Helicobacter pylori and autoimmune disease: Cause or bystander

Table 1 Autoimmune diseases or autoimmune disease-related disorders which have been studied for their possible (direct or indirect) relation with Helicobacter pylori infection

	AID or AID-related disorders linked to H. pylori		AID or AID-related disorders linked to H. pylori
1	Alopecia areata	49	Juvenile diabetes (Type 1 diabetes)
2	Antiphospholipid syndrome	50	Kawasaki syndrome
3	Autoimmune angioedema	51	Leukocytoclastic vasculitis
4	Autoimmune hepatitis	52	Lichen planus
5	Autoimmune hyperlipidemia	53	Linear IgA disease
6	Autoimmune hemolytic anemia	54	Lupus (SLE)
7	Autoimmune myocarditis	55	Microscopic polyangiitis
8	Autoimmune oophoritis	56	Mixed connective tissue disease
9	Autoimmune pancreatitis	57	Mooren’s ulcer
10	Autoimmune polyglandular syndromes	58	Multiple sclerosis
11	Autoimmune thrombocytopenic purpura	59	Myositis
12	Autoimmune thyroid disease	60	Narcolepsy
13	Autoimmune urticaria	61	Neuromyelitis optica (Devic’s)
14	Axonal and neuronal neuropathies	62	Neutropenia
15	Behcet’s disease	63	Ocular cicatricial pemphigoid
16	Bullous pemphigoid	64	Optic neuritis
17	Cardiomyopathy	65	Palindromic rheumatism
18	Celiac disease	66	Pars planitis (peripheral uveitis)
19	Chagas disease	67	Pemphigus
20	Chronic inflammatory demyelinating polyneuropathy	68	Peripheral neuropathy
21	Chronic recurrent multifocal osteomyelitis	69	Perivenous encephalomyelitis
22	Crohn’s disease	70	Pernicious anemia
23	Cogans syndrome	71	Polyarteritis nodosa
24	Demyelinating neuropathies	72	Polymyalgia rheumatica
25	Dermatitis herpetiformis	73	Polymyositis
26	Dermatomyositis	74	Primary biliary cirrhosis
27	Devic’s disease (neuromyelitis optica)	75	Primary sclerosing cholangitis
28	Eosinophilic esophagitis	76	Psoriasis
29	Eosinophilic fasciitis	77	(Idiopathic) pulmonary fibrosis
30	Erythema nodosum	78	Pyoderma gangrenosum
31	Experimental allergic encephalomyelitis	79	Raynaud’s phenomenon
32	Fibromyalgia	80	Reactive Arthritis
33	Fibrosing alveolitis	81	Reiter’s syndrome
34	Giant cell arteritis (temporal arteritis)	82	Relapsing polychondritis
35	Giant cell myocarditis	83	Rheumatoid arthritis
36	Glomerulonephritis	84	Sarcoidosis
37	Goodpasture’s syndrome	85	Scleroderma (systemic sclerosis)
38	Graves’ disease	86	Sjogren’s syndrome
39	Guillain-Barre syndrome	87	Temporal arteritis/Giant cell arteritis
40	Hashimoto’s thyroiditis	88	Thrombocytopenic purpura
41	Henoch-Schonlein purpura	89	Transverse myelitis
42	Hypogammaglobulinemia idiopathic thrombocytopenic purpura	90	Type 1 diabetes
43	IgA nephropathy	91	Ulcerative colitis
44	IgG4-related sclerosing disease	92	Undifferentiated connective tissue disease
45	Immunoregulatory lipoproteins	93	Uveitis
46	Inclusion body myositis	94	Vasculitis (other forms)
47	Interstitial cystitis	95	Vesiculobullous dermatosis
48	Juvenile arthritis

The list includes diseases in alphabetic order as they have been deposited in the official website of AARDA (American Autoimmune Related Diseases Association) with minor revisions. Diseases with at least one study (Pubmed Search) investigating Helicobacter pylori (H. pylori) as a trigger have been included. AID: Autoimmune disease.

Table 2 Autoimmune diseases or autoimmune diseases-related disorders which have not been studied for their possible (direct or indirect) relation with Helicobacter pylori infection

	AID or AID-related disorders not linked to H. pylori
1	Acute Disseminated Encephalomyelitis
2	Acute necrotizing hemorrhagic leukoencephalitis
3	Addison's disease
4	Agammaglobulinemia
5	Amyloidosis
6	Ankylosing spondylitis
7	Anti-GBM/Anti-TBM nephritis
8	Autoimmune aplastic anemia
9	Autoimmune dysautonomia
10	Autoimmune immunodeficiency
11	Autoimmune inner ear disease
12	Autoimmune retinopathy
13	Balo disease
14	Castleman disease
15	Chronic fatigue syndrome
16	Churg-Strauss syndrome
17	Cicatricial pemphigoid/benign mucosal pemphigoid
18	Congenital heart block
19	Coxsackie myocarditis
20	CREST disease
21	Essential mixed cryoglobulinemia
22	Discoid lupus
23	Dressler’s syndrome
24	Endometriosis
25	Evans syndrome
26	Granulomatosis with Polyangiitis (formerly called Wegener’s Granulomatosis)
27	Hashimoto’s encephalitis
28	Herpes gestationis
29	Juvenile myositis
30	Lambert-Eaton syndrome
31	Lichen sclerosus
32	Ligneous conjunctivitis
33	Lyme disease,
34	(Chronic) Meniere’s disease
35	Mucha-Habermann disease
36	Myasthenia gravis
37	Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus
38	Paraneoplastic cerebellar degeneration
39	Paroxysmal nocturnal hemoglobinuria
40	Parry Romberg syndrome
41	Parsonage-Turner syndrome
42	POEMS syndrome
43	Postmyocardial infarction syndrome
44	Postpericardiotomy syndrome
45	Progesterone dermatitis
46	Psoriatic arthritis
47	Pure red cell aplasia
48	Reflex sympathetic dystrophy
49	Restless legs syndrome
50	Retroperitoneal fibrosis
51	Rheumatic fever
52	Schmidt syndrome
53	Scleritis
54	Sperm and testicular autoimmunity
55	Stiff person syndrome
56	Subacute bacterial endocarditis
57	Susac’s syndrome
58	Sympathetic ophthalmia
59	Takayasu’s arteritis
60	Tolosa-Hunt syndrome
61	Vitiligo

The list includes diseases in alphabetical order as they have been deposited in the official website of AARDA (American Autoimmune Related Diseases Association) with minor revisions. Diseases with at least one study (Pubmed Search) investigating Helicobacter pylori (H. pylori) as a trigger have been included. AID: Autoimmune disease.

Table 3 Evidence in support or against the role of Helicobacter pylori in autoimmune disease

Autoimmune condition	Evidence in support and/or against the role of H. pylori	Overall opinion
SjS	Support:	Inconclusive
	Oral cavity populated with H. pylori
	Higher level of anti-H. pylori antibodies in SjS patients
	Increased incidence of mucosal associated lymphoid tissue and lymphomas in parotid and lacrimal glands of SjS patients
	Against:
	Low levels of anti-H. pylori antibodies in SjS patients compared to controls
SSc	Support:	Inconclusive
	Higher incidence of H. pylori antibodies in SSc patients than controls
	H. pylori eradication improves Raynaud's in SSc patients
	Possible protective role against Barrett's esophagus
	Higher level of CagA strain H. pylori infected patients
	Against:
	Low incidence of anti-H. pylori antibodies compared to controls
RA	Support:	Unlikely
	Increased rheumatoid factor IgM from B cells chronically stimulated with H. pylori urease
	Against:
	Low prevalence of anti-H. pylori in RA patients
	Unchanged clinical course or symptomatology after H. pylori eradication
SLE	Support:	Unlikely
	H. pylori urease exposure induced anti-ssDNA antibody production in an animal model of SLE
	Against:
	Low levels of anti-H. pylori found among SLE patients, at levels comparable to controls
	Negative association between H. pylori seropositivity and the development of SLE in African-American women
ITP	Support:	Probable
	Improvement of platelet counts following H. pylori eradication (CagA type H. pylori in particular)
	Anti-CagA antibodies cross-react with peptides on platelets of ITP patient
	Platelet associated IgGs declined following H. pylori eradication
	Found in high prevalence in some ITP cohorts
	Platelet eluates from ITP patients recognize H. pylori CagA
	Against:
	Low levels of H. pylori found in ITP patients
AiTD	Support:	Probable in Graves’ disease
	Higher seropositivity and positive stool cultures for H. pylori in Graves’ disease patients
	CagA strain predominant among Graves’ disease patients
	Amino acid similarities between CagA and thyroid peroxidase
	Reduction in anti-thyroid antibodies following H. pylori eradication
	Against:	Unlikely in Hashimoto’s thyroiditis
	Low levels of infection among Hashimoto’s thyroiditis patients
MS and NMO	Support:	Probable in NMO
	High rate of H. pylori infection among NMO patients
	Correlation between H. pylori infection and presence of aquaporin-4 antibodies
	Against:	Unlikely in MS
	H. pylori infection rates in MS patients similar to or lower than control groups
Psoriasis	Support:	Probable
	Higher levels of anti-H. pylori antibodies in patients
	Appears to be correlation between H. pylori infection and disease severity
	Clinical improvement following H. pylori eradication
	Against:
	No difference in anti-H. pylori levels compared to controls
	No difference of CagA seropositivity between patients and controls
Behçet’s disease	Support:	Unlikely
	Higher infection prevalence in patients
	Some clinical improvement noted after eradication
	Against:
	No difference between patients and controls
Alopecia areata	Support:	Unlikely
	Higher infection prevalence
	Against:
	No difference in infection prevalence between patients and controls
PBC	Support:	Unlikely
	Higher prevalence of anti-H. pylori antibodies among PBC patients
	Amino acid similarities between pyruvate dehydrogenase E2 (PDC-E2) and urease beta of H. pylori
	Against:
	No differences of infection found between patients and controls
	No immunological cross reactivities at the B or CD4 T-cell level
	No crossreactivity between H. pylori VacA and PDC-E2
AIH	Support:	Unlikely
	No current evidence
	Against:
	No differences in anti-H. pylori antibodies between patients and controls
	No significant difference between H. pylori in liver tissues in patients compared to controls
PSC	Support:	Unlikely
	Detectable H. pylori DNA in PSC liver samples
	CagA in samples from PSC patients
	Concomitant ulcerative colitis may be related to H. pylori translocation from the gut to the liver
	Against:
	No difference in H. pylori prevalence among pediatric or adult PSC patients compared to controls
	No significant difference between H. pylori in liver tissues in patients compared to controls

Helicobacter pylori (H. pylori) has been implicated in the development of several autoimmune diseases. This table summarizes some of the evidence in support or against this hypothesis in various autoimmune diseases. Overall opinions reflect an inconclusive evidence base, those which are unlikely, and those which have a relatively strong or strong (probable) evidence base. SjS: Sjogren’s syndrome; SSc: Systemic sclerosis; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; ITP: Immune thrombocytopenic purpura; AiTD: Autoimmune thyroid disease; MS: Multiple Sclerosis; NMO: Neuromyelitis optica; PBC: Primary biliary cirrhosis; AIH: Autoimmune hepatitis; PSC: Primary sclerosing cholangitis.