Regulatory T cells and minimal change nephropathy: in the midst of a complex network

Abstract

SummaryMinimal change nephrosis (MCN) is an important cause of morbidity in children. In spite of successful therapies having been developed in the last three decades, most aspects related to pathogenesis still remain poorly defined. Evolution in basic immunology and results deriving from animal models of the disease suggest a complex interaction of factors and cells starting from activation of innate immunity and continuing with antigen presentation. Oxidants, CD80 and CD40/CD40L have probably a relevant role at the start. Studies in animal models and in human beings also suggest the possibility that the same molecules (i.e. CD80, CD40) are expressed by podocytes under inflammatory stimuli, representing a direct potential mechanism for proteinuria. B and T cells could play a relevant role this contest. Implication of B cells is suggested indirectly by studies utilizing anti-CD20 monoclonal antibodies as the main therapy. The role of regulatory T cells (T regs ) is supported mainly by results in animal models of nephrotic syndrome (i.e. adriamycin, puromycin, lipopolysaccharide), showing a protective effect of direct T reg infusion or stimulation by interleukin 2 (IL-2). Limited studies have also shown reduced amounts of circulating T regs in patients with active MCN cells. The route from bench to bedside would be reduced if results from animal models were confirmed in human pathology. The expansion of T regs with recombinant IL-2 and new anti-CD20 monoclonal antibodies is the beginning. Blocking antigenpresenting cells with cytotoxic T lymphocyte antigen (CTLA-4)-Ig fusion molecules inhibiting CD80 and/or with blockers of CD40-CD40 ligand interaction represent potential new approaches. The hope is that evolution in therapies of MCN could fill a gap lasting 30 years.

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

“…A substantial proportion of these children have a genetic disorder; almost 20 new genes have been discovered, documenting the involvement of the podocyte structure and function in the mechanisms of the disease (4). Despite genetic evolutions, the pathogenesis of nephrotic syndrome is poorly defined; it has been considered a T cell disorder for years (5), but evolution in basic immunology now suggests a more articulated immune cell interaction (6).…”

“…Deficit in B cells produces immunologic rebounds linked to the lack of their activity. In particular, B cells may act at several levels of the immune response: They modulate adaptive immunity and regulate the T-cell compartment via CD80 and CTLA4; CD80 is a costimulatory molecule expressed by antigen-presenting cells and by B cells (6). Via SMPDL-3b/ASM, rituximab also modulates IL-17 production by Th17; CD39 and CD161 may serve as surface markers of IL-17 and modulate, in turn, ASM SMPDL-3b-mediated signal transduction (STAT3) (44).…”

“…This is of particular interest because idiopathic nephrotic syndrome in children has historically been considered a T cell disorder, whereas outcome improvement after rituximab treatment points to a multifactorial pathogenesis (6). B cells may be just one of the possible targets of rituximab (Figure 1).…”

“…It has been suggested that rituximab interaction with SMPDL-3b prevents podocyte actin remodeling induced by serum of patients with FSGS preserving the structure and function of podocytes. It is also of interest that both SMPDL-3b and ASM are expressed on Th17 (44), a cell lineage whose activation is considered a key element in the pathogenesis of nephrotic syndrome (6). Other studies also demonstrated that rituximab reduces Th17 cell response in rheumatoid arthritis (45), thus making a logical connection among rituximab, Th17, and nephrotic syndrome.…”

Reduced frequency of circulating CD4+CD25brightCD127lowFOXP3+ regulatory T cells in primary myelofibrosis

“…[2][3][4][5][6][7] Abnormalities in Tregs are associated with autoimmune diseases, [8][9][10][11][12][13][14][15] and a Treg deficit resulting from a FoxP3 mutation is associated with aggressive autoimmunity and early death. 16 There are contradictory data on numbers of Tregs in persons with PMF.…”