Damage-Associated Molecular Patterns (DAMPs) and autoimmunity (Literature review)

Inflamed tissue can become antigenic under certain circumstances. During inflammation, tissue damage and immune responses can lead to the release of self-antigens (molecules derived from the body’s own tissues) or modified self-antigens that may be recognized by the immune system. This process can occur in the following ways:

1. Release of Damage-Associated Molecular Patterns (DAMPs):

• Inflammation caused by injury or infection leads to the release of DAMPs from damaged cells. These molecules can act as signals to activate immune cells and may also serve as antigens that are presented to T cells, potentially triggering an immune response against self-tissues.

2. Antigen Presentation in Inflammatory Sites:

• During inflammation, antigen-presenting cells (APCs) like macrophages and dendritic cells are activated and can present antigens derived from inflamed or damaged tissues to T cells. This process can enhance the immune system’s recognition of these antigens.

3. Inflammation-Associated Self-Antigens:

• Some self-antigens are upregulated in inflamed tissues as part of the inflammatory response. These molecules may overlap spatially and temporally with foreign antigens, making it challenging for the immune system to distinguish between self and non-self. If tolerance mechanisms fail, these inflammation-associated self-antigens can trigger autoimmune responses.

4. Chronic Inflammation and Autoimmunity:

• Chronic inflammation increases the likelihood of self-antigen presentation and immune activation, which can lead to autoimmunity. For example, prolonged exposure of immune cells to tissue antigens in an inflammatory environment may result in a breakdown of tolerance and the development of diseases like rheumatoid arthritis or lupus.

In conclusion, inflamed tissue can indeed become antigenic when tissue damage or immune activation exposes or modifies self-antigens, potentially leading to immune responses against the body’s own tissues. This phenomenon is a key factor in the development of autoimmune diseases and chronic inflammatory conditions.

Damage-Associated Molecular Patterns (DAMPs) are implicated in a variety of diseases, particularly those involving inflammation and immune dysregulation. Below are examples of diseases associated with DAMPs:

Examples of DAMP-Associated Diseases

1. Autoimmune Diseases:

• Rheumatoid Arthritis (RA): DAMPs such as HMGB1 and S100 proteins contribute to joint inflammation and cartilage destruction by activating innate immune responses.

• Systemic Lupus Erythematosus : DAMPs like nuclear DNA and mitochondrial DNA are released during cell damage, exacerbating inflammation and promoting autoimmunity.

2. Cardiovascular Diseases:

• Atherosclerosis: DAMPs, including HMGB1 and S100 proteins, are involved in plaque formation and inflammation in arterial walls, contributing to the progression of atherosclerosis.

• Myocardial Infarction (MI): DAMPs released during ischemia-reperfusion injury, such as ATP and HMGB1, trigger sterile inflammation and tissue damage.

3. Neurodegenerative Diseases:

• Alzheimer’s Disease (AD): Elevated levels of HMGB1 and S100B in the brain contribute to neuroinflammation and blood-brain barrier dysfunction, worsening disease progression.

• Parkinson’s Disease: Similar mechanisms involving DAMP-induced neuroinflammation are observed in Parkinson’s.

4. Metabolic Diseases:

• Type 2 Diabetes Mellitus (T2DM): DAMPs generated by metabolic stress, such as ER stress-induced molecules, promote chronic inflammation that contributes to insulin resistance and tissue damage.

5. Infectious Diseases:

• Sepsis: High concentrations of DAMPs like nuclear DNA (nDNA), mitochondrial DNA (mtDNA), and heat shock proteins correlate with disease severity and poor outcomes in sepsis patients.

6. Cancer:

• Certain DAMPs, such as HMGB1, play dual roles in cancer by promoting tumor growth through inflammation or enhancing anti-tumor immunity under specific conditions.

7. Osteoarthritis (OA):

• Elevated levels of HMGB1 in synovial fluid and cartilage are associated with increased inflammation and cartilage destruction in OA patients.

DAMPs participate in the pathogenesis of many inflammatory, autoimmune, metabolic, neurodegenerative, cardiovascular, infectious, and degenerative diseases. Their involvement makes them potential biomarkers for diagnosis and targets for therapeutic intervention.

High Mobility Group Box 1 (HMGB1) is a highly conserved, non-histone nuclear protein that plays diverse roles depending on its location within or outside the cell. It is involved in DNA-related functions in the nucleus and acts as a damage-associated molecular pattern (DAMP) molecule when released extracellularly, triggering immune and inflammatory responses.

Functions of HMGB1

1. In the Nucleus:

• Acts as a DNA chaperone, maintaining chromosomal structure and regulating transcription, replication, DNA repair, and nucleosome assembly.

• Helps stabilize the genome and supports normal cellular processes.

2. In the Cytoplasm:

• Promotes autophagy by interacting with proteins such as BECN1 (Beclin-1), which is critical for cellular survival under stress conditions.

3. Extracellularly:

• Functions as a DAMP molecule, signaling tissue damage or danger.

• Activates immune responses by binding to receptors such as TLR4 (Toll-like receptor 4) and RAGE (Receptor for Advanced Glycation End-products).

• Triggers the production of pro-inflammatory cytokines and chemokines via pathways like NF-κB and MAP kinase signaling.

• Plays a role in recruiting immune cells to sites of injury or infection and amplifies inflammation.

Role in Diseases

HMGB1 is implicated in numerous pathological conditions due to its ability to sustain inflammation and immune activation:

• Neuroinflammatory Diseases: Involved in Parkinson’s disease, stroke, epilepsy, and multiple sclerosis by promoting neuroinflammation.

• Autoimmune Diseases: Contributes to diseases like rheumatoid arthritis and lupus by enhancing immune cell activation and autoantibody production.

• Cardiovascular Diseases: Plays a role in atherosclerosis and myocardial infarction through inflammatory pathways.

• Cancer: Can promote tumor growth or anti-tumor immunity depending on the context.

• Sepsis and Trauma: Acts as a key mediator of sterile inflammation in response to injury or infection.

Mechanisms of HMGB1 Release

• HMGB1 can be actively secreted by immune cells (e.g., macrophages, dendritic cells) during activation or passively released by necrotic or damaged cells.

• Its release is tightly regulated, and factors like oxidative stress or hypoxia can influence its secretion.

Therapeutic Potential

Targeting HMGB1 has shown promise in preclinical studies for various diseases:

• HMGB1 antagonists (e.g., glycyrrhizin) can reduce inflammation and tissue damage.

• Neutralizing antibodies against HMGB1 are being explored for autoimmune diseases, neuroinflammation , and sepsis.

In summary, HMGB1 is a multifunctional protein with critical roles in both homeostasis and disease. Its ability to act as an alarming makes it a key player in inflammatory processes, but it also presents opportunities for therapeutic intervention in conditions where excessive inflammation is detrimental.