Systemic Lupus Erythematosus

Pathogenesis and pathophysiology

We will talk about:

Pathogenesis aetiology or contributing

factors

Pathophysiology

Key events in development of the disease

In one sentence!SLE results from recurrent activation of

immune system with production of antibodies and other protein products

contributing to inflammation and tissue damage.

Aetiology & Pathogenesis

Contributing factors•Environmental factors•Genetic factors•Hormonal factors

Environmental factors

1. EBV infection •Epstein–Barr virus (EBV) has been

identifed as a possible factor inthe development of lupus.

•EBV may reside in and interact with B cells and promotes (IFNα) production by plasmacytoid dendritic cells, suggesting that elevated IFNα in lupus may be—at least in part—due to aberrantly controlled chronic viral infection.

2.Drugs •Over 100 drugs have been reported to

causedrug-induced lupus (DIL), including a number of the newer biologics and antiviral agents.

•Autoimmunity not hypersensitivity! •t is believed that the development of DILE

requires a certain degree of genetic susceptibility.

Theories proposed in the pathogenesis of DIL•Theory 1: altering T-cell cell DNA

methylation, which has a primordial role in the regulation and expression of genes and cell differentiation.

•Theory 2: autoreactive B cells are activated by drug-specific T cells.

•Theory 3:the culprit drug subverts de novo acquisition of B-cell tolerance if it is present in the thymus as these cells develop.

3. UV light•UV light may induce breaks in in DNA

that might alter gene expression or lead to apoptotic or necrotic cell death.

Genetic factors

•Concordance rate in monozygotic twins is 10 times more frequent than in dizygotic twins.

•Siblings of SLE patients are approximately 30 times more likely to develop SLE compared with individuals without an affected sibling.

Genetic Factors• A feature common to SLE-associated genes: the

vast majority encode proteins involved in immune system function.

• HLA class III genes, particularly those encoding complement components C2 and C4

• deficiencies of C1q, C1r/s, and C2.4 leads to a decrease in complement activity could promote disease susceptibility by impairing the neutralisation and clearance of self and foreign antigens.

Genes involved in human SLEHLA genes    DR2, DR3 (relative risk 2–5)    DR2, DR3, DR7, DQw1, DQw2, DQA1, DQB1, B8 (anti-Ro)    DR3, DR8, DRw12 (anti-La)    DR3, DQw2, DQA1, DQB1, B8 (anti-Ro and anti-La)    DR2, DR3, DR7, DQB1 (anti-DNA)    DR2, DR4, DQw5, DQw8, DQA1, DQB1 (anti-U1 ribonuclear protein)    DR2, DR4, DR7, DQw6, B61 (anti-Sm)    DR4, DR7, DQ6, DQ7, DQw7, DQw8, DQw9 (anticardiolipin or lupus anticoagulant)    Complement genes (C2, C4, C1q)Non-HLA genes    Mannose binding lectin polymorphisms    Tumour necrosis factor α    T cell receptor    Interleukin 6    CR1    Immunoglobulin Gm and Km    FcγRIIA (IgG Fc receptor)    FcγRIIIA (IgG Fc receptor)    PARP (poly-ADP ribose polymerase)    Heat shock protein 70    Humhr 3005

•Involved genes can be grouped on the basis of their role in immune function:

1.genes related to generation of self antigen

2.Genes related to activation of innate immune response.

3.Genes related to activation of adaptive immune response.

4.Genes related to target-organ damage

1. Generation of self antigen•Defect in clearance, processing, and

presenting apoptotic cells and debris to lymphocytes.

• Increased availability of nuclear debris can provide sufficient self-antigen for induction of self-reactive t-cells or activation of innate immune response.

•Examples: MHC 8.1 haplotype block carrying short C4B gene , C1q deficiency

2. Activation of innate immunity•Large numbers of single nucleotide

polymorphism (SNPs) are found in the genes that encode proteins inducing type I interferon (IFN).

•single nucleotide polymorphisms (SNPs) of genes encoding TLR7, TLR8,and TLR9

Type I interferon (IFN I)• Type I interferons (IFNs) are polypeptides that

are secreted by infected cells.• They have 3 functions:

▫ they induce cell-intrinsic antimicrobial states in infected and neighbouring cells that limit the spread of infectious agents

▫ promotes antigen presentation and natural killer cell functions while restraining pro-inflammatory pathways and cytokine production (balanced innate immunity).

▫ activate the adaptive immune system,(antigen-specific T-cells and B-cells and immunological memory

• increase in IFN-I-related genes was identified in the peripheral blood monocytes (PBMCs) from patients with SLE.

• overproduction of type I interferon canpromote the expression of proinflammatory cytokines and chemokines, the maturation of dendritic cells, the activation of autoreactive B and T cells, the production of autoantibodies, and loss of self-tolerance.

Toll-like receptors• a class of proteins that that activate the innate

immune system in response to a variety of pathogen-associated molecular patterns (PAMPs).

• Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity.

Toll-like receptors

•The TLRs that act as nucleic acid receptors are TLR3, TLR7 (and TLR8 in humans), and TLR9.

•TLR9 is expressed in the endoplasmic reticulum of macrophages and dendritic cells

Toll-like receptors

3. Activation of adaptive immunity•T-cell abnormalities

▫Decreased proliferation of T-cell in response to allogenic (non-self) antigens

▫Produce less IL-2, that contributes to T-cell regulation

▫Hypomethylation of DNA▫Though lymphopenia, expansion of T-helper

population that mediates differentiation of autoantigen – specific B-cells.

•B-cell abnormalities▫Polyclonal B-cells overactivity▫Pssible mechanisms:

intrinsic hyper-reactivity leading to polyclonal B-cell activation with disturbed activation thresholds and ineffective negative selection

lack of immunoregulatory functions Secondary to overactivation of T-helper cells Disturbed cytokine production

SLE pathogenesisKey events

Key events in the pathophysiology of SLE1. Apoptosis2. Nucleic acids3. Innate immunity4. Adaptive immunity

1. Apoptosis• Source of autoantibodies.

• In SLE: increased spontaneous apoptosis, increased rates of ultraviolet-induced apoptosis in skin cells, or impaired clearance of apoptotic peripheral blood cells.

2. Nucleic acids (DNA & RNA)• Their recognition as foreign bodies is prevented in healthy

individuals.

• In SLE, they are recognized and served to intracellular sensors (e.g. Toll-like receptors)

3. Innate immunity• Toll-like receptors :Toll-like receptors : detect DNA as non self – antigen

presentation.

• Dendritic cellsDendritic cells: IFN-α production – antigen presentation and recruitment of T cells– impaired tolerance.

• Interferon-Interferon-αα: : recruitment of T-cells and tissue damage

• ComplementComplement: impaired clearance of apoptotic material.

• NeutrophilsNeutrophils: proinflammatory and vascular damage

• Endothelial cells: Endothelial cells: IFN- α production and also propagated endothelial damage.

4. Adaptive immunity• Activation of T-helper cells by the previous events.

• B-cell differentiation to antibody-producing plasma cells.

• Cytokines and chemokines produced by T and B cells also shape the immune response and promote tissue damage.

• Excess production of immune complexes, with impaired clearance leads to deposition and tissue damage.

Summary !

Thanks “He who issues forth in search of knowledge is busy in the cause of Allah till he returns from his quest.”

Prophet Muhammad (PBUH)

Reference • Bertasias G., Cervera R., Boumpas D. T., systemic lupus erythematosus : pathogenesis and

clinical features. EULAR Textbook on Rheumatic Diseases (2012).

• CROW, M. etiology and pathogenesis of systemic lupus erythematosus. In: FIERSTEIN, G., et al. Kelly's textbook of rheumatology. 9th. ed. philadelphia: Elsevier Saunders, v. 3, 2013. Cap. 79, p. 1269.