Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Review Series

Autoimmunity

Series edited by Antonio La Cava

Autoimmune disease encompasses a diverse group of over 80 chronic disorders. Each of these diseases has distinct clinical manifestations that are due to the differences in the cells and organ systems involved; however, these diseases are universally characterized by a loss of self-tolerance, resulting in autoreactive immune cells, autoantibodies, and elevated levels of inflammatory cytokines. Reviews in this series examine mechanisms underlying autoimmunity, including failure of B cell tolerance checkpoints, the generation of autoantibodies, cytokine dysregulation, aberrant T cell signaling, and the loss of immune suppressive cells and functions. They also explore the influence of genetic background, environment, microRNAs, and sex-specific factors on the loss of immune homeostasis.

Articles in series

Putting together the autoimmunity puzzle
Antonio La Cava
Antonio La Cava
Published June 1, 2015
Citation Information: J Clin Invest. 2015;125(6):2184-2186. https://doi.org/10.1172/JCI82041.
View: Text | PDF

Putting together the autoimmunity puzzle

  • Text
  • PDF
Abstract

Autoimmune diseases classically present with a complex etiology in which different factors concur in the generation and maintenance of autoreactive immune responses. Some mechanisms and pathways that lead to the development of imbalanced immune homeostasis and loss of self-tolerance have been identified as common to multiple autoimmune disorders. This Review series focuses on the general concepts of development and progression to pathogenic autoimmune phenotypes. A mechanistic discussion of the most recent advances in the field, together with related considerations of possible therapies, make this series of particular interest to both the basic and translational science communities.

Authors

Antonio La Cava

×

Sexual dimorphism in autoimmunity
Kira Rubtsova, … , Philippa Marrack, Anatoly V. Rubtsov
Kira Rubtsova, … , Philippa Marrack, Anatoly V. Rubtsov
Published April 27, 2015
Citation Information: J Clin Invest. 2015;125(6):2187-2193. https://doi.org/10.1172/JCI78082.
View: Text | PDF

Sexual dimorphism in autoimmunity

  • Text
  • PDF
Abstract

Autoimmune diseases occur when the immune system attacks and destroys the organs and tissues of its own host. Autoimmunity is the third most common type of disease in the United States. Because there is no cure for autoimmunity, it is extremely important to study the mechanisms that trigger these diseases. Most autoimmune diseases predominantly affect females, indicating a strong sex bias. Various factors, including sex hormones, the presence or absence of a second X chromosome, and sex-specific gut microbiota can influence gene expression in a sex-specific way. These changes in gene expression may, in turn, lead to susceptibility or protection from autoimmunity, creating a sex bias for autoimmune diseases. In this Review we discuss recent findings in the field of sex-dependent regulation of gene expression and autoimmunity.

Authors

Kira Rubtsova, Philippa Marrack, Anatoly V. Rubtsov

×

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity
Jolien Suurmond, Betty Diamond
Jolien Suurmond, Betty Diamond
Published May 4, 2015
Citation Information: J Clin Invest. 2015;125(6):2194-2202. https://doi.org/10.1172/JCI78084.
View: Text | PDF

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

  • Text
  • PDF
Abstract

In this Review we focus on the initiation of autoantibody production and autoantibody pathogenicity, with a special emphasis on the targeted antigens. Release of intracellular antigens due to excessive cell death or to ineffective clearance of apoptotic debris, modification of self-antigens during inflammatory responses, and molecular mimicry contribute to the initiation of autoantibody production. We hypothesize that those autoreactive B cells that survive and produce pathogenic autoantibodies have specificity for self-antigens that are TLR ligands. Such B cells experience both B cell receptor (BCR) activation and TLR engagement, leading to an escape from tolerance. Moreover, the autoantibodies they produce form immune complexes that can activate myeloid cells and thereby establish the proinflammatory milieu that further negates tolerance mechanisms of both B and T cells.

Authors

Jolien Suurmond, Betty Diamond

×

Checkpoints that control B cell development
Fritz Melchers
Fritz Melchers
Published May 4, 2015
Citation Information: J Clin Invest. 2015;125(6):2203-2210. https://doi.org/10.1172/JCI78083.
View: Text | PDF

Checkpoints that control B cell development

  • Text
  • PDF
Abstract

B cells differentiate from pluripotent hematopoietic stem cells (pHSCs) in a series of distinct stages. During early embryonic development, pHSCs migrate into the fetal liver, where they develop and mature to B cells in a transient wave, which preferentially populates epithelia and lung as well as gut-associated lymphoid tissues. This is followed by continuous B cell development throughout life in the bone marrow to immature B cells that migrate to secondary lymphoid tissues, where they mature. At early stages of development, before B cell maturation, the gene loci encoding the heavy and light chains of immunoglobulin that determine the B cell receptor composition undergo stepwise rearrangements of variable region-encoding gene segments. Throughout life, these gene rearrangements continuously generate B cell repertoires capable of recognizing a plethora of self-antigens and non–self-antigens. The microenvironment in which these B cell repertoires develop provide signaling molecules that play critical roles in promoting gene rearrangements, proliferation, survival, or apoptosis, and that help to distinguish self-reactive from non–self-reactive B cells at four distinct checkpoints. This refinement of the B cell repertoire directly contributes to immunity, and defects in the process contribute to autoimmune disease.

Authors

Fritz Melchers

×

Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity
Patrick R. Burkett, … , Gerd Meyer zu Horste, Vijay K. Kuchroo
Patrick R. Burkett, … , Gerd Meyer zu Horste, Vijay K. Kuchroo
Published May 11, 2015
Citation Information: J Clin Invest. 2015;125(6):2211-2219. https://doi.org/10.1172/JCI78085.
View: Text | PDF

Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity

  • Text
  • PDF
Abstract

Cytokines play a critical role in controlling the differentiation of CD4 Th cells into distinct subsets, including IL-17–producing Th17 cells. Unfortunately, the incidence of a number of autoimmune diseases, particularly those in which the IL-23/IL-17 axis has been implicated, has risen in the last several decades, suggesting that environmental factors can promote autoimmunity. Here we review the role of cytokines in Th17 differentiation, particularly the role of IL-23 in promoting the differentiation of a pathogenic subset of Th17 cells that potently induce autoimmune tissue inflammation. Moreover, we highlight emerging data that indicate that environmental factors, including the intestinal microbiota and changes in diet, can alter normal cytokine regulation with potent effects on Th17 differentiation and thus promote autoimmunity, which has strong implications for human disease.

Authors

Patrick R. Burkett, Gerd Meyer zu Horste, Vijay K. Kuchroo

×

T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity
Vaishali R. Moulton, George C. Tsokos
Vaishali R. Moulton, George C. Tsokos
Published May 11, 2015
Citation Information: J Clin Invest. 2015;125(6):2220-2227. https://doi.org/10.1172/JCI78087.
View: Text | PDF

T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity

  • Text
  • PDF
Abstract

Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease that results from a break in immune tolerance to self-antigens, leading to multi-organ destruction. Autoantibody deposition and inflammatory cell infiltration in target organs such as kidneys and brain lead to complications of this disease. Dysregulation of cellular and humoral immune response elements, along with organ-defined molecular aberrations, form the basis of SLE pathogenesis. Aberrant T lymphocyte activation due to signaling abnormalities, linked to defective gene transcription and altered cytokine production, are important contributors to SLE pathophysiology. A better understanding of signaling and gene regulation defects in SLE T cells will lead to the identification of specific novel molecular targets and predictive biomarkers for therapy.

Authors

Vaishali R. Moulton, George C. Tsokos

×

Mechanisms of human autoimmunity
Michael D. Rosenblum, … , Kelly A. Remedios, Abul K. Abbas
Michael D. Rosenblum, … , Kelly A. Remedios, Abul K. Abbas
Published April 20, 2015
Citation Information: J Clin Invest. 2015;125(6):2228-2233. https://doi.org/10.1172/JCI78088.
View: Text | PDF

Mechanisms of human autoimmunity

  • Text
  • PDF
Abstract

Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution (indicated by clinical remissions) and exacerbations (indicated by symptomatic flares). The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. Studies in humans and experimental animal models are revealing the genetic and environmental factors that contribute to autoimmunity. A major goal of research in this area is to exploit this knowledge to better understand the pathogenesis of autoimmune diseases and to develop strategies for reestablishing the normal balance between effector and regulatory immune responses.

Authors

Michael D. Rosenblum, Kelly A. Remedios, Abul K. Abbas

×

Genetic basis of autoimmunity
Alexander Marson, … , William J. Housley, David A. Hafler
Alexander Marson, … , William J. Housley, David A. Hafler
Published June 1, 2015
Citation Information: J Clin Invest. 2015;125(6):2234-2241. https://doi.org/10.1172/JCI78086.
View: Text | PDF

Genetic basis of autoimmunity

  • Text
  • PDF
Abstract

Autoimmune diseases affect up to approximately 10% of the population. While rare Mendelian autoimmunity syndromes can result from monogenic mutations disrupting essential mechanisms of central and peripheral tolerance, more common human autoimmune diseases are complex disorders that arise from the interaction between polygenic risk factors and environmental factors. Although the risk attributable to most individual nucleotide variants is modest, genome-wide association studies (GWAS) have the potential to provide an unbiased view of biological pathways that drive human autoimmune diseases. Interpretation of GWAS requires integration of multiple genomic datasets including dense genotyping, cis-regulatory maps of primary immune cells, and genotyped studies of gene expression in relevant cell types and cellular conditions. Improved understanding of the genetic basis of autoimmunity may lead to a more sophisticated understanding of underlying cellular phenotypes and, eventually, novel diagnostics and targeted therapies.

Authors

Alexander Marson, William J. Housley, David A. Hafler

×

MicroRNA regulation of lymphocyte tolerance and autoimmunity
Laura J. Simpson, K. Mark Ansel
Laura J. Simpson, K. Mark Ansel
Published June 1, 2015
Citation Information: J Clin Invest. 2015;125(6):2242-2249. https://doi.org/10.1172/JCI78090.
View: Text | PDF

MicroRNA regulation of lymphocyte tolerance and autoimmunity

  • Text
  • PDF
Abstract

Understanding the cell-intrinsic cues that permit self-reactivity in lymphocytes, and therefore autoimmunity, requires an understanding of the transcriptional and posttranscriptional regulation of gene expression in these cells. In this Review, we address seminal and recent research on microRNA (miRNA) regulation of central and peripheral tolerance. Human and mouse studies demonstrate that the PI3K pathway is a critical point of miRNA regulation of immune cell development and function that affects the development of autoimmunity. We also discuss how miRNA expression profiling in human autoimmune diseases has inspired mechanistic studies of miRNA function in the pathogenesis of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and asthma.

Authors

Laura J. Simpson, K. Mark Ansel

×

T cells in the control of organ-specific autoimmunity
Jeffrey A. Bluestone, … , Mickie Cheng, Mark Anderson
Jeffrey A. Bluestone, … , Mickie Cheng, Mark Anderson
Published May 18, 2015
Citation Information: J Clin Invest. 2015;125(6):2250-2260. https://doi.org/10.1172/JCI78089.
View: Text | PDF

T cells in the control of organ-specific autoimmunity

  • Text
  • PDF
Abstract

Immune tolerance is critical to the avoidance of unwarranted immune responses against self antigens. Multiple, non-redundant checkpoints are in place to prevent such potentially deleterious autoimmune responses while preserving immunity integral to the fight against foreign pathogens. Nevertheless, a large and growing segment of the population is developing autoimmune diseases. Deciphering cellular and molecular pathways of immune tolerance is an important goal, with the expectation that understanding these pathways will lead to new clinical advances in the treatment of these devastating diseases. The vast majority of autoimmune diseases develop as a consequence of complex mechanisms that depend on genetic, epigenetic, molecular, cellular, and environmental elements and result in alterations in many different checkpoints of tolerance and ultimately in the breakdown of immune tolerance. The manifestations of this breakdown are harmful inflammatory responses in peripheral tissues driven by innate immunity and self antigen–specific pathogenic T and B cells. T cells play a central role in the regulation and initiation of these responses. In this Review we summarize our current understanding of the mechanisms involved in these fundamental checkpoints, the pathways that are defective in autoimmune diseases, and the therapeutic strategies being developed with the goal of restoring immune tolerance.

Authors

Jeffrey A. Bluestone, Hélène Bour-Jordan, Mickie Cheng, Mark Anderson

×

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts