Chapter Two - Cellular and Molecular Mechanisms of Autoimmunity and Lupus Nephritis

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Abstract

Autoimmunity involves immune responses directed against self, which are a result of defective self/foreign distinction of the immune system, leading to proliferation of self-reactive lymphocytes, and is characterized by systemic, as well as tissue-specific, inflammation. Numerous mechanisms operate to ensure the immune tolerance to self-antigens. However, monogenetic defects or genetic variants that weaken immune tolerance render susceptibility to the loss of immune tolerance, which is further triggered by environmental factors. In this review, we discuss the phenomenon of immune tolerance, genetic and environmental factors that influence the immune tolerance, factors that induce autoimmunity such as epigenetic and transcription factors, neutrophil extracellular trap formation, extracellular vesicles, ion channels, and lipid mediators, as well as costimulatory or coinhibitory molecules that contribute to an autoimmune response. Further, we discuss the cellular and molecular mechanisms of autoimmune tissue injury and inflammation during systemic lupus erythematosus 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.

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