Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis
worldwide and is a leading cause of chronic kidney disease (CKD) and
renal failure. Approximately 10-20% of patients reach end-stage renal
disease (ESRD) 10 years after diagnosis (1-3).
Significant advances in understanding the pathogenesis of IgAN have been
made in recent years. It is now widely accepted that IgAN does not arise
from a single pathogenic “hit”, but rather arises due to multiple
pathogenic “hits”, often referred to as the “multi-hit” hypothesis:
an increased level of poorly O-galactosylated IgA1 glycoforms (Gd-IgA1)
(Hit 1), production of O-glycan-specific antibodies (Hit 2), and the
development of GdIgA1-containing immune complexes (GdIgA1-IC) (Hit 3).
Deposition of GdIgA1-IC in the glomerular mesangium leads to mesangial
cell proliferation and overproduction of extracellular matrix, cytokines
and chemokines, culminating in glomerular injury (Hit 4) (4-7).
Currently, there is a consensus that aberrant IgA1 glycosylation is not
able to induce renal injury on its own. A chain of immune responses,
arising from plasma cells, T cells and antigen presenting cells (APCs)
have an impact on disease outcomes. So far, the exact source of Gd-IgA1
during B cell maturation and trafficking is not fully delineated.
Moreover, the level of crosstalk between relocated B cells and different
T cell- and monocyte subsets needs further investigation.
Given the complex pathophysiology in IgAN, the interaction between
different parts of the immune system needs to be further explored. Our
approach was to apply a clinically feasible method using limited cell
surface markers and minimal ex-vivo manipulation. We mapped the immune
cells by phenotyping subsets of B cells, monocytes and T cells in the
peripheral circulation of IgAN patients in comparison to those in
healthy controls as well as in a disease control group. We also
investigated the associations between cell subsets, inflammatory
cytokines and renal function.
Our hypothesis was that an imbalance in the analyzed immunological
network would disclose potential pathophysiological mechanisms.