Understanding how a key group of immune cells is born
A Sydney-based scientist has demonstrated for the first time how an important class of immune cells, essential for the development of antibodies, comes into being.
‘Follicular dendritic cells’ (FDCs) play a critical role in allowing us to fight infections and create a strong armory of antibodies for future use.
FDCs first make sure that our antibody-generating B cells receive samples of an invading organism. They then help to identify and nurture the B cells that manufacture the highest quality antibodies.
Many of our immune cells, including B cells, are white blood cells and so arise out of stem cells in bone marrow. FDCs are not blood cells, and their origin has been a mystery until now.
Scientists have been able to see FDCs in tonsils, spleen and lymph nodes – where they are formed during embryonic development and soon after birth. They have also seen FDCs at sites of chronic inflammation later in life – such as in a liver inflamed by hepatitis, or in joints inflamed by rheumatoid arthritis.
Dr Nike Krautler from Sydney’s Garvan Institute of Medical Research and Professor Adriano Aguzzi from the Institute of Neuropathology, University Hospital of Zurich, have now shown that FDCs arise from the ‘mural cells’ that surround our blood vessels. The importance of their finding is underlined by its publication in the very prestigious international journal Cell.
"This story was interesting to us because follicular dendritic cells are thought to be stationary cells and can’t migrate through our bodies like B cells, which move through the lymph system or blood stream," said Dr Nike Krautler.
"We could see that they were present in the lymphoid organs, such as the spleen or lymph nodes, right from the start – from when the tissue was formed."
"We couldn’t understand, though, how they arose in other parts of the body during inflammation or autoimmune disease, unless they had been there in some form all along" Dr Krautler told reporters.
"By using genetic markers* we could see that they appeared to come from a particular kind of precursor, or stem cell, that surrounds blood vessels."
"We confirmed this theory by placing the precursor cells into animals without follicular dendritic cells, then watched them form when we triggered an inflammatory response."
Dr Krautler now believes that "during chronic inflammation or autoimmune disease, precursor cells are recruited to the site and form follicular dendritic cells. B cells also migrate there and highly specialised germinal centres form."
"Germinal centres are localised powerhouses of antibody generation, actually driven by follicular dendritic cells. In a healthy person, they are found only in the lymphoid organs.
"When someone has an autoimmune disease such as rheumatoid arthritis, or a chronic inflammation of some kind, germinal centres form at other sites in the body and help sustain inflammation or disease.
"So while this is a basic science finding, it is really central to our understanding of how chronic inflammation is triggered – and perhaps in gaining insights about how to prevent them."
Dr Krautler performed her study in Zurich, and completed her work at Garvan in the lab of Associate Professor Robert Brink, an expert on B cell biology. Krautler and Brink will be working together to investigate the role of follicular dendritic cells in germinal centres, both in healthy immune responses and in disease.
Understanding antibody generation is critical in fighting disease and in creating effective vaccines.
*One of the genetic markers for mural cells is PDGRF beta (Platelet Derived Growth Factor Receptor beta). Although this protein is no longer expressed in mature follicular dendritic cells, by using a genetic tracer it can be determined that the protein was once expressed. At the same time, FDC markers can be found perivascularly in precursor cells.
So mature FDCs, arising from precursors, retain FDC protein markers, but lose the PDGRF beta markers.