Predominantly Antibody-Deficient Patients With Non-infectious Complications Have Reduced Naive B, Treg, Th17, and Tfh17 Cells

Abstract

Background: Patients with predominantly antibody deficiency (PAD) suffer from severe and recurrent infections that require lifelong immunoglobulin replacement and prophylactic antibiotic treatment. Disease incidence is estimated to be 1:25,000 worldwide, and up to 68% of patients develop non-infectious complications (NIC) including autoimmunity, which are difficult to treat, causing high morbidity, and early mortality. Currently, the etiology of NIC is unknown, and there are no diagnostic and prognostic markers to identify patients at risk.Objectives: To identify immune cell markers that associate with NIC in PAD patients.Methods: We developed a standardized 11-color flow cytometry panel that was utilized for in-depth analysis of B and T cells in 62 adult PAD patients and 59 age-matched controls.Results: Nine males had mutations in Bruton's tyrosine kinase (BTK) and were defined as having X-linked agammaglobulinemia. The remaining 53 patients were not genetically defined and were clinically diagnosed with agammaglobulinemia (n = 1), common variable immunodeficiency (CVID) (n = 32), hypogammaglobulinemia (n = 13), IgG subclass deficiency (n = 1), and specific polysaccharide antibody deficiency (n = 6). Of the 53, 30 (57%) had one or more NICs, 24 patients had reduced B-cell numbers, and 17 had reduced T-cell numbers. Both PAD–NIC and PAD+NIC groups had significantly reduced Ig class-switched memory B cells and naive CD4 and CD8 T-cell numbers. Naive and IgM memory B cells, Treg, Th17, and Tfh17 cells were specifically reduced in the PAD+NIC group. CD21lo B cells and Tfh cells were increased in frequencies, but not in absolute numbers in PAD+NIC.Conclusion: The previously reported increased frequencies of CD21lo B cells and Tfh cells are the indirect result of reduced naive B-cell and T-cell numbers. Hence, correct interpretation of immunophenotyping of immunodeficiencies is critically dependent on absolute cell counts. Finally, the defects in naive B- and T-cell numbers suggest a mild combined immunodeficiency in PAD patients with NIC. Together with the reductions in Th17, Treg, and Tfh17 numbers, these key differences could be utilized as biomarkers to support definitive diagnosis and to predict for disease progression.

Defective formation of IgA memory B cells, Th1 and Th17 cells in symptomatic patients with selective IgA deficiency

“…Another essential cytokine in the regulation of IgA class switching is TGF‐β1. More than two decades ago, Muller et al ., 40 using a cell bioassay, noted a moderate reduction in serum concentrations of TGF‐β1 in sIgAD patients, and these correlated negatively with the numbers of CD19 + B cells 38 . In contrast, we found increased TGF‐β1 in plasma in five out of 8 patients.…”

“…Patients with predominantly antibody deficiency, including CVID, have reduced numbers of Th17 cells along with increased numbers of CD21 low B cells 36‐38 . Interestingly, we found decreased Th17 and Th1 cell numbers in adult sIgAD patients.…”

T lymphocytes in IgA nephropathy (Review)

“…Meanwhile, Th2 cells secrete anti-inflammatory cytokines, including IL-4 and IL-10, which are essential for humoral-mediated immunity of extracellular pathogens (31)(32)(33). In addition, Th17 cells include another subset of Th cells characterized by the secretion of IL-17 (34). The Th17 lineage has been revealed to play an important role in the early response to bacterial pathogens and the initiation of autoimmune diseases, such as rheumatoid arthritis, IgAN and allergen-specific responses (35).…”

Influenza‐specific IgG1+ memory B‐cell numbers increase upon booster vaccination in healthy adults but not in patients with predominantly antibody deficiency

“…[1][2][3][4][5] Patients are defined by an impaired antibody (Ab) response to antigen stimulation. [6][7][8] Within the group of PAD patients, those with a complete absence of serum immunoglobulin (Ig) and of circulating B cells are defined as having agammaglobulinemia. This subgroup is genetically well defined with the majority being males having X-linked inheritance because of mutations in the BTK gene, 9,10 and others having autosomal recessive inheritance because of mutations in pre-B-cell receptor signalling molecules or critical transcription factors.…”

“…6,[18][19][20] Patients with hypogammaglobulinemia (HGG) have reduced IgG in the context of normal IgA and IgM. 6,18,20 Finally, patients with impaired vaccination responses in the context of normal total IgG distinguish those with IgG subclass deficiency and those with specific Ab deficiency. 5,6,20,21 Typically, treatment of PAD involves Ig replacement therapy (IgRT) and prophylactic antibiotics to reduce the number and severity of infections.…”