Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect

Mol Immunol. 2020 May;121:28-37. doi: 10.1016/j.molimm.2020.02.014. Epub 2020 Mar 6.


Introduction: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS).

Aim: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect.

Patient and methods: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide.

Results: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1β and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient.

Conclusion: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.

Keywords: Autoinflammation; Combined immunodeficiency; Degenerative arhritis; H syndrome; Pure red cell aplasia.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autoimmunity / genetics*
  • Contracture / drug therapy
  • Contracture / genetics*
  • Contracture / immunology
  • Contracture / pathology
  • Glucocorticoids / therapeutic use
  • Hearing Loss, Sensorineural / drug therapy
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / immunology
  • Hearing Loss, Sensorineural / pathology
  • Histiocytosis / drug therapy
  • Histiocytosis / genetics*
  • Histiocytosis / immunology
  • Histiocytosis / pathology
  • Humans
  • Immunoglobulins, Intravenous / therapeutic use
  • Immunologic Deficiency Syndromes / drug therapy
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Deficiency Syndromes / pathology
  • Inflammasomes / immunology
  • Lysosomes / immunology
  • Lysosomes / pathology
  • Male
  • Mitochondria / immunology
  • Mitochondria / pathology
  • Nucleoside Transport Proteins / genetics*
  • Treatment Outcome


  • Glucocorticoids
  • Immunoglobulins, Intravenous
  • Inflammasomes
  • Nucleoside Transport Proteins
  • SLC29A3 protein, human

Supplementary concepts

  • Histiocytosis with joint contractures and sensorineural deafness