Researchers drill deep to find T cell defect in antibody deficiency disease

Dr Emily Edwards (first author) and 

A/Prof Menno van Zelm (last author) 

by Anne Crawford

Patients with predominantly antibody deficiency (PAD) suffer from severe and recurrent infections that disrupt their lives and which require lifelong treatment. Added to this, up to 70% of these patients develop non-infectious complications (NIC) including autoimmunity, autoinflammation, gastrointestinal disease, and lymphoid malignancies, which are difficult to treat, putting them at risk of high morbidity and early mortality. PAD represents the largest group of primary immunodeficiencies (PIDs), affecting about 1 in 25,000 people worldwide.


In a study in Frontiers in Immunology this month, Dr Emily Edwards, Associate Professor Menno van Zelm and colleagues from the Central Clinical School, investigated the state of the immune cells present in a cohort of PAD patients to fill gaps in knowledge about the aetiology of the condition and to find diagnostic and prognostic markers to identify patients at risk of NIC.

“Because the disease presentations are so variable, we wanted to study the immune cells to see if there was any specific signature in those cells that helps us understand it better and help us classify these patients into subgroups that make more sense to then follow up genetically,” Associate Professor van Zelm said.

“These NIC complicate diagnosis – patients are often identified with these complications before being diagnosed as having PAD which is something that impacts on treatment strategy,” he said.

The researchers split the patient cohort into two groups, those who had NIC and those who did not, and compared the clinical information from peripheral blood samples from the two groups. They confirmed previous findings elsewhere that memory B cells – immune cells that remember antigens – were reduced in patients with complications and that total B cell numbers were also down in number.

“It wasn’t just the memory cells but the naive B cells. This has never been found in a solid way before,” Associate Professor van Zelm said.

The study also suggested that previous observations about aberrant B cells with low expression of CD21, a surface molecule, were incorrect, he said.

“The amount of CD21lo B cells was always thought to be important in this disease because it was found to be increased relative to total B cells. But because total B cells are reduced the absolute number is not higher,” he said.

“The main conclusion that we have is that patients have a defect in the T cells – that’s something that’s never been remarked on or has never been addressed.

“Potentially we can now study those cells and abnormalities in those cells that might underlie the impaired responses in the patients.”

Dr Edwards, the first author, said the study found a reduction in naïve CD4 and CD8 T cells in both patient groups.

“Reduction in naïve B or T cells has been shown to have implications for responses to primary infection, so for any infection you haven’t seen previously if you don’t have that broad mix of naïve B cells and T cells that can react to the pathogen it’s likely you don’t get memory responses and you get clinical disease,” Dr Edwards said. “That works in terms of responses to vaccination; the idea behind effective vaccination is you’re able to generate memory for that particular pathogen,” she said.

Dr Edwards said the study pointed to the need to investigate mechanisms behind the reduced levels of naïve B cells and T cells and, as in work with the ageing, the need to boost those levels so there is a pool of naïve cells ready to be mobilised, whether in the context of natural infection or vaccination.

Impaired immunity in primary infection and vaccination, renders patients more prone to severe and often lethal infections, the study says.

It also reports that;

• IgM memory cells were reduced in all patients but especially those with NIC;
• defects in naive B- and T cell numbers, together with reductions in Th17, Treg, and Tfh17 numbers, could be utilised as biomarkers to support definitive diagnosis and to predict for disease progression.

Associate Professor van Zelm said he hoped the findings would better define the subgroup of PAD patients with NIC so that new treatment options could be found for them and that genetic defects affecting them could be identified.

Edwards ES, Bosco JJ, Aui PM, Stirling RG, Cameron PU, Chatelier J, Hore-Lacy F, O'Hehir RE, van Zelm MC. Predominantly antibody-deficient patients with non-infectious complications have reduced naive B, Treg, Th17, and Tfh17 cells Front. Immunol., 15 November 2019 https://doi.org/10.3389/fimmu.2019.02593