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The patient with systemic lupus erythematosus: overview and pathogenesis 

The patient with systemic lupus erythematosus: overview and pathogenesis
Chapter:
The patient with systemic lupus erythematosus: overview and pathogenesis
Author(s):

Johan van der Vlag

, and Jo H. M. Berden

DOI:
10.1093/med/9780199592548.003.0161

June 28, 2018: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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date: 11 December 2019

Essentials

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations. The hallmark of SLE is the presence of antibodies against nuclear constituents, such as double-stranded (ds)DNA, histones, and nucleosomes. Local deposition of antinuclear antibodies in complex with nuclear autoantigens induces serious inflammatory conditions that can affect several tissues and organs, including the kidney.

The levels of antinucleosome and anti-dsDNA antibodies seem to correlate with glomerulonephritis and these autoantibodies can often be detected years before the patient is diagnosed with SLE. Apoptotic debris is present in the extracellular matrix and circulation of patients with SLE due to an aberrant process of apoptosis and/or insufficient clearance of apoptotic cells and apoptotic debris. The non-cleared apoptotic debris in patients with SLE may lead to activation of both the innate (myeloid and plasmacytoid dendritic cells) and adaptive (T and B cells) immune system. In addition to the activation by apoptotic debris and immune complexes, the immune system in SLE may be deregulated at the level of (a) presentation of self-peptides by antigen-presenting cells, (b) selection processes for both B and T cells, and (c) regulatory processes of B- and T-cell responses. Lupus nephritis may be classified in different classes based on histological findings in renal biopsies. The chromatin-containing immune complexes deposit in the capillary filter, most likely due to the interaction of chromatin with the polysaccharide heparan sulphate. A decreased renal expression of the endonuclease DNaseI further contributes to the glomerular persistence of chromatin and the development of glomerulonephritis.

Current treatment of lupus nephritis is not specific and aims to reduce the inflammatory response with general immunosuppressive therapies. However, research has revealed novel potential therapeutic candidates at the level of dendritic cells, B cells, and T cells.

Overview

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations. The hallmark of SLE is the presence of antibodies against nuclear constituents, like double-stranded (ds)DNA, histones, and nucleosomes (Mohan et al., 1993; Burlingame et al., 1994). Local deposition of antinuclear antibodies in complex with nuclear autoantigens induces serious inflammatory conditions that can affect several tissues and organs, including the kidney (Tsokos, 2011).

The levels of antinucleosome and anti-dsDNA antibodies seem to correlate with glomerulonephritis and these autoantibodies can often be detected years before the patient is diagnosed with SLE (Arbuckle et al., 2003). Apoptotic debris is present in the extracellular matrix and circulation of patients with SLE (Rumore and Steinman, 1990; Grootscholten et al., 2003; van Bavel et al., 2011) due to an aberrant process of apoptosis and/or insufficient clearance of apoptotic cells and apoptotic debris (Dieker et al., 2004; Munoz et al., 2008). The non-cleared apoptotic debris in patients with SLE may lead to activation of both the innate (myeloid and plasmacytoid dendritic cells) and adaptive (T and B cells) immune system (Fransen et al., 2010; Bouts et al., 2012). In addition to the activation by apoptotic debris and immune complexes, the immune system in SLE may be deregulated at the level of (a) presentation of self-peptides by antigen-presenting cells, (b) selection processes for both B and T cells, and (c) regulatory processes of B- and T-cell responses (Tsokos, 2011; Guerra et al., 2012; Liu and Davidson, 2012).

Lupus nephritis (see Chapter 162) may be classified in different classes based on histological findings in renal biopsies (Weening et al., 2004). The chromatin-containing immune complexes deposit in the capillary filter, most likely due to the interaction of chromatin with the polysaccharide heparan sulphate (van Bavel et al., 2008; O’Flynn et al., 2011; van der Vlag and Berden, 2011). A decreased renal expression of the endonuclease DNaseI further contributes to the glomerular persistence of chromatin and the development of glomerulonephritis (Zykova et al., 2010; Fismen et al., 2011; Seredkina and Rekvig, 2011). Current treatment of lupus nephritis (see Chapter 163) is not specific and aims to reduce the inflammatory response with general immunosuppressive therapies. However, research has revealed novel potential therapeutic candidates at the level of dendritic cells, B cells, T cells, and cytokines (Tsokos, 2011; Liu and Davidson, 2012).

Pathogenesis: introduction

SLE particularly affects women during their fertile age. In the United States, the prevalence of SLE is about 50 per 100,000 persons. Autoantibodies against double-stranded (ds)DNA, nucleosomes, histones are characteristic for SLE (Mohan et al., 1993; Burlingame et al., 1994). Glomerulonephritis is one of the most serious clinical manifestations in SLE. The American College of Rheumatology (ACR) has designated 11 criteria for lupus covering the major clinical and laboratory features of the disease (see Table 161.1). A patient meeting four or more criteria out of 11 is diagnosed with SLE with 95% specificity and 85% sensitivity (Tan et al., 1982; Hochberg, 1997).

Table 161.1 ACR revised classification criteria for systemic lupus erythematosus

Criterium

Definition

Malar rash

Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

Discoid rash

Erythematous raised patches with adherent keratotic scaling and follicular plugging

Photosensitivity

Skin rash as a result of unusual reaction to sunlight

Oral ulcers

Oral or nasopharyngeal ulceration

Arthritis

Non-erosive arthritis involving two or more peripheral joints

Serositis

  • A. Pleuritis or

  • B. Pericarditis

Renal disorder

  • A. Persistent proteinuria (> 0.5 g/day) or

  • B. Cellular casts

Neurologic disorder

  • A. Seizures, or

  • B. Psychosis

Haematologic disorder

  • A. Haemolytic anaemia or

  • B. Leucopenia or

  • C. Lymphopenia or

  • D. Thrombocytopenia

Immunologic disorder

  • A. Abnormal titre of antibodies to native DNA or

  • B. Presence of antibody to Sm nuclear antigen or

  • C. Positive finding of antiphospholipid antibodies

ANA

Abnormal titre of antinuclear antibodies

From Tan et al. (1982) and Hochberg (1997).

SLE has a multifactorial aetiology that is still not fully understood. The pathogenesis depends on a genetic predisposition, with contributing factors that may include infections, environmental factors, like sunlight and toxins, and hormonal factors (Tsokos, 2011). In the online database Online Mendelian Inheritance in Man ((OMIM) <http://www.ncbi.nlm.nih.gov/omim>) > 140 genes have been genetically associated in one way or another with SLE, while in PubMed (<http://www.ncbi.nlm.nih.gov/pubmed?db=pubmed>), the term lupus reveals > 66,000 scientific articles, which underscores the complexness of the pathogenesis of SLE.

The levels of antinucleosome and anti-dsDNA antibodies seem to correlate with glomerulonephritis and are already detectable before disease manifestations (Arbuckle et al., 2003). The main question that can be raised is how in SLE an autoimmune response is mounted against chromatin that normally is shielded from the immune system due to its location in the nucleus. Apoptotic material is present in the extracellular matrix and the circulation of patients with SLE (Rumore and Steinman, 1990; Grootscholten et al., 2003; van Bavel et al., 2011). The presence of apoptotic material may be the result of an aberrant process of apoptosis, either caused by an increased rate of apoptosis or apoptosis at the wrong moment or location (see Table 161.3 for an overview of factors) (Dieker et al., 2004; Munoz et al., 2008; Fransen et al., 2009). An insufficient clearance of apoptotic cells and debris provides an additional explanation for the persistent presence of apoptotic material in patients with SLE (see Table 161.4 for an overview) (Dieker et al., 2004; Fransen et al., 2009). The innate and adaptive immune system may thereby be activated in several ways: (a) apoptotic blebs and apoptotic chromatin, containing apoptosis-induced modifications, may lead to activation of myeloid dendritic cells (mDCs) via ligation of toll-like receptors (TLRs).These activated mDCs may present histone peptides in an immunogenic fashion to autoreactive T cells. Activated autoreactive T cells may activate autoreactive B cells specific for chromatin; (b) particular RNA-containing immune complexes may activate plasmacytoid dendritic cells (pDCs) via ligation of TLR7, leading to the production of type I interferons like IFN-α‎. Also chromatin-containing constituents of granulocytes, NETs (neutrophil extracellular traps) lead to activation of pDCs; (c) autoreactive B cells may be directly activated by apoptotic chromatin (Ronnblom et al., 2009; Fransen et al., 2010; Tsokos, 2011; Bouts et al., 2012; Liu and Davidson, 2012). This chapter will mainly focus on the first two pathways of immune activation. In addition to the three aforementioned pathways of immune activation, the immune system in SLE may be deregulated at the level of (a) presentation of self-peptides by antigen-presenting cells, (b) selection processes for both B and T cells, and (c) regulatory processes of B- and T-cell responses, including cytokines (Tsokos, 2011; Guerra et al., 2012; Liu and Davidson, 2012). See Table 161.2 for an overview of key factors implicated in the pathogenesis of SLE.

Table 161.3 Factors associated with apoptosis and survival defects in SLE

Factor name

Abbreviation

Function

Integrin alpha M

ITGAM (CD11/CD18)

Regulator of apoptosis in neutrophils and binds to C3b-coated apoptotic cells

Fas receptor

FasR (CD95)

Inducer of apoptosis

Fas ligand

FasL (CD95L)

Inducer of apoptosis

BCL2-like 11 (apoptosis facilitator)

BCL2L11 or Bim

Inducer of apoptosis

B-cell lymphoma protein family

Bcl-2, BFl-1, Bcl-XL

Inhibitor of apoptosis

Src homology 2 domain-containing transforming protein C1

Shc1 or p66Shc

Mediator of apoptosis in T cells

B-cell activating factor receptors

  • BAFFR

  • TACI

  • BCMA

Survival signal for B cells

B-cell activating factor

BAFF (BLyS)

Survival signal for B cells (binds to all BAFF receptors)

A proliferation-inducting ligand

APRIL

Survival signal for B cells (binds to TACI and BCMA)

Coronin-1A

Coro1a

Survival factor for T cells

From Fransen et al. (2009) and Guerra et al. (2012).

Table 161.4 Factors associated with clearance defects in SLE

Factor name

Abbreviation

Function

Integrin alpha M

  • ITGAM

  • (CD11/CD18)

Binds to C3b-coated apoptotic cells and regulates apoptosis in neutrophils

Milk fat globule-EGF factor 8 protein

MFGE8

Binds to PS on apoptotic (B) cells and mediates uptake by phagocytes

c-mer proto-oncogene tyrosine kinase

MERTK

Mediates uptake of apoptotic cells by phagocytes

Macrophage receptor with collagenous structure

MARCO

Binds and clears apoptotic cells in the marginal zone of the spleen and in the thymus

Mannan-binding lectin

MBL

Binds to apoptotic cells and mediates uptake by phagocytes

Complement component 1, q subcomponent

C1q

Binds to apoptotic cells and mediates uptake by phagocytes

Pentraxin-related gene

PTX3

Binds to apoptotic cells and mediates uptake by phagocytes

Serum amyloid P-component

SAP

Binds to apoptotic cells and mediates uptake by phagocytes

C-reactive protein

CRP

Binds to apoptotic cells and mediates uptake by phagocytes

Fcγ‎ receptor IIB

FCGRIIB (CD32)

Clears IgG immune complexes

Fcγ‎ receptor IIA

  • FCGRIIA

  • (CD32)

Clears IgG immune complexes

3′–5′ repair exonuclease 1

TREX1

Degrades single-stranded DNA reversed transcribed from retroviral elements

Deoxyribonuclease I

DNase1

Fragments chromatin

From Fransen et al. (2009) and Guerra et al. (2012).

Table 161.2 Pathogenic factors associated with SLE

Factor name

Abbreviation

Function

Major histocompatibility complex class II

HLA-DRB1

Binding and presenting antigenic peptides to T cells

Protein C-ets-1

ETS1

Transcription factor controlling differentiation and activation of B and T lymphocytes

Ikaros family zinc finger protein 1

IKZF1

Transcription factor controlling differentiation and activation of B and T lymphocytes

Protein tyrosine phosphatase, non-receptor type 22

PTPN22

Tyrosin phosphatase involved in B- and T-lymphocyte activation

Tumour necrosis factor (ligand) superfamily4

TNFSF4

Activation and adhesion of T cells

Programmed cell death-1

  • PDCD-1

  • (PD-1)

Negative regulator of activated T cells; required for development of regulatory T cells

Src homology 2 domain-containing transforming protein C1

Shc1 or p66Shc

Negative regulator of activated T cells

Signal transducer and activator of transcription4

STAT4

Transcription factor regulating T-cell development, T-cell activation, and cytokine production

cAMP-responsive element modulator

CREM

Transcription factor regulating IL-2 and IL-17 transcription in T cells

B-cell scaffold protein with ankyrin repeats

BANK1

Activation of B cells

B-lymphocyte kinase

BLK

Tyrosine kinase involved in B-cell activation

Toll-like receptor 2

TLR2

Receptor on phagocytes; binds nucleosome-associated high mobility group box protein 1 (HMGB1)

Toll-like receptors 7 and 9

TLR7 and -9

Endosomal receptor in phagocytes; binds single-stranded RNA/DNA, double-stranded DNA, respectively

Interleukin-1 receptor-associated kinase1

IRAK1

Kinase in downstream signalling pathways of the interleukin-1 receptor and toll-like receptors

Interferon regulatory factors 5 and 7

IRF5 and 7

Transcription factors regulating interferon alpha and beta production

Interferon regulatory factor 8

IRF8

Transcription factor controlling differentiation and activation of dendritic cell subsets

Interferon alpha

IFN-α‎

Cytokine with multiple effector functions (e.g. affecting T- and B-cell responses and survival)

Factors related to apoptosis and clearance are listed in Tables 161.3 and 161.4.

From Fransen et al. (2009), Guerra et al. (2012), and Tiffin et al. (2012).

The pathogenesis of lupus nephritis is as complex as the aetiology of SLE, and several histological classifications have been proposed (Weening et al., 2004). The chromatin-containing immune complexes deposit in the capillary filter, most likely due to the interaction of positively charged histones in chromatin with the negatively charged polysaccharide heparan sulphate in the glomerular basement membrane and endothelial glycocalyx (van Bavel et al., 2011; van der Vlag and Berden, 2011; O’Flynn et al., 2011). A decreased renal expression of the endonuclease DNaseI further contributes to the development of glomerulonephritis (Zykova et al., 2010; Fismen et al., 2011; Seredkina and Rekvig, 2011). Current treatment of lupus nephritis is not specific and aims to reduce the inflammatory response with general immunosuppressive drugs. However, research in the last decade has revealed novel therapeutic targets at the level of dendritic cells, B cells, T cells, and cytokines (Tsokos, 2011; Kulkarni and Anders, 2012; Liu and Davidson, 2012).

Apoptosis and survival defects in systemic lupus erythematosus

Background of apoptosis and survival defects in SLE

Apoptosis is the process of programmed cell death and is involved in the formation, shaping, and maintenance of tissues and organs, including the regulation of the immune response by deletion of B and T cells. Apoptosis can be induced by intrinsic factors, such as DNA damage, and by extrinsic factors, such as, for example, the binding of Fas ligand to the Fas receptor. Apoptosis follows a cascade of signal transduction pathways that include caspases and endonucleases. Characteristic for apoptosis at the molecular level is the fragmentation of chromatin and at the cellular level the segregation of apoptotic blebs. Apoptotic blebs contain autoantigens targeted in SLE. In patients with SLE, apoptotic cells and immune complexes with nuclear autoantigens, such as nucleosomes, have been observed in several tissues, such as the germinal centre of the lymph nodes, the epidermis, the kidneys, and the circulation. A list of factors associated with apoptosis and SLE is provided in Table 161.3 (Fransen et al., 2009; Guerra et al., 2012). Data are derived from studies in both patients and mice, and some key factors will be briefly discussed.

Aberrant apoptosis induction and survival signals in SLE

One of the classical pathways which lead to the induction of apoptosis involves the Fas receptor (CD95; FasR) and Fas ligand (CD95L; FasL) couple. FasL is only expressed on immune cells, whereas FasR is expressed on non-immune cells as well. Mice deficient in FasR (lpr) or FasL (gld) show lymphoproliferation and development of SLE-like features. Mutations in the genes encoding FasR or FasL in humans lead to familial autoimmune lymphoproliferative syndrome, but not to SLE. In patients with juvenile onset of SLE an increased expression of FasR on T cells has been detected (Fransen et al., 2009).

Proteins of the Bcl-2 family are important regulators of apoptosis associated with SLE, and can be either anti-apoptotic (e.g. Bcl-2) or pro-apoptotic (e.g. Bim). Defects in Bim lead to the persistence of autoreactive B and T cells, the survival of antigen-presenting cells, like DC, and are thereby facilitating the induction of autoimmunity. An increased expression of Bcl-2 on the other hand leads to apoptosis-resistant (autoreactive) lymphocytes (Fransen et al., 2009).

Integrin alpha-M, (ITGAM (CD11/CD18)) has been identified in genome-wide screens to be associated strongly with SLE. ITGAM functions in the regulation of apoptosis in neutrophils, but also in leucocyte adhesion and complement C3b binding. The precise function of ITGAM in neutrophil survival remains unclear (Nath et al., 2008).

A lack of survival signals also can lead to apoptosis. B-cell survival signals affected in SLE include the cytokine B-cell activating factor (BAFF), also known as BLyS, which binds to the BAFF-receptors, BAFFR, TACI, and BCMA. BAFF signalling is required for the maintenance of autoreactive B cells in the marginal zone, and an increased BAFF expression in mice results in the development of autoimmunity and SLE-like manifestations. Mouse models for lupus, like MRL/lpr and (NZBxNZW)F1, are characterized by a high expression of BAFF, whereas treatment of these lupus mice with a soluble receptor for BAFF, TACI, decreases mortality and inhibits the development of proteinuria (Cancro et al., 2009). In patients with SLE, elevated BAFF levels are present, which correlate with anti-dsDNA titres. In patients with SLE, a polymorphism in APRIL, related to the BAFF protein, has been identified as well. Recently a monoclonal antibody directed against BAFF, belimumab, was successfully used in patients with SLE (Dooley et al., 2013). Coronin-1A was identified in genome-wide screens to be associated with SLE and appeared to be a survival signal for T cells. Coronin-1A is associated with the actin cytoskeleton and a mutation in Coronin-1A is able to suppress autoimmunity and lupus nephritis in animal models for SLE (Haraldsson et al., 2008).

Neutrophil extracellular traps in SLE

Neutrophils may play an important role in the pathogenesis of SLE. Neutrophils can spill so-called neutrophil extracellular traps (NETs), which consist of their total chromatin and associated peptides with anti-microbial activity like LL37 and HNP. This process of NET formation is called NETosis and can be considered as a special case of apoptosis (Fuchs et al., 2007). The NETs are meant to capture microbes, but can also have adverse effects, as insufficient degradation of NETs is linked to SLE and lupus nephritis. Serum of patients with SLE contains anti-LL37 and anti-HNP antibodies, which correlate with anti-DNA antibody titres, indicating that these DNA-antimicrobial peptide complexes may serve as B cell autoantigens. These anti-LL37 and anti-HNP antibodies further facilitate the process of NETosis (Bouts et al., 2012). In particular, the NETs are able to activate plasmacytoid dendritic cells (see ‘The role of plasmacytoid dendritic cells and IFN-α‎ in SLE’) (Hakkim et al., 2010; Garcia-Romo et al., 2011; Kaplan, 2011; Lande et al., 2011; Bouts et al., 2012). Histones within NETs contain post-translational modifications including acetylation and methylation, which also may play a role in breaking the tolerance to NET-associated proteins; however, this mechanism has not yet been confirmed (Liu et al., 2012).

Apoptosis-induced autoantigen modifications in systemic lupus erythematosus

Autoantigens can be modified during apoptosis, whereby these modifications may facilitate breaching of tolerance. Autoantigens in SLE are prone to cleavage by caspases and endonucleases. Cleavage products of caspase and granzyme B, a protease that is activated in cytotoxic T-cell-induced apoptosis, appear to be more immunogenic than the intact molecules (Casciola-Rosen et al., 1999; Utz et al., 2000). In addition, autoantigens, including chromatin, may be post-translational modified through covalent addition of acetyl, phosphoryl, methyl, ubiquitin, citruline, ADP, or glutamine moieties. Autoantibodies against the aforementioned modifications are present in patients with SLE (Utz and Anderson, 1998; Doyle and Mamula, 2005; Munoz et al., 2008). Specific apoptosis-induced hyperacetylation patterns on histones H2A, H2B, and H4, as well as a specific methylation pattern on H3 have been associated with SLE (Dieker et al., 2007; van Bavel et al., 2009, 2011; Price et al., 2012). Plasma from patients with SLE and lupus mice reveal a higher reactivity with the identified acetylation and methylation patterns on histones, whereas hyperacetylated nucleosomes lead to maturation of DC from lupus-prone mice (see ‘Dendritic cells in SLE’) (Dieker et al., 2007).

In summary, several factors involved in the induction of apoptosis, anti-apoptotic factors, and survival factors are associated with SLE and glomerulonephritis. See Table 161.3 for an overview of factors related to apoptosis and survival defects in SLE. In addition, apoptosis-induced chromatin modifications and NETs have been linked to SLE.

Clearance defects in systemic lupus erythematosus

Background of clearance defects in SLE

The mechanisms described in the previous paragraph explain how normally inaccessible autoantigens can become exposed to the immune system. In addition to an aberrant apoptosis, an impaired removal may lead to the accumulation of apoptotic cells and debris. Normally, apoptotic cells are swiftly removed through phagocytosis by professional phagocytes, such as macrophages, B cells and dendritic cells in a non-inflammatory or even anti-inflammatory manner. Depending on the context, phagocytosis of apoptotic cells may also result in a pro-inflammatory response, as will be detailed in later sections. The swift removal of apoptotic cells and debris normally prevents potentially harmful molecules being released. In the case of SLE the clearance capacity is apparently insufficient, and consequently apoptotic blebs will segregate from apoptotic cells. These apoptotic blebs contain clustered SLE-autoantigens, such as (modified) chromatin (Rosen and Casciola-Rosen, 1999). As discussed, in addition to apoptotic blebs, NETs can be released from neutrophils and be considered as apoptotic chromatin as well. The release of apoptotic chromatin autoantigens not only leads to the induction of autoimmunity but also to the formation of immune complexes. These immune complexes can deposit in the glomerular basement membrane thereby inciting a severe glomerulonephritis. So, both for the initiation of the immune response and the local inflammatory response, insufficient clearance may be a contributing factor in SLE. There is convincing evidence for clearance defects of apoptotic cells and debris in SLE. In fact it was clearly demonstrated that the clearance of apoptotic material by phagocytes is impaired in both lupus mice and patients (Herrmann et al., 1998; Licht et al., 2004). Downregulation of the expression of the endonuclease DNaseI in the kidney further contributes to the development of lupus nephritis (Seredkina and Rekvig, 2011). Factors associated with clearance defects in SLE are listed in Table 161.4 (Fransen et al., 2009; Guerra et al., 2012). Data are derived from studies in both patients and mice, and some key factors will be briefly discussed.

Aberrant recognition and opsonization of apoptotic cells in SLE

Cells undergoing apoptosis display ‘come and get me’ signals, like the lipid phosphatidylcholine (PC) or the protein thrombospondin, and ‘eat me’ signals, like the lipid phosphatidylserine (PS). These signals attract phagocytes and facilitate phagocytosis mediated by receptors on phagocytes. Bridging molecules, such as, for example, opsonins, serve as an additional link between the signals on the surface of the apoptotic cell and the receptors on the phagocyte. Deficiencies in these components can lead to decreased clearance of apoptotic cells and to the development of SLE in humans and mice (Savill et al., 2002; Munoz et al., 2008; Fransen et al., 2009).

An important apoptotic cell signal for clearance is PS that is present at the outer cell membrane rapidly after the induction of apoptosis. PS is bound directly by receptors on the phagocyte or indirectly via bridging molecules or opsonins. The phagocytic cells express multiple receptors including the PS receptor, Milk fat globule-EGF factor 8 protein (MFGE8), complement factor C1q receptor, c-Mer proto-oncogene tyrosine kinase (MERTK), ITGAM, and macrophage receptor with collagenous structure (MARCO), which all enable binding of apoptotic cells. Macrophages deficient in these receptors show an impaired clearance of apoptotic cells and mice deficient in these receptors develop an increased number of antinuclear autoantibodies, indicating that defects in these receptors play a role in the development of SLE (Munoz et al., 2008; Fransen et al., 2009).

Bridging molecules and opsonins that play an important role in the clearance of apoptotic cells include complement C1q, pentraxins (PTX3), mannan-binding lectin (MBL), C-reactive protein (CRP), and serum amyloid P protein (SAP). Targeting of these molecules leads to autoimmunity and SLE-like features, including glomerulonephritis. The complement molecules C1q and MBL bind to late apoptotic cells in particular. C1q is an opsonin and required for uptake of degraded chromatin. Mice lacking C1q develop SLE, while in humans C1q deficiency always is associated with SLE. Polymorphisms in the MBL gene and low serum levels of MBL have been associated with SLE as well. CRP binding to apoptotic debris in conjunction with anti-CRP antibodies facilitates phagocytosis with a pro-inflammatory outcome. Binding of autoantibodies to apoptotic cells and particles is the classical example of opsonization, thereby facilitating phagocytosis via Fc-receptors on phagocytes (Sarmiento et al., 2007). Both the Fcγ‎RIIA and Fcγ‎RIIB receptor are genetically associated with the susceptibility to develop lupus nephritis (Munoz et al., 2008; Fransen et al., 2009).

DNaseI, the major endonuclease that fragments chromatin during apoptosis, is associated with SLE. DNaseI deficiency leads to the accumulation of non-fragmented apoptotic chromatin (Napirei et al., 2000). The 3′–5′ repair exonuclease (TREX1), another DNA metabolizing enzyme, is also associated with SLE (Rice et al., 2009). TREX1 facilitates the degradation of the reversed transcribed single-stranded DNA from retroviral elements. TREX1 deficiency leads to the accumulation of single-stranded DNA and the production of IFN-α‎ by pDCs. Insufficient endonuclease activity also leads to the persistent presence of NETs (see ‘Neutrophil extracellular traps in SLE’).

Aberrant clearance of apoptotic cells in germinal centres in SLE

In addition to the systemic presence of apoptotic chromatin in the extracellular matrix and circulation, the accumulation of apoptotic debris in germinal centres of patients with SLE has been shown. In normal lymph nodes, apoptotic nuclei can be detected inside tangible body macrophages. Non-ingested apoptotic nuclei are often found outside these cells in SLE. Sometimes nuclear debris can be observed at the surfaces of follicular dendritic cells, which normally retain complement-opsonized immune complexes on their surfaces, thereby facilitating affinity maturation of B cells. Therefore, in SLE, clearance deficiency leads to the accumulation of apoptotic material on the follicular dendritic cells. The presence of not cleared apoptotic material at those sites may explain the loss of peripheral B-cell tolerance (Baumann et al., 2002; Munoz et al., 2008).

In summary, several factors involved in the attraction, recognition, and phagocytosis of apoptotic cells, and fragmentation of chromatin, are associated with SLE and glomerulonephritis. See Table 161.4 for an overview of factors related to clearance defects in SLE.

Dendritic cells in systemic lupus erythematosus

The role of myeloid dendritic cells in SLE

Two main subsets of dendritic cells can be distinguished, mDCs and pDCs, which differ in their lineage and their expression of receptors, including the TLRs. In patients with SLE, soluble apoptotic chromatin is present in the circulation and the extracellular matrix (Rumore and Steinman, 1990; Grootscholten et al., 2003; van Bavel et al., 2011). In addition, apoptotic blebs are present that contain clustered autoantigens, including apoptosis-induced chromatin (Rosen and Casciola-Rosen, 1999). The classical view is that macrophages can ingest apoptotic cells, blebs, and debris in an anti-inflammatory manner, which is characterized by the production of transforming growth factor beta and interleukin (IL)-10. In addition, dendritic cells encountering autoantigens without being activated will induce immunological tolerance. The balance between immunity and tolerance apparently is skewed towards autoimmunity in SLE. mDCs can be activated by apoptotic blebs and modified chromatin, and after ingestion mDCs present the modified histone peptides in a pro-inflammatory manner to T cells, thereby initiating an autoimmune response (Fransen et al., 2010). In vitro apoptotic bleb and apoptotic chromatin-matured mDCs show an increased expression of co-stimulatory molecules (CD86 and CD40) and increased secretion of proinflammatory cytokines (IL-1β‎, IL-6, and tumour necrosis factor alpha (TNF-α‎)) (Boule et al., 2004, 2012; Fransen et al., 2009a, 2009b). Chromatin of viable cells is less potent in activating mDCs. The effect of apoptotic blebs on mDCs is probably independent from TLR-3, -7, and -9. High-mobility group protein B1 (HMGB1) remains attached to apoptotic chromatin and appears crucial in activation of mDCs. TLR2 binds the HMGB1-complexed chromatin (Urbonaviciute et al., 2008). Presentation by activated mDCs of the ingested modified chromatin to autoreactive T cells may be the first step in breaking the immunological tolerance that may occur in patients with SLE. The secretion of IL-2, IFN-γ‎, and IL-17 in co-cultures of mDCs and T cells suggests T-cell polarization towards the T helper (Th)-1 and Th17 subtypes, while there is proof for a Th17 response in patients with SLE (Fransen et al., 2009b, 2010). IL-6 concentrations, produced by activated mDCs, are high in patients with SLE, which inhibit the development of regulatory T cells (TREG) while it stimulates the development of Th17 cells, a feature linked to other autoimmune diseases as well. Th17 cells may activate autoreactive B cells and recruit inflammatory cells to specific organs (Garrett-Sinha et al., 2008). Activated autoreactive T cells, specific for apoptosis-modified histone peptides can also activate B cells which recognize either modified or unmodified parts of chromatin with their receptor, which results in the production of autoantibodies directed to modified and unmodified chromatin (DNA, histones, nucleosomes) via epitope spreading. After formation of autoantibodies, immune complexes with circulating chromatin are formed that can activate mDCs, thereby creating an amplification loop in the immune response against apoptotic chromatin.

The role of plasmacytoid dendritic cells and IFN-α‎ in SLE

Plasmacytoid DC express TLR7 and TLR9, whereas mDCs from human blood do not abundantly express these specific TLRs. pDCs are not so big eaters as mDCs, and, for example, do not ingest apoptotic blebs. Immune complexes composed of nucleic acids and antibodies specific for these nucleic acids or associated proteins are ingested by pDCs via Fcγ‎RIIA. Subsequently, via ligation of TLR7 and TLR9 the pDCs are activated, thereby initiating the production of type I IFNs, with IFN-α‎ as key cytokine. In patients with SLE, a type I IFN response is frequently observed, indicating that pDC activation is a central event in the pathogenesis of SLE. IFN-α‎ has a broad range of effector functions, which include mDC maturation, B-cell activation, T-cell activation, and enhancing NETosis, thereby amplifying the autoimmune response against chromatin (Ronnblom et al., 2009). In addition to nucleic acid-containing immune complexes, the previously introduced NETs also trigger pDCs to produce IFN-α‎ (Garcia-Romo et al., 2011; Kaplan, 2011; Lande et al., 2011; Bouts et al., 2012).

Renal pathogenicity of antichromatin autoantibodies in lupus nephritis

The deposition of immune complexes containing anti-chromatin and chromatin in basement membranes is typical for a type III immunological reaction of which SLE is the prototype disease. Essentially two models exist to explain the pathogenicity in lupus nephritis of anti-chromatin antibodies in general, and anti-dsDNA antibodies in particular. In the first model, cross-reactivity of anti-dsDNA antibodies with intrinsic glomerular structures such as laminin, type IV collagen, or α‎-actinin initiates the inflammatory reaction. In the second model, chromatin mediates the binding of anti-chromatin antibodies to glomerular structure such as heparan sulphates that are present in the glomerular basement membrane and in the glomerular endothelial glycocalyx (van Bavel et al., 2008; van der Vlag and Berden, 2011). Most evidence is in favour of the second model. The presence of chromatin bound to anti-dsDNA antibodies used in research could serve as an explanation for apparent cross-reactive binding, since removal of chromatin from these antibody preparations leads to loss of the cross-reactivity (Termaat et al., 1990). Now it is clear that in vivo bound anti-chromatin antibodies in lupus nephritis only co-localize with deposited chromatin, and not with intrinsic glomerular structures (Kalaaji et al., 2006a, 2006b; van Bavel et al., 2008). The accumulation of large chromatin fragments in the kidney is enhanced and facilitated by a specific and local shutdown of DNaseI (Zykova et al., 2010; Fismen et al., 2011; Seredkina and Rekvig, 2011).

Treatment of lupus nephritis

For the treatment of SLE four primary classes of drugs can be distinguished: non-steroidal anti-inflammatory compounds (NSAIDs), antimalarials (e.g. hydroxychloroquine), corticosteroids (e.g. prednisone), and cytotoxic/immunosuppressive agents (e.g. azathioprine, mycophenolate mofetil, ciclosporin, and cyclophosphamide). Current therapies in general are not lupus specific and aim to suppress the autoimmune response. However, novel therapies for lupus are emerging; they include antibodies against B cells (e.g. rituximab, ocrelizumab, and epratuzumab) and compounds affecting the survival of B cells (e.g. belimumab and belatacept that bind BlyS and APRIL). Antibodies neutralizing key cytokines in the pathogenesis of SLE (e.g. for TNF-α‎, IFN-α‎, or IL-6), complement inhibitors, and blockers for the costimulatory interactions between B and T cells, and APC and T cells (e.g. for CD40L, CTLA4-Ig) are currently available or developed (Tsokos, 2011; Kulkarni and Anders, 2012; Liu and Davidson, 2012). Although promising, these novel therapies are not specific for treatment of SLE and lupus nephritis. The holy grail in treatment of SLE is to induce tolerance against chromatin. Histone-peptides can induce tolerance in mouse models for lupus, which is characterized by autoantigen-specific expansion of regulatory T cells and contraction of Th17 cells (Kang et al., 2005, 2007). A leading example of a lupus-specific tolerizing peptide is Lupuzor™ (P140 peptide), which is in the clinical trial phase. Lupuzor™ is based on a peptide (peptide 140) derived from the U1-70K snRNP protein, which contains a residue (serine 140) that is phosphorylated during apoptosis. In lupus mouse models, administration of the P140 peptide reduces mortality and proteinuria. In a phase 2a study, Lupuzor™ led to a significant reduction of anti-DNA antibodies and improvement of the SLE disease activity index (SLEDAI) (Baumann et al., 2002; Dieker et al., 2008; Muller et al., 2008).

Concluding remarks

Despite the research conducted and the large number of papers published, we do not yet fully understand the aetiology of SLE. During the last decades, important factors and processes have been identified that may contribute to the development of autoimmunity and lupus nephritis. In Fig. 161.1, an integrated hypothesis for the initiation and amplifying processes in SLE is depicted. Central processes in the pathogenesis of SLE seem to be apoptosis, including NETosis, and the clearance of apoptotic material and NETs. Apoptosis-induced chromatin modifications, present in soluble chromatin, apoptotic blebs, and immune complexes may lead to the activation of mDCs and pDCs. Activated mDCs may initiate a mixed Th1/Th17 response, whereas activated pDCs produce type I IFNs, with IFN-α‎ as a key player, affecting B and T cells, which chronifies the disease. Novel therapeutics should interfere with these central processes and aim to induce tolerance.

Fig. 161.1 Integrated model for the pathogenesis of SLE. (1) Apoptotic blebs and chromatin is ingested by immature myeloid dendritic cells (mDC), which, thereby, (2) are matured and present (apoptosis-modified) chromatin in their MHC to autoreactive T cells. (3) Activated autoreactive T cells assist autoreactive B cells to produce autoantibodies directed against chromatin. (4) Immune complexes between autoantibodies and chromatin are formed. (5A) Immune complexes are ingested by plasmacytoid dendritic cells (pDCs), which, thereby are activated and (5B) start to produce type I interferons, including IFN-α‎. (5C) IFN-α‎ primes neutrophils, and (6A, 6B) autoantibodies against chromatin, and NET-associated proteins LL37 and HNP, induce NETosis, which is normally triggered by microbes (7). (8) Chromatin and NET-associated proteins (LL37, HNP) spewed into the extracellular space function as autoantigens for the B cell, which leads to anti-LL37, anti-HNP, and anti-chromatin autoantibodies that may form immune complexes with NET (9), thereby facilitating their uptake by pDC (10). This establishes a loop between pDC and neutrophils that chronifies and/or exacerbates the autoimmune response and the inflammatory condition in SLE.

Fig. 161.1 Integrated model for the pathogenesis of SLE. (1) Apoptotic blebs and chromatin is ingested by immature myeloid dendritic cells (mDC), which, thereby, (2) are matured and present (apoptosis-modified) chromatin in their MHC to autoreactive T cells. (3) Activated autoreactive T cells assist autoreactive B cells to produce autoantibodies directed against chromatin. (4) Immune complexes between autoantibodies and chromatin are formed. (5A) Immune complexes are ingested by plasmacytoid dendritic cells (pDCs), which, thereby are activated and (5B) start to produce type I interferons, including IFN-α‎. (5C) IFN-α‎ primes neutrophils, and (6A, 6B) autoantibodies against chromatin, and NET-associated proteins LL37 and HNP, induce NETosis, which is normally triggered by microbes (7). (8) Chromatin and NET-associated proteins (LL37, HNP) spewed into the extracellular space function as autoantigens for the B cell, which leads to anti-LL37, anti-HNP, and anti-chromatin autoantibodies that may form immune complexes with NET (9), thereby facilitating their uptake by pDC (10). This establishes a loop between pDC and neutrophils that chronifies and/or exacerbates the autoimmune response and the inflammatory condition in SLE.

Adapted from Bouts et al. (2012).

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