Basic and Translational Concepts of Immune-Mediated Glomerular Diseases 1 (1)
The Innate Immune Response
Toll-Like Receptors
Toll-like receptors (TLRs) are ancient and ubiquitous pattern recognition receptors present on all cell membranes and intracellularly between cytoplasm and endosomes. TLRs recognize conserved immunostimulatory molecular patterns (antigens) like peptidoglycans, LPSs, and bacterial and viral nucleic acids (pathogen-associated molecular patterns [PAMPs]) as well as endogenous cell-derived patterns (danger-associated molecular patterns [DAMPs]). TLRs activate multiple signaling pathways that lead to local release of a variety of cytokines, chemokines, and other inflammatory mediators by all cells, including glomerular cells.
Complement
The complement system and its regulatory proteins are also ancient components of the innate immune system with multiple roles in human GN. IgG subclasses 1 and 3 and IgM are classic complement pathway activators, whereas IgG 2 and 4, IgA, IgD, and IgE activate complement poorly. Activation of the mannose binding lectin (MBL) pathway proceeds when MBL binds to mannose residues on pathogens and activates the serine proteases, MASP-1 and MASP-2, leading to activation of C4 and C2. The alternative pathway is activated spontaneously by hydrolysis of C3 and amplified by defects in complement regulation. Non-Ig zymogens such as damaged cells and bacterial and viral proteins can also activate the alternative pathway beginning directly at C3. The same initiating event may activate more than one pathway. All complement activation pathways proceed through cleavage of C3 and C5 leading to release of chemotactic factors such as C5a that attract inflammatory cells (neutrophils, macrophages, and platelets) when abutting the circulation as well as formation of the terminal membrane attack complex (C5b-9). Complement activation in vivo is tightly regulated by a number of circulating and cell-bound complement regulatory proteins (CRPs).
Abnormalities in serum complement profiles are sometimes helpful in assessing the nature of the underlying disease and its activity, but significant complement-mediated injury may occur locally without alterations in circulating complement components.
The Adaptive Immune Response
Ig
CD4 T helper cells stimulate B cells and plasma cells to make antibodies specific for particular antigens. Antiglomerular antibody models (nephrotoxic nephritis; NTN) demonstrate that antibody deposition activates complement through the classic complement pathway generating chemotactic factors that attract circulating inflammatory effector cells, which then cause tissue injury. Typical granular IC deposits can also form locally, or in situ, due to antibody binding to either exogenous planted antigens or endogenous glomerular components.
(1) where the deposits form—ICs of the same composition in a subendothelial distribution lead to exudative inflammatory cell infiltrates, in the mesangium to mesangial cell proliferation and matrix expansion, and in a subepithelial distribution to a noninflammatory lesion with podocyte injury, effacement, and heavy proteinuria.
(2) the biologic properties of the antibody (or antigen) itself—particularly complement activating capacity, Fc receptor affinity, ability to form lattices, or cryoprecipitability.
(3) the mechanism of deposit formation—when ICs form in situ, the process usually induces local tissue injury, whereas passive trapping of ICs formed in the circulation has not been well shown to be nephritogenic.
(4) the quantity—the more deposits form, the more severe the disease.
T Cells
All subsets of T cells are now implicated in GN, including dendritic antigen-presenting cells (DCs) and CD4 helper cells of the Th1, Th2, and T regulatory (Treg) lineages, especially, IL17-producing Th17 cells likely account for much of T cell–induced inflammation. Th17 cells are attracted by mechanisms involving chemokines and their receptors, and release cytokines such as IL9, IL17, IL21, IL22, and TNFα, which induce other cells to produce additional proinflammatory chemokines that attract neutrophils and monocytes and also activate resident glomerular cells.
