TB Lecture Slides 2024 PDF

The immune response against Mycobacterium tuberculosis MBChB II Dysfunction module  MTB infection and disease 1/3 of world population is infected (infection does not equal disease) – Latent MTB infection (LTBI), dormant bacilli – Huge reservoir for future disease Active...

The immune response against Mycobacterium tuberculosis MBChB II Dysfunction module  MTB infection and disease 1/3 of world population is infected (infection does not equal disease) – Latent MTB infection (LTBI), dormant bacilli – Huge reservoir for future disease Active infection= ‘tuberculosis’ (>9M new cases/year, leading cause of death due to bacterial infection, ±3M deaths /year) Interplay between HIV and MTB Multi‐drug resistant (MDR) or Extensive drug resistant (XDR) strains on the increase  MTB transmission Spread by inhalation of small aerosolized droplet nuclei (coughing, talking or sneezing Particles remain airborne for long Inhaled, particles are deposited in the terminal airways. A single cough can generate (up to 3000 infectious droplets from a single cough and many more from sneezing) Large respiratory droplets and fomites are not important sources of MTB transmission Transmission mostly occurs indoors after prolonged exposure and multiple inocula. The risk of infection is determined by the closeness of the contact (often household or institutional) as well as the infectiousness of the source case (more in smear positive cases, people with lung cavities if HIV negative. In HIV positives transmission occurs also without cavities)  MTB Infection and TB disease Not all exposed people become infected (approx 1/3) Not all transmission leads to persistent infection Only 3‐5% of infected people become diseased within 12 months and 5‐15% in their lifetime Impaired immunity may lead to TB disease: host genetic factors (i.e. IFNγ receptor deficiency), HIV/AIDS, malnutrition, alcoholism, renal failure, immunosuppressive therapy and diabetes mellitus  Proposed new paradigm of tuberculosis according to the International Consensus for Early TB (ICE‐TB):including subclinical TB Conceptual Macroscopic Symptoms and Microbiology Notes states pathology signs I. Mtb infection Absent Absent Absent Based on immune reactivity (pos TST or IGRA) II. Subclinical TB, Present (CXR or Absent Absent Historically ‘Closed TB’ or minimal TB non‐infectious CT) III. Subclinical Present (CXR or Absent Present (culture Approximately half of prevalent TB, infectious CT) or PCR positive) infectious PTB IV. Clinical TB, Present Present Absent Extrapulmonary TB, majority of non‐infectious children, miliary TB, non‐cavitary pulmonary disease V. Clinical TB, Present Present Present ‘Active TB’, approximately 50% of infectious prevalent TB. Lancet Resp. Med. 2024: Coussens AK et al  Subclinical TB Bacterial burden in the lung 36 – 80% of prevalent TB is subclinical/asymptomatic Detection limit Subclinical Activ Relapse Imaging: TB e TB – CXR- subtle or minimal changes; – 4% of general population in high-prevalence setting; – 10% of close contacts Microbiology: scanty or low positive GeneXpert test or liquid culture of sputum samples Progression: – In high incidence setting: 0.8 - 1% per year of general population – Close contacts 2-3% – Subclinical TB: 10% in one year and 25% in 3 years – vast majority of subclinical TB don’t progress but substantial % do  Immune Diagnosis of MTB infection Delayed type hypersensitivity Tuberculin skin test, Mantoux test, PPD test Also multiple puncture tests like Tine, Heaf tests The stages of a delayed type hypersensitivity reaction.  New tests for MTB infection: interferon gamma Figure 12‐25 release assays= IGRA’s Overnight culture (whole blood [Quantiferon] or peripheral blood mononuclear cells (PBMC’s) [T‐ Spot.TB] in the presence of MTB antigens Rely on pre‐existing memory T cells against MTB antigens More specific that TST Quantiferon test T‐Spot.TB test As sensitive as TST More expensive than TST (>10 US$) Requires lab expertise More standardized that TST Require only one visit to health care worker (i.e., can phone result through) Less useful in high incidence settings Naïve T cells differentiate into effector and memory cells Effector cells are short‐lived Interaction via MHC/T cell Naïve receptor T cell Infected Each T cell has macrophage or receptors that other antigen Clonal expansion: Memory cells remain at only recognize differentiated effector higher frequencies than presenting cell one antigen cells, all with the same T naïve T cells with same cell receptors. specificity, are long‐lived, Different phenotypes provide protection and develop (Th1, 2, 17, Treg are used for tests of prior etc) exposure  The role of cytokines in protection and susceptibility to MTB Treg Protection from Immunopathology Inhibits effective anti- TGFβ, MTB responses IL-10 IL-10, IL-4, IL-5 Th2 Th1 Protection from INF Immunopathology Inhibits effective anti- IL-10, IL-4, IL-12, IL-18, MTB responses IL-5 IL-23, IL-27 INF, TNFα Granuloma disintegration, Protection from immunopathology Granuloma integrity, Containment of Mtb Mtb infected IL-23 macrophage For illustration only Th17 Adapted from Ronacher et al: CYTOKINES IN PULMONARY TUBERCULOSIS Multiple ways to subvert macrophage function during MTB infection Interference with phagosome‐lysosome fusion Prevention of phago‐ lysosome acidification Decreased induction by IFN‐ gamma Down‐regulation and degradation of MHC class II Lack of upregulation of co‐ stimulatory molecules Pathogenesis: innate immune cells induce T cells After infection via aerosol, alveolar macrophages and probably interstitial dendritic cells (DCs), which have engulfed M.TB in the lung, migrate along two routes: Route 1: Infected macrophages and DCs enter draining lymph nodes and stimulate antigen‐specific T cells. The lung lesion plus these lymph nodes form the Ghon complex. ‐Mycobacterial antigens from incapacitated phagocytes are presented to highly professional antigen presenting cells (APCs), primarily DCs. ‐Infected macrophages undergo apoptosis ‐APC’s activate the following cells: ‐CD4+ T cells (via MHC class II) ‐CD8+ T cells (via MHC class I) ‐Unconventional T cells ‐with γ/δ T‐cell receptor instead of α/β ‐T cells with MHC class I like molecules of CD1 family …Pathogenesis: innate immune cells induce T cells Route 2: Infected macrophages and DCs enter the lung parenchyma where they initiate inflammatory foci to which blood monocytes are attracted. Mononuclear phagocytes accumulate and serve as the starting point for the formation of a granuloma orchestrated by T cells. The granuloma is surrounded by a fibrotic wall, which separates it from the surrounding tissue and its center becomes necrotic. M.tb is now contained and dormant, unable to cause disease until host is weakened. …Pathogenesis: the bug shuts down its metabolism, temporarily… ‐In the granuloma: hypoxic conditions. M.tb switches its gene expression from highly active, replicative to dormancy (DosR regulon). No growth, reduced respiration and metabolism. Become non‐stainable by conventional methods like Ziehl Neelsen acid fast stain. ‐Once the lesion is disrupted: M.tb synthesizes RNA and DNA, divide, become resuscitated. M.tb releases resuscitation promoting factor s (RPF’s) secreted by a few metabolically active bugs‐ act as pheromones for dormant bacteria. These rpf’s are enzymes that dissolve cell walls. ‐MTB then flourishes in liquefied lesion and is transmitted through blood stream or airways to other parts of the body. Multiple caseating granulomas in the lung  So, what goes wrong with the adaptive immune system in TB? Loss of immune memory MTB changes antigens: Naïve or memory T cells become effector T cells when they encounter their antigen. Effector cells that are generated during early infection keep things in check but are not as long lived as memory cells and decrease over time. MTB has 4000 genes, can change antigen expression, making memory cellsfrom initial stage of infection useless. Exhaustion of memory: persistent antigen coupled with strong stimulation also leads to loss of memory cells (to counter immunopathology).  So, what goes wrong with the adaptive immune system in TB? Misbalanced T cell phenotypes ‐Th1 cells are needed (produce IFNγ, TNFα, IL‐12 etc) for effective control of MTB infection. ‐Th2 cells(produce IL4, IL5, IL‐10, IL‐13, etc) and regulatory T cells (produce IL‐10, TGFβ) prevent immunopathology but also suppress Th1 cells and if this balance is disturbed MTB may escape immune control. The pathology of tuberculosis  Antigen presenting cell (i.e. macrophage) Granuloma formation Antigen Epitheloid cell (activated Giant cell macrophages) Lymphocyte Macrophage Monocytes Fibroblast Ghon focus Ghon complex  M. tuberculosis infection Primary tuberculosis (Ghon focus + hilar nodes= Ghon complex) Primary progressive TB Subclinical infection, possibly in fibrotic granuloma (‘latent infection’) Reactivation during immune suppression Secondary/post‐primary TB Secondary TB with cavity formation in upper lobe. Ghon focus is a fibrotic, calcified lesion. A cavity can break through into a bronchus and infectious material is then disseminated throughout the bronchial tree, causing bronchopneumonic TB. Cavities that have broken through into a bronchus with bronchogenic spread of TB Endobroncheal spread can cause laryngeal or tracheal TB or contralateral lung TB Erosion into blood vessels can lead to bleeding and hemoptysis. Although the pulmonary arterial system is shown on the left, the bronchial arterial system is most often involved in life‐threatening hemoptysis (comes from aorta). Breakthrough into pulmonary arteries leads to segmental miliary TB‐ characterized by a large number of millet‐like (2mm mean, 1‐5 mm range) nodules.  Breakthrough into pulmonary veins goes through left ventricle and to rest of body, including to meninges, liver, spleen, bone marrow and other http://www.patho.hku.hk organs, also as miliary TB. Often in young children, immune compromised patients (HIV co‐infected, diabetes, the elderly). Spinal TB: hematogenous dissemination can present as cold abscess and can lead to severe deformities and even paraplegia.  TB’s effect on tissues ‐Destruction of tissue: ‐Acute: loss of function of involved organs ‐Chronic sequelae: bronchiectasis with secondary infections ‐Granulomas: act as space‐occupying lesions, i.e. in brain ‐Induces fibrosis ‐in hollow organs‐ GIT: obstruction; Fallopian tubes: infertility ‐in destroyed tissues: scarring with further loss of function ‐in body cavities (pleura, pericardium, peritoneum, meninges): loss of function, obstruction, restriction ‐Destroys blood vessels: leads to hemorrhage ‐Cavities in lungs: aspergillomas (results in hemorrhage) Secondary TB pathogenesis Apical lesions Lymphatic Cavitation (’open TB’) vessels Breaks through branch Cough or gravity of pulm vein R heart Pulm artery Pulm artery Inhale Swallow Spread to Left heart and trachea/larynx systemic circulation Lung segment Whole lung ‐Bronchogenic Intestinal Endotracheal Disseminated TB, Miliary TB restricted dissemination TB or laryngeal TB miliary TB or to lung ‐Bronchopneumonia extraplumonary TB ‐Pleural spread