22 Jul 2016

Findings shed light on autoimmune role in thymus

Associate Professor Menno van Zelm
by Anne Crawford

It has been known for almost three decades that B cells exist in the thymus but their function there has been unclear. Associate Professor Menno van Zelm explored this neglected area and has arrived at world-first findings answering this riddle which may lead to a better understanding of the origin of autoimmune diseases.

B cells – immune system cells that make antibodies – are normally generated in bone marrow. Their counterpart, T cells, are specifically generated in the thymus and are involved in cellular immune responses.

A/Prof van Zelm, who heads the B Cell Differentiation Laboratory in the Monash Department of Immunology and Pathology, worked with researchers at the Erasmus Medical Centre in Rotterdam, the Netherlands, to test the idea that B cells found in the thymus were involved in selection of T cells.

T cells need to ‘see’ autoantigens during their development to make sure they recognise them – if not, they are deleted according to negative selection.

The team hypothesised that the B cells presented the autoantigens to the T cells, an idea that had been suggested previously but never proved, A/Prof van Zelm said.

The researchers used tissue from children who had part of their thymus removed before undergoing heart surgery so that cardiologists could better access the heart. They extracted B cells from the tissue, made recombinant antibodies for single B cells and then tested whether these antibodies could react against autoantigens.

“We found that relatively more of these B cells react to autoantigens than B cells that you would normally find in blood,” A/Prof van Zelm said. “The thymus seemed to be enriched for autoreactive B cells.”

Binding to autoantigens enables B cells to process these and present them to the T cells using MHC Class II molecules.

But more work is needed to test how important B cells are in thymic selection, he said.

The team’s paper, published in early June in The Journal of Immunology, has already met with a positive reception – the journal highlighted it as being among the edition’s top 10 per cent of articles.

A/Prof van Zelm conducted the research with colleagues in Rotterdam before moving to Melbourne last year to accept an appointment at Monash University. A lab scientist, his main focus is on B cell biology and the mechanisms in which B cells contribute to immunity.

He is known for his pioneering work into stepwise human B cell differentiation in bone marrow, for describing the first antibody-deficient patients with CD19 gene defects and for identifying the first CD81 deficiency.

The recent paper has led to a collaboration with physicians at the Royal Children’s Hospital to investigate DiGeorge syndrome, a genetic disorder affecting the thymus of children. Patients with the syndrome have symptoms ranging from heart defects, poor immune system function, cleft palate to developmental disorders.

A/Prof van Zelm hopes the research will give more insights into what’s going wrong with patients who don’t respond well to existing treatment, point to markers for this, and then to markers in other patient groups.

Reference: J Immunol. DOI: 10.4049/jimmunol.1501992

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