'Big Eater' Macrophages May Be the Key to Treating Autoimmune Disease, According to Cellular Custodians

Researchers observed the TBMs' eating patterns and nutrition using genetically modified mice and cutting-edge microscopy, shedding light on their crucial function in halting the formation of dangerous antibodies. This research might hold the key to curing autoimmune disorders, which are now incurable.

Here are some important things to note:

1. It has been discovered that tingible body macrophages (TBMs) eat B cells, which is essential for immunity and avoiding the formation of dangerous antibodies.

2. A study using mice that had been genetically altered showed that TBMs selectively target mutated B cells in the lymph nodes, indicating a strategic and selective role.

3. The origin of TBMs has been linked to the bone marrow, and B cell training affects the timing of their entry into the lymph nodes, highlighting their function in the immune response's cleanup phase.

Weizmann Institute of Science, a source

Parents advise their kids to finish every last morsel of food on their plates. Some cells in our lymph nodes faithfully carry out this directive, like well-behaved children.

Although German biologist Walther Flemming initially identified these cells as a subset of macrophages, or "big eaters," in 1884, it was unclear where they originated from or how they functioned until recently.

Researchers from the Weizmann Institute of Science led by Prof. Ziv Shulman have uncovered discoveries that largely demystify the tingible body macrophages (TBMs) in a study that was published in the Journal of Experimental Medicine.

To help shield our bodies from damage, these tingible (i.e., stainable) immune cells actually turn out to devour every last scrap of an opposing sort of immune cell.

The antibody-producing B cells, which dwell in lymph nodes and are ready for invasion by pathogens like viruses or bacteria, are the cells that will end up on your dinner plate. They become active, divide quickly, and enter ephemeral structures known as germinal centers when an invasion takes place.

These centers serve as "training camps" where the B cells hone their defenses against a specific foe. They are located in defined niches within lymph nodes. The B cells go through a kind of rapid evolution, undergoing random mutations one million times more quickly than normal cells, which boosts the affinity of the antibodies they make.

Rarely, though, other B cells may develop the capacity to create autoantibodies that are directed towards and harmful to the body's own healthy tissues rather than infections.

Cells that have received advantageous mutations survive for the most part by the conclusion of the "training program," while cells with inefficient or even dangerous changes "suicide" through a mechanism of programmed cell death. Despite being dormant, these dead B cells might still produce dangerous antibodies.

How can this be avoided?

The "big eaters" come into play in this situation. Researchers from the Systems Immunology Department at the Weizmann Institute of Science employed genetically modified mice in the current study to determine the feeding habits and diet of TBMs. The team was headed by research student Neta Gurwicz.

The "big eaters" were marked with sparkling green, and the B cells in the training camps had bright red fluorescent protein genes.

As anticipated, training camp sites opened within lymph nodes a week after the mice received the vaccination to activate the B cells, and B cells started to grow, mutate, and go through selection.

The researchers used microsurgery to expose lymph nodes in the knees of the mice, and they then affixed a cutting-edge microscope with a resolution of one millionth of a meter, allowing them to see biological processes taking place inside a living body.

The "big eaters" remained in place near the training camp during this live broadcast, periodically stretching out with octopus-like arms to capture dead B cells and devour them. The team observed B cells moving continuously inside the training camp.

The TBMs did so very quickly, with each one capturing a B cell about every ten minutes. The researchers calculated that it would take roughly 30 TBMs to clear a single training camp of all of its dead cells.

An average of 25 TBMs were seen in each camp throughout the live broadcast, showing that the cleaning system is effective and thorough.

Recycling bins for lymph nodes

The researchers then inquired as to whether TBMs are picky. Do they eat any passing B cells, or do they favor the ones in the training camps as a snack? The study found that TBMs did not "swallow the bait," concentrating only on the modifying B cells when exposed to dormant B cells.

One issue, however, persisted: whence do TBMs originate?

In order to answer that conundrum, the researchers gave the animals radiation treatment before infusing progenitor blood cells containing the genes necessary to make future TBMs green into their bone marrow.

Seventy-five percent of the surrounding TBMs were green, indicating that the training camps' true origin is in the bone marrow, when they appeared in the lymph nodes as a result of the vaccine. However, the green cells didn't start to show up near those training camps until a few weeks after immunization, suggesting that they may have made a halt somewhere along the way.

The experiment was again repeated, but this time the lymph nodes were shielded from the radiation, allowing just the immune cells within them to survive while the rest were destroyed.

Most of the TBMs lining up for the feast were not green, as was the case in the previous trial; instead, they formed from cells that were already present in lymph nodes before vaccination.

The study's findings showed that TBMs originate from progenitor cells that emerge from the bone marrow, but instead of pausing, they proceed directly to lymph nodes and wait there for a time.

The reason why progenitor cells leave the bone marrow and enter lymph nodes was also uncovered by the researchers. Small concentrations of modifying B cells first appeared in the training camps five days after immunization, and then considerable numbers of TBMs appeared nearby.

This gave the researchers the idea that B cell training influences when TBMs arrive and that the TBMs' specific duty is to clean up after an immune system campaign that is incredibly successful but also rather wasteful.

The scientists also wanted to know when the TBMs start to devour the B cells during the process that leads to their suicide. Surprisingly, they saw B cells being swallowed alive as they breathed their deaths inside the TBMs.

This demonstrates that the "big eaters" are not only "cleaning workers," as previously believed, but also make up a biological "recycle bin" that collects dead cells before they begin to decompose, preventing dangerous waste from accumulating in the first place.

According to Shulman, poor TBM cleansing could result in the development of autoantibodies that are intended to attack dead B cells but end up harming healthy tissues.

"This could be a contributing factor to autoimmune conditions like lupus. The development of therapies for autoimmune diseases may be facilitated by a basic understanding of the origin of TBMs and their mechanisms of action.

We may have the solution to the treatment of currently incurable diseases if we can figure out how to make TBMs more successful at clearing away the "training camps."

Dr. Liat Stoler-Barak of the Weizmann Institute's Systems Immunology Department, as well as Niklas Schwan, Dr. Arnab Bandyopadhyay, and Prof. Michael Meyer-Hermann of the Braunschweig Integrated Centre of Systems Biology in Germany, also contributed to the work.

Funding: The Moross Integrated Cancer Center, the Rising Tide Foundation, the Azrieli Foundation, the Ben B. and Joyce E. Eisenberg Foundation, the Wolfson Family Charitable Trust and Wolfson Foundation, Elie Hirschfeld and Dr. Sarah Schlesinger, Miel de Botton, and others provide funding for Prof. Ziv Shulman's research.

Abstract

From progenitors that reside in lymph nodes, tingible body macrophages develop, and dendrites capture B cells.

Germinal centers (GCs) are required for antibody affinity maturation and are formed in lymph nodes.

A large percentage of B cells undergo apoptosis as a result of this process, and these cells are eliminated by tingible body macrophages (TBMs), a specialized subgroup of phagocytes. Although clinical diseases are linked to abnormalities in these cells, it is still unknown who their ancestors are and how dead GC B cells are eliminated.

Here we show that TBMs reach the lymph node follicles in a GC-dependent way from pre-existing lymph node-resident precursors. TBMs are stationary cells that specifically phagocytose GC B cells via very dynamic protrusions and accommodate the last phases of B cell death, according to intravital imaging.

It was discovered that GC B cells induce TBM development from bone marrow-derived progenitors stationed within lymphoid organs before the immunological assault by cell-specific depletion and chimeric animal models.

Understanding TBM dynamics and function may help explain how various autoimmune diseases caused by antibodies first appeared.