A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects

Abstract

Introduction: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management.

Methods: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES).

Results: The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαβ⁺CD4^-CD8^-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA⁺ (TEMRA) Th were documented. Large PD1⁺ population, increased memory, and enlarged follicular helper T cell population in the CD4⁺ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT.

Conclusion: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA⁺ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

Keywords: Hsct; LATAIE; LRBA deficiency; Malignancy.

Fig. 1

Some of the patients initially followed with the diagnosis of ALPS and CVID were found to have LRBA defect

Fig. 2

Functional tests for LRBA defects. a Low LRBA, CTLA-4 and CD25 expression of CD4⁺FoxP3⁺ T cells in P8 compared to healthy donor (HD). b More memory (CD45RA⁻) CD4⁺ T cells are present, and T follicular helper (CD4⁺CXCR5⁺PD-1⁺) cells are increased in P8 (CD4⁺ gated cells are shown), compared to HD. c Low LRBA and CTLA-4 expression of CD4⁺FoxP3⁺ T cells in P14, compared to HD1 and HD2. d Western Blotting: No LRBA protein is seen in P8 and P14 compared to healthy donor. e Western Blotting: LRBA protein in P4 before and after HSCT

Fig. 3

LRBA protein map that illustrates its possible multidomain sites. ConA conconavalin A-like lectin/gluconase domain, DUF domain of unknown functions 4704, A type Armadillo type fold, PH PH domain associated with Beige/BEACH, BEACH Beige and Chediak Higashi, YVTN WD40/YVTN repeat–like containing domain (The figure is drawn by the help of Ensemble, PFAM, Gen3D, superfamily, SMART databases.)

Fig. 4

Algorithm for the diagnosis and follow-up of patients with LRBA defect