Correspondence
Systemic Lupus Erythematosus
N Engl J Med 2012; 366:573-574February 9, 2012
- Article
To the Editor:
In the Mechanisms of Disease article on systemic lupus erythematosus (SLE), Tsokos (Dec. 1 issue)1 notes that a lack of C1q leads to deficient clearance of waste material. I would like to add the role of C1q in the regulation of interferon-α production in response to immune complexes. Recently, Santer and colleagues found that interferon-α production of purified plasmacytoid dendritic cells increased after the addition of C1q to SLE immune complexes.2 In contrast, in the presence of CD14+ monocytes, almost the whole immune complex adhered to monocytes rather than to plasmacytoid dendritic cells in vitro.2 C1q inhibited interferon-α production induced by immune complexes indirectly through a monocyte-dependent mechanism. Exploration of the linkage between C1q and interferon-α production may be important when developing new therapeutic strategies to suppress the activated plasmacytoid dendritic cells in patients with SLE.
Eun Chun Han, M.D.
Korea Advanced Institute of Science and Technology, Daejeon, South Korea
f1849@kaist.ac. kr No potential conflict of interest relevant to this letter was reported.
2 References1
Tsokos GC . Systemic lupus erythematosus. N Engl J Med 2011;365:2110-2121
Full Text | Web of Science | Medline2
Santer DM ,Hall BE ,George TC , et al. C1q deficiency leads to the defective suppression of IFN-α in response to nucleoprotein containing immune complexes. J Immunol 2010;185:4738-4749
CrossRef | Web of Science | Medline
To the Editor:
In his recent review, Tsokos comprehensively describes the mechanisms underlying SLE, including T-cell signaling aberrations. Defective signaling along the p21 ras–MAP kinase pathway plays a central role in SLE development and should be included among these mechanisms. This notion is supported by a number of findings. First, lymphocytes in patients with SLE are characterized by down-regulated early signaling of the p21 ras–MAP kinase pathway, resulting in unsuppressed enhanced constitutive activity of its downstream elements.1 Second, T cells and B cells in SLE-prone NZB×NZW mice have defective ras signaling, which disappears on reversal of their disease by immune modulation.2 Third, the activity of two downstream key elements of the p21 ras pathway — namely, ERK and JNK — correlates with disease activity in patients with SLE.3 It should also be pointed out that various aberrations along this pathway have been detected in various autoimmune diseases, including type 1 diabetes mellitus, celiac disease, and chronic idiopathic urticaria.4 Thus, it is conceivable that signaling defects along this key pathway constitute a common denominator of several autoimmune diseases.
Micha Rapoport, M.D.
Olga Bloch, Ph.D.
Assaf Harofeh Medical Center, Zerifin, Israel
mrapoport@asaf.health. gov. il No potential conflict of interest relevant to this letter was reported.
4 References1
Rapoport MJ ,Bloch O ,Amit-Vasina M ,Yona E ,Molad Y . Constitutive abnormal expression of RasGRP-1 isoforms and low expression of PARP-1 in patients with systemic lupus erythematosus. Lupus 2011;20:1501-1509
CrossRef | Web of Science | Medline2
Rapoport MJ ,Sharabi A ,Aharoni D , et al. Amelioration of SLE-like manifestations in (NZBxNZW)F1 mice following treatment with a peptide based on the complementarity determining region 1 of an antibody is associated with a down-regulation of apoptosis and of the pro-apoptotic factor JNK kinase. Clin Immunol 2005;117:262-270
CrossRef | Web of Science | Medline3
Molad Y ,Amit-Vasina M ,Bloch O ,Yona E ,Rapoport MJ . Increased ERK and JNK activities correlate with disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis 2010;69:175-180
CrossRef | Web of Science | Medline4
Rapoport MJ ,Bloch O ,Amit-Vasina M . “Something is wrong in the Ras kingdom” -- evidence for the involvement of p21Ras/MAP kinase in autoimmune diseases. Curr Rheumatol Rev 2011;7:301-305
CrossRef
Author/Editor Response
It is true that many important contributions could not be included in the synoptic review article. I should have asked for the understanding of hundreds of colleagues whose work was not mentioned explicitly.
Indeed, C1q modulates several aspects of the immune response, and besides the article by Sander et al. cited by Han, earlier articles had identified C1q as being important in the regulation of dendritic-cell function and the pathogenesis of SLE1 and specifically as a suppressor of interferon-α production.2
With regard to the letter by Rapoport and Bloch: I would like to note that the laboratory of Richardson3 detected abnormalities in the ras–MAP kinase and linked it to DNA hypomethylation in T cells, whereas the laboratory of Datta4 linked ERK activity to increased CD40 ligand expression in T cells.
A large number of articles such as those mentioned by the correspondents and others were not mentioned in the review article but have made important contributions to our understanding of SLE.
George C. Tsokos, M.D.
Harvard Medical School, Boston, MA
gtsokos@bidmc.harvard. edu Since publication of his article, the author reports no further potential conflict of interest.
4 References1
Ghebrehiwet B ,Peerschke EI . Role of C1q and C1q receptors in the pathogenesis of systemic lupus erythematosus. Curr Dir Autoimmun 2004;7:87-97
CrossRef | Medline2
Lood C ,Gullstrand B ,Truedsson L , et al. C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum 2009;60:3081-3090
CrossRef | Web of Science | Medline3
Deng C ,Kaplan MJ ,Yang J , et al. Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis Rheum 2001;44:397-407
CrossRef | Web of Science | Medline4
Yi Y ,McNerney M ,Datta SK . Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. J Immunol 2000;165:6627-6634
Web of Science | Medline
