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Related Concept Videos

Pulmonary Tuberculosis II01:28

Pulmonary Tuberculosis II

Tuberculosis, or TB, is a bacterial infectious disease caused by Mycobacterium tuberculosis. While its primary impact is on the lungs, leading to pulmonary tuberculosis, it can also affect various other organs, a condition referred to as extrapulmonary tuberculosis.
Here is a detailed explanation of its pathophysiology:
Transmission: The process begins when a person inhales droplet nuclei containing M. tuberculosis. These are typically released into the air when an individual with pulmonary or...
Pulmonary Tuberculosis I01:29

Pulmonary Tuberculosis I

Tuberculosis, often called TB, is a contagious illness primarily caused by Mycobacterium tuberculosis. It mainly affects the lung parenchyma but can also impact other body parts.
Causative Organism
The primary infectious agent causing tuberculosis is Mycobacterium tuberculosis, a slow-growing, acid-fast, aerobic rod that exhibits sensitivity to heat and ultraviolet light. Instances of Mycobacterium bovis and Mycobacterium avium contributing to the development of TB infection are rare.
Mode of...
Pulmonary Tuberculosis V01:28

Pulmonary Tuberculosis V

Medical management of tuberculosis (TB) patients involves a comprehensive approach that includes diagnosis, treatment, and monitoring. The specific strategies can vary depending on the type of tuberculosis (latent or active), the patient's overall health status, and other considerations.
Latent tuberculosis infection occurs when TB bacteria are present in a person's body, but are not causing illness or symptoms. It is not contagious, and preventive treatment is crucial to avoid the progression...
Pulmonary Tuberculosis III01:31

Pulmonary Tuberculosis III

Tuberculosis (TB) is a contagious infection primarily affecting the lung parenchyma but which can also affect other body parts. TB can be classified based on disease development, presentation, and the affected anatomical site.
The first classification is based on the development of the disease, and it includes the following categories:
Exon Recombination02:32

Exon Recombination

The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of new gene formation. It is observed across vertebrates, invertebrates, and in some plants such as potatoes and sunflowers. During exon recombination, exons from the same or different genes recombine and produce new exon-intron combinations, which might evolve into new genes. 
Exon shuffling follows “splice frame rules.” Each exon has three reading...
Tuberculosis01:23

Tuberculosis

Tuberculosis (TB) remains a significant global health concern, primarily targeting the lungs and spreading through airborne transmission. Infection begins when aerosolized droplet nuclei, expelled by an individual with active TB, are inhaled by another person. These microscopic particles carry Mycobacterium tuberculosis, the causative agent of TB. Upon reaching the alveoli, the bacilli are engulfed by alveolar macrophages. However, due to their specialized lipid-rich cell wall, these pathogens...

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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
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Rethinking TYK2 P1104A: a flawed evolutionary trade-off in tuberculosis?

Pere-Joan Cardona1,2,3,4,5

  • 1Experimental Tuberculosis Unit (UTE), Institut de Recerca Germans Trias i Pujol (IGTP), Badalona, Spain.

Frontiers in Immunology
|July 1, 2026
PubMed
Summary

The TYK2 P1104A variant offers protection against autoimmunity but may not increase tuberculosis risk as previously thought. This genetic trait appears to fine-tune immune responses, potentially influencing susceptibility to various infections.

Keywords:
IL-12/IFN-γ axisIL-23/IL-17 pathwayTYK2 P1104Aevolutionary geneticshost–pathogen interactionsimmune modulationplaguetuberculosis

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Area of Science:

  • Immunology
  • Evolutionary genetics
  • Human genetics

Background:

  • The TYK2 P1104A variant has been considered an evolutionary trade-off, conferring protection against autoimmunity while increasing tuberculosis (TB) susceptibility.
  • This variant's frequency decline in European populations since the Bronze Age has been attributed to this supposed compromise.
  • Recent evidence challenges the simplicity of this evolutionary trade-off narrative.

Purpose of the Study:

  • To re-evaluate the mechanistic impact of the TYK2 P1104A variant on immune signaling pathways.
  • To investigate the variant's role in host defense against Mycobacterium tuberculosis and other pathogens.
  • To explore the implications of the variant's effects on immune regulation and evolutionary pressures.

Main Methods:

  • Analysis of TYK2 catalytic activity and downstream cytokine signaling (IL-12, IL-23, type I interferon).
  • Assessment of immune cell responses, including interferon-gamma production and Th17 cell differentiation.
  • Review of clinical data on IL-23 and IL-17 inhibitor use and TB reactivation rates.

Main Results:

  • The P1104A variant reduces TYK2 activity but preserves IL-12-dependent interferon-γ responses crucial for antimycobacterial immunity.
  • The variant selectively impairs IL-23 signaling, attenuating Th17 responses, and dampens type I interferon signaling.
  • Clinical data show no significant increase in TB reactivation with IL-23/IL-17 inhibition, questioning the essential role of these pathways in TB defense.

Conclusions:

  • The TYK2 P1104A variant may fine-tune immune responses by uncoupling protective Th1 immunity from detrimental inflammation, rather than simply increasing TB susceptibility.
  • The variant's effects could influence TB outcomes by modulating pathology and immune suppression.
  • Multiple infectious pressures, not solely TB, may have driven the evolutionary trajectory of the TYK2 P1104A variant.