Last week I talked some general issues about autoimmunity, and gave a brief background on NKT cells. Today I’ll talk about the paper that spawned that discussion.1

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,
  • Sphingomonas

  • 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)
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.

Novosphingobium aromaticivoransThe 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[]