High IgA and Chronic Infections - Unraveling the Intricate Link

Understanding IgA: A Guardian of Immunity and Its Role in Chronic Infections

Immunoglobulin A (IgA) serves as a cornerstone of mucosal immunity, acting as the body's frontline defense at sites like the gut, respiratory tract, and urogenital surfaces. This antibody exists in two distinct forms: serum IgA, which circulates systemically, and secretory IgA, which coats mucosal surfaces to trap pathogens and regulate microbial communities. Elevated IgA levels are frequently observed in chronic infections, autoimmune conditions, and allergic disorders. This article examines the intricate relationship between persistently high IgA and recurrent infections, focusing on conditions such as Helicobacter pylori infections, candidiasis, post-COVID immune responses, and gastrointestinal disorders.

High IgA and Stomach Pain: Exploring Gastrointestinal Connections

• The Role of Helicobacter pylori in IgA Elevation

Chronic Helicobacter pylori infections are closely linked to elevated IgA levels, particularly in individuals experiencing recurrent stomach pain. The bacterium's CagA protein, a key virulence factor, stimulates a robust IgA response as the immune system attempts to neutralize the infection. Patients with IgA nephropathy, a kidney disorder characterized by immune complex deposition, often show higher prevalence rates of H. pylori infection compared to healthy individuals. This association suggests that unresolved H. pylori infections may contribute to systemic immune dysregulation, manifesting as gastrointestinal symptoms and elevated IgA.

• Saccharomyces cerevisiae Antibodies and Inflammatory Bowel Disease

Elevated IgA and IgG antibodies targeting Saccharomyces cerevisiae (ASCA) are strongly associated with Crohn's disease, a subtype of inflammatory bowel disease (IBD). These antibodies are particularly prevalent in patients with ileocolonic involvement and stricturing disease patterns. For example, ASCA-IgA positivity occurs in 60–75% of Crohn's patients, compared to fewer than 5% in those with ulcerative colitis. This highlights how chronic mucosal inflammation can drive IgA overproduction, reinforcing the link between gut-specific immune hyperactivity and systemic antibody elevation.

Post-COVID Immune Responses: The Persistence of High IgA

Emerging evidence highlights prolonged IgA elevation in individuals recovering from COVID-18. Longitudinal studies reveal that nasal IgA levels remain elevated in a significant proportion of patients for months after infection. While this sustained response may reflect durable mucosal immunity, excessive IgA production has been linked to autoimmune-like complications such as IgA vasculitis (IgAV), a condition marked by abdominal pain, joint inflammation, and renal impairment. These observations emphasize the dual nature of IgA in post-viral recovery—protective yet potentially harmful if regulatory mechanisms fail.

Fig.1 Model: pathogenesis of IgA vasculitis.^1,3

Candida Overgrowth and IgA: A Marker of Fungal Invasion

Chronic candidiasis, particularly infections caused by Candida albicans, is another condition tied to elevated IgA. Persistent fungal colonization in immunocompromised hosts often triggers sustained IgA production. Patients with recurrent oral or vaginal candidiasis frequently exhibit higher serum IgA levels compared to those with acute infections. Subclass analysis of IgA (IgA1 vs. IgA2) may provide insights into the infection's localization. For instance, IgA1 predominates in mucosal responses, whereas elevated IgA2 often correlates with systemic or invasive candidiasis.

Allergies and High IgA: Balancing Protection and Pathology

While IgA deficiency is a recognized risk factor for allergies, paradoxically elevated IgA has also been implicated in hypersensitivity disorders. Patients with atopic dermatitis or allergic rhinitis often display increased IgA levels in mucosal secretions. Research suggests that IgA may modulate allergic responses by binding allergens and inhibiting IgE-mediated mast cell activation. However, excessive IgA can form immune complexes, exacerbating inflammation in conditions like allergic bronchopulmonary aspergillosis (ABPA). This duality underscores the need for precise biomarker analysis to distinguish protective from pathogenic IgA activity.

Diagnosing High IgA: A Multifaceted Approach

Identifying the underlying cause of elevated IgA requires a comprehensive strategy:

1. Serum Testing: Quantifying total IgA levels via ELISA or nephelometry.

2. Pathogen-Specific Antibody Panels: Testing for anti-H. pylori IgA, anti-Candida IgA, and ASCA-IgA/IgG.

3. Mucosal Sampling: Measuring secretory IgA in saliva or stool to assess localized immune activity.

4. Tissue Biopsy: Evaluating kidney or gastrointestinal tissues for IgA deposition in suspected vasculitis or nephropathy.

Clinicians must correlate laboratory findings with clinical symptoms. For example, a patient with high IgA, chronic stomach pain, and positive H. pylori serology may require antibiotic therapy, while ASCA-IgA positivity in a patient with diarrhea warrants endoscopic evaluation for Crohn's disease.

Treatment Innovations: Managing High IgA in Chronic Infections

• Targeted Antimicrobial Therapies

Eradicating H. pylori: Combination therapies involving proton pump inhibitors and antibiotics reduce IgA levels and resolve gastritis.

Antifungal Agents: Azoles (e.g., fluconazole) for mucosal candidiasis; echinocandins for invasive fungal disease.

Biologic Therapies: Agents targeting inflammatory pathways, such as IL-17 inhibitors, show efficacy in reducing ASCA-IgA in severe Crohn's disease.

• Novel Approaches for IgA-Driven Disorders

APRIL/BAFF Pathway Blockers: Experimental therapies that inhibit B-cell signaling pathways reduce pathogenic IgA production in IgA nephropathy.

Renoprotective Agents: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, initially developed for diabetes, slow renal decline in IgA nephropathy by reducing glomerular hyperfiltration.

Fig.2 The proposed pathogenesis of IgA nephropathy and APRIL/BAFF-targeting therapy.^2,3

Conclusion: Deciphering the IgA Puzzle in Chronic Disease

Elevated IgA levels occupy a paradoxical space in immunology—acting as both a defender against pathogens and a potential contributor to chronic inflammation. Persistent infections, whether bacterial, fungal, or viral, can drive sustained IgA production, leading to complications such as vasculitis, nephropathy, or gastrointestinal disorders. Advances in diagnostic precision and targeted therapies offer new avenues for managing these conditions, though further research is needed to unravel the molecular mechanisms linking IgA to immune dysregulation. By integrating mucosal immunology and pathogen-specific diagnostics, clinicians can refine treatment strategies to restore immune equilibrium and improve patient outcomes.

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References

1. Song, Yan, et al. "Pathogenesis of IgA vasculitis: an up-to-date review." Frontiers in immunology 12 (2021): 771619. https://doi.org/10.3389/fimmu.2021.771619
2. Muto, Masahiro, Hitoshi Suzuki, and Yusuke Suzuki. "New Insights and Future Perspectives of APRIL in IgA Nephropathy." International Journal of Molecular Sciences 25.19 (2024): 10340. https://doi.org/10.3390/ijms251910340
3. Distributed under the Open Access license CC BY 4.0, without modification.

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