Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Systemic lupus erythematosus (SLE) is a remarkably complex and heterogeneous systemic autoimmune disease. Disease complexity within individuals and heterogeneity among individuals, even genetically identical individuals, is driven by stochastic execution of a complex inherited program. Genome-wide association studies (GWAS) have progressively improved understanding of which genes are most critical to the potential for SLE and provided illuminating insight about the immune mechanisms that are engaged in SLE. What initiates expression of the genetic program to cause SLE within an individual and how that program is initiated remains poorly understood. If we extrapolate from all of the different experimental mouse models for SLE, we can begin to appreciate why SLE is so heterogeneous and consequently why prediction of disease outcome is so difficult. In this review, we critically evaluate extrinsic versus intrinsic cellular functions in the clearance and elimination of cellular debris and how dysfunction in that system may promote autoimmunity to nuclear antigens. We also examine several mouse models genetically prone to SLE either because of natural inheritance or inheritance of induced mutations to illustrate how different immune mechanisms may initiate autoimmunity and affect disease pathogenesis. Finally, we describe the heterogeneity of disease manifestations in SLE and discuss the mechanisms of disease pathogenesis with emphasis on glomerulonephritis. Particular attention is given to discussion of how anti-DNA autoantibody initiates experimental lupus nephritis (LN) in mice.

Original languageEnglish (US)
Pages (from-to)495-517
Number of pages23
JournalSeminars in Immunopathology
Volume36
Issue number5
DOIs
StatePublished - Jan 1 2014

Fingerprint

Inborn Genetic Diseases
Genetic Heterogeneity
Systemic Lupus Erythematosus
Autoimmunity
Nuclear Antigens
Lupus Nephritis
Genome-Wide Association Study
Glomerulonephritis
Autoantibodies
Autoimmune Diseases
Theoretical Models
Mutation
DNA

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

@article{42f4143c835b4a8787c0c806fcd67cb5,
title = "Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus",
abstract = "Systemic lupus erythematosus (SLE) is a remarkably complex and heterogeneous systemic autoimmune disease. Disease complexity within individuals and heterogeneity among individuals, even genetically identical individuals, is driven by stochastic execution of a complex inherited program. Genome-wide association studies (GWAS) have progressively improved understanding of which genes are most critical to the potential for SLE and provided illuminating insight about the immune mechanisms that are engaged in SLE. What initiates expression of the genetic program to cause SLE within an individual and how that program is initiated remains poorly understood. If we extrapolate from all of the different experimental mouse models for SLE, we can begin to appreciate why SLE is so heterogeneous and consequently why prediction of disease outcome is so difficult. In this review, we critically evaluate extrinsic versus intrinsic cellular functions in the clearance and elimination of cellular debris and how dysfunction in that system may promote autoimmunity to nuclear antigens. We also examine several mouse models genetically prone to SLE either because of natural inheritance or inheritance of induced mutations to illustrate how different immune mechanisms may initiate autoimmunity and affect disease pathogenesis. Finally, we describe the heterogeneity of disease manifestations in SLE and discuss the mechanisms of disease pathogenesis with emphasis on glomerulonephritis. Particular attention is given to discussion of how anti-DNA autoantibody initiates experimental lupus nephritis (LN) in mice.",
author = "Tony Marion and Arnold Postlethwaite",
year = "2014",
month = "1",
day = "1",
doi = "10.1007/s00281-014-0440-x",
language = "English (US)",
volume = "36",
pages = "495--517",
journal = "Seminars in Immunopathology",
issn = "1863-2297",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus

AU - Marion, Tony

AU - Postlethwaite, Arnold

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Systemic lupus erythematosus (SLE) is a remarkably complex and heterogeneous systemic autoimmune disease. Disease complexity within individuals and heterogeneity among individuals, even genetically identical individuals, is driven by stochastic execution of a complex inherited program. Genome-wide association studies (GWAS) have progressively improved understanding of which genes are most critical to the potential for SLE and provided illuminating insight about the immune mechanisms that are engaged in SLE. What initiates expression of the genetic program to cause SLE within an individual and how that program is initiated remains poorly understood. If we extrapolate from all of the different experimental mouse models for SLE, we can begin to appreciate why SLE is so heterogeneous and consequently why prediction of disease outcome is so difficult. In this review, we critically evaluate extrinsic versus intrinsic cellular functions in the clearance and elimination of cellular debris and how dysfunction in that system may promote autoimmunity to nuclear antigens. We also examine several mouse models genetically prone to SLE either because of natural inheritance or inheritance of induced mutations to illustrate how different immune mechanisms may initiate autoimmunity and affect disease pathogenesis. Finally, we describe the heterogeneity of disease manifestations in SLE and discuss the mechanisms of disease pathogenesis with emphasis on glomerulonephritis. Particular attention is given to discussion of how anti-DNA autoantibody initiates experimental lupus nephritis (LN) in mice.

AB - Systemic lupus erythematosus (SLE) is a remarkably complex and heterogeneous systemic autoimmune disease. Disease complexity within individuals and heterogeneity among individuals, even genetically identical individuals, is driven by stochastic execution of a complex inherited program. Genome-wide association studies (GWAS) have progressively improved understanding of which genes are most critical to the potential for SLE and provided illuminating insight about the immune mechanisms that are engaged in SLE. What initiates expression of the genetic program to cause SLE within an individual and how that program is initiated remains poorly understood. If we extrapolate from all of the different experimental mouse models for SLE, we can begin to appreciate why SLE is so heterogeneous and consequently why prediction of disease outcome is so difficult. In this review, we critically evaluate extrinsic versus intrinsic cellular functions in the clearance and elimination of cellular debris and how dysfunction in that system may promote autoimmunity to nuclear antigens. We also examine several mouse models genetically prone to SLE either because of natural inheritance or inheritance of induced mutations to illustrate how different immune mechanisms may initiate autoimmunity and affect disease pathogenesis. Finally, we describe the heterogeneity of disease manifestations in SLE and discuss the mechanisms of disease pathogenesis with emphasis on glomerulonephritis. Particular attention is given to discussion of how anti-DNA autoantibody initiates experimental lupus nephritis (LN) in mice.

UR - http://www.scopus.com/inward/record.url?scp=84930794780&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930794780&partnerID=8YFLogxK

U2 - 10.1007/s00281-014-0440-x

DO - 10.1007/s00281-014-0440-x

M3 - Article

VL - 36

SP - 495

EP - 517

JO - Seminars in Immunopathology

JF - Seminars in Immunopathology

SN - 1863-2297

IS - 5

ER -