Saudi Journal of Kidney Diseases and Transplantation

: 2008  |  Volume : 19  |  Issue : 6  |  Page : 986--989

Systemic lupus erythematosus understanding grows

E Nigel Wardle 
 MD 37 Princess Road, Camden, London NW1 8JS, United Kingdom

Correspondence Address:
E Nigel Wardle
MD 37 Princess Road, Camden, London NW1 8JS
United Kingdom

How to cite this article:
Wardle E N. Systemic lupus erythematosus understanding grows.Saudi J Kidney Dis Transpl 2008;19:986-989

How to cite this URL:
Wardle E N. Systemic lupus erythematosus understanding grows. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2021 Jan 25 ];19:986-989
Available from:

Full Text

To the Editor,

As a medical student I recall hearing a lecture on the LE cell phenomenon, which refers to the ingestion of an apoptotic leucocyte by a neutrophil. At that time we did not use the term "apoptosis", but we all understood that a dead leucocyte was being phagocytosed by a live one. Not surprisingly, free DNA or nuc­leosomal material can be liberated into the plasma of such patients, and immune com­plexes might form.

The concepts and terminology of molecular biology sometimes leave one aghast. My re­cent article on Toll-like Receptors and Glome­rulonephritis [1] may have amazed some nephro­logists because of the gap that seems to have arisen between practice and theory. However, I feel sure that we all appreciate that there are troublesome concepts to be elucidated, and that in due course the new information will bring benefits for patients.

As a consequence of recent work, we are much nearer to recognizing what is SLE. Yet to avoid much of the jargon that is involved, the new ideas are best presented on a Question and Answer basis, as might happen in the classroom.

Question 1. Can you now appreciate that the immune defenses against microbial agents arise from the recognition of surface PAMPs (Pathogen Associated Molecular Patterns) on bacteria and viruses by PRMs (Pattern Recog­nition Molecules) on the surfaces of immune defense cells like macrophages, neutrophils and NK cells? [1]

Question 2. Have you noted that double-stran­ded RNA is recognized by cell surface TLR3 molecules, single stranded RNA by TLR7 mo­lecules sited in endosomes and bacterial or human DNA by TLR9 molecules also situated in endosomes? [2]

Answer 2. The significance of the endosomal siting of Toll-Like Receptors 7 and 9 is that endogenous RNA and DNA originating from apoptotic or necrotic host cells will only acti­vate plasmacytoid dendritic cells (pDCs) or B lymphocytes when immune complexes formed of these antigens are ingested by such cells. Nucleosomal material is actually clustered in the cell surface blebs of apoptotic cells. Nor­mally apoptotic debris will be cleared by macrophages, which in humans do not express TLRs 7 and 9!

Question 3. If macrophages of a normal person can clear apoptotic cells without causing a pa­thology, what is the difference in persons who are predisposed to SLE?

Answer 3. Humans who develop SLE often have a genetic complement factor deficiency, such as lack of C2 or C4 or C1q. Lack of C3 is not so significant. Mice too will develop SLE in a strain dependent fashion when they are lacking IgM or C1q, [3] or when they are deficient in the cell surface receptors for C3b or C4b. In these situations apoptotic cells are cleared from the circulation only slowly. Hence they are a source of nucleosome and phospholipids anti­gens to which auto antibodies will form.

Another possibility is that DNA is removed poorly from plasma in subjects in whom there is deficiency of DNAse-1, or deficiency of exonuclease TREX-1. Lupus prone MRL lpr/ lpr mice and NZB/W F1 mice have low serum activity of the enzyme deoxyribonuc-lease I­ like [3],[4]

A third possibility is that, as in SLE prone mice,humans with SLE have a deficiency in clearances by macrophage scavenger recep­tors, as a result of the development of anti­Marco antibodies. [5]

Question 4. Does deficiency of C1q have other effects?

Answer 4. Yes. C1q regulates the threshold of activation of dendritic cells (antigen presenting cells). Hence its deficiency could explain hy­peractive DCs. [6]

Question 5. One will recall that when New Zealand Black (NZB) and New Zealand White (NZW) mice are crossed, it is observed that the NZBxW hybrids are prone to early death as a result of a Coomb`s positive hemolytic ane­mia, together with a progressive glomerulo­nephritis caused by the deposition of DNA­antiDNA antibody immune complexes into the kidneys. Anti-nuclear antibodies (ANA) de­velop. We now speak of anti-nucleosomal anti­bodies. To what does that refer?

Answer 5. A nucleosome is a subunit of a chromosome that consists of DNA helix that is coiled around histone proteins. If antibodies develop to nucleosomes, this means that there must be "a loss of tolerance" to H2A/H2B/ DNA sub-nucleosomes. Actually such loss of tolerance corresponds to a murine susceptibi­lity locus Sle.1. [7] There is another reason for fascination with locus Sle.1. It is that these genes control the numbers of regulatory T cells (T reg), and they are deficient in SLE! [8]

Question 6. Why is SLE mainly a disease of women?

Answer 6. Women have two X-chromosomes and one is inactivated by DNA methylation. Now CD40LG is a costimulatory molecule for B lymphocytes that is encoded by the X­chromosome. Since the regulatory sequences on the inactive X are de-methylated in women who have SLE, their B cells will be hyper­ active. [9]

Question 7. We have known for 20 years that serum IFN alpha is raised in SLE persons.

Now we know that immune complexes of SLE patients trigger production of IFN a by plas­macytoid dendritic cells (pDCs). The type I IFN genes cluster at human chromosome 9p22. What are consequences of upregulated type I IFN (IFNα)? [10]

Answer 7. Firstly type I IFN induces the gene­ration of mature myeloid dendritic cells, that capture nuclear antigens and present the anti­gens to CD4 T cells. In turn activated T cells stimulate autoreactive B cells to produce auto­antibodies, i.e. antiDNA/antinucleosomal anti­bodies. So, in immunological parlance, we say that there is a "loss or breakdown of peripheral tolerance".

Secondly type I IFN causes macrophages, NK cells and CD8 T cells to become cytotoxic, so worsening tissue damage and the release of nucleosomes.

Thirdly type I interferons provoke the release of chemokines, [11] which attract immune cells to sites of tissue inflammation. After all, if you have a virus infection, you will expect imme­diate help from interferon release that results in immune defense cells being attracted * to all sites of virus invasion.

Question 8. Is there another means by which pDCs are stimulated?

Answer 8. Well, yes. DNA that is released from apoptotic cells to form immune com­plexes, which interact with TLR9 receptors, is helped by cytokine HMGB1 that has been released from necrotic cells to stimulate RAGE receptors on the pDCs. [12]

Question 9. Do you know of this cytokine HMGB-1, high mobility group box-1 protein?

Answer 9. This is the TNFα-like cytokine, an alarmin, that is released late in inflammatory reactions or in septic shock, and which has profound effects on both innate and adaptive immunity. [13]

Question 10. When there is so much apoptosis and inflammation, are you surprised that SLE plasma contains high levels of reactive oxygen species (ROS) and reactive nitrogen interme­diates (RNIs)?

Answer 10. Really I am not surprised. I saw ref. [14] Furthermore I know that SLE patients develop premature atherosclerosis. [15] Apoptosis of their endothelial cells, created in part by anti-endothelial cell antibodies, engenders en­dothelial microparticles that promote the for­mation of "tissue factor" thromboplastin, so that there is then a liability to thrombosis. [16]

Question 11. I suppose you realize that there are strange abnormal T lymphocytes in SLE. [17] What do you make of that?

Answer 11. Well I realize that SLE T lympho­cytes have abnormal signal transduction, mani­fest in various ways. Essentially they seem to be deprived of interleukin 2, which was the original T cell growth factor. This fact could explain their abnormal participation in immune tolerance. [17]

We are confronted also with another puzzling set of facts concerning the role of Th-17 pro­inflammatory T cells. These are newly recog­nised lymphocytes that release interleukin17. We do know that there is reciprocal deve­lopment of Th-17 cells and Treg cells. I have indicated that T reg cells are low in SLE, and so we can expect Th-17 cells to be dominant. [18] Embarrassingly, Th-17 cells are known to cause autoimmune disease. [19] Unfortunately, little is known about them in nephrology, be­cause suitable markers are not yet established. However we can predict that they will be nuisance cells in SLE!

Question 12. SLE is an immune disease cha­racterized by B cell hyperactivity. [7],[20] In mice, B1 lymphocytes accumulate in the target organs. We know that estrogen sustains B lymphocytes. [21] But should we not leave all that to immunologists for understanding of the network of cytokines is required? [22],[23]

Answer 12. As a nephrologist I have to agree that life gets complicated if I have to worry about B cells and their maintenance by cyto­kines like BAFF (BLys). [24] I perhaps should be more concerned about the relevance to my patients of anti-dsDNA antibody, or perhaps why alpha-actinin, an apparent cytoplasmic antigen, elicits anti-chromatin antibodies! [25] Both of these are relevant to SLE nephritis.

Question 13. Just a minute. Do you talk to rheumatologists, since they must know as much about SLE as we do?

Answer 13. Yes, B lymphocyte depletion the­rapy by means of Rituximab is now being established as a treatment for SLE and the reports of efficacy are good. [26] It remains to be seen how far the kidneys might be protected.

Addendum * As described by Bauer et al, [27] 12 chemokines are up-regulated in blood mono­nuclear cells of patients with SLE. They are CCL2, CCL3, CCL7, CCL8, CCL17, CCL19, CXCL2, CXCL8, CXCL9, CXCL10, CXCL11 and CXCL13. Furthermore CXCL11 (I-Tac), CXCL13 (BLC), CXCL10 (IP-10) and CCL3 (MIP-1a) have high serum levels in patients with renal disease. Thus serum chemokines might serve as convenient biomarkers for disease activity in SLE.


1Wardle EN. Toll-like receptors and glomerulo­nephritis. Saudi J Kidney Dis Transpl 2007; 18(2):159-72.
2Pawar RD, Patole PS, Elwart A, et al. Ligands to nucleic acid specific Toll-like receptors and the onset of lupus nephritis. J Am Soc Nephrol 2006;17:3365-73.
3Manderson AP, Botto M, Walport MJ. The role of complement in the development of SLE. Ann Rev Immunol 2004;22:431-56.
4Wilber A, O`Connor TP, Lu ML, et al. DNAse I-13 deficiency in lupus prone MRL and NZB/W F1 mice. Clin Exp Immunol 2003; 134:46-52.
5Wermeling F, Chen Y, Pikharainen T et al. Class A scavenger receptors regulate tolerance against apoptotic cells and autantibodies against these receptors predicts systemic lupus. J Exp Med 2007;204:2259-65.
6Castellano G, Woltman AM, Schlagwein N, et al. Immune modulation of human dendritic cells by complement. Eur J Immunol 2007;37: 2803-11.
7Li L, Mohan C. Genetic basis of murine lupus nephritis. Semin Nephrol 2007;27:12-21.
8Cuda CM, Wan S, Sobel ES, et al. Murine lupus susceptibility locus Sle.1a controls regu­latory T cells number and function. J Immunol 2007;179:7439-47.
9Lu Q, Wu A, Tesmer L, et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 2007;179:6352-­8.
10Pascual V, Farkas L, Banchereau J. Systemic lupus erythematosus: All roads lead to type I interferons. Curr Opin Immunol 2006;18:676­-82.
11Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006;354:610-21.
12Tian J, Avalos AM, Mao SY, et al. TLR9 dependent activation by DNA containing immune complexes is mediated by HMGB1 and RAGE. Nat Immun 2007;8:487-96.
13Bianchi ME, Manfredi AA. HMGB.1 protein at the crossroads between innate and adaptive immunity. Immunol Rev 2007;220:35-46.
14Oates JC, Farrelly LW, Hofbauer AF, et al. Association of reactive oxygen and nitrogen intermediates and complement levels with apoptosis of peripheral blood mononuclear cells in lupus patients. Arthr Rheum 2007;56: 3738-47.
15Belmont AH, Abramson SD, Liu JT. Patho­logy and pathogenesis of vascular injury in SLE. Arthr Rheum 1996;39:9-22.
16Kaplan MJ. Apoptosis in SLE. Clin Immunol 2004;112:210-8.
17Crispin JC, Kyttaris VC, Juang YT, Tsokos GC. SLE: New molecular targets. Ann Rheumat Dis 2007;66:65-9.
18Bettelli E, Carrier Y, Gao W, et al. Reciprocal development of pathogenic effector Th17 and regulatory T cells. Nature 2006;441:235-8.
19Betteli E, Oukka M, Kuchroo VK. Th17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007;8:345-50.
20Lipsky PE. SLE: An autoimmune disease of B cell hyperactivity. Nat Immunol 2001;2:762-6.
21Vidaver R. Role of estrogen in lupus. Trend Immunol 2002;23:229-30.
22Hillion S, Garaud S, Devauchelle V, et al. Il-6 is responsible for aberrant B cell receptor mediated regulation of RAG in SLE. Immu­nology 2007;122:371-80.
23Kilman MA, Wagner NJ. Macrophages prevent differentiation of autoreactive B cells by secreting CD40ligand and Il-6. Blood 2007;110:1595-602.
24Binard A, Le Pottier L, Saraux A, et al. Does BAFF dysregulation play a major role in the pathogenesis of SLE. J Autoimmun 2008;30(1­2):63-7.
25Deocharan B, Zhou Z, Antar K, et al. Alpha­actinin immunization elicits antichromatin autoimmunity in non-autoimmune mice. J Immunol 2007;179:1313-21.
26Cambridge G, Isenberg DA, Edwards I, et al. B cell depletion therapy in SLE. Ann Rheumat Dis 2007,Oct 25,ahead of print.
27Bauer JW, Baechler EC, Petri M, et al. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human SLE. PLosMed 2006;3:e491.