OMIM 614878

[sbello]

Please add a new disease term autoinflammation, antibody deficiency, and immune dysregulation syndrome (OMIM label)

Def: An autoimmune disease characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, the eye, and the gastrointestinal tract that has_material_basis in heterozygous mutation in PLCG2 on chromosome 16q23. def xref - PMID:23000145 (https://pubmed.ncbi.nlm.nih.gov/23000145/)

Not sure that autoimmune disease is the best parent, would be good to double check this. The Orphanet parent is Mixed autoinflammatory and autoimmune syndrome

synonyms autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (Orphanet and Gard label) APLAID (OMIM and Orphanet) AUTOINFLAMMATION, ANTIBODY DEFICIENCY, AND IMMUNE DYSREGULATION, PLCG2-ASSOCIATED (OMIM)

xref: MIM:614878 ORDO:324530 GARD:17486

Mouse model in PMID:36997670

[allenbaron]

Thanks. I'll work on this soon. With the need to review the parent assignment, it will take a bit longer but should be in the October release.

[allenbaron]

Parentage

Looking into parentage I noticed that this has overlapping features and is allelic to 'familial cold autoinflammatory syndrome 3' (commonly called PLAID; DOID:0090064). That is a descendant of 'primary immunodeficiency disease' (DOID:612), which has the definition:

An immune system disease that results when one or more essential parts of the immune system is missing or not working properly at birth due to a genetic mutation.

The "not working properly" portion of the definition of primary immunodeficiency disease may be open for misinterpretation.

Suggested parents

Immune deficiency does appear to be a feature of APLAID (respiratory infections are common[^1]), as it is for PLAID. So, 'primary immunodeficiency disease' (DOID:612) would probably be a better parent than autoimmune disease.

Another option, which might be better still, would be to add 'autoinflammatory disease' as a new grouping term. I usually want to avoid new grouping terms but I think it's warranted in this case.

'autoinflammatory disease' is defined as:

Autoinflammatory diseases refer to problems with the innate immune system’s reactions. Immune cells target the body’s own healthy tissues by mistake, signaling the body to attack them. This can cause intense episodes of inflammation that result in such symptoms as fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal buildup of a blood protein in vital organs.[^2]

It is also referred to as 'systemic autoinflammatory disease'[^3]. If we could access it UpToDate might have some information to help us distinguish/disambuiguate autoinflammatory and immune deficiency diseases[^4].

Additional Info about autoinflammatory diseases

The autoinflammatory diseases mentioned in sources include:

• Familial Mediterranean Fever[^2][^3] - DOID:2987 (parent: autoimmune disease)
• Tumor Necrosis Factor Receptor-Associated Periodic Syndrome[^2][^3] - DOID:0090018 (parent: primary immunodeficiency disease)
• Deficiency of the Interleukin-1 Receptor Antagonist[^2] - not in DO (https://www.omim.org/entry/612852)
• Behçet’s disease[^2] - DOID:13241 (parent: vasculitis) & DOID:0080944 (parent: primary immune deficiency)
  • DOID:0080944 should likely be a child of DOID:13241
• Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature[^2] - DOID:0060913 (parent: syndrome)
• Periodic fevers, cervical adenitis, pharyngitis, and aphthous stomatitis[^3] - DOID:0081451 (parent: autoimmune disease)
• Mevalonate kinase deficiency[^3] - DOID:0050452 (parent: peroxisomal disease)
• Cryopyrin-associated periodic syndromes[^3] - various, see below
• Neonatal Onset Multisystem Inflammatory Disease[^2][^3] - DOID:0090029 (parent: autoimmune disease)
  • this may be a type of cryopyrin-associated periodic syndrome (a grouping term at Orphanet) and synonym from OMIM not annotated to this disease
  • MISSING some synonyms/acronyms, see OMIM
• Muckle-Wells syndrome[^3] - DOID:0050854 (parent: syndrome)
  • this is a type of cryopyrin-associated periodic syndrome (a grouping term at Orphanet) and synonym in DO
• Familial cold autoinflammatory syndrome[^3] - DOID:0090061 (parent: primary immune deficiency)
  • this may be a type of cryopyrin-associated periodic syndrome, or possibly a subset of these may be suggesting there may be different groupings preferred by Orphanet and OMIM

Autoinflammatory/Autoimmune caution

At least 2 publications suggest that the distinction between autoimmune and autoinflammatory diseases is unwarranted and they should be considered one group of diseases across a spectrum[^5][^6]. I don't find the arguments in either of these particularly compelling.

Back to APLAID & parentage

The immune deficiency of APLAID appears to be minimal compared to the over-active innate immune response. We could reasonably classify it as a 'primary immune deficiency' or an 'autoinflammatory disease', or even both.

@lschriml, thoughts?

[^1]: Zhou Q, Lee GS, Brady J, Datta S, Katan M, Sheikh A, Martins MS, Bunney TD, Santich BH, Moir S, Kuhns DB, Long Priel DA, Ombrello A, Stone D, Ombrello MJ, Khan J, Milner JD, Kastner DL, Aksentijevich I. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet. 2012 Oct 5;91(4):713-20. doi: 10.1016/j.ajhg.2012.08.006. Epub 2012 Sep 20. PMID: 23000145; PMCID: PMC3484656. https://pubmed.ncbi.nlm.nih.gov/23000145/ [^2]: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Health Topics, Autoinflammatory Diseases. https://www.niams.nih.gov/health-topics/autoinflammatory-diseases [^3]: Boston Children's Hospital. Systemic Autoinflammatory Diseases (SAIDs). https://www.childrenshospital.org/conditions/systemic-autoinflammatory-diseases-saids [^4]: The autoinflammatory diseases: An overview. UpToDate. Walters Kluwer. https://www.uptodate.com/contents/the-autoinflammatory-diseases-an-overview [^5]: Doria A, Zen M, Bettio S, Gatto M, Bassi N, Nalotto L, Ghirardello A, Iaccarino L, Punzi L. Autoinflammation and autoimmunity: bridging the divide. Autoimmun Rev. 2012 Nov;12(1):22-30. doi: 10.1016/j.autrev.2012.07.018. Epub 2012 Aug 2. PMID: 22878274. https://pubmed.ncbi.nlm.nih.gov/22878274/ [^6]: El-Shebiny, E.M., Zahran, E.S., Shoeib, S.A. et al. Bridging autoinflammatory and autoimmune diseases. Egypt J Intern Med 33, 11 (2021). https://doi.org/10.1186/s43162-021-00040-5