Clinical manifestations and immune response to tuberculosis

Abstract

Tuberculosis is a far-reaching, high-impact disease. It is among the top ten causes of death worldwide caused by a single infectious agent; 1.6 million tuberculosis-related deaths were reported in 2021 and it has been estimated that a third of the world's population are carriers of the tuberculosis bacillus but do not develop active disease. Several authors have attributed this to hosts' differential immune response in which cellular and humoral components are involved, along with cytokines and chemokines. Ascertaining the relationship between TB development's clinical manifestations and an immune response should increase understanding of tuberculosis pathophysiological and immunological mechanisms and correlating such material with protection against Mycobacterium tuberculosis. Tuberculosis continues to be a major public health problem globally. Mortality rates have not decreased significantly; rather, they are increasing. This review has thus been aimed at deepening knowledge regarding tuberculosis by examining published material related to an immune response against Mycobacterium tuberculosis, mycobacterial evasion mechanisms regarding such response and the relationship between pulmonary and extrapulmonary clinical manifestations induced by this bacterium which are related to inflammation associated with tuberculosis dissemination through different routes.

Keywords: Clinical manifestations; Immune response; Mycobacterium tuberculosis; Tuberculosis.

Fig. 1

Immune response to and clinical manifestations of tuberculosis. Once the mycobacteria enter a host’s body by airway ① they are perceived by its immune system ② and this can lead to three outcomes. ③ An innate immune response may become overwhelmed; complement factors can bind to mycobacteria and create a pore leading to microorganism lysis while cells such as neutrophils (N) macrophages (Mφ) and dendritic cells (DCs) try to control the infection by engulfing the mycobacteria and, in turn, antigen presentation occurs. An adaptive immune response is thus induced during which Mtb-specific antibodies (Ab) are produced, having different effector functions targeting the microorganism, along with cytokine production by B-lymphocytes (BL). Such Ab production is often mediated by CD4 + T-lymphocytes (TL), which convert BL into Ab-producing plasma cells. CD4 + TL cells also help eliminate mycobacteria intracellularly in infected cells, whilst cytotoxic cells (CD8 + TL) directly destroy cells carrying the tubercle bacillus. The role of trained immunity is worth noting; such a concept proposes that immune system cells and Abs have previously been trained to attack pathogens, whether they are similar or different to those that gave rise to the initial immune reaction. ④ However, Mtb has developed different evasion mechanisms against a host’s immune response by manipulating cells such as Mφ where it can establish a niche and multiply, in addition to manipulating alveolar epithelial cells (AEC) and neutrophils (N) leading to necrosis. It also avoids antigen processing and presentation for which phagolysosome formation is essential and during which Mtb must be destroyed, however, Mtb avoids or tolerates it. The lack of antigen presentation affects a lymphocyte-mediated immune response, mainly a T-mediated one. Granuloma formation is designed to contain and eliminate Mtb; this is used by the pathogen to remain in a state of latency while waiting to become able to colonise other host cells. Mtb has genes that encode PE-PGRS proteins thereby enabling it to survive in a host and favourably immunomodulate its response. ⑤ Thus, if a host’s immune response is deficient and/or Mtb can correctly evade it, such infection can result in active tuberculosis, i.e. pulmonary TB causing the greatest amount of cases worldwide and extrapulmonary TB. Figure created using Biorender.com.

Fig. 2

Innate immune response. A Mtb enters a host when patients having active TB inhale microdroplets which reach the bronchial trees where it then comes into contact with the respiratory mucosa; this is coated by airway surface liquid (ASL), containing antimycobacterial peptides, immunoglobulins, cytokines and chemokines. The microorganism can escape from the respiratory mucosa and reach alveoli made up by type II epithelial cells (AECII), macrophages (MA) and dendritic cells (DCs). Natural killer (NK) cells mediate cell cytotoxicity through IL-2-induced degranulation and cytokine signalling, such as IFN-γ. B An innate immune response is mediated by neutrophils (N) which produce cytokines that control Mtb infection. C Monocytes (MO) differentiate into macrophages (Mφ) which produce apoptotic bodies (apoptosis) promoting the escape of the bacillus, whilst other macrophages phagocytose it and control the infection. Figure created using Biorender.com

Fig. 3

Adaptive immune response. A An adaptive immune response is mediated by the HLA-II-peptide-TCR interaction enabling the development of effector memory CD4 + TL. Th1 TL induce reactive oxygen species (ROS)-mediated bactericidal activity, increasing HLA-II expression, promoting apoptosis and autophagy. B Mtb infection leads to Th2 lymphocytes inducing the production of cytokines associated with Mφ activation, Th17 produces IL-17 (involved in recruiting cells having a Th1 profile) and regulatory T-cells (Treg) which are involved in inhibiting control of Mtb infection, decreasing IFN-γ production in people having active TB. C Lymphocytes having unconventional receptors, such as gamma/delta (γδ) TCR, recognise Mtb antigens and produce significant granules for counteracting Mtb infection and MAIT cells that reduce the level of IFN-γ are also present. Figure created using Biorender.com

Fig. 4

Humoral immune response. A BL contribute to an Ab production-mediated humoral response and present antigens that can induce cytokine and chemokine production. B Abs acting against Mtb have been reported to enhance phagocytosis for killing the pathogen, increase phagolysosome fusion, restrict Mtb growth and promote inflammasome activation in Mφ to kill Mtb. C. Granuloma prevent Mtb spread to other tissues and lead to its rapid destruction within such granuloma

Fig. 5

Tuberculosis antigens in clinical trials. Summary of TB vaccine candidates currently in clinical trials (last update October 2022) (https://www.tbvi. eu/what-we-do/pipeline- vaccines/, accessed on 19th April 2023)