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Studying Immune Responses

Research Title: Immuno-pathogenesis of Paget’s disease of Bone: a preliminary study

Award date: 2019

Principle investigator: Dr Julie Walker, who is a Consultant Histopathologist at The James Cook University Hospital, Middlesbrough.

Paget’s Disease of Bone is common but becoming rarer. It can be caused by genetic mutations that result in uncontrolled bone cell activity, in particular with the osteoclast cells (the cells which remove old bone). These mutations cause the osteoclast cells to become overactive and result in the unusual bone structure that is characteristic of Paget’ disease.

It is possible that the genetic mutation may also increase our immune responses to infection, giving affected people a survival advantage e.g. in fighting infections like tuberculosis. This may explain why Paget’s disease has persisted since at least Roman times. The infection could activate the immune system but have the unwanted side effect of also activating bone cells, causing Paget’s disease to materialise many years later. There are examples of this type of phenomenon occurring e.g. sickle cell disease is a blood disorder, but it also makes the individual resistant to malaria.

If this theory is correct, studying immune responses in blood from people with Paget’s disease may provide insights into its causes and potential targets for treating and/or preventing it. If the proposed theory is true, then one reason for the fall in incidence of Paget’s in the past 20-30 years may be diminished evolutionary pressure because of reduced exposure to infections, probably through a combination of improved public health, antibiotics and vaccination e.g. against diphtheria and tuberculosis. If this is confirmed by this research then there will be a plausible explanation for the observed changes in epidemiology. If immune responses are altered then exposure to infections, such as mycobacteria, will stimulate both immune and osteoclastic activity. This would bring an explanation for the development of the condition a step nearer and it may be possible to manipulate the immune response to prevent or treat the condition.

This is a small, preliminary study to test this hypothesis by taking blood from 15 men with Paget’s disease and from 15 healthy men without bone problems. Cells from their blood will then be grown in culture and their responses to infectious stimuli tested, including various bacteria and tuberculosis.