). What’s more, I think it’s not merely that the targets are out there yet haven’t been identified. More likely, there simply are not many shared tumor-specific antigens.

The next-best category, as far as safety and effectiveness is concerned, is the unique antigens. These may be great as far as safety and effectiveness are concerned, but there are major technical problems in identifying them in a clinical context. Because they’re unique, you can’t pre-design the vaccine; you need to customize the antigen to each patient. And (at least with present techniques) by the time there is enough tumor available to look for unique antigens, the disease is likely to be pretty far advanced (and advanced tumors are more likely to be resistant to vaccination, for several reasons). There’s a lot of interest in making preparations of tumors that would contain unique antigens, without the trouble of identifying the antigen, but as far as I know that hasn’t made it very far into clinical trials yet.

So that leaves overexpressed and differentiation antigens. These are both, by definition, found in normal cells, and that means either the immune system is already tolerized to the antigen, or that targeting these antigens with a vaccine risks triggering an autoimmune reaction.

In fact, clinical trials using these kinds of vaccines against melanomas have found that successful tumor attack is almost invariably associated with an autoimmune effect, usually manifesting as vitiligo (de-pigmented patches on the skin).

It is expected that immune responses to such peptides will be compromised by self-tolerance or, alternatively, that stimulation of effective immune responses will be accompanied by autoimmune vitiligo. ¹

I believe the first record of this goes back to 1964.² Vitiligo is not, as autoimmune diseases go, a terrible problem, and certainly one would be delighted to trade melanoma for vitiligo. However, there are more serious potential problems as well, and one of them was recently reported by Nick Restifo’s group. ³ In this case, a highly active anti-melanoma vaccine not only killed the tumor, it also triggered severe autoimmune destruction of the eye; and the more effective the vaccine, the worse the autoimmune disease:

Thus, in the present model, the efficacies of the antitumor immune therapies were directly correlated with the induction of autoimmunity in the eye. … Our data suggest that, as tumor immunotherapies improve, these autoimmune manifestations may become more prevalent.

(My emphasis.) The autoimmune disease in these melanoma patients is still probably manageable (they mention using 30 months of steroid treatment in one of the most severely affected patients), and even if not, again the tradeoff is one most people would probably take (blindness vs. death). But other tumors may make the decision much more difficult:

Although the autoimmune side effects of melanocyte/melanoma-targeted therapies have been manageable, the unintended autoimmunity of therapies targeting colorectal, brain, or lung cancer might prove more severe.

1. Antigens derived from melanocyte differentiation proteins: self-tolerance, autoimmunity, and use for cancer immunotherapy. Engelhard VH, Bullock TN, Colella TA, Sheasley SL, Mullins DW. Immunol Rev. 2002 Oct;188:136-46. [↩]
2. Vitiligo In A Case Of Vaccinia Virus-Treated Melanoma. Burdick Kh, Hawk Wa. Cancer. 1964 Jun;17:708-12.[↩]
3. Palmer, D.C., Chan, C., Gattinoni, L., Wrzesinski, C., Paulos, C.M., Hinrichs, C.S., Powell, D.J., Klebanoff, C.A., Finkelstein, S.E., Fariss, R.N., Yu, Z., Nussenblatt, R.B., Rosenberg, S.A., Restifo, N.P. (2008). From the Cover: Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proceedings of the National Academy of Sciences, 105(23), 8061-8066. DOI: 10.1073/pnas.0710929105 [↩]

We walk a fine line between death due to immune deficiency, smothered under the weight of pathogens and parasites, and death by hyperimmunity, eaten alive by our own defenses. It’s amazing that our immune system can be tuned so precisely as to recognize anything foreign, yet ignore the vast antigenic universe of our own normal self.

Of course, sometimes the immune system fails, in both directions. We often hear about deaths from pathogens, and autoimmune diseases in general are pretty common. There are many ways by which (it’s believed) the immune system can become self-reactive, but a very common observation is that there are both genetic and environmental predisposing causes to autoimmunity. That is, you may have the genetic makeup to be autoimmune, but until you’re exposed to some environmental trigger, autoimmunity never develops. So, for example, if your identical twin has an autoimmune disease, you are much more likely than someone in the general population to develop the disease; but you still have a good to excellent chance of never getting the disease.

In many cases the neither the environmental triggers nor the genetic factors are well understood. The most likely environmental trigger, though, is some kind of microbe. In some cases, this may be because of “molecular mimicry” — the microbe has an antigen that looks like self antigen; the self antigen is normally ignored, because the immune system needs some kind of “danger” signal before it becomes activated; the microbial antigen is seen in the context of microbial “danger” signals; an immune response forms against the microbial antigen; the immune response cross-reacts with the self antigen; self cells are damaged by this immune response; the dead cells release more danger signals along with self antigen; and a positive feedback loop drives a full-fledged autoimmune disease.

That’s the model, but there aren’t many, if any, diseases where the whole process has been tracked through step by step; in fact, I think that there has been so much difficulty getting clear molecular connections between microbes and autoimmunity that there’s a robust search for other mechanisms. However, in the latest issue of Cell Host and Microbe, Albert Bendelac’s group shows a series of links between bacterial infection and the autoimmune disease human primary biliary cirrhosis (PBC).¹ (There’s also a helpful, if rather dry, commentary² by Sebastian Joyce and Luc van Kaer in the same issue.) Rather than trying to cover everything today I’m going to give background here, and then talk about the specific findings in a few days.

One interesting thing about Bendelac’s paper is that they link CD1 to the disease, through NKT cells. CD1 is an MHC class I family member; I talked about it back here, and that’s its mug shot to the left here (click for a larger version). CD1, like many members of the MHC class I family, has a “groove” in its “top” side. MHC class I proper binds peptides in that groove, but CD1 has a much more hydrophobic groove that binds to greasy things like lipids, glycolipids, and lipopeptides. These kinds of molecules are typically found in some kinds of bacteria — especially mycobacteria, like tuberculosis and leprosy, but also other kinds of bacteria such as the commensal microbe Sphingomonas.

MHC class I molecules, with their peptides, are recognized by cytotoxic T lymphocytes (CTL),³ but CD1 molecules and their lipids are recognized by a specialized subset of T cells, “natural killer-like” T cells (NKT cells). The function of this CD1/NKT system really isn’t all that clear. The early guesses that this was a branch of the immune system specialized for dealing with mycobacteria has been weakened as NKT cells have been linked to resistance to various viruses, and also as various viruses have been shown to block CD1 — suggesting that CD1 and NKT cells would otherwise eliminate them.

OK, enough for now. In my next post I’ll talk more about the disease itself, and then try to spell out the process by which, according to Bendelac, NKT are central to the autoimmune reaction; as well as how this abnormal reaction suggests some of the normal functions of NKT and CD1.

1. Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J et al. (2008) Liver Autoimmunity Triggered by Microbial Activation of Natural Killer T Cells. Cell Host & Microbe 3:304-315.[↩]
2. Joyce S, Van K, Luc (2008) Invariant Natural Killer T Cells Trigger Adaptive Lymphocytes to Churn Up Bile. Cell Host & Microbe 3:275-277.[↩]
3. And natural killer cells, but let’s not go into that now[↩]

Autoimmunity is surprisingly common, and amazingly complex. About 5% of people will develop some form of autoimmune disease — that’s tens of millions of people in North America alone — yet the causes underlying the diseases are still not known. It’s clear that there are both genetic and non-genetic factors, because if one identical twins has an autoimmune disease the other is much more likely to also develop it; but even with identical twins the concordance is far from perfect, usually being well under 50%.

In this genomic age, the genetic side of the equation is becoming more accessible, and large-scale genomic scans for gene variants that affect risk of autoimmune disease are becoming routine. But again — apart from outright mutations that cause autoimmune disease with very high penetrance, such as AIRE deficiency¹ — there are clearly environmental factors that are at least as important as all the genetic factors put together. What’s the rest of the story?

The usual assumption has been that the environmental factors are infections. If you’re genetically predisposed to autoimmune disease, this argument goes, then exposure to a particular pathogen may tip you over the brink. This might be because of cross-reactivity — the pathogen contains epitopes that look like self epitopes; the self epitopes are usually ignored because they are not seen in an inflammatory (“danger”) context; but the pathogen epitope is seen in such a context and drives the activation and expansion of cross-reactive T cells, that then return home and attack the self antigen, causing autoimmune disease that can then expand and become more severe.

There are some problems with this argument, at least as a universal explanation. In particular, at least some animal models of autoimmune disease do show the typical long latency and sporadic disease that is expected with an infectious trigger, yet the disease continues to appear in pathogen- and germ-free animals. ² In fact, it’s even argued that autoimmune disease, like allergy, is associated with reduced exposure to pathogens — an extension of the “Hygiene Hypothesis”.³

New ideas

Perhaps springing from the general sense of dissatisfaction with the present explanations for autoimmune disease, there are two recent papers that propose a new, conceptually similar, but different explanations; and a letter to the editor that notes some weaknesses in one of the hypothesis.

The first I ran across⁴ was
GOODNOW, C. (2007). Multistep Pathogenesis of Autoimmune Disease. Cell, 130(1), 25-35. DOI: 10.1016/j.cell.2007.06.033

To make a long story short⁵ Goodnow draws parallels between cancer (especially lymphoid cancer) and autoimmune disease:

the potential for relentless growth of self-reactive lymphocytes is normally blocked by a series of checkpoint mechanisms that also prevent lymphoid neoplasia and … autoimmune outgrowths only develop when multiple checkpoints are eventually bypassed.

He proposes that, in fact, autoimmune disease and lymphoid cancer share a common pathogenesis: Somatic mutations. Lymphocytes have a relatively high mutation rate (perhaps because they undergo somatic mutation as part of their normal maturation process), and perhaps some forms of this mutation cause dysregulation of the lymphocytes without causing cancer — a dysregulation presenting as abnormal self reactivity rather than uncontrolled growth. He puts forward a number of ancillary arguments and evidence supporting this, as well.

By comparison, I think that most models of autoimmune disease postulate that the self-reactive lymphocytes are broadly normal; that everyone carries potentially self-reactive lymphocyte, but they aren’t activated by self antigen either because they are actively suppressed, and/or because they don’t receive adequate support during the self recognition process, or because the self antigen is normally hidden and not presented to the immune system.

The second paper, by Pederson,⁶ addresses the third of these possibilities. His is also a somatic mutation hypothesis, but it’s quite different from Goodnow’s. He suggests that the somatic mutation may hit the target cell, rather than the lymphocyte.

It is here postulated that mutant proteins are formed randomly in non-malignant cells and can influence the immune system towards priming against self-antigens. If mutations are the result of somatic mutations in a stemcell such proteins will persist, but possibly cause no immediate harm … However, such mutant proteins might be pivotal in the break down of tolerance and induction of autoimmunity.

Basically, Pederson’s hypothesis is that a mutated protein might be misfolded and/or degraded faster and this will result in increased recognition even of normal (“self”) epitopes in the mutant protein. This is a fairly plausible suggestion in itself — however, I’m not quite convinced. We’re talking here, I think, about quantitative increase in presentation, whereas most models of autoimmunity consider it to be somehow qualitatively different. (Of course, if you get quantitative enough, things become qualitative, if you see what I mean. Still, it seems like a relatively conservative hypothesis, somehow.) As Pederson points out himself, testing this hypothesis might be extremely difficult, because you’d have to identify a very small population of mutated protein swimming in the pool of normal unmutated protein. (Also — my own addition to the difficulty — by the time the disease is apparent, the mutated cells would have probably been destroyed by the initial autoimmune response.) Overall, I have a hard time getting very excited by this hypothesis — not by any means because it is self-evidently wrong, but it’s not clear to me how to test it, or where to take the next step in using it in a model for pathogenesis or treatment.

Questions resurface

Back to Goodnow’s more radical, and exciting, hypothesis. In his paper Goodnow adds a note crediting F.M. Burnet for a previous iteration of the idea:

Since submitting this manuscript, my colleague Dr. Stephen Daley has drawn my attention to F.M. Burnet’s extraordinary 1972 book (Burnet, 1972). This monograph assembled the limited information about lymphocytes at that time to arrive at the same hypothesis developed here-that the stochastic onset of autoimmunity reflects “a conditioned malignancy” caused by emergence of “forbidden clones” through a combination of germline and somatic mutations that disrupt the normal mechanisms for eliminating or inactivating self-reactive lymphocytes.

… which brings me to the letter to the editor, by Thomas Brodnicki:⁷

I was reminded of a graduate lecture course given by Professor Roderick MacLeod in 1995 at the University of Illinois. While introducing F.M. Burnet’s clonal selection theory to our small class, Professor MacLeod mentioned Burnet’s idea that germline and somatic mutations provide the inherited and stochastic mechanisms that disrupt tolerance and result in autoimmunity.

Brodnicki points out four flaws in Goodnow’s model, none of which strikes me⁸ as being overwhelming, but which together make me say “Hmm”. His four points are that Goodnow’s (or Burnet’s) somatic mutation hypothesis doesn’t account for:

1. age (cancer hits older people, as you’d expect with somatic mutations that should become more common over time; autoimmune disease often hits fairly young people more than old);
2. sex (autoimmune disease often affects females far more often than males — or in some cases affects males more often than females — which is hard to explain by somatic mutations);
3. epitope spreading (how does the autoimmune reaction “spread” from the epitope recognized by the initial hypothetically-mutated lymphocyte clone, to recognize the wide range of targets that are typical of autoimmune diseases); and
4. infectious disease (why is increased incidence of autoimmune disease linked with reduced incidence of infectious disease?)

As I say none of these points is itself insuperable; there are reasonable explanations that could account for all of them. But as far as I can think of there is no single explanation that will account for all of them, so we are multiplying William of Occam’s entities to an uncomfortable point.

Nevertheless, I think Goodnow’s hypothesis is a very interesting — and testable — one, that also offers conceptual avenues toward treatment and prevention; even if it’s wrong, I think it’s wrong in an interesting way. I’m looking forward to seeing what happens to it in the next couple years.

1. For example, Pereira, L.E., Bostik, P., & Ansari, A.A., 2005. The development of mouse APECED models provides new insight into the role of AIRE in immune regulation. Clinical & developmental immunology, 12(3), p.211-6.[↩]
2. In some other autoimmune disease models, exposure to pathogens, or to normal intestinal flora, does seem to increase the incidence of disease, as predicted. So it’s complicated.[↩]
3. Bach, J., 2002. The Effect of Infections on Susceptibility to Autoimmune and Allergic Diseases. N Engl J Med, 347(12), p.911-920. [↩]
4. Actually, to tell the truth, the first I ran across was the letter to the editor, which intrigued me so that I looked again at Goodnow’s paper, and then while following up on Goodnow I found Pederson’s paper. Obviously I don’t follow the autoimmune literature as closely as I should. I hereby resolve to turn over a new leaf.[↩]
5. Actually, it’s not all that long. In fact Goodnow’s paper is well worth reading if you’re interested — it’s well written and easy enough to follow[↩]
6. Pedersen, A., 2007. The potential for induction of autoimmune disease by a randomly-mutated self-antigen. Medical Hypotheses, 68(6), p.1240-1246. [↩]
7. Brodnicki, T.C., 2007. Somatic Mutation and Autoimmunity. Cell, 131(7), p.1220-1221.) [↩]
8. Or Brodnicki, for that matter[↩]