How Rogue Autoantibodies Cause Disease

The immune system plays a vital role in defending the body against harmful pathogens and maintaining overall health. A central component of this defense is B cell-produced antibodies, which recognize and neutralize foreign antigens. However, this protective mechanism can sometimes malfunction, resulting in a phenomenon known as autoimmunity, in which the immune system mistakenly targets the body’s own tissues, recognizing self-antigens as threats.¹ This triggers lymphocyte production of autoantibodies, which can cause or contribute to disease development and progression.

In this article, explore how the body defends itself against immune system dysfunction, the distinction between natural and pathogenic autoantibodies, and the role that autoantibodies play in disease processes.

What Are Autoantibodies?

Autoantibodies are antibodies that target the body’s own antigens. These antigens may consist of proteins, nucleic acids, carbohydrates, or lipids expressed ubiquitously throughout the body or only in specific cells.² Autoimmunity and autoantibody production have been linked to a wide range of conditions, including autoimmune disorders, certain cancers, infectious diseases, and neurodegenerative illnesses. Autoantibodies also play a key role in diagnosing disease, monitoring treatment, and potentially serving as therapeutic targets.

Preventing autoimmunity

The body has evolved several mechanisms to limit self-antigen recognition and autoantibody production. One primary safeguard is central tolerance, in which the body eliminates or inactivates immature lymphocytes that recognize self-antigens.³ Immature B cells in the bone marrow that are self-reactive either undergo programmed cell death or receptor editing to become unresponsive to the self-antigen.⁴ Immature self-reactive T lymphocytes in the thymus undergo similar processes.³

After lymphocytes exit the bone marrow and thymus, peripheral tolerance becomes essential to prevent autoimmune responses. At this stage, potential autoimmunity occurs when lymphocytes recognize antigens without the usual danger signals that come from infection or injury.⁴ A key mechanism of peripheral tolerance is anergy, a state in which self-reactive lymphocytes become functionally inactive, often due to disrupted signal transduction pathways, among other mechanisms.⁵ Regulatory T cells (Tregs) also contribute to peripheral tolerance by suppressing immune activation. Additionally, immune checkpoint molecules such as CTLA-4 and PD-1 help rein in peripheral immune responses. Finally, T cells that react to self-antigens with high affinity undergo apoptosis, further eliminating potentially autoreactive cells.

While the immune system actively limits high-affinity self-reactivity, a baseline level of low-affinity self-antigen recognition is required for routine immune surveillance. This minimal self-reactivity typically does not reach the threshold required to trigger an immune response.² Autoimmune disease arises only when this threshold is surpassed due to an adverse stimulus such as an infection, or changes in self-antigen availability or volume that expose the immune system to previously sequestered targets. Environmental exposures and genetic predisposition can also increase susceptibility to self-tolerance loss.

Autoantibody types

Certain autoantibodies fulfill essential physiological functions and are not pathogenic. For instance, the body produces natural autoantibodies (NAAs) without prior exposure to antigens.⁶ Most NAAs are polyreactive, pentavalent immunoglobulin M (IgM) antibodies capable of strongly binding multiple separate antigens with low-to-moderate affinity. As a result of their polyreactivity, IgM-NAAs recognize not only self-antigens but also pathogen-associated molecules, suggesting a role in early immune defense. Moreover, they can recognize and bind to self-reactive immunoglobulin G (IgG), thus mitigating the activity of pathogenic IgG autoantibodies. Lastly, IgM-NAAs help facilitate the clearance of apoptotic cells and reduce inflammation by binding to leukocytes.

In contrast, pathogenic autoantibodies are most commonly IgG and may, in some cases, undergo somatic hypermutation to develop high-affinity binding.² Factors such as genetic predisposition, IgM- and IgG-NAA deficiency, self-reactive B cell persistence, and impaired apoptotic cell clearance can trigger pathogenic autoantibody production. Once formed, pathogenic autoantibodies contribute to disease through multiple mechanisms, including inflammation induction, aberrant receptor stimulation, signaling pathway disruption or blockade, complement activation, lymphocyte activation, and cell lysis.⁷

Autoantibodies and Disease

Autoantibodies are linked to a variety of clinical conditions, ranging from autoimmune and neurodegenerative diseases to cardiovascular disorders and cancer.

Autoimmune disease

Autoantibodies are most commonly recognized for their role in autoimmune diseases. Several well-characterized conditions are defined, in part, by the presence of specific autoantibodies.

• Graves’ disease is characterized by autoantibodies that target thyroid-specific proteins, including thyroid peroxidase (TPO), thyroglobulin (Tg), and the thyroid-stimulating hormone receptor (TSHR).⁸
• Systemic lupus erythematosus (SLE) is strongly associated with antinuclear antibodies (ANAs), a broad autoantibody category that includes several subtypes. Key SLE-associated autoantibodies include anti-double stranded DNA, anti-Sm, and anti-ribonucleoprotein. Anti-histone antibodies are particularly associated with drug-induced lupus. The autoantibody profile in SLE is notably heterogeneous.⁹
• Sjögren’s syndrome involves autoantibodies directed against ribonucleoproteins, most commonly anti-SSA and anti-SSB in the exocrine glands, such as tear and salivary glands.¹⁰
• Systemic sclerosis (scleroderma) is linked to a spectrum of autoantibodies in both limited and diffuse disease subtypes. Limited scleroderma is typically associated with anti-centromere antibodies, while diffuse scleroderma is linked to anti-topoisomerase I (anti-Scl-70) and anti-RNA polymerase III antibodies.¹¹

Neurological disease

Autoantibodies contribute to a range of neurological disorders through both direct pathogenic mechanisms and indirect associations. In some cases, autoantibodies are causative, while in others, they serve as markers of disease activity. Their specificity, sensitivity, and clinical significance vary across different conditions. Notable examples include the following.

• Neuromyelitis optica (NMO): Pathogenic IgG autoantibodies targeting the aquaporin-4 (AQP4) water channel protein are a key diagnostic marker for NMO. The identification of AQP4 antibodies has been instrumental in distinguishing NMO from multiple sclerosis.¹²
• Anti-N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis: This neuropsychiatric disorder is associated with pathogenic autoantibodies directed against the NMDA receptor subunit 1 (NR1) protein expressed on neuronal surfaces.¹²

Cancer

Tumor-associated autoantibodies are present in a range of malignancies, including head and neck, lung, breast, colorectal, gastrointestinal, genitourinary, and skin cancers. While some of these autoantibodies aid in diagnosis, others function as prognostic biomarkers, offering insight into the risk of recurrence, metastasis, and survival.¹³ Examples of clinically useful autoantibodies include antibodies against sperm protein 17 (Sp17) in head and neck neoplasms, O-6-methylguanine-DNA methylase (MGMT) in gliomas, mucin-4 (MUC-4) in pancreatic cancers, cyclic AMP-responsive element-binding protein 3 (CREB3) in ovarian cancer, and tumor protein p53 (TP53) in a multitude of cancers.

Relevance of Autoantibodies to Clinical Care and Research

Autoantibodies play a crucial role in diagnosing various conditions. Detecting these antibodies helps differentiate between diseases, classify specific subtypes, and assess illness severity. Diagnostic testing frequently relies on blood samples and, for neurological conditions, may involve cerebrospinal fluid. Enzyme immunoassays (EIAs) are commonly used to detect autoantibodies. These techniques include, but are not limited to, the following.

• Enzyme-linked immunosorbent assays (ELISA): In this method, scientists coat a microwell with a capture antibody that selectively binds the antigen of interest. A second antibody, conjugated to a reporter enzyme, then binds the primary antibody. The enzyme catalyzes a chemical reaction that produces a detectable signal, such as fluorescence, whose intensity indicates the amount of antigen present.¹⁴
• Immunofluorescence (IF): This technique employs fluorescently labeled antibodies that enable researchers to visualize specific pathogenic autoantibodies in tissue samples under a fluorescence microscope.¹⁵
• Chemiluminescent immunoassay (CLIA): This method is similar to ELISA. Unlike ELISA, which uses a chromogenic substrate that produces a color change upon reaction for signal detection, CLIA utilizes a luminescent substrate for signal amplification.¹⁵

The diagnostic utility of autoantibodies varies considerably across different diseases, and not all autoantibodies possess the same prognostic significance. For instance, ANAs are high sensitivity indicators for SLE; a negative ANA test effectively excludes the diagnosis in many cases. However, many autoantibodies demonstrate lower predictive value, underscoring the importance of interpreting serologic results within the broader clinical context.

Autoantibodies are not only central to disease pathogenesis but are increasingly relevant to therapeutic strategies. Traditionally, autoimmune disease treatment has focused on depleting B lymphocytes to reduce pathogenic autoantibody production, particularly when they target extracellular proteins.¹⁶ In cases involving intracellular antigens, therapies often aim to inhibit pro-inflammatory cytokines or disrupt immune signaling pathways. More recently, select therapies have been developed to directly target autoantibodies themselves. For instance, the myasthenia gravis treatments rozanolixizumab and efgartigimod alfa inhibit the neonatal fragment crystallizable (Fc) receptor, thereby blocking IgG recycling and promoting the clearance of circulating pathogenic IgG autoantibodies.^17,18

Conclusion

While the immune system serves as a critical defense against threats to the host, it is not infallible. When dysregulated, it can generate pathogenic autoantibodies that contribute to disease through a variety of mechanisms. Despite their detrimental effects, these autoantibodies also hold clinical value, offering opportunities for diagnosis, treatment monitoring, and targeted medication development.