B Cells Shed Light on Diminished Vaccine Responses in Obesity

Compromised immune function due to obesity is a growing public health concern. Chronic inflammation from immune cells supports obesity-associated metabolic dysfunction, and lower vaccine efficacy suggests the importance of immune perturbations in people with obesity (1,2). However, few studies have identified mechanisms by which obesity modifies the ability of immune cells to perform their seminal task: pathogen clearance. Although numerous clinical studies have supported the idea that immune responses are perturbed in obesity, a skewed focus of the field on myeloid cells (monocytes/macrophages, dendritic cells) and T cells in obesity-associated immune responses downplays the critical importance of B cells and their unique ability to produce pathogen-neutralizing antibodies. A handful of studies show that B cells promote obesity-induced inflammation through a pro-inflammatory cytokine profile, diabetogenic antibodies, or an ability to support T cell inflammation (Ref. 3 and references therein), but the vast majority of studies do little to address the relationship between altered B cell (or other immune cell) responses and defective pathogen clearance in obesity.

In this issue of Obesity, Frasca et al. (4) demonstrate that inflammatory B cells, identified based on constitutive TNFα production (5), have compromised function, as measured by early (~4 weeks) flu-specific antibody production in subjects with obesity, regardless of age. The authors take advantage of these findings to provide novel insights into obesity-associated defects in the molecular machinery of B cell optimization. These defects in unstimulated B cells from individuals with obesity mirror aging, with obesity compounding aging-associated deficiencies. The authors’ findings contrast with published work, which showed early anti-flu antibody responses are similar (or even slightly increased) in subjects with obesity compared to lean subjects (1,6). However, follow-up analysis showed anti-flu antibody titers at 12 months were significantly lower in subjects with obesity (1), suggesting defects in memory B cell production akin to defects demonstrated by Frasca et al. (4). Therefore, the disparity among the studies is the ability of obesity to blunt early immune responses most relevant to the flu season that immediately follows vaccination. One reasonable explanation for this discrepancy is that Sheridan et al. (1) assayed individual responses to each of three vaccine strains in the first 1–2 years in which those strains were included in the vaccine, while Frasca et al. (4) summarized the mixed response to vaccine, with one of the strains included in the vaccine for three to four consecutive flu seasons.

This explanation of differences in these studies suggests that the impact of obesity on immune responses depends on a complex series of variables, including cumulative exposure to antigen, parallel immune responses, age, and metabolic variation, which for these studies was bundled into two groups, obese or lean (although Sheridan et al. (6) conclude that type 2 diabetes does not impact anti-flu antibody over obesity alone). This complexity of immune responses is consistent with the broader immunological literature and cautions that future studies must carefully integrate design and outcomes of published work to yield clinically relevant insights into pathogen clearance deficiencies and new strategies to overcome these deficiencies in obesity.