Current wisdom has it that most modern diseases are, in a sense, man-made. Thus, chimpanzees bequeathed mankind the AIDS virus because their African habitat was disrupted by agriculture and "monkey meat" - consumption of chimp cuts by hungry humans.
Malaria is another case in point, with its Anopheles mosquito pushed to proliferate because of stagnant water collecting in ponds and discarded tires. The self-blaming list goes on.
But thousands of years ago, the skeletons inside mummies of Egyptian burials revealed that the Pharaohs and their retinues suffered from such present-day afflictions as gallstones and kidney stones, plus mastoiditis, and up-to-date rheumatoid arthritis (RA).
Immunologist/rheumatologist David Lee at Harvard-affiliated Brigham & Women's Hospital in Boston, points out, "Anywhere from 0.8 percent to 1.5 percent of Americans have RA. Its prevalence," he added, "is often quoted as 1 percent of the population. That's a huge number. RA is a major subset of inflammatory arthritis [IA]," Lee explained.
"The difference between the symptomologies of RA and IA," he said, "is like chest pain and heart attack, where different factors can cause chest pain, of which the major portion is heart failure. The pattern of joint-pain inflammation and accompanying symptoms differentiate the different types of IA, the most common one being rheumatoid disease. That presents generally with distal joints like feet and ankles, as well as fingers, hands, wrists, elbows and shoulders, [but less common in the hips]. Those joints are all tender, swollen, painful. They end up getting destroyed over the long term in RA."
Lee is first author of a paper in Science, dated Sept. 6, 2002. Its title: "Mast cells: A cellular link between autoantibodies and inflammatory arthritis."
"I think the major finding in this paper," he told BioWorld Today, "is highlighted in these immunologic cell types - the mast cells - that play a role in the context of inflammatory arthritis. That hadn't been prominently demonstrated previously. Its implication, of course, is seen in mouse arthritis. We rheumatologists certainly want to model human diseases as closely as we can. The extent to which mice are similar to humans is that this mast cell plays a more dominant or a more prominent role in human inflammatory disease than was previously appreciated."
Mast Cells' Ubiquitous Bag Of Tricks
"The mast cell is an interesting cell type," Lee continued. "It is not generally thought of as a circulating white blood cell. It tends to be a tissue-bound immunologic cell, full of granules containing large amounts of inflammatory mediator. Some of those are specific to the mast cell. Enzymes such as tryptases and kinases are called mast cell proteases. In addition," Lee went on, "they also make a lot of other known mediators called cytokines. In fact, they have pre-formed tumor necrosis factor in their bag of granules. They're located inside the cytoplasm of the mast cell and are membrane-bound little bags of fluid.
"Presumably a mast cell starts out as a progenitor cell in the bone marrow," Lee recounted. "In fact, people have identified very rare populations of progenitors, or pre-mast cells that circulate in the blood. It is thought that they then migrate to the tissue, more fully differentiate from their progenitor into the mast cells there, then turn into their more mature phenotype.
"The function of mast cells in the mammalian or human is an active area of investigation," Lee allowed. "In fact, mast cells, compared to some other cell types, are relatively understudied. It's known that they're important in fighting off infections, both parasitic-like worms in the intestinal tract and bacterial infection. That comes from more remote work the last 10 years looking at sepsis models in mice. Naturally, mast-cell-deficient mice tend to be much more susceptible to overwhelming bacterial infections.
"We see several things in the human world that we put in this broad rubric, inflammatory arthritis. The allergy community has studied the mast cell quite a bit. It's got a receptor on its surface for the ImmunoglobulinE antibody, which tends to be more prominent in allergic diseases. A lot of the mast cell mediators - the inflammatory parts they put out - have been studied in inflammation and asthma diseases. Less is known to my knowledge in targeting infectious diseases in humans. Mast cells live in a tissue and may play a sensing role, but that's more hypothetic than research in humans."
When it comes to the etiology of RA, Lee relies on two strains of mice, one transgenic. "We know in this mouse model of human disease there's a lot of theories - the translation of all the animal and human data is not entirely clear at this point. This transgenic mouse was developed by scientists at the Jocelyn Institute here in Boston. They had inserted a gene into the mice for the specificity of T-cell receptor genes. And they found that when they put this genetic mutation onto a certain genetic background, all the offspring of that class got arthritis. Subsequent analysis of these transgenic mice revealed the immune B cells and T cells that made an autoantibody. And they could in fact switch this arthritic phenotype of the disease by transferring serum from sick mice into healthy mice. The mice that got the antibody got arthritis. The antibody is programmed against an enzyme called glucose-6 phosphate isomerase - a protein that's expressed almost everywhere. But why it targets the joints remains an open question."
Why Autoantibody Hits Joints? Good Question
Lee and his co-authors demonstrated that the same mice that were mast-cell deficient, and therefore incapable of developing arthritis, became susceptible to the disease when re-introduced to mast cells.
"This research provides us with a cellular link to better understanding one of the possible causes of inflammatory arthritis," he observed. "And it may explain why these cells are found in such abundance in the tissue of people affected with rheumatoid arthritis." He cautioned, though, that "more research needs to occur before the exact role of mast cells in arthritis can be established and that therapeutic treatments targeting mast cells in RA," he concluded, "are probably years away."