The shaping of immunological responses through natural selection after the Roma Diaspora

Dobón Berenguer, Begoña, 1987-; Ter Horst, Rob; Laayouni, Hafid, 1968-; Mondal, Mayukh, 1989-; Bianco, Erica; Comas, David, 1969-; Ioana, Mihai; Bosch Fusté, Elena; Bertranpetit, Jaume, 1952-; Netea, Mihai G.

doi:http://dx.doi.org/10.1038/s41598-020-73182-1

The shaping of immunological responses through natural selection after the Roma Diaspora

License

Citation

Dobon B, Ter Horst R, Laayouni H, Mondal M, Bianco E, Comas D, Ioana M, Bosch E, Bertranpetit J, Netea MG. The shaping of immunological responses through natural selection after the Roma Diaspora. Sci Rep. 2020; 10(1):16134. DOI: 10.1038/s41598-020-73182-1

Abstract

Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient's B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.