Three checkpoints in lupus development: central tolerance in adaptive immunity, peripheral amplification by innate immunity and end-organ inflammation

  title={Three checkpoints in lupus development: central tolerance in adaptive immunity, peripheral amplification by innate immunity and end-organ inflammation},
  author={Hasna Kanta and Chandra Mohan},
  journal={Genes and Immunity},
Although the etiology of systemic lupus erythematosus (SLE) remains to be fully elucidated, it is now apparent that multiple genetic and environmental factors are at play. Over the past decade, several studies have helped uncover genetic associations and susceptibility loci in human and murine lupus. In particular, recent genome-wide association studies have uncovered a large number of associated genes in human SLE. Given this plethora of candidate genes, the next challenge for lupus biologists… 

Toll-like receptors in systemic lupus erythematosus: potential for personalized treatment

This review focuses on TLR polymorphisms and TLR expression in SLE patients and discusses their potential as biomarkers for individualized treatment.

A novel pathogenetic concept—antiviral immunity in lupus nephritis

The available data indicating that innate immunity triggers antiviral immunity in systemic lupus erythematosus is summarized and the related implications for innovative therapeutic strategies are discussed.

miRNA-Mediated Control of B Cell Responses in Immunity and SLE

What is currently known about miRNA function in both normal and SLE B cell responses is focused on, primarily highlighting miRNAs with confirmed functions in mouse models and whether the development of miRNA-centric therapeutics may be a viable alternative for the treatment of SLE.

Protection against lupus-like inflammatory disease is in the LAP of non-canonical autophagy.

Systemic lupus erythematosus (SLE) is often described as the quintessential autoimmune disease, with disease manifestations existing in multiple tissues throughout the body, particularly the skin, kidneys and brain.


iNKT cells are identified as a promising therapeutic target in SLE patients, MARCO as a novel autoantigen and a multifaceted role for the splenic MZ macrophage involved in removing apoptotic cells and (dependent on the type of stimuli) the ability to both activate and dampen the immune system are described.

Autoimmune kidney damage correlates with autoantibody specificity and inflammatory mononuclear cell phenotype in the CD45 mutant mouse model of lupus

The findings demonstrate that genetic background influences both autoantibody profiles and renal immune cell subsets and provide new insights into mechanisms governing the transition from autoreactivity to autoimmunity in lupus nephritis.

Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis.

Unbiased Modifier Screen Reveals That Signal Strength Determines the Regulatory Role Murine TLR9 Plays in Autoantibody Production

A novel role for TLR9 signal strength in central tolerance is demonstrated, providing insight into the interplay of disease-associated polymorphisms at a discrete step of systemic lupus erythematosus pathogenesis.



Genetics of Systemic Autoimmunity in Mouse Models of Lupus

A genome wide mapping effort that has defined loci for component phenotypes for lupus-prone NZB, NZW, MRL-Faslpr and BXSB strains and begun to identify genes that can induce or modify autoimmunity in nonautoimmune and lupu-prone background mice.

Genetic susceptibility to systemic lupus erythematosus.

Since the genes that predispose to autoimmunity are probably related to key events in pathogenesis, their identification in patients and murine models will almost certainly provide important insight into the breakdown of immunological self-tolerance and the cause of autoimmune disease.

Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromosome 4 leads to B cell hyperactivity.

Sle2 harbors a gene that leads to B cell hyperactivity and elevated B1 cell formation, however, Sle2 by itself on the normal B6 background is insufficient to generate IgG antinuclear Abs (ANA) or nephritis.

Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains.

  • L. MorelB. Croker E. Wakeland
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
The results demonstrate the fulfillment of the genetic equivalent of Koch's postulate, where susceptibility loci in a lupus-prone strain are identified by a genome scan, isolated and functionally characterized by congenic dissection, and finally shown to mediate full disease expression when recombined in a normal genome.

The genetics of SLE: an update in the light of genome-wide association studies.

The current understanding of the functional role of the key susceptibility genes is discussed and by considering how these genes fall into clusters with shared function can begin to understand how dysregulation at a number of key immunological steps may predispose to the development of SLE.

A Tlr7 translocation accelerates systemic autoimmunity in murine lupus.

Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included Tlr7, and FISH analysis demonstrated the translocation of this segment onto the yaa chromosome, suggesting that Sles1 modulates the activation of adaptive immunity in response to innate immune signaling.

Several Genes Contribute to the Production of Autoreactive B and T Cells in the Murine Lupus Susceptibility Locus Sle1c1

Results show that Sle1c results in the production of autoreactive B and T cells through the expression of three different genes, one of which is consistent with Cr2, based on the phenotypes of the Cr2-deficient mice, and the other two corresponding to as yet unidentified genes.

The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes.

It is determined that three loci within this congenic interval, termed Sle1a, Sle1b, and Sle1c, can independently cause a loss of tolerance to chromatin, indicating that the potent autoimmune phenotype caused by the Sle1 genomic interval reflects the combined impact of four, separate, susceptibility genes.

CD19 hyperexpression augments Sle1-induced humoral autoimmunity but not clinical nephritis.

These findings allude to the presence of an additional distal checkpoint that dissociates pathogenic autoantibody formation and renal immunoglobulin deposition from the progression to clinical nephritis in lupus.

Genetic Dissection of Systemic Lupus Erythematosus Pathogenesis: Evidence for Functional Expression of Sle3/5 by Non-T Cells1

Experiments strongly suggest that a gene within the B6.Sle3/5 interval was expressed by a bone marrow-derived, nonlymphocyte population in the thymus and periphery and was affecting T cell selection and/or survival.