An Inflammatory Story: Antibodies in Tuberculosis Comorbidities

Abstract

Mycobacterium tuberculosis (Mtb) resides in a quarter of the world's population and is the causative agent for tuberculosis (TB), the most common infectious reason of death in humans today. Although cellular immunity has been firmly established in the control of Mtb, there is growing evidence that antibodies may also modulate the infection. More specifically, certain antibody features are associated with inflammation and are divergent in different states of human infection and disease. Importantly, TB impacts not just the healthy but also those with chronic conditions. While HIV represents the quintessential comorbid condition for TB, recent epidemiological evidence shows that additional chronic conditions such as diabetes and kidney disease are rising. In fact, the prevalence of diabetes as a comorbid TB condition is now higher than that of HIV. These chronic diseases are themselves independently associated with proinflammatory immune states that encompass antibody profiles. This review discusses isotypes, subclasses, post-translational modifications and Fc-mediated functions of antibodies in TB infection and in the comorbid chronic conditions of HIV, diabetes, and kidney diseases. We propose that inflammatory antibody profiles, which are a marker of active TB, may be an important biomarker for detection of TB disease progression within comorbid individuals. We highlight the need for future studies to determine which inflammatory antibody profiles are the consequences of comorbidities and which may potentially contribute to TB reactivation.

Systems serology detects functionally distinct coronavirus antibody features in children and elderly

“…Fc-effector functions, while beneficial against many pathogens 20 , 28 , 54 , 55 , can also enhance infection and pathogenesis in other infectious diseases, including dengue, where disease severity is associated with afucosylated IgG1 that enhances FcγRIIIa affinity 56 . This is also observed with other respiratory diseases including tuberculosis, where greater overall inflammation, including inflammatory Fc glycosylation is associated with poorer disease outcomes 55 , 57 . IgG with reduced fucosylation has been detected in COVID-19 patients and further implicated with COVID-19 progression, with the critically ill showing aggravated afucosylated-IgG responses against spike, while mild cases displayed higher levels of fucosylation of spike-specific IgG 58 , 59 .…”

“…Overall, our in-depth serological profiling of healthy children, elderly and COVID-19 patients brings us closer to understanding why the elderly are more susceptible to COVID-19 and provides insights into Ab Fc signatures associated with convalescence of mild/moderate symptomatic individuals. This knowledge is important for the development of improved serological diagnostics 57 , evaluation of convalescent plasma therapeutic trials, and will inform immunogenicity assessment of Ab-based SARS-CoV-2 vaccine strategies, which could potentially extend beyond neutralizing Abs.…”

Distinct systems serology features in children, elderly and COVID patients

“…Fc effector functions, while beneficial against many pathogens 15,16,22,36 , can also enhance infection and pathogenesis in other infectious diseases, including dengue, where disease severity is associated with afucosylated IgG1 that enhances FcγRIIIa affinity 37 . This is also observed with other respiratory diseases including tuberculosis, where greater overall inflammation, including inflammatory Fc glycosylation is associated with poorer disease outcomes 36,38 . It is important for future larger SARS-CoV-2 serological studies to assess not only quantitative changes in Ab titers, but also qualitative differences between patients with mild and severe disease, whereas in our study the majority of patients had mild-to-moderate COVID-19.…”

B-Cells and Antibodies as Contributors to Effector Immune Responses in Tuberculosis

“…The cumulative work presented above clearly indicates the pleiotropic effect of Abs in the immune response to Mtb, in which the particular Ab effector function utilized is dependent on Ag specificity, Ab isotype and subclass ( 28 , 42 , 59 , 210 ). The pulmonary compartment represents the predominant route of Mtb-infection, and the distribution of Ig isotypes in the mucosal lining includes predominantly secretory IgA (sIgA), lower amounts of soluble IgM, and even lower soluble IgG.…”