The Clatworthy lab is interested in understanding how B cell activation and IgG antibody effector function is regulated in different tissues, particularly in the kidney and the gut using cellular and molecular immunology, single cells RNA Sequencing and two-photon microscopy.
How can we regulate B cell activation and antibody generation in human disease?
We are interested in understanding humoral immunity in humans, how this goes wrong in disease and how this can be manipulated therapeutically using experimental medicine studies. We have recently completed a study investigating how belimumab, an anti-BAFF antibody, affects the B cell compartment in renal transplant recipients, in collaboration with Glaxo-Smith-Kline. We found that belimumab suppressed new antibody formation and skewed residual B cells to an IL10-producing, regulatory phenotype.
Which immune cells are capable of responding to IgG in the kidneys, and how are their position and function influenced by the kidney microenvironment and cross-talk with other resident immune cells?
Autoantibodies are associated with a number of kidney diseases, and antibody-mediated rejection has a negative impact on transplant outcomes. We are using human kidney tissue to profile resident immune cells using multiparameter flow cytometry, mass cytometry, and RNA sequencing, as well as complementary mouse models to understand function. We have recently shown how the intrarenal sodium gradient can influence mononuclear phagocyte position and function to optimize defence against ascending infection (Berry et al. 2017).
What role do IgG and FcgR play in the gastrointestinal tract?
Although IgA is the dominant antibody isotype found at mucosal surfaces during health, genetic variation in FcgRs can influence susceptibility to inflammatory bowel disease (IBD), suggesting that IgG may be important during inflammation. We are currently investigating how the induction of IgG in the gastrointestinal tract can activate gut-resident cells, how this is regulated, and whether this is important in IBD.
How does FcgR-crosslinking by IgG affect immune cell metabolism?
There is increasing evidence that immune cells change their metabolism in response to activation signals and that some of these changes may be required for their function. We are investigating how IgG immune complexes affect macrophage metabolism and influence IgG-associated tissue inflammation.
Young MD … Clatworthy MR … Behjati S; Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science 2018. DOI: 10.1126/science.aat1699
Stark AK … Clatworthy MR … Okkenhaug K; δ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner. Nature Communications 2018. DOI: 10.1038/s41467-018-05674-8
Banham GD, Flint SM … Clatworthy MR; in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial. Lancet 2018. DOI: 10.1016/S0140-6736(18)30984-X
Berry MR, Mathews RJ … Clatworthy MR;Renal Sodium Gradient Orchestrates a Dynamic Antibacterial Defense Zone. Cell 2017. DOI: 10.1016/j.cell.2017.07.022