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Neutrophils are the most abundant leukocytes in circulation and are key "first responders" in the immune response to infectious and non‐infectious stimuli. Unlike other immune cells, neutrophils can mount a robust response (including a change in surface markers and the production of extracellular traps and reactive oxygen species) just minutes after sensing a disturbance. It has been speculated that, in some individuals, the activation of neutrophils inadvertently leads to the generation of anti‐neutrophil cytoplasmic autoantibodies (ANCA) against particular neutrophil proteins (antigens) such as myeloperoxidase (MPO) and proteinase 3 (PR3). In these individuals, continuous ANCA‐antigen interactions are thought to drive persistent activation of neutrophils, chronic immune activation, and disease, most notably, small vessel vasculitis. There are significant gaps however in our understanding of the underlying mechanisms and even the pathogenicity of ANCA given that vasculitis can develop in the absence of ANCA, and that ANCA have been found in circulation in other conditions with no apparent contribution to disease. These gaps are particularly evident in the context of human studies. Herein, we review knowledge on neutrophil‐derived ANCA antigens PR3 and MPO, ANCA generation, and ANCA‐antigen interaction(s) that may promote immune activation and disease. [ABSTRACT FROM AUTHOR]

Nearly two billion people are latently infected with Mtb (LTBI). Detection of LTBI with high risk to develop active tuberculosis (aTB) is considered the cornerstone to control the disease. The current challenge is to identify markers that better classify LTBI versus aTB. It has been previously shown that Rv0140, a reactivation‐associated antigen of Mtb, induces significantly higher IFN‐γ production in LTBI individuals as compared to aTB patients. Herein, we show that Rv0140 induces high granzyme B level by PBMCs derived from LTBI (n = 34) as compared to aTB (n = 18). Receiving operator characteristic (ROC) curves were used to evaluate the capacity of Rv0140 to discriminate between LTBI and aTB by measuring IFN‐γ and granzyme B secretion. Our results show that, in response to Rv0140, granzyme B seems to allow better discrimination of LTBI from aTB with areas under the curve (AUC) of 0.88 (95% CI 0.79–0.98) as compared to IFN‐γ with AUC of 0.85 (95% CI 0.74–0.96) even though CI overlap. Intracellular staining (ICS) experiments and the use of anti‐MHC I antibody showed that granzyme B is mainly produced by CD8+ T cells in response to Rv0140. Thus, we propose granzyme B as a host marker to help identify LTBI individuals. Rv0140‐induced Granzyme B biomarker discriminates TB infection status [ABSTRACT FROM AUTHOR]

Differences in acquisition and boosting of anti‐malarial antibodies among African children exposed to malaria. Antibodies play a key role in acquired human immunity to Plasmodium falciparum (Pf) malaria and target merozoites to reduce or prevent blood‐stage replication and the development of disease. Merozoites present a complex array of antigens to the immune system, and currently, there is only a partial understanding of the targets of protective antibodies and how responses to different antigens are acquired and boosted. We hypothesized that there would be differences in the rate of acquisition of antibodies to different antigens and how well they are boosted by infection, which impacts the acquisition of immunity. We examined responses to a range of merozoite antigens in 2 different cohorts of children and adults with different age structures and levels of malaria exposure. Overall, antibodies were associated with age, exposure, and active infection, and the repertoire of responses increased with age and active infection. However, rates of antibody acquisition varied between antigens and different regions within an antigen following exposure to malaria, supporting our hypothesis. Antigen‐specific responses could be broadly classified into early response types in which antibodies were acquired early in childhood exposure and late response types that appear to require substantially more exposure for the development of substantial levels. We identified antigen‐specific responses that were effectively boosted after recent infection, whereas other responses were not. These findings advance our understanding of the acquisition of human immunity to malaria and are relevant to the development of malaria vaccines targeting merozoite antigens and the selection of antigens for use in malaria surveillance. [ABSTRACT FROM AUTHOR]