ImmunologyTier 2Medical Sciences concept

Molecular mimicry in autoimmune disease (rheumatic fever, Guillain-Barré)

Core concept

A microbial epitope structurally resembles a self-epitope -> an appropriate anti-microbial response cross-reacts with host tissue

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Infection

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The tell is the LATENCY: disease begins 1-6 weeks after the infection, when the organism is no longer culturable
Molecular mimicry alone is not sufficient - it requires a permissive HLA background and loss of peripheral tolerance

Disease	Organism	Mimicked self-antigen
Acute rheumatic fever	Strep pyogenes M protein (rheumatogenic types)	Cardiac myosin, laminin, valve endothelium; N-acetylglucosamine of group A carbohydrate. Latency 2-4 weeks
Guillain-Barre (AMAN variant)	Campylobacter jejuni lipo-oligosaccharide	GM1, GD1a gangliosides on axolemma. Latency 1-3 weeks
Miller Fisher variant	C. jejuni, H. influenzae	GQ1b - dense in oculomotor nerves -> ophthalmoplegia, ataxia, areflexia
Reactive arthritis	Chlamydia, Salmonella, Shigella, Yersinia, Campylobacter	HLA-B27-presented peptides. Latency 1-4 weeks
Rheumatic chorea (Sydenham's)	Strep pyogenes	Basal ganglia neuronal antigens
Post-streptococcal GN	Strep (nephritogenic types)	Immune complex, not pure mimicry - latency 1-2 wk (throat) or 3-6 wk (skin)
Type 1 diabetes	Coxsackie B4	GAD65 vs P2-C protein homology
Multiple sclerosis	EBV EBNA1	GlialCAM, myelin basic protein - EBV infection is now regarded as a near-necessary cause of MS
Ankylosing spondylitis	Klebsiella	HLA-B27 homology (contested)
Coeliac disease	(not infection)	Gliadin deamidated by tTG - the antigen is dietary, not microbial

Acute rheumatic fever - the model in detail

Jones criteria (revised 2015, with a low-risk vs high-risk split; Australia uses the high-risk pathway for Aboriginal and Torres Strait Islander populations)
- Major: carditis (subclinical on echo counts), polyarthritis (monoarthritis or polyarthralgia counts in high-risk), chorea, erythema marginatum, subcutaneous nodules
- Minor: fever, arthralgia, raised ESR/CRP, prolonged PR
- Plus evidence of preceding GAS infection (ASOT, anti-DNase B, throat swab)
Mitral valve is the most affected (regurgitation acutely, stenosis chronically)
Rheumatic fever follows pharyngitis; in high-burden Australian settings, skin infection and scabies are also implicated

Secondary prophylaxis after ARF is the highest-value intervention in the whole topic
- Benzathine benzylpenicillin G IM every 4 weeks (28 days), for at least 10 years or to age 21 (whichever is longer), and longer or lifelong with established rheumatic heart disease
- RHD is a major cause of preventable cardiac death in Aboriginal and Torres Strait Islander Australians
GBS: Campylobacter-associated AMAN has a worse prognosis; IVIG or plasma exchange - not corticosteroids (ineffective in GBS); monitor FVC, not oximetry
Do not treat reactive arthritis with prolonged antibiotics - the organism has usually gone; NSAIDs, then sulfasalazine or anti-TNF
Mimicry is also invoked for vaccine-associated autoimmunity, but the evidence is weak apart from the 1976 swine flu-GBS association and narcolepsy with Pandemrix

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