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systemic lupus erythematosus

Thursday 16 October 2003

Digital case

- JRC:10585 : Cutaneous lupus erythematosus.

Definition: Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by autoantibodies specific for highly conserved nuclear antigens, such as double-stranded DNA, histones and ribonuclear proteins.

The requirements for the activation and response of self-reactive B cells — the source of autoantibodies — seem to be similar to those of normal, mature B cells.

Encounter with cognate self-antigen in the presence of T-cell help induces activation. Activated B cells then form germinal centres, where they undergo class-switch recombination, somatic hypermutation and clonal selection — forming both effector and memory B cells.

Effector B cells release IgG autoantibodies into the circulation, where they form immune complexes in the presence of ligands (SLE antigens).

Despite the normal mechanisms (such as the complement system) for the uptake and clearance of immune complexes, excess immune complexes accumulate in the small vessels of organs, such as the kidney, where they become pathogenic.

Accumulated immune complexes induce inflammation through local activation of the complement system and/or the binding of Fc receptors, which leads to the degranulation of mast cells and the infiltration of neutrophils and macrophages.

Localization

- cutaneous lupus erythematosus
- renal lupus erythematosus
- nodal lupus erythematosus
- cardiac lupus erythematosus

Susceptibility

- locus 1q23: polymorphism at the C-reactive protein locus (14645206)
- locus 1q31
- locuss 1q41-q42
- locus 2q34-q35: SLEN2
- locus 2q37.3
- locus 4p16-p15.2
- locus 10q22.3: SLEN1
- locus 11p15.5: SLEN3
- locus 11q14
- locus 12q24

- Polymorphisms (variants) in

  • tyrosine kinase 2 gene (TYK2) (15657875)
  • interferon regulatory factor 5 gene (IRF5) (15657875)
  • TNFSF4 (MIM.603594) (18059267)
  • ITGAM (MIM.120980)
  • KIAA1542 (MIM.611780)
  • PXK (MIM.611450)

Innate immune system

Genetic deficiency in components of the innate immune system — such as complement component 1q (C1q), C4, serum amyloid protein, natural IgM or complement receptor 2 (CR2) — leads to increased susceptibility to systemic lupus erythematosus (SLE).

Two general hypotheses have been proposed to explain the genetic association with disease:

- a | The clearance hypothesis states that failure to clear apoptotic bodies — a principal source of SLE antigens — leads to inappropriate activation of mature, self-reactive B and T cells.

Accordingly, apoptotic bodies are usually sequestered from the adaptive immune system by efficient recognition, binding and uptake by components of the innate immune system. So, SLE antigens are effectively ’hidden’ from self-reactive lymphocytes.

Defects in clearance of apoptotic bodies, such as those that occur in the absence of C1q or C4, would lead to the exposure of self-antigens to autoreactive lymphocytes and the development of SLE.

- b | The tolerance hypothesis states that innate immunity is important in the negative selection of self-reactive lymphocytes, especially B cells that are specific for SLE antigens.

The innate immune pathway functions to recognize, degrade and bind SLE antigens to stromal cells present in the bone marrow and spleen. Immature B cells that encounter concentrations of cognate antigen above a certain threshold are negatively selected; that is, they undergo receptor editing, clonal deletion or anergy.

C1q and C4 function to enhance ’presentation’ of SLE antigens to specific immature B cells in the bone marrow. Alternatively, coupling of C4b to self-antigen could result in co-receptor stimulation of immature B cells displaying the CR1–CD19–CD81 co-receptor.

The co-receptor is expressed at the surface of immature B cells during transitional stages in the spleen, in which co-ligation with the B-cell receptor could result in enhanced negative selection and ’escape’ of self-reactive B cells into the peripheral mature compartment, where they encounter SLE antigens and become activated.

Videos

- renal SLE

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See also

- systemic lupus erythematosus

References

- Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008 Feb 28;358(9):929-39. PMID: 18305268

- Prokunina L, Alarcon-Riquelme M. The genetic basis of systemic lupus erythematosus—knowledge of today and thoughts for tomorrow. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R143-8. PMID: 14764622

- A protective role for innate immunity in systemic lupus erythematosus. Michael C. Carroll. Nature Reviews Immunology 4, 825-831 (October 2004)

Portfolio

  • Innate immunity and SLE
  • Lupus physiopathology