Chapter Two - Cellular and Molecular Mechanisms of Autoimmunity and Lupus Nephritis
Introduction
Autoimmunity implies immune responses that are directed against the self. It is usually considered a pathological process that should be avoided by a clear self/foreign distinction of the immune system. Historically, this perspective originates from clinical syndromes of organ destruction by noninfectious triggers for which certain autoantigens and autoantibodies could be identified. However, bioassays used to detect such autoantibodies often display their persistent presence also in healthy people or their transient presence upon infections that provide an unspecific stimulus to clonal lymphocyte expansion—for example, a transient increase of cryoglobulins after mycoplasma infection or persistent levels of low-affinity antinuclear antibodies. Indeed, autoimmunity is a common biological phenomenon that does not always cause a disease.
Complex organisms need to maintain their integrity in response to all sorts of threats. For example, threats by infectious organisms require particular host defense mechanisms such as intact barriers, secretory molecules, or local inflammatory responses, referred to as innate immunity. The molecular mechanisms of innate immunity have raised considerable attention since the discovery of the Toll-like receptors (TLRs), and the last decade has much increased our knowledge about how infectious organisms alert the immune system in an antigen-independent manner. It is also of note that the vast majority of the past and present species on this planet entirely rely on the innate immune system for host defense. The evolution of the adaptive immune system introduced a completely new way of immune activation that relies on “antigens,” small supramolecular structures of peptides, and lipid or nucleic acid complexes that are presented to the host's effector cell repertoire. The way in which priming of adaptive immune responses and imprinting of immune memory evolved it holds the risk for misinterpretations in terms of self-foreign discrimination. This was not a new problem.
Errors in self-foreign discrimination also exist at the level of the innate immune system and can contribute to considerable tissue destruction, e.g., in sterile forms of inflammation, where danger-associated molecular patterns (DAMPs) activate TLRs to initiate unnecessary inflammation causing additional tissue injury. However, innate immunity-related errors in self-foreign discrimination do not imprint any immune memory.
The numerous mechanisms of immune tolerance assure that potentially autoreactive elements of the adaptive immune system are kept to a minimum and hardly activated. However, the genetic variability of the population implies that some people are able to maintain immune tolerance better than others. In the end, autoimmunity presents like most other noncommunicable diseases. Most people do not experience autoimmune diseases during a lifetime. Very few individuals suffer from monogenetic defects of immune tolerance and experience autoimmune disease early in life. However, a small part of the population carries unfortunate combinations of genetic variants that considerably weaken immune tolerance at different levels, which, eventually triggered by environmental factors, primes an immune response and potentially immune memory upon presentation of an autoantigen.
This chapter will describe in detail the molecular and cellular mechanisms of immune tolerance and autoimmunity. The presentation is focused on the understanding of diseases in general and may show additional features in specific autoimmune diseases. A detailed description of the pathogenesis of all the different kinds of autoimmune diseases is beyond the scope of this chapter, but it should prepare the reader well for further studying more specific literature.
Section snippets
The Phenomenon of Immune Tolerance
The immune system identifies and mounts a prompt response to eliminate foreign/nonself-antigens while abstaining the harmful response to self-antigens. This inherent feature of the immune system has been termed as immune tolerance (Burnet and Fenner, 1949, Jerne, 2004). Broadly, immune tolerance can be divided into two categories, viz., natural or self-tolerance and inducible tolerance. Natural or self-tolerance is further subclassified based on the anatomical sites into central and peripheral
Genetic Factors and Autoimmunity
Genetic variation influences the immune tolerance and autoimmune disease outcomes. The mechanisms that induce genetic variations include sexual reproduction, mutation, migration, random genetic drift, recombination, and natural selection (Ramos et al., 2015). The recombination events mimic the natural selection shaping the diversity of human genome as well as increasing the risk of genetic diseases. For example, lymphocytes achieve their surface receptor diversity by the genomic alterations
Epigenetics and Transcription Factors
Gene transcription is an essential process for cellular functions and is regulated by epigenetic modifications. Numerous studies reported that epigenetic modifications occur on the gene loci that encode transcription factors and thus act as an additional regulatory factor for biological functions and disease pathogenesis. Epigenetics is one of the promising areas of investigation in the pathogenesis of autoimmune diseases such as SLE, rheumatoid arthritis, and autoimmune diabetes (Ballestar,
Costimulatory and Coinhibitory Pathways in Autoimmunity
Activation of naive T cells requires two signals acting simultaneously. Interaction of TCR with MHC-peptide molecules comprises signal 1, while costimulation via costimulatory receptors and their corresponding ligands on APCs requires signal 2 for activation of naïve T cells (Lafferty and Cunningham, 1975, Mueller et al., 1989). These costimulatory mechanisms provide molecular checkpoints to ensure that the immune system produces a controlled response to foreign antigens while avoiding
PRRs in Autoimmunity
Pioneers like Beutler, Janeway, Medzhitov, and colleagues initiated scientific interest in the field of innate immunity over the past decades (Beutler, 2000, Janeway and Medzhitov, 1999). It is now clear that immune cells use a set of evolutionarily conserved PRRs to detect foreign microorganisms via PAMPs (Cao, 2016). However, these PRRs can also sense mammalian motifs that are delivered by stressed or dying cells (Cao, 2016). Such signals include the release and intracellular engagement of
Immune Complexes
The binding of autoantibodies to soluble autoantigens results in the formation of immune complexes. Immune complexes are involved in several immune responses—for example, phagocytosis, opsonization, and complement activation. Mononuclear phagocytes or red blood cells that bear the complement and Fc receptors usually efficiently clear the immune complexes from the body. However, impairment in their clearance machinery leads to their deposition and subsequent tissue injuries resulting in
Genetic Risk Factors for Organ Manifestations in Human Autoimmune Diseases
Loss of organ-specific tolerance can be attributed to either lack of thymic presentation of organ-specific antigen or altered antigenicity within the target organ. The identification of the common genetic risk variants, their frequencies in the population (risk allele frequency), and the risks of disease they confer (odds ratio) by the genome-wide association studies (GWASs) have revealed very important information on the genetic risk factors for human autoimmune diseases (Goris and Liston, 2012
Lupus Nephritis
SLE and its most common organ manifestation, LN, strikingly reflect the implications of systemic autoimmunity and autoimmune tissue injury in clinical reality. In this chapter, we will recapitulate the factors involved in breaking tolerance against self during SLE and describe the mechanisms acting inside the nephritic kidney.
Summary
Unlike autoinflammation and alloimmunity, autoimmunity originates from a spontaneous loss of tolerance against self-proteins and other structures. A number of environmental factors such as drugs, infections, and acquired epigenetic modifications altering gene regulation determine and enhance the susceptibility to the loss of tolerance. Gene variants can weaken or break the checkpoints that maintain immune tolerance in the immune system. Beyond extremely rare monogenetic forms of autoimmunity,
Acknowledgments
S.R.M. is supported by the Deutsche Forschungsgemeinschaft (MU 3906/1-1). H.-J.A. is supported by the European Union's Horizon 2020 research and innovation program under Grant Agreement No. 668036 (RELENT). The views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out.
Conflict of interest statement: None.
References (614)
- et al.
Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies
Blood
(2009) - et al.
GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4 + T cells
Immunity
(2003) Pseudoviral immunity—a novel concept for lupus
Trends Mol. Med.
(2009)- et al.
Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice
Clin. Immunol.
(2008) - et al.
Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers
Am. J. Pathol.
(2001) - et al.
CD40 on NOD CD4 T cells contributes to their activation and pathogenicity
J. Autoimmun.
(2008) - et al.
Personalized immunomonitoring uncovers molecular networks that stratify lupus patients
Cell
(2016) - et al.
An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes
Blood
(1996) - et al.
A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis
Am. J. Hum. Genet.
(2004) - et al.
MicroRNAs prevent the generation of autoreactive antibodies
Immunity
(2010)
Endotoxin, toll-like receptor 4, and the afferent limb of innate immunity
Curr. Opin. Microbiol.
Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo
Blood
Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma
Am. J. Pathol.
Revisiting and revising suppressor T cells
Immunol. Today
Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome
Blood
The role of monocytes in ANCA-associated vasculitides
Autoimmun. Rev.
Calcium influx, a new potential therapeutic target in the control of neutrophil-dependent inflammatory diseases in bovines
Vet. Immunol. Immunopathol.
Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses
Immunity
CD134 plays a crucial role in the pathogenesis of EAE and is upregulated in the CNS of patients with multiple sclerosis
J. Neuroimmunol.
PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis
J. Neuroimmunol.
Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus
Immunity
Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry
J. Immunol. Methods
A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes
Cell
Autoimmunity in patients with selective IgA deficiency
J. Investig. Allergol. Clin. Immunol.
Direct exosome stimulation of peripheral human T cells detected by ELISPOT
Eur. J. Immunol.
Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort
Arthritis Rheum.
Molecular Biology of the Cell
Viral 5'-triphosphate RNA and non-CpG DNA aggravate autoimmunity and lupus nephritis via distinct TLR-independent immune responses
Eur. J. Immunol.
Viral RNA and DNA trigger common antiviral responses in mesangial cells
J. Am. Soc. Nephrol.
Lymphoid neogenesis in chronic inflammatory diseases
Nat. Rev. Immunol.
IL-17 promotes murine lupus
J. Immunol.
Ion channel blockers inhibit B cell activation at a precise stage of the G1 phase of the cell cycle. Possible involvement of K + channels
J. Immunol.
Toll-like receptors and danger signaling in kidney injury
J. Am. Soc. Nephrol.
Immunopathology of lupus nephritis
Semin. Immunopathol.
Glomerular disease: personalized immunomonitoring in lupus and lupus nephritis
Nat. Rev. Nephrol.
Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus
Eur. J. Immunol.
Unmet medical needs in lupus nephritis: solutions through evidence-based, personalized medicine
Clin. Kidney J.
Projection of an immunological self shadow within the thymus by the aire protein
Science
The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice
J. Exp. Med.
miRNA-transcription factor interactions: a combinatorial regulation of gene expression
Mol. Genet. Genomics
The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis
Arthritis Rheum.
CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice
J. Immunol.
Epigenetics lessons from twins: prospects for autoimmune disease
Clin. Rev. Allergy Immunol.
TLR4 links podocytes with the innate immune system to mediate glomerular injury
J. Am. Soc. Nephrol.
Ultraviolet radiation and systemic lupus erythematosus
Lupus
Iodination of murine thyroglobulin enhances autoimmune reactivity in the NOD.H2 mouse
Clin. Exp. Immunol.
IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs
Proc. Natl. Acad. Sci. U.S.A.
Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles
J. Clin. Invest.
Protein kinase cdelta deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation
Arthritis Rheum.
Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes
Arthritis Res. Ther.
Cited by (15)
Traditional Chinese medicine compounds ameliorating glomerular diseases via autophagy: A mechanism review
2022, Biomedicine and PharmacotherapyCitation Excerpt :In an inflammatory environment, dendritic cells recognize nucleic acid fragments as self-antigens, mature, and produce large amounts of type I interferons. This causes neutrophils to release neutrophil extracellular traps (NETs) and activate reactive T cells, ultimately leading to the production of autoantibodies[4,22]. Autophagy plays an important role in both innate and adaptive immunity in LN and has an obvious bidirectional regulatory effect[100,152]: Attenuation of autophagy can lead to reduced autoantibody production and attenuated type 1 interferon signaling, thereby ameliorating LN and kidney injury.
Extracellular vesicles and lupus nephritis - New insights into pathophysiology and clinical implications
2020, Journal of AutoimmunityCitation Excerpt :In addition, EV-associated pro-inflammatory molecules may directly act on target cells and cause the release of pro-inflammatory cytokines [101–104], thus contribute to inflammation and tissue damage. The inflammatory milieu, induced by EVs and EV-ICs, may induce podocyte injury and foot process effacement, proliferation of mesangial and parietal epithelial cells, leading to leakage of plasma and proteinuria and glomerular dysfunction [51,105,106]. Increased circulating ECs and endothelial EVs have been detected in patients with LN [107] or SLE [108], reflecting microvascular injury in these patients.
Protopanaxadiol improves lupus nephritis by regulating the PTX3/MAPK/ERK1/2 pathway
2024, Journal of Natural MedicinesLupus Nephritis Biomarkers: A Critical Review
2024, International Journal of Molecular SciencesRole of Sex Hormones in Prevalent Kidney Diseases
2023, International Journal of Molecular SciencesJuvenile systemic lupus erythematosus
2023, Padiatrische Praxis