Impaired memory B‐cell development and antibody maturation with a skewing toward IgE in patients with STAT3 hyper‐IgE syndrome

Abstract

Background: Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is caused by heterozygous mutations in the STAT3 gene and is associated with eczema, elevated serum IgE, and recurrent infections resembling severe atopic dermatitis, while clinically relevant specific IgE is almost absent. Methods:To investigate the impact of STAT3 signaling on B-cell responses, we assessed lymph node and bone marrow, blood B and plasma cell subsets, somatic hypermutations in Ig genes, and in vitro proliferation and antibody production in STAT3-HIES patients and healthy controls. Results: Lymph nodes of STAT3-HIES patients showed normal germinal center architecture and CD138 + plasma cells residing in the paracortex, which expressed IgE, IgG, and IgM but not IgA. IgE + plasma cells were abundantly present in STAT3-HIES bone marrow. Proliferation of naive B cells upon stimulation with CD40L and IL-4 was similar in patients and controls, while patient cells showed reduced responses to IL-21. IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations. | 2395 van de veen et al.

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

“…The exact mechanism by which hyper-IgE occurs remains unclear, though the elevated IgE levels seen in dominant and recessive IL6ST [10,28] and recessive IL6R [35] mutations support a role for IL-6 in IgE homeostasis. STAT3-HIES patients demonstrate a skew towards IgE + class-switch recombination of memory B-lymphocytes with increased numbers compared to other immunoglobulin classes [67], possibly driven by IL-4, which acts independently of STAT3 [68]. The reduced affinity of STAT3-HIES IgE may result from impaired affinity maturation from direct switching from IgM to IgE production [67].…”

AllergoOncology: ultra-low IgE, a potential novel biomarker in cancer—a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI)

“…Several immunodeficiencies are associated with very high and extremely high IgE levels due to regulatory T cell dysfunction, T cell oligoclonality and increased IL‐4 production (Table 3 ) [83 ]. Some of these rare primary immunodeficiencies caused by STAT3 mutations [31, 84 ] are characterized by extremely high serum IgE levels (often above 10,000 kU/L) and are associated with a pruritic eczematous skin rash, eosinophilia and impairments of other organ systems including intelligence and motor function. These human hyper‐IgE syndromes (HIES) include the autosomal dominant Job´s syndrome and autosomal recessive PGM3 (phosphoglucomutase 3) and SPINK5 (Serine Peptidase Inhibitor Kazal Type 5) syndromes, that can be successfully treated with anti‐IgE antibody therapy [85 ] or stem cell transplantation [86 ].…”

“…In clinical practice, these patients are referred to Allergy clinics for suspected allergic disorders or other conditions associated with elevated IgE levels. For example, atopic dermatitis and hyper‐IgE syndrome are among the disorders with the highest serum IgE levels (often IgE greater than 10,000 kU/L), followed by asthma, parasitosis and allergic rhinitis [29–31 ].…”

Recent developments and highlights in food allergy

“…62 This suggests the activation of pools from allergen-specific B-cell subsets, for example, from IgG1-positive allergen-specific B cells upon switch factors and stimulation. 63 Recent data on STAT3 on the regulation of antibody diversity in general and IgE specifically have added to our understanding on IgE regulation 64 and allergic inflammation. 65 Recently, the soluble form of the high-affinity IgE receptor (FcεRI has been described as an endogenous inhibitor of mast cell activation, 66 as a potential biomarker for IgE-mediated disease, and also as a potential confounder to affect IgE measurement.…”