Immune tolerance breakdown occurs through a complex interplay of genetic, environmental, and physiological factors. From genetic predisposition to environmental triggers, these elements can disrupt the delicate balance of self-tolerance, potentially leading to autoimmune responses.

Molecular mimicry and epitope spreading are key mechanisms in autoimmunity progression. These processes involve cross-reactive immune responses and the expansion of immune targets, respectively, contributing to the development and worsening of autoimmune diseases.

Factors Leading to Breakdown of Immune Tolerance

Factors in immune tolerance breakdown

• Genetic predisposition influences susceptibility to autoimmunity through HLA associations and SNPs in immune-related genes (CTLA-4, PTPN22)
• Environmental triggers disrupt immune balance including infections (EBV), toxins (cigarette smoke), dietary factors (gluten), and stress (cortisol elevation)
• Epigenetic modifications alter gene expression without changing DNA sequence (DNA methylation, histone modifications)
• Hormonal influences affect immune responses explaining gender differences in autoimmunity (estrogen, testosterone)
• Dysregulation of immune checkpoints disrupts self-tolerance mechanisms (PD-1/PD-L1 pathway)
• Alterations in gut microbiome composition impact immune regulation (reduced diversity, pathogenic overgrowth)

Molecular mimicry in autoimmunity

• Structural similarity between pathogen and self-antigens leads to cross-reactive immune responses
• Cross-reactive T cells and antibodies recognize both foreign and self-antigens
• Rheumatic fever patients develop antibodies against Streptococcus pyogenes that cross-react with heart valve proteins
• Multiple sclerosis involves T cells recognizing myelin basic protein similar to Epstein-Barr virus antigens
• T cell activation occurs through shared epitope recognition between pathogens and self-proteins
• Molecular mimicry breaks self-tolerance initiating autoimmune processes

Progression and Regulation of Autoimmune Responses

Epitope spreading in disease progression

• Immune responses expand to recognize additional epitopes on the same or different antigens
• Intramolecular spreading involves recognition of new epitopes within the same protein
• Intermolecular spreading extends to epitopes on different proteins
• Chronic inflammation drives epitope spreading through tissue damage and antigen release
• Autoimmune responses amplify as more self-antigens become targets
• Multiple sclerosis progression involves spreading from myelin basic protein to other myelin components
• Systemic lupus erythematosus shows spreading from nuclear antigens to various organ-specific targets

T cell balance for immune homeostasis

• Effector T cells (Th1, Th2, Th17) promote immune responses and inflammation
• Regulatory T cells (Tregs) suppress excessive immune activation and maintain self-tolerance
• Tregs inhibit effector cells through cytokine production (IL-10, TGF-β) and cell-cell contact
• Cytokine milieu and co-stimulatory molecules influence Treg/effector T cell balance
• Imbalance in autoimmune diseases leads to excessive effector T cell activity and reduced Treg function
• Therapeutic approaches aim to restore balance by expanding Tregs (low-dose IL-2) or suppressing effector T cells (anti-TNF-α)