Autoimmunity

Autoimmunity arises when the immune system mistakenly targets self-antigens, leading to chronic inflammation and tissue injury. Central tolerance in the thymus and bone marrow eliminates or inactivates high-affinity self-reactive lymphocytes, while peripheral tolerance mechanisms—anergy, deletion and regulatory T-cell (Treg) suppression—control escaped autoreactive clones. In the absence of danger signals, self-antigen presentation fails to induce costimulatory cues and instead promotes tolerance. However, stressed or injured tissues emit damage-associated molecular patterns (DAMPs) that engage pattern recognition receptors on dendritic cells and macrophages, triggering costimulatory molecule upregulation, cytokine release and inflammasome activation. This switch converts silent self-antigens into immunogenic targets, activating autoreactive T and B cells, forming immune complexes and perpetuating injury. Genetic predisposition—particularly HLA polymorphisms—environmental factors such as infections, and stochastic events contribute to tolerance breakdown, while epigenetic modifications shape susceptibility. The interplay between innate sensing of DAMPs and adaptive autoreactivity underlies the initiation and progression of autoimmune diseases, which range from organ-specific disorders like type 1 diabetes to systemic conditions such as lupus and rheumatoid arthritis.

Research from Nature Portfolio

Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Studies demonstrate that CTLA-4 captures both B7 ligands but traffics differently: CD80 engagement leads to CTLA-4 ubiquitylation and lysosomal degradation, whereas CD86 binding permits pH-dependent release and rapid recycling. Mutations disrupting CD86 transendocytosis hinder peripheral tolerance and are linked to autoimmune phenotypes, highlighting CD86 removal as crucial for sustaining self-tolerance.

Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2. Neutrophil extracellular traps (NETs) release histones that bind Toll-like receptor 2 on naïve T cells, triggering STAT3 phosphorylation and skewing differentiation toward interleukin-17–producing Th17 cells. This direct innate-to-adaptive pathway provides a mechanistic link between NET formation and Th17-driven autoimmunity, suggesting therapeutic targets for diseases characterized by pathogenic Th17 responses.

Research from all publishers

An Iranian case–control study found that the miR-499 rs3746444 polymorphism is associated with increased risk of Hashimoto’s thyroiditis. Analysis revealed both heterozygous and homozygous genotypes altered complement activity and immunorecognition pathways, implicating this microRNA variant in thyroid autoimmunity and offering a potential biomarker for susceptibility.

A European investigation into mixed connective tissue disease identified associations between miR-146a rs2910164 and miR-143 cluster variants and disease susceptibility. These polymorphisms correlated with clinical features such as scleroderma and serositis and were linked to upregulated TRAF6, IRAK1 expression and elevated pro-inflammatory cytokines, highlighting microRNA genetics in autoimmunity.

Seminal work on systemic lupus erythematosus uncovered a functional promoter variant in miR-146a (rs57095329) that diminishes binding of transcription factor Ets-1, reduces microRNA expression and amplifies type I interferon signalling. This variant contributes to genetic risk by impairing a key regulatory microRNA, underscoring the importance of non-coding RNA in autoimmunity.

Autoimmunity publication trend

The graph below shows the total number of articles in autoimmunity across all publications each year (not limited to Nature Index journals).

Technical terms

Central tolerance: Elimination or inactivation of high-affinity self-reactive lymphocytes during development in the thymus or bone marrow.

Peripheral tolerance: Mechanisms in secondary lymphoid and non-lymphoid tissues—anergy, deletion, Treg suppression—that silence escaped autoreactive lymphocytes.

Anergy: A hyporesponsive state induced in lymphocytes when antigen receptor engagement occurs without costimulatory signals.

Damage-associated molecular patterns (DAMPs): Endogenous molecules released or exposed by stressed or dying cells that activate innate immune receptors.

Neutrophil extracellular traps (NETs): Web-like DNA structures loaded with histones expelled by neutrophils to trap pathogens, which can also promote autoimmunity.

Transendocytosis: Process by which CTLA-4 captures and internalizes B7 ligands (CD80/CD86) from antigen-presenting cells, regulating costimulation.

References

1. Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Nature Immunology (2022).
2. Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2. Nature Communications (2022).
3. Association of miR-499 Polymorphism and Its Regulatory Networks with Hashimoto Thyroiditis Susceptibility: A Population-Based Case-Control Study. International Journal of Molecular Sciences (2021).
4. Association study between immune-related miRNAs and mixed connective tissue disease. Arthritis Research & Therapy (2021).
5. A Functional Variant in MicroRNA-146a Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus. PLOS Genetics (2011).