LETTER TO THE EDITOR
Year : 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
E Nigel Wardle
MD 37 Princess Road, Camden, London NW1 8JS
|How to cite this article:|
Wardle E N. Systemic lupus erythematosus understanding grows.Saudi J Kidney Dis Transpl 2008;19:986-989
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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: https://www.sjkdt.org/text.asp?2008/19/6/986/43481
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  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? 
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? 
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,  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 ,
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. 
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. 
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.  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! 
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. 
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)? 
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,  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. 
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. 
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.  Furthermore I know that SLE patients develop premature atherosclerosis.  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. 
Question 11. I suppose you realize that there are strange abnormal T lymphocytes in SLE.  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. 
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.  Embarrassingly, Th-17 cells are known to cause autoimmune disease.  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. , In mice, B1 lymphocytes accumulate in the target organs. We know that estrogen sustains B lymphocytes.  But should we not leave all that to immunologists for understanding of the network of cytokines is required? ,
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).  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!  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.  It remains to be seen how far the kidneys might be protected.
Addendum * As described by Bauer et al,  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.
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