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NDT Advance Access originally published online on July 24, 2006
Nephrology Dialysis Transplantation 2006 21(9):2378-2379; doi:10.1093/ndt/gfl333
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Translational Nephrology

Genetic predisposition—is lupus nephritis a question of copy numbers?*

Andreas Schwarting

Johannes-Gutenberg-Universitat Mainz, I. Medizinische Klinik und Poliklinik, Mainz, Germany

Correspondence and offprint requests to: Andreas Schwarting, Email: Aschwart{at}mail.uni-mainz.de

Keywords: genetics; lupus nephritis

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a broad spectrum of clinical features, better defined as an ‘autoimmune syndrome’ characterized by the presence of autoantibodies and immune complex deposition affecting various organ systems.

The aetiology is multifactorial with environmental, hormonal, ethnic and genetic factors.

There is strong evidence for a genetic component based on a high concordance rate of SLE in monozygotic twins (14–57%) and occurrence of SLE in 5–12% of the relatives of affected patients [1–3].

Multiple gene association and linkage analysis studies have been performed targeting the major histocompatibility complex (MHC), various genes encoding proteins of the complement system, various cytokine and cytokine receptor genes and the Fcg receptor (FcgR) genes [4].

Genome-wide scanning in affected sibling pairs revealed at least eight loci on six different chromosomes to be significantly linked to SLE [5].

The presence of MHC class II DR2 and DR3 alleles, for example, with a clear association to SLE in the Caucasian population, has been linked to an altered abnormal antigen presentation to T-cells resulting in a dysregulated immune response, while deficient components of the complement system (C1q, C2, C4) are presumed to increase the susceptibility of lupus development by impaired clearance of apoptotic material [5,6].

The receptors for immunoglobulin (Ig) Fc portion, FcRs, have been extensively studied in recent years. A few distinct classes of FcgR can be distinguished by ligand-binding affinity, cell distribution and functional properties: the high affinity IgG receptor FcgRI and the low-affinity IgG receptors FcgR II and FcgR III [7]. The cross-linking of Fc receptors by immunoglobulins in immune complexes initiates phagocytosis by macrophages, antibody-dependent cell-mediated cytotoxicity, degranulation of mast cells and the transcriptional activation of cytokine genes resulting in an inflammatory cascade. The effector responses will be down-regulated by the unique inhibitory type FcgR IIB. Furthermore, the clearance of immune complexes by internalization leading to degradation and antigen presentation is another important function in the immune system to eliminate the antigen (and the immune complex). Thus, it is not surprising that strong efforts have been made to identify genetic differences between human FcgRs in patients with various (especially immune complex-mediated) autoimmune diseases.

A single nucleotide polymorphism (SNP) on the FcgRIIa (substitution of arginine for histidine at position 131) has been associated with a 1.3-fold increased risk in developing SLE and also with lupus nephritis in African-Americans [8,9]. An international meta-analysis on an SNP on FcgRIIIa (substitution of phenylalanine for valine at position 158) conferred a 1.2-fold greater risk for the development of lupus nephritis among lupus patients [10,11]. Both SNPs are thought to result in less efficient clearance of immune complexes [12].

The FcgRIIB gene is a strong candidate gene due to its inhibitory functions. In addition, certain mouse strains lacking the FcgRIIB develop autoantibodies and autoimmune glomerulonephritis [13]. However, polymorphisms in the FcgRIIB gene, such as the 232 T/T genotype, were inconsistently found in different ethnic groups (high ratio in Japanese, Thai and Chinese, but not in Caucasian or African-Americans, suggesting that epistatic effects may be very important in human lupus [14–16].

While these studies emphasize the complexity of the genetic background of lupus, they cannot clarify the multitude of clinical abnormalities seen in SLE patients.

In the February issue of Nature, Aitman and colleagues [17] examined the FcgrIIIB gene in individuals with lupus nephritis. They provide evidence for a different underlying molecular alteration: the copy number of FcgRIIIB can differ among individuals from none to four copies in a cell and a lower copy number among lupus patients is an independent risk factor for the development of lupus nephritis. Thus, simply a change in the number of copies of a gene can alter the susceptibility to a complex autoimmune disease.

Could this observation provide a clue to pathogenesis? Since human FcgRIIIB is mainly expressed on neutrophils linking neutrophils to immune complexes, a low copy number of FcgRIIIB may result in reduced expression of FcgRIIIB resulting in reduced glomerular clearance of immune complexes and susceptibility to autoimmune renal disease.

Moreover, copy number variation may contribute to the inter-individual variation observed in immune responses and may help to unravel the heterogeneous ‘mystique’ disease pattern among lupus patients.

Copy number variation is a major type of genetic variation in humans and inbred strains of mice. Analysis of the growing number of copy number variations revealed that there is an enrichment for genes involved in general defence responses (immune response, xenobiotic stimuli and regulation of cell surface integrity and cell surface antigens)[18].

Further support for the importance of copy number variation as ‘disease-modifiers’ comes from a recent study by Gonzalez et al. [19] They demonstrated significant inter-individual and inter-population differences in copy number variation at the CLL3L1 chemokine receptor genes. A lower copy number of CLL3L1 (compared with the population average) was associated with the markedly increased susceptibility for HIV.

SLE presents an ongoing challenge to physicians because of its heterogeneous disease manifestations and unpredictable clinical course, ranging from inactive periods of remission to overt disease flares. The results of this study will help clinicians to identify those patients among lupus patients susceptible to developing glomerulonephritis.

It will be interesting to see in further studies whether copy number variation of FcgRIIIB can be expanded to other ethnic populations or other subgroups of lupus patients or even other glomerulonephritides.

Based on these studies there is good reason to hope that structural variation will shed further light on the pathophysiology of lupus and other complex multifactorial diseases.



   Notes
 
*Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Comment on Aitman TJ, Dong R, Vyse TJ et al. Nature 2006; 439: 851–855. Back



   References
Top
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Received for publication: 23. 4.06
Accepted in revised form: 11. 5.06


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This Article
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