Autoantibodies

Overview

Autoantibodies are antibodies produced by the immune system that recognize and bind to the body’s own self-antigens—proteins and other molecules that are normal components of an organism’s tissue and cells.^[1]  Unlike antibodies that fight infections by targeting foreign pathogens, autoantibodies mistakenly target the body’s own cells and tissues, attacking what should be recognized as “self”.^[2]  This loss of immune tolerance represents a fundamental breakdown in one of the immune system’s most important mechanisms: the ability to distinguish between self and non-self.

Natural Autoantibodies and Their Complex Roles

Interestingly, autoantibodies are not always pathogenic. Research reveals that natural autoantibodies circulate in healthy individuals at low levels, suggesting they may serve beneficial functions in maintaining physiological homeostasis.^[3]  These natural autoimmune processes participate in clearing cellular debris and potentially decreasing inflammatory processes.^[4] However, the distinction between protective and pathogenic autoantibodies remains incompletely understood, representing a paradox in immunology where the same molecules can serve both defense and disease mechanisms.

Generation of Autoantibodies

The development of autoantibodies involves complex mechanisms. One well-established pathway is molecular mimicry, where structural similarities between foreign pathogen antigens and self-antigens lead to cross-reactive antibodies.^[5] During certain infections, the immune system generates autoantibodies as an unintended consequence of fighting the pathogen. For example, during γ-herpesvirus infection, approximately 40% of germinal center B cells become self-reactive, with many being polyreactive and generated through somatic hypermutation.^[x]  In COVID-19, the intricate interaction between the virus’s spike protein and human proteins can engender autoreactive antibodies through molecular mimicry, potentially escalating into overt autoimmunity.^[8] 

Pathogenic Mechanisms and Clinical Significance

In autoimmune diseases, autoantibodies drive tissue damage through multiple mechanisms. They can directly bind to self-antigens and disturb cellular homeostasis, activate complement cascades, form pathogenic immune complexes, or trigger antibody-dependent cellular cytotoxicity.^[9]  For instance, in systemic lupus erythematosus (SLE), multiple autoantibodies target nuclear components, including DNA and RNA, leading to widespread inflammation and organ dysfunction.^[10] In myositis, disease-specific autoantibodies targeting intracellular proteins correlate with distinct clinical manifestations and serve as critical diagnostic biomarkers.^[11]  Anti-neuronal autoantibodies in neurodegenerative diseases can contribute to demyelination, axonal loss, and cognitive dysfunction.^[12] 

Regulation and Tolerance Mechanisms

The immune system normally prevents autoantibody formation through multiple tolerance mechanisms. Regulatory T cells, particularly CD4+ FOXP3+ cells, suppress autoreactive B cells and limit autoantibody production.^[13] Additionally, germinal center B cells undergo apoptosis to prevent excessive antibody responses and maintain self-tolerance.^[14] When these regulatory mechanisms fail—through genetic predisposition, environmental triggers, or infections—uncontrolled autoantibody production ensues, causing disease.

Clinical Applications of Autoantibodies

Measuring specific autoantibodies has become invaluable for disease diagnosis and prognosis. They serve as biomarkers enabling early identification of various autoimmune conditions and predicting disease progression and severity across diverse conditions, including cardiovascular disease and cancer.^[15] Understanding autoantibody generation and regulation continues driving the development of novel therapeutic approaches targeting fundamental autoimmune mechanisms.

FAQs

What are Autoantibodies and How Do They Differ From Normal Antibodies?

Autoantibodies are antibodies produced by the immune system that mistakenly target the body’s own self-antigens—normal tissue and cellular proteins.^[16]  Unlike conventional antibodies that recognize and eliminate foreign pathogens, autoantibodies attack the body’s own cells and tissues, representing a loss of immune tolerance.^[17] This fundamental breakdown distinguishes autoantibodies from protective antibodies, as they damage rather than defend the organism against external threats.

Are Autoantibodies Always Harmful?

No. Surprisingly, natural autoantibodies circulate in healthy individuals at low levels and may serve beneficial functions in clearing cellular debris and maintaining physiological homeostasis.^[18] However, when autoantibodies expand beyond normal levels or develop high affinity for self-antigens, they become pathogenic. The distinction between protective and harmful autoantibodies remains incompletely understood, suggesting autoimmunity involves complex regulatory mechanisms that can shift between beneficial and destructive states.^[19]

How Do Autoantibodies Cause Disease?

Autoantibodies damage tissue through multiple mechanisms: directly binding self-antigens and disrupting cellular function, activating complement cascades, forming pathogenic immune complexes, and triggering antibody-dependent cellular cytotoxicity.^[20] In systemic lupus erythematosus, anti-DNA antibodies cause widespread inflammation affecting multiple organs.^[21]  In myositis, autoantibodies targeting intracellular proteins trigger muscle destruction. The specific autoantigen targeted determines which tissues are affected and disease manifestations.^[22]

Update History

References

1. Dual role of autoantibodies to heat shock proteins in autoimmune diseases.. Tukaj.. (Frontiers in Immunology. 2024.)
2. Antibody Cross-Reactivity in Auto-Immune Diseases.. N. Trier, Gunnar Houen.. (International Journal of Molecular Sciences. 2023.)
3. Natural Autoantibodies: An Undersugn Hero of the Immune System and Autoimmune Disorders—A Point of View.. S. Avrameas, H. Alexopoulos et al.. (Frontiers in Immunology. 2018.)
4. Contribution of the Commensal Microflora to the Immunological Homeostasis and the Importance of Immune-Related Drug Development for Clinical Applications.. Vanessa M. Beutgen, Carsten Schmelter et al.. (International Journal of Molecular Science. Aug. 2021.)
5. Antibody Cross-Reactivity in Auto-Immune Diseases.. N. Trier, Gunnar Houen.. (International Journal of Molecular Sciences. 2023.)
6. IgG4 autoantibodies and autoantigens in the context of IgG4-autoimmune disease and IgG4-related disease.. Rodrigo V Motta, Emma L Culver et al.. (Frontiers in Immunology. 2024.)
7. Self-reactive and polyreactive B cells are generated and selected in the germinal center during γ-herpesvirus infection.. S. Sakakibara, T. Yasui et al.. (International Immunology. 2019.)
8. Unveiling the intricacies of COVID‐19: Autoimmunity, multi‐organ manifestations and the role of autoantibodies.. Zetao Ding, Xingyi Wei. (Scandinavian Journal of Immunology. 2023.)
9. IgG4 autoantibodies and autoantigens in the context of IgG4-autoimmune disease and IgG4-related disease.. Rodrigo V Motta, Emma L Culver. (Frontiers in Immunology. 2024.)
10. Lupus Nephritis.. J S Cameron.. (Journal of the American Society of Nephrology. 1999.)
11. Myositis‐specific autoantibodies: an important tool to support diagnosis of myositis.. Zo Betteridge, NJ McHugh.. (Journal of Internal Medicine. 2015.)
12. Role of Specific Autoantibodies in Neurodegenerative Diseases: Pathogenic Antibodies or Promising Biomarkers for Diagnosis.. Dimitrina Miteva, G. Vasilev et al.. (Antibodies. 2023.)
13. Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses.. Xin Chen, Mustafa Ghanizada et al.. (Nature Immunology. 2025.)
14. EAF2 mediates germinal centre B-cell apoptosis to suppress excessive immune responses and prevent autoimmunity.. Yingqian Li, Yoshimasa Takahashi et al.. (Nature Communications. 2016.)
15. Role of Specific Autoantibodies in Neurodegenerative Diseases: Pathogenic Antibodies or Promising Biomarkers for Diagnosis.. Dimitrina Miteva, G. Vasilev et al.. (Antibodies. 2023.)
16. Dual role of autoantibodies to heat shock proteins in autoimmune diseases.. S. Tukaj.. (Frontiers in Immunology. 2024.)
17. Antibody Cross-Reactivity in Auto-Immune Diseases.. N. Trier and G. Houen.. (International Journal of Molecular Sciences. 2023.)
18. Natural Autoantibodies: An Undersugn Hero of the Immune System and Autoimmune Disorders—A Point of View.. S. Avrameas, H. Alexopoulos et al.. (Frontiers in Immunology. 2018.)
19. Contribution of the Commensal Microflora to the Immunological Homeostasis and the Importance of Immune-Related Drug Development for Clinical Applications.. Vanessa M. Beutgen, Carsten Schmelter et al.. (International Journal of Molecular Sciences. Aug. 2021.)
20. IgG4 autoantibodies and autoantigens in the context of IgG4-autoimmune disease and IgG4-related disease.. Rodrigo V Motta, Emma L Culver.. (Frontiers in Immunology. 2024.)
21. Lupus Nephritis.. J S Cameron.. (Journal of the American Society of Nephrology. 1999.)
22. Myositis‐specific autoantibodies: an important tool to support diagnosis of myositis.. Zo Betteridge, NJ McHugh.. (Journal of Internal Medicine. 2015.)