Elsevier

Seminars in Nephrology

Volume 35, Issue 5, September 2015, Pages 410-426
Seminars in Nephrology

Neutrophils, Dendritic Cells, Toll-Like Receptors, and Interferon-α in Lupus Nephritis

https://doi.org/10.1016/j.semnephrol.2015.08.003Get rights and content

Summary

Finding better treatments for lupus nephritis requires an understanding of the pathogenesis of the causative systemic disease, how this leads to kidney disease, and how lupus nephritis progresses to end-stage kidney disease. Here, we provide a brief conceptual overview on the related pathomechanisms. As a main focus we discuss in detail the roles of neutrophils, dendritic cells, Toll-like receptors, and interferon-α in the pathogenesis of lupus nephritis by separately reviewing their roles in extrarenal systemic autoimmunity and in intrarenal inflammation and immunopathology.

Section snippets

Conceptual Overview on the Pathogenesis Of LN

Because the pathogenesis of SLE and LN was described recently elsewhere in detail,1 we provide only a brief summary of the major concepts (Fig. 1).

Neutrophils and NETs in Systemic Autoimmunity

Lupus patients have increased numbers of abnormal neutrophils or low-density granulocytes in the circulation.13 These neutrophils show a proinflammatory phenotype characterized by reduced phagocytotic activity and an increased production of type I IFNs.13 In fact, bone marrow macrophages and neutrophils currently are considered the major IFN-α–producing cells and the prime producers of IFN-α. Low-density granulocytes also have a higher tendency to release NETs.1314 NET release, also referred to

Dendritic Cells in Systemic Autoimmunity

Human DCs can be classified as either conventional CD11c+ CD123lo (c)DCs or CD11c- CD123high pDC.26 The majority of DCs are cDCs, which are efficient antigen-presenting cells secreting large amounts of TNF, IL-6, Il-12, and IL-10 according to their activation state. cDCs express TLR1, TLR2, TLR4, TLR5, and TLR6 on their surface and TLR3 and TLR8 inside endosomes.27, 28 In contrast, pDCs represent only 1% of circulating leukocytes. pDCs also are capable of antigen presentation, but they differ

Toll-Like Receptors in Systemic Autoimmunity

TLRs are pattern-recognition receptors of the innate immune system that are involved in host defense to pathogens, as well as in the pathogenesis of SLE.4, 5

Interferon-α in Systemic Autoimmunity

IFNs are a subgroup of cytokines mediating antiviral and antibacterial host defense in a complex manner (Table 1). The IFNs can be divided into type I IFNs (IFN-α, IFN-β, IFN-ω, IFN-τ, IFN-κ, IFN-δ, and IFN-ε), type II IFN (IFN-γ), and type III IFN (IFN-λ).31, 124 Among the several family members comprising the type I IFNs, the best studied are IFN-α, with 13 genetic variants, and IFN-β. Although IFN-β can be produced by a broad spectrum of cells, the major source of IFN-α is pDCs.

Summary and Conclusions

The pathogenesis of LN is based on mechanisms causing loss of tolerance and systemic autoimmunity against nuclear autoantigens. The link between SLE and kidney disease is in situ immune complex formation in the different renal compartments, namely the glomerulus. Kidney injury then is driven by intrarenal inflammation, which involves additional mediators and cell types. Neutrophils, NETs, DCs, TLRs, and IFN-α contribute on both levels to the pathogenesis of LN, but although DCs and IFN-α are

Acknowledgment

The authors thank Maciej Lech for help with Figure 2.

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    Financial support: Supported by the Medical Faculty of the University of Munich (Förderung von Forschung und Lehre (FöFoLe) program to G.L.).

    Conflict of interest statement: none.

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