A common general model for autoimmune goes something like this:

• If you have a genetic predisposition toward autoimmunity²
• And you are exposed to a microbial antigen,



• That is somewhat similar to one of your body’s own antigens
• And the exposure involves inflammation, which sends a “Danger!” signal to the immune system,
• Then immune cells that are normally tolerant to the self antigen
• Become reactive toward the microbial antigen
• And cross-react with the self antigen. This low-level self-reactive inflammation
• Causes cell death, releasing more antigen in the the presence of cell-death “Danger” signals.
• Causing a runaway feedback loop that results in outright autoimmune disease

But as I said, it’s been very difficult to track through a reaction from beginning to end, to support or refute this model.

Matter et al., Fig 3 (Inflamed bile duct)

Primary biliary cirrhosis (PBC) is an autoimmune disease³ of the liver characterized by inflammation of the bile ducts (here is the American Liver Foundation’s PBC information page). The immunity seems to be mainly targeted at mitochondrial antigens, which raises the question of why the liver is specifically involved — mitochondria are found in just about every cell type.

NKT cells recognize CD1, which binds to lipid-type antigens typical of bacterial cell walls. Bendalac’s group found that they could cause a PBC-like disease in mice by infecting them with a particular bacterium⁴ that is normally considered to be a fairly innocuous commensal. They tested this bacterium because it was previously shown to trigger antibodies that cross-react with the mitochondrial antigens that are targets in PBC. (Remember that mitochondria are historically extremely symbiotic bacteria, so the cross-reactivity doesn’t come completely out of the blue.)

Antibodies are produced by B cells. However, the disease could be blocked by preventing NKT cells from getting activated (by infecting mice lacking the NKT target, CD1). The rationale for doing this experiment was that innate immune responses to this particular bacterium are, a little unusually, normally driven by NKT cells.

The autoimmune-type disease lasted in these mice long after they had eliminated the bacteria — months, compared to a week or two to eliminate the actual infection. What’s more, even though NKT cells were essential to get the disease going, once it had started up, the disease could be transferred to new mice by swapping across classical T cells only (i.e. T cells but no NKT cells) — even into mice that had never seen the bacteria and didn’t even have CD1, which were doubly protected against having the disease start on its own. In other words, NKT cells start the disease, but don’t keep it going.

So what seems to be happening is that the NKT cells recognize the bacteria and produce massive inflammation. Because NKT cells tend to home to the liver⁵, they are able to overcome tolerance of cross-reactive cells in the liver, making liver antigens more at risk. The cross-reactive T and B cells, enraged by the constant roar of inflammation the NKT cells produce, attack the cross-reactive self antigens, damaging the cells and causing a constant inflammatory trigger. At this point the disease has become self-perpetuating, and you don’t need the NKT cells any more (and indeed, they quiet down about this time, as the bacteria are eliminated).

These findings establish the missing connection between the microbial innate immune trigger and chronic effector T and B lymphocyte attack of small bile ducts observed in PBC. ⁶

This is probably not a universal effect in detail — NKT cells are likely not important in the majority of autoimmune diseases — but it does give support to the general concepts that have been floating around for a while now.

1. Mattner, J., Savage, P., Leung, P., Oertelt, S., Wang, V., Trivedi, O., Scanlon, S., Pendem, K., Teyton, L., Hart, J. (2008). Liver Autoimmunity Triggered by Microbial Activation of Natural Killer T Cells. Cell Host & Microbe, 3(5), 304-315. DOI: 10.1016/j.chom.2008.03.009
2. Usually the mechanism is unknown
3. Probably. There us still some uncertainty, but that is the best bet
4. Novosphingobium aromaticivorans
5. For reasons that are not, as far as I know, understood
6. Invariant Natural Killer T Cells Trigger Adaptive Lymphocytes to Churn Up Bile. Sebastian Joyce and Luc Van Kaer. Cell Host & Microbe (15 May 2008) 3:275-277

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

CD1 is (actually, CD1 are, since these are a family of related molecules) members of the MHC class I family, with many of the traditional MHC class I features — binding to β₂-microglobulin, a “groove” made of two alpha-helices on top of a beta-pleated sheet ( (in classical MHC, the peptide-binding groove: the “bun” of the peptide’s “hot dog”).

I previously wrote a field guide to the MHC family that shows these features across a wide range of the MHC family, but here are some comparisons of CD1d (PDB number 2GAZ) to classical MHC (HLA-A2; PDB number 2GTW). Here I’m showing the “heavy chain” of the complex in red, the ligand that fits in the binding groove is green, and β₂-microglobulin in blue. (The “top view” is looking “down” at the molecule more or less as a T cell would “see” it; the ribbon view lets you see the ligand interactions a little more easily; the “ligand only” view shows the thing that goes in the groove with all the MHC or CD1 resides removed.) (Click on a molecule for a larger version.)

	Side view	Top view	Top view (ribbon)	Ligand only
CD1d
HLA-A2

The similarities are pretty obvious, but it’s the difference that makes CD1 particularly interesting. Classical MHC molecules present peptide ligands; CD1d presents, instead, very hydrophobic molecules: lipids, glycolipids, and lipopeptides. These sorts of things are typically found in mycobacteria (as with phosphatidylinositol mannoside, shown in the images here), and I’ve thought of CD1 as an example of how our physiology has been shaped by pathogens — this whole branch of the immune system, devoted to detection and elimination of tuberculosis and leprosy.

My view started to slip in around 2000, with Frank Chisari’s observation that NKT cells may be involved in control of hepatitis B virus in his transgenic mouse model.¹ (NKT cells are the main lymphocytes that recognize CD1 molecules.) I’ve talked about Chiasri’s HBV mouse model before — it’s so artificial that I always am hesitant to extrapolate from it. That said, his findings in that model have all (as far as I know) held up in more natural systems, and the NKT observation is no exception; several other groups have seen similar things. ²

What really confirmed to me that CD1 can be antiviral, though, was the virus’s side of the story. Viruses employ an arsenal of anti-immune molecules, presumably targeting whichever immune components that are especially dangerous to the particular virus. Over the past few years, there’s been an increasing number of sightings of viruses that block CD1-mediated presentation. The first (that I know of) was HIV,³ and since then vaccinia virus⁴ and herpes simplex⁵ have also been shown to block CD1-mediated antigen presentation. The latest addition to the list is human cytomegalovirus.⁶ These viruses (HIV, poxviruses, and herpesviruses) are particularly good at blocking classical MHC class I presentation as well; I don’t know if this dual blockade is typical, or if people have mainly looked in those viruses most renowned for immune evasion — in other words, maybe we’re seeing this double action because people are looking under the streetlamps.

It’s interesting that HSV and HCMV (though not HIV, which blocks both classical MHC class I and CD1 with the same protein, nef) have apparently developed separate systems to block CD1 and classical MHC. The molecules responsible for their CD1 blockade are not yet identified, but they don’t seem to be the same as the ones that block MHC class I. If CD1 blockade is the main function of these genes (and not a side-effect of blocking some other aspect of immunity, say), the implication is that CD1 is an important-enough player in controlling these viruses that they have had to maintain distinct pathways to escape from it.

I wonder what it’s doing.

1. Kakimi, K., Guidotti, L. G., Koezuka, Y., and Chisari, F. V. (2000). Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 192, 921-930.
2. For example, Grubor-Bauk, B., Simmons, A., Mayrhofer, G., and Speck, P. G. (2003). Impaired clearance of herpes simplex virus type 1 from mice lacking CD1d or NKT cells expressing the semivariant V alpha 14-J alpha 281 TCR. J Immunol 170, 1430-1434.
3. Shinya, E., Owaki, A., Shimizu, M., Takeuchi, J., Kawashima, T., Hidaka, C., Satomi, M., Watari, E., Sugita, M., and Takahashi, H. (2004). Endogenously expressed HIV-1 nef down-regulates antigen-presenting molecules, not only class I MHC but also CD1a, in immature dendritic cells. Virology 326, 79-89.
4. Webb, T. J., Litavecz, R. A., Khan, M. A., Du, W., Gervay-Hague, J., Renukaradhya, G. J., and Brutkiewicz, R. R. (2006). Inhibition of CD1d1-mediated antigen presentation by the vaccinia virus B1R and H5R molecules. Eur J Immunol 36, 2595-2600.
5. Sanchez, D. J., Gumperz, J. E., and Ganem, D. (2005). Regulation of CD1d expression and function by a herpesvirus infection. J Clin Invest 115, 1369-1378.
   and
   Yuan, W., Dasgupta, A., and Cresswell, P. (2006). Herpes simplex virus evades natural killer T cell recognition by suppressing CD1d recycling. Nat Immunol 7, 835-842.
6. Raftery, M.J., Hitzler, M., Winau, F., Giese, T., Plachter, B., Kaufmann, S.H., Schonrich, G. (2008). Inhibition of CD1 Antigen Presentation by Human Cytomegalovirus. Journal of Virology, 82(9), 4308-4319. DOI: 10.1128/JVI.01447-07