Immune dysregulation, lymphoproliferation and autoinflammatory disease

Picture three children in a single clinic. An infant with bloody diarrhoea, severe eczema and new type-1 diabetes. A four-year-old with big, painless glands and a low platelet count that keeps dropping. A two-year-old with clockwork fevers every five weeks, a red throat and mouth ulcers, perfectly well between attacks. Each looks like a different problem — a gut disease, a blood disease, a fever mystery. They are not. Each is a single control-point of the immune system failing, and the framework on this page is built so a registrar can sort all three into the right lane and know what to do first. ^{[1] [2]}

Overview & Definition

Immune dysregulation, lymphoproliferation and autoinflammatory disease are grouped in the International Union of Immunological Societies classification as inborn errors of immunity in which the problem is not susceptibility to infection (the classical immunodeficiency) but a loss of the controls that keep the immune response aimed, sized and switched off. Picard and the IUIS committee placed them in the immune-dysregulation and autoinflammatory groups of the 2015 classification, and Tangye and colleagues' 2022 update expanded the catalogue substantially as new genes were identified. ^{[1] [2]}

The unifying idea is mechanistic. A normal immune response has to (1) avoid attacking self, (2) contract back down once a threat is cleared, and (3) wind up and down the innate inflammatory engine in proportion to danger. Each of those steps is held in place by specific genes. When a gene in step one breaks, self-tolerance fails and the child develops organ-specific autoimmunity — that is immune dysregulation. When a gene in step two breaks, activated lymphocytes fail to die and accumulate — that is lymphoproliferation. When a gene in step three breaks, innate cytokines such as interleukin-1 surge without provocation and recur — that is autoinflammation. ^[2]

The distinction between autoimmunity and autoinflammation is worth holding onto even when it blurs. Autoimmunity is adaptive and self-antigen-driven — T cells and antibodies attack a defined target, which is why you find autoantibodies and organ-specific damage. Autoinflammation is innate and largely antigen-independent — it is the inflammasome and cytokine machinery misfiring, which is why attacks recur without infection and why acute-phase markers swing. CTLA4 and LRBA deficiency show why the boundary is porous: a single gene can produce both lymphoproliferation and organ-specific autoimmunity at once. ^[3]

References17ShowHide

1. [1]Picard C Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. Journal of Clinical Immunology, 2015.PMID 26482257
2. [2]Tangye SG Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. Journal of Clinical Immunology, 2022.PMID 35748970
3. [3]Kuehn HS Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science, 2014.PMID 25213377
4. [4]Verbsky JW Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Current Opinion in Pediatrics, 2013.PMID 24240290
5. [5]Ferré EMN Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. Frontiers in Pediatrics, 2021.PMID 34790633
6. [6]Rieux-Laucat F Scaling the tips of the ALPS. Biomedical Journal, 2021.PMID 34438083
7. [7]George LA Optimal Management of Autoimmune Lymphoproliferative Syndrome in Children. Paediatric Drugs, 2016.PMID 27139496
8. [8]Henter JI HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric Blood and Cancer, 2007.PMID 16937360
9. [9]Jordan MB How I treat hemophagocytic lymphohistiocytosis. Blood, 2011.PMID 21828139
10. [10]Ravelli A Macrophage Activation Syndrome. Hematology/Oncology Clinics of North America, 2015.PMID 26461152
11. [11]Gattorno M Classification criteria for autoinflammatory recurrent fevers. Annals of the Rheumatic Diseases, 2019.PMID 31018962
12. [12]Romano M The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist. Annals of the Rheumatic Diseases, 2022.PMID 35623638
13. [13]Stojanov S Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proceedings of the National Academy of Sciences, 2011.PMID 21478439
14. [14]Ozen S EULAR recommendations for the management of familial Mediterranean fever. Annals of the Rheumatic Diseases, 2016.PMID 26802180
15. [15]Wouters CH Blau syndrome, the prototypic auto-inflammatory granulomatous disease. Pediatric Rheumatology, 2014.PMID 25136265
16. [16]Holland SM STAT3 mutations in the hyper-IgE syndrome. New England Journal of Medicine, 2007.PMID 17881745
17. [17]Toubiana J Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood, 2016.PMID 27114460