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Case Report
expansion of B cells and plasmablasts leads to IgG4 pro- Correspondence:
duction, which may contribute to IgG4-RD pathogene- sis9. Plasmablasts from patients with IgG4-RD show extensive immunoglobulin somatic hypermutation, upregulation of FAS/CD95, and active proliferation and secretion of IgG4.10 Conceivably, dysregulation of FAS signaling in plasmablasts in ALPS patients may con- tribute to a preponderance of plasmablasts, and if skewed toward IgG4+ to IgG4-RD. The extensive immunoglobulin somatic hypermutation in plasmablasts suggests a T-cell-dependent germinal center-derived ontology. As such, T lymphocytes have also been impli- cated in the pathogenesis of IgG4-RD, particularly T-fol- licular helper cells (TFH), T-follicular regulatory cells (Tregs), and CD4+ cytotoxic T lymphocytes (CD4 CTL). Cytokine production by these T-cell subsets appear to contribute to IgG4-RD pathogenesis. Namely, IL-4 and IL-10 produced by T and T promote IgG4 isotype
CTL promote fibrosis.11-13 While CD4+ T cells are the best characterized, Carruthers et al. have shown that expansion of DNT may also occur in IgG4-RD, however it is unknown if DNT contribute to disease pathogene- sis.14 A recent study by Maccari et al. has identified and characterized αβ+DNT in ALPS patients using RNA sequencing, mass cytometry (CyTOF) and functional cytokine analysis. They found that ALPS-DNT show a unique surface marker profile with high expression of CD38, CD45RA, CD27, CD28, CLTA4, TIGIT and TIM3, and additionally show upregulation of IL-10 tran- scripts and protein levels.15 Conceivably, ALPS-DNT may participate in IL-10-mediated class switching of B- cells/plasmablasts to IgG4, however further studies are needed to test this hypothesis.
In conclusion, this case demonstrates the utility of assessing for expanded αβ+DNT in patients with IgG4- RD, which revealed the diagnosis of ALPS-FAS in our patient. Future studies are needed to investigate a poten- tial mechanistic link between these entities.
Nivaz Brar,1* Michael A. Spinner,2* Matthew C. Baker,3 Ranjana H. Advani,2 Yasodha Natkunam,1 David B. Lewis4 and Oscar Silva1
1Department of Pathology, Stanford University School of Medicine; 2Division of Oncology, Department of Medicine, Stanford University School of Medicine; 3Division of Immunology and Rheumatology, Department of Medicine Stanford University School of Medicine and 4Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
*NB and MAS contributed equally as co-first authors.
OSCAR SILVA MD, PhD - osilva@stanford.edu doi:10.3324/haematol.2021.279297
Received: June 9, 2021.
Accepted: August 26, 2021.
Pre-published: September 2, 2021.
Disclosures: no conflicts of interest to disclose
Contributions: NB, MAS and OS collected data, generated figures and wrote the initial draft of the manuscript. All authors contributed to the writing and/or editing of the manuscript.
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FH regs
switching, whereas IL-1 and TGFβ produced by CD4
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