Vaccines | Free Full-Text | Impaired IgM Memory B Cell Function Is Common in Coeliac Disease but Conjugate Pneumococcal Vaccination Induces Robust Protective Immunity

Coeliac disease (CD) is a common immune illness triggered by dietary gluten with an estimated global seroprevalence of 1.4% [1]. The typical enteropathy of CD is mediated by pro-inflammatory intestinal HLA-restricted CD4⁺ T cells responding to specific gluten peptides, with gut plasma cells implicated as the major antigen-presenting cell [2,3,4]. In this context, B cells provide help to gluten-specific T cells to amplify the pathogenic response to gluten. Although primarily a small intestinal disease, the systemic inflammatory response of CD leads to extraintestinal complications such as reduced bone density and an increased risk of lymphoproliferative malignancy [5]. One of these, hyposplenism, an acquired impairment of spleen function [6,7,8,9], is reported in 12–80% [10,11,12,13] of CD sufferers, especially those with autoimmunity, refractory CD (non-response to treatment with a gluten-free diet; GFD), or those diagnosed after 50 years of age [10].

A concern with hyposplenism is the increased susceptibility to serious infections with encapsulated bacteria [14,15,16,17,18,19], most commonly Streptococcus pneumoniae (pneumococcus). Large population studies have shown that the increased risk of pneumococcal sepsis contributes to elevated morbidity and mortality in CD. The excess risk of pneumococcal infection in hospitalised CD patients compared to the general population is significant (HR = 3.90, 95% CI 2.20–7.00) [19]. Screening for hyposplenism assesses the spleen’s filtering function, with impairment indicated by the presence of Howell–Jolly bodies (HJBs), nuclear inclusion remnants in red blood cells [20,21], or pitted red cells (PRCs) resulting from the accumulation of membrane vacuoles [22]. The immunodeficiency linked to hyposplenism is attributed to reduced numbers of circulating IgM memory B cells. These cells require intact spleen function for their development and survival, unlike switched memory B cells, which are present at normal frequencies in asplenic patients [23,24,25,26]. IgM memory B cells are critical for protective responses to T cell-independent (TI) stimuli, particularly encapsulated bacteria [23,27,28,29]. While a reduced IgM memory B cell population is associated with hyposplenism in CD [10,24,25], their function in CD has not been investigated. Furthermore, it remains uncertain whether screening for hyposplenism based on HJBs or PRCs is sufficiently sensitive to identify patients with suboptimal spleen function who remain at risk of pneumococcal sepsis.

While pneumococcal vaccination is recommended for patients with asplenia or hyposplenism with HJBs present [30,31,32], there is no consensus recommendation for vaccination in CD [33,34,35]. Two frequently employed pneumococcal vaccines are a 23-valent pneumococcal capsular polysaccharide formulation (23vPPV) encompassing serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 20, 22F, 23F, and 33F, and a 13-valent pneumococcal conjugate vaccine (13vPCV) encompassing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. The polysaccharide formulation of 23vPPV leads to the direct activation of B cells independent of T cells (TI), which induces anti-capsular IgG antibodies as well as short-lived IgM+ plasmablasts, but does not typically generate a long-lived memory B cell response [27]. The serotype-specific IgG response to 23vPPV is an important test used in the investigation of suspected immune deficiency. In contrast to 23vPPV, the protein-conjugated 13vPCV induces T cell-dependent (TD) responses, which generates higher avidity antibodies and immunologic memory [36]. As PCV13 generates the formation of both serotype-specific antibodies and memory B cells, it is associated with a longer duration of vaccine-induced protection. Protective immunity following 13vPCV is more effective in splenectomised patients [37]. Notably, the comparative immunogenicity of 23vPPV and 13vPCV in CD, and the effect of IgM memory B cell deficits in this population, have not been assessed. These data are needed to inform vaccination recommendations.