In 2014, researchers at the Centre for Personalised Immunology (CPI) led by Professor Matthew Cook described a novel form of human immune dysregulation, that is characterised by B cell deficiency.
Since then, more than 50 cases of this syndrome have been reported around the world, but the mechanism of autoimmunity remains unclear.
The latest research conducted by PhD candidate Ainsley Davies (ANU) and Dr Rushika Wirasinha (Monash University) has uncovered a new mechanism of autoimmunity by looking at the variants of the NFKB2 gene, and the resulting changes in immune proteins.
The research was led by Professor Matthew Cook, co-director of the CPI, and Dr Stephen Daley laboratory head at Monash University and a large team of collaborators from Australia and internationally.
“All of these cases arise from genetic variants located in the same domain of the NFKB2 gene, but the severity of immune disorders varies considerably from patient to patient,” said, Professor Cook.
“Some patients experience the loss of all body hair, known as alopecia, and hypopituitarism which is a serious hormonal deficiency affecting thyroid disease, adrenals, and sex hormones. Other patients have had inflammation of lung tissue and arthritis”
Despite being a significant chronic health problem in Australia and New Zealand, the mechanisms of autoimmune disease remain largely unknown.
Each of our lymphocytes, including T cells, is specific for a single antigen and we have over a billion different types.
This variety is essential because we need T cells that can recognise antigens from the pathogens we encounter. But, because the process of making these T cells is random, it also means we have T cells that are specific for cells and proteins that make up our own bodies.
“A central problem for the immune system is dealing with these self-reactive T cells, and most are removed in the thymus,” Professor Cook said.
“When the process of removing the self-reactive T cells doesn’t work, this leads to autoimmune disease, especially organ-specific autoimmune diseases like alopecia.”
“After patients with genetic variants in NFKB2 were identified, it was assumed that this lead to autoimmunity through a deficiency in the p52 protein, but this doesn’t explain the substantial patient to patient variation in symptoms,” Professor Cook explained.
“We were surprised to discover this assumption is the opposite of what actually occurs. Instead, the problem turns out to be due to the inhibitory action of p100 which happens as a result of genetic changes.”
Researchers are able to uncover genetic mutations in genes such as NFKB2 using human genome sequencing, but it is a bigger challenge is to understand how genetic changes cause disease.
The goal of the research team at the Centre for Personalised Immunology (CPI) is to find the genetic changes and understand how these changes causes disease to help diagnose and treat patients living with immune conditions.
“In this research NFKB2 variants now emerge as only the second monogenic form of human autoimmune disease to be explained by defective thymic selection of T cells,” Professor Cook said.
“NFKB2 encodes a protein called p100, which is a regulator of the cells in the immune system and maintains the normal tolerance mechanisms that operate in the thymus.”
The research shows that genetic variants in NFKB2 found in patients result in small changes at one end of the protein that prevent p100 from being processed to p52.
The consequence of this is that selection of T cells, and therefore the risk of autoimmunity, is exquisitely sensitive to small changes in p100 abundance.
“This is a new mechanism of human autoimmunity.”
Professor Cook explained this discovery enables researchers at the CPI to provide a definite diagnosis to patients. In addition, however, uncovering this mechanism by which the disease arises is crucial.
“Our approach involves looking at single gene variants, which has provided important insights into human immune dysregulation,” he said.
“In this case we have shown how a gene variant causes autoimmunity.”
“Importantly, we will be able to apply this discovery more widely in patients with autoimmune disease.”
The research has been published in The Journal of Experimental Medicine.