Patterns of Immune Dysregulation in Primary Immunodeficiencies: A Systematic Review

Published:November 10, 2020DOI:


      Immune dysregulation is as important as susceptibility to infection in defining primary immunodeficiencies (PIDs). Because of the variability and nonspecificity of the symptoms of PIDs, diagnosis can be delayed—especially if a patient presents with immune dysregulation. Diagnosis is then based on certain combinations of symptoms and relies on the clinician's ability to recognize a pattern. So far there is no large report linking patterns of immune dysregulations to the underlying genetic defects.


      To identify immune dysregulatory patterns associated with PIDs and to help clinicians to detect an underlying PID in certain patients with noninfectious inflammatory diseases.


      A systematic literature review was performed.


      We included 186 articles that reported on n = 745 patients. The most common immune dysregulation category was “autoimmunity” (62%, n = 463), followed by “intestinal disease” (38%, n = 283) and “lymphoproliferation” (36%, n = 268). Most patients (67%) had 1 or more symptoms of immune dysregulation. Autoimmune hemolytic anemia, the most common autoimmune phenotype, was most frequently reported in patients with LPS responsive beige-like anchor protein deficiency (when combined with hypogammaglobulinemia or gastrointestinal symptoms), activation-induced cytidine deaminase deficiency (when combined with autoimmune hepatitis), or RAG1 deficiency (when it was the only symptom of immune dysregulation). Eczema, allergies, and asthma were reported in 34%, 4%, and 4% of the patients, respectively.


      Patterns of immune dysregulation may help the physician to recognize specific PIDs. This systematic review provides clinicians with an overview to better assess patients with immune dysregulation.

      Key words

      Abbreviations used:

      AID (Activation-induced cytidine deaminase), AIHA (Autoimmune haemolytic anaemia), AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften), BTK (Bruton's tyrosine kinase), CTLA4 (Cytotoxic T-lymphocyte-associated protein 4), CVID (Common variable immunodeficiency), DOCK8 (Dedicator of cytokinesis 8), FOXP3 (Forkhead box P3), GARFIELD (Granuloma, autoimmunity, recurrent fever, eczema, lymphoproliferation, intestinal disease), GOF (Gain of function), IPEX (Immunodysregulation polyendocrinopathy enteropathy X-linked), ITP (Immune thrombocytopenia), IUIS (International Union of Immunological Societies), LRBA (LPS responsive beige-like anchor protein), NFKB (Nuclear factor kappa-light-chain-enhancer of activated B cells), PGM3 (Phosphoglucomutase 3), PID (Primary immunodeficiency), PLCG2 (Phospholipase C Gamma 2), RAG (Recombination-activating genes), RMRP (RNAse Mitochondrial RNA-processing), SLE (Systemic lupus erythematosus), STAT (Signal transducer and activator of transcription), TNFRSF13B (TNF Receptor Superfamily Member 13B), TTC7A (Tetratricopeptide repeat domain 7A), WAS (Wiskott-Aldrich Syndrome)
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