Johnson2022 - Infectious Diseases Autoantibodies and Autoimmunity

Full citation: Johnson D, Jiang W. Infectious diseases, autoantibodies, and autoimmunity. J Autoimmun. 2023 May;137:102962. doi:10.1016/j.jaut.2022.102962

Raw file: [[raw/Jhonson2022.pdf]]

(Note: raw filename is “Jhonson2022.pdf” — misspelling in the deposited file; author’s name is Johnson.)

Summary

This narrative review surveys the mechanisms by which infectious diseases — viral, bacterial, fungal, and parasitic — can trigger autoantibody production and autoimmune disease. The authors synthesise evidence across three core mechanisms (molecular mimicry, bystander activation, and epitope spreading) and discuss host risk factors that modulate susceptibility to infection-triggered autoimmunity. The review covers a wide range of pathogens and associated autoimmune diseases, with particular attention to viruses (EBV, influenza, SARS-CoV-2, HBV, HIV) and bacteria (Campylobacter jejuni, Staphylococcus aureus, Mycobacterium tuberculosis).

A notable finding from the review is that COVID-19 does not appear to specifically increase ANA positivity: one study found no significant difference in ANA rates between COVID-19-positive and COVID-19-negative ICU patients, suggesting that bystander polyclonal B cell activation in severe viral infections is not reliably associated with ANA elevation. The review also emphasises the hygiene hypothesis context — parasite co-infections may suppress inappropriate autoimmunity through Th2 polarisation and immune regulation.

Study Design

• Type: Narrative review
• Funding: National Institutes of Health (NIH); HHS Public Access author manuscript
• Scope: Viruses, bacteria, fungi, parasites → autoantibodies and autoimmune diseases
• No primary data collected

Key Findings

Three Mechanisms of Infection-Triggered Autoimmunity

1. Molecular Mimicry

• Definition: A pathogen-derived antigen shares sufficient sequence or structural similarity with a host self-antigen that immune responses against the pathogen cross-react with host tissue
• Evidence: Anti-ganglioside antibodies (anti-GM1, anti-GD1a, anti-GQ1b) triggered by Campylobacter jejuni → Guillain-Barré syndrome (GBS); ~30–40% of GBS follows bacterial infection
• B cell mechanism: Pathogen antigen activates self-reactive B cells when pathogen epitope closely resembles a self-epitope; tolerance mechanisms are bypassed
• T cell mechanism: Viral peptide-MHC complexes activate self-reactive T cells that were not eliminated by central tolerance
• Limitation: Sequence similarity alone is insufficient; cross-reactive immune responses do not always cause disease

2. Bystander Activation

• Definition: Non-specific polyclonal T and B cell activation driven by cytokines (IFN-α/γ, IL-1, IL-6, TNF) released during infection, without antigen-specific stimulation
• Evidence: SARS-CoV-2 induces broad autoantibody production (anti-IFN, anti-cytokine, anti-nuclear) primarily attributed to bystander mechanisms; however, Trahtemberg et al. found NO significant difference in ANA between COVID-19+ and COVID-19- ICU patients — suggesting that bystander activation in severe infection is not uniformly ANA-inducing
• Mechanism: IFN-α activates plasmacytoid dendritic cells → polyclonal B cell activation → transient autoantibodies, often without affinity maturation

3. Epitope Spreading

• Definition: Initial immune response to a pathogen antigen damages host tissue → releases cryptic self-antigens → immune response expands to target additional self-epitopes beyond the original cross-reactive target
• Evidence: In animal models, initial anti-viral response → secondary anti-self response against previously unexposed nuclear or cytoplasmic antigens
• This mechanism may explain the diversity of autoantibody specificities observed after infections — including detection of multiple ANA specificities (as in Berlin2007 - Autoantibodies in Nonautoimmune Individuals during Infections)

Host Risk Factors for Infection-Triggered Autoimmunity

• Female sex: TLR7 on the X chromosome (two active copies in females), estrogen-driven immune activation, X-chromosome gene dosage effects → higher innate immune activation and autoimmune susceptibility
  • “Notably, autoantibodies like anti-nuclear antibodies occur in ~20% of healthy women.” — Johnson & Jiang 2022
• Genetics: HLA-DR alleles (specific associations with GBS, SLE, SS), complement gene deficiencies (C1q, C2, C4 → impaired IC clearance → SLE risk), BANK1 polymorphisms
• Innate immunity: TLR2, TLR4, TLR7, TLR9 polymorphisms — loss-of-function variants reduce microbial clearance; gain-of-function or duplication may increase autoimmune activation
• Age and sex interactions: Female predominance strongest at reproductive ages; male/female ratio changes with age (paralleling autoimmune disease demographics)

Specific Pathogen-Autoimmunity Links (Table 1, selected)

Pathogen	Autoantibody/Mechanism	Associated Disease
EBV	Molecular mimicry, epitope spreading	Sjögren’s syndrome, SLE, multiple sclerosis
Coxsackievirus B / MCMV	Bystander activation	Myocarditis
Influenza	Anti-phospholipid antibodies	Type 1 diabetes, GBS, anti-phospholipid syndrome
HBV	Molecular mimicry	CNS demyelination
SARS-CoV-2	Bystander polyclonal activation	Broad autoantibodies (not disease-specific)
HIV	Anti-CD4 IgG	Immune dysfunction
C. jejuni	Anti-ganglioside (GM1, GD1a, GQ1b)	Guillain-Barré syndrome
S. aureus PGN	TLR2-mediated activation	SLE-like anti-dsDNA
LPS (Gram-negative bacteria)	Polyclonal B cell activation	Anti-dsDNA

COVID-19 and ANA — A Key Negative Finding

• Trahtemberg et al. (cited in Johnson2022) found no significant difference in ANA prevalence between COVID-19-positive ICU patients and COVID-19-negative ICU patients
• Interpretation: Severe viral infection with bystander activation does not specifically drive ANA elevation — the ANA elevation seen in other viral contexts (including potentially dengue) may require specific mechanisms beyond non-specific ICU illness

Parasites and the Hygiene Hypothesis

• Parasite co-infection may suppress autoimmunity through Th2 polarisation, regulatory T cell induction, and IL-10 production
• Plasmodium falciparum and helminth infections downregulate Th1/Th17 responses that drive autoimmune disease
• Relevant to dengue: Cuba (where Garcia2009 cohort is from) has low parasitic disease burden, which could reduce this immune suppression and potentially increase autoimmune susceptibility

Bacterial Mechanisms

• S. aureus peptidoglycan (PGN) activates TLR2 → anti-dsDNA production in mouse models
• Gram-negative LPS triggers polyclonal B cell activation → transient anti-dsDNA
• Microbiome dysbiosis → bacterial translocation → systemic LPS → possible ANA induction

Methods Used

(Review paper — no primary methods; describes studies using Indirect Immunofluorescence ANA Test, ELISA, and molecular techniques)

Entities Mentioned

• FcγRIIa Receptor (indirectly — Fc receptor-mediated IC clearance mentioned in complement/IC context)

Concepts Addressed

• Infection-Triggered Autoimmunity
• Autoimmunity in Dengue (by extension — mechanisms apply directly)
• Antinuclear Antibodies
• Antibody-Dependent Enhancement (Fc receptor context)

Relevance & Notes

Johnson2022 is a mechanistic complement to the empirical ANA data in this wiki. While the healthy-population ANA papers (Tan1997, Satoh2012, Li2019, Dinse2022) establish what ANA rates to expect in healthy people, and Berlin2007 shows what ANA rates are seen during acute infections, Johnson2022 explains why infections can trigger autoantibodies at all.

For interpreting Garcia2009 - Long-term Clinical Symptoms Post-Dengue’s 23.1% ANA finding, the three mechanisms are directly applicable:

• Molecular mimicry: Dengue NS1 protein shares structural homology with endothelial and platelet proteins (well-established in dengue literature) — this same mechanism could produce cross-reactive nuclear autoantibodies
• Bystander activation: The intense cytokine storm of severe dengue (IFN-α, IL-6, TNF) could non-specifically activate autoreactive B cells, consistent with the ANA findings; however, the COVID-19 negative result suggests this mechanism alone may not be ANA-specific
• Epitope spreading: If dengue causes post-dengue tissue damage, released nuclear antigens could drive secondary ANA responses — consistent with the persistent nature of Garcia2009’s findings at 2 years

The Johnson2022 review does not cover dengue specifically, but its mechanistic framework and risk factor analysis (female sex, genetics, innate immune genes) are directly applicable to interpreting the Cuban post-dengue cohort.

Limitation: Narrative review without systematic literature search; selective citation; no dengue-specific data.

Questions Raised

• Does dengue specifically induce nuclear cross-reactive antibodies via molecular mimicry (i.e., are dengue antigens structurally similar to nuclear targets like Sm, SSA, or dsDNA)?
• Is the ANA elevation in Garcia2009 driven by one dominant mechanism (molecular mimicry, bystander, or epitope spreading) or a combination?
• Would the same 23.1% ANA rate be seen in asymptomatic dengue-recovered individuals (testing the bystander vs. symptomatic/severe mechanisms)?
• What is the timeline of dengue-induced ANA? Does it follow the transient pattern described for acute viral hepatitis (Berlin2007), or does it persist beyond 2 years as Garcia2009 implies?